Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][CH2:37][CH3:38])(=[O:35])[CH2:33][OH:34].O=[C:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH:41]1[C:46]#[N:47].[H-].[Na+]>C1COCC1>[CH2:37]([O:36][C:32]([C:33]1[O:34][C:40]2[CH2:45][CH2:44][CH2:43][CH2:42][C:41]=2[C:46]=1[NH2:47])=[O:35])[CH3:38]
Reactant: N#CC1CCCCC1=O
Reactant: CCOC(=O)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1oc2c(c1N)CCCC2
Temperature: 25 °C
Yield: 42 %

Procedure:
A solution of resin bound PPh3 (Polymer Laboratories, 1.48 mmol/g, 150-300 μM; 3.8 g, 5.7 mmol) in THF (35 mL) at 0° C. was treated with diethyl azodicarboxylate (40% wt. in hexane; 2.60 mL, 5.7 mmol), ethyl glycolate (0.54 mL, 5.7 mmol) and a solution of 2-oxo-cyclohexanecarbonitrile (0.5 g, 4.1 mmol) in THF (10 mL). The reaction mixture warmed to rt over 12 h. Filtration and concentration afforded the uncyclized intermediate, which was dissolved in THF (25 mL) and added drop-wise to a slurry of sodium hydride (95%; 0.29 g, 11.4 mmol) in THF (10 mL) at 0° C. The reaction mixture was heated to 40° C. for 12 h. The reaction was quenched with satd. aq. NH4Cl (5 mL) and the mixture was extracted with EtOAc (3×50 mL). The combined organic layers were dried (by using, for example, Na2SO4) and concentrated. Purification by FCC (50% EtOAc/hexanes) afforded the desired product as a pale yellow solid (0.36 g). MS: 210.2. 1H NMR (400 MHz, CD3OD) δ ppm 4.26 (q, J=7.1, Hz, 2H), 2.55-2.47 (m, 2H), 2.35-2.28 (m, 2H), 1.90-1.79 (m, 2H), 1.79-1.71 (m, 2H), 1.33 (t, J=7.1, Hz, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:13][C:14]1[O:18][C:17]([CH:19]([CH3:23])[CH2:20][CH:21]=O)=[CH:16][CH:15]=1.[BH4-].[Na+]>CO.Cl>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][CH2:21][CH2:20][CH:19]([C:17]2[O:18][C:14]([CH3:13])=[CH:15][CH:16]=2)[CH3:23])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(CN)cc1
Reactant: Cc1ccc(C(C)CC=O)o1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(C(C)CCNCc2ccc(C(C)(C)C)cc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73 %

Procedure:
0.26 ml of 4-tert-butylbenzylamine (1.5 mmol) and 346 mg of [rac]-3-(5-methyl-furan-2-yl)-butyraldehyde (2.25 mmol) were dissolved in 4.5 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2.5 h. After cooling down to rt, 68 mg (1.8 mmol) of sodium borohydride were added and after stirring for 15 min at rt, the reaction mixture was then refluxed for 2¼ h. After cooling down to rt again 68 mg of sodium borohydride were added and the mixture was again refluxed for additional 18 h. After cooling down to rt, the reaction mixture was treated with 3 drops 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 1:2) to give 328 mg light yellow oil (73%). MS (ISP) 300.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5](O)=[O:6].S(Cl)([Cl:14])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([Cl:14])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1Cl
Reactant: O=S(Cl)Cl
Product: Cc1ccc(C(=O)Cl)cc1Cl

Procedure:
3-Chloro-4-methylbenzoyl chloride is prepared by refluxing together 30 g. (0.175 mole) of 3-chloro-4-methyl benzoic acid and 85 ml. thionyl chloride for about 2.5 hours, after which the excess thionyl chloride is distilled off under vacuum. The aroyl chloride product, 3-chloro-4-methylbenzoyl chloride, distills over at b.p. 70°-74°C., 10.25 mm. Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][C@@H:18]([CH3:22])[CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C@@H:18]([CH3:22])[CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1ccc(Br)cc1
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: Cc1ccccc1
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1c1ccc(Cl)cc1
Temperature: 110 °C
Yield: 50.8 %

Procedure:
To a mixture of 4-chlorobromobenzene (1.05 g, 5.5 mmol) and 3-(S)-Methyl-piperazine-1-carboxylic acid tert-butyl ester (1 g, 5 mmol) in toluene (30 mL) was added tris(dibenzylideneacetone) dipalladium(0) (0.057 g, 0.063 mmol), BINAP (0.12 g, 0.19 mmol) and sodium-t-butoxide (2.02 g, 21 mmol). The resulting mixture was heated 110° C. for 20 h. The solvent was evaporated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. Column chromatography (10% ethyl acetate/hexane) provided 0.79 g (51%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](I)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[CH3:13][C:14]1[CH:15]=[CH:16][C:17](B2OC(C)(C)C(C)(C)O2)=[C:18]([CH:21]=1)[C:19]#[N:20].C(=O)([O-])[O-].[Cs+].[Cs+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:9]=[C:10]([C:17]2[CH:16]=[CH:15][C:14]([CH3:13])=[CH:21][C:18]=2[C:19]#[N:20])[CH:11]=1
Reactant: Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(C#N)c1
Reactant: COC(=O)c1cc(Br)cc(I)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: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(Br)cc(-c2ccc(C)cc2C#N)c1

Procedure:
Into a microwave vial were charged methyl 3-bromo-5-iodobenzoate (1.3 g, 3.8 mmol), 5-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile (1.1 g, 4.6 mmol), cesium carbonate (3.1 g, 9.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (44q mg, 0.38 mmol), water (3 mL) and toluene (8 mL). The reaction mixture was subjected to microwave irradiation at 100° C. for 1 h. After cooling, the reaction was filtered and concentrated. The residue was purified by reversed phase HPLC (acetonitrile:water gradient) to the title compound as a white solid. LC-MS: 331.1 [M+1]+; 1H NMR (400 MHz, CDCl3): 8.16 (s, 1H), 8.03 (t, J=1.3 Hz, 1H), 7.76 (t, J=1.8 Hz, 1H), 7.53 (s, 1H), 7.33 (dd, J=1.6, 9.4 Hz, 1H), 7.25 (d, J=8.1 Hz, 1H), 3.93 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:28]=[CH:27][N:26](S(C5C=CC(C)=CC=5)(=O)=O)[C:13]=4[N:14]=[C:15]([NH:17][C:18]4[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=4)[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1.ClC1C=CC=C(C(OO)=O)C=1.[OH-:50].[K+]>CC(C)=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11]3[C:12]4[CH:28]=[CH:27][NH:26][C:13]=4[N:14]=[C:15]([NH:17][C:18]4[CH:19]=[CH:20][C:21]([S:24]([CH3:25])=[O:50])=[CH:22][CH:23]=4)[N:16]=3)[CH:8]=2)[CH:3]=[N:2]1
Reactant: [OH-]
Reactant: CSc1ccc(Nc2nc(Nc3ccc4cn[nH]c4c3)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n2)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Solvent: CC(C)=O
Product: CS(=O)c1ccc(Nc2nc(Nc3ccc4cn[nH]c4c3)c3cc[nH]c3n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.4 %

Procedure:
To a solution of N4-(1H-indazol-6-yl)-N2-(4-(methylthio)phenyl)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (102 mg, 0.19 mmol) in acetone (4 mL), m-chloroperbenzoic acid (mCPBA) (70%, 34 mg, 0.14 mmol) was added. After being stirred at room temperature for 2 h, the mixture was concentrated in vacuo. The residue was dissolved in dioxane (3 mL) and aq. 1N KOH (1.5 mL, 1.5 mmol) was added. After being stirred at 70° C. for 24 h, the mixture was concentrated in vacuo. The residue was acidified with acetic acid (HOAc) (2 mL) before it was purified by HPLC to give N4-(1H-indazol-6-yl)-N2-(4-(methylsulfinyl)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (21 mg), MS 404.1 (M+H) (Compound 10-2); and N4-(1H-indazol-6-yl)-N2-(4-(methylthio)phenyl)-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamine (10 mg), MS 388.1 (M+H) (Compound 10-1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH:14][CH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>C1COCC1.N1C=CC=CC=1.CN(C)C1C=CN=CC=1.O>[O:18]1[CH2:19][CH2:20][CH:15]([O:14][C:4](=[O:5])[C:3]2[CH:7]=[CH:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][C:2]=2[OH:1])[CH2:16][CH2:17]1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1O
Reactant: OC1CCOCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(OC1CCOCC1)c1ccc([N+](=O)[O-])cc1O
Temperature: 45 °C
Yield: 29.4 %

Procedure:
2-Hydroxy-4-nitro-benzoyl chloride (0.82 g, 4.07 mmol) in THF (15 mL) was added portionwise to a solution of 4-hydroxytetrahydropyran (0.8 mL, 8.1 mmol) in pyridine (4 μL) at 0° C., followed by a catalytic amount of 4-(dimethylamino)-pyridine (DMAP). The mixture was maintained overnight at 40-50° C. then diluted with water and extracted with ethyl acetate. The organic extract was washed successively with saturated sodium bicarbonate solution, water and brine solution, dried and concentrated to give a residue which was triturated with a mixture of DCM and petroleum ether. The residue was purified by flash column chromatography on silica, eluting with ethyl acetate/petroleum ether (2-15%) to give 2-hydroxy-4-nitro-benzoic acid tetrahydro-pyran-4-yl ester (0.32 g, 29%).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([C:22](=[O:31])[C:23]([CH3:30])([CH3:29])[CH2:24][O:25]C(=O)C)[CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[CH2:10][C@H:9]1[C:32]([O:34]C)=[O:33])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>CO.O>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:14]2[CH2:19][CH2:18][C:17]([CH3:21])([CH3:20])[CH2:16][CH2:15]2)[C:22](=[O:31])[C:23]([CH3:30])([CH3:29])[CH2:24][OH:25])[CH2:10][C@H:9]1[C:32]([OH:34])=[O:33])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: COC(=O)[C@@H]1C[C@H](N(C(=O)C(C)(C)COC(C)=O)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)CCC(N(C(=O)C(C)(C)CO)[C@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)CC1
Reaction time: 12 h
Yield: 94.9 %

Procedure:
Methyl(2S,4S)-1-BOC-4-{[3-(acetoxy)-2,2-dimethylpropanoyl](4,4-dimethylcyclohexyl)amino}pyrrolidine-2-carboxylate (0.88 g, 1.77 mmol) obtained in Step A was dissolved in MeOH (8 mL) and water (1.6 mL). NaOH (213 mg, 5.31 mmol) was added thereto. The reaction solution was stirred for 12 hours. After the reaction was completed, the reaction solution was concentrated in vacuo, acidified with 1N HCl and extracted with EtOAc. The extracted organic solution was washed with 1N HCl solution, dried over MgSO4 and concentrated in vacuo to give the title compound (0.74 g, 95%).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.CCN(C(C)C)C(C)C.O>CN(C=O)C>[F:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=2[N+:12]([O-:14])=[O:13])=[CH:18][CH:17]=1
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: Nc1ccc(F)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Nc2ccc(F)cc2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 4-fluoro-3-nitrobenzoate 60a (1 g, 5.02 mmol), 4-fluoroaniline 60b (4.34 mL, 5.02 mmol), and DIPEA (1.04 mL, 6.03 mmol) in DMF (10 mL) was stirred at room temperature for 2 h. Water was added to the mixture; the resulting solid was filtered, washed with water, and dried. The crude product 60c was used in the next reaction without purification.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@:10]2([CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH:32]=[CH:31][C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:33]C)[CH:29]=5)[C:24]4=[O:35])=[CH:19][CH:18]=3)[CH2:13]2)[CH2:9]1)=O)(C)(C)C.Br>>[CH2:13]1[C@@:10]2([CH2:11][CH2:12][NH:8][CH2:9]2)[CH2:16][CH2:15][N:14]1[C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[C:28]([OH:33])[CH:29]=3)[C:24]2=[O:35])=[CH:19][CH:18]=1
Reactant: COc1ccc2c(=O)n(-c3ccc(N4CC[C@]5(CCN(C(=O)OC(C)(C)C)C5)C4)cc3)ccc2c1
Agent: Br
Product: O=c1c2ccc(O)cc2ccn1-c1ccc(N2CC[C@]3(CCNC3)C2)cc1

Procedure:
According to Method L, (S)-7-[4-(6-methoxy-1-oxo-1H-isoquinolin-2-yl)-phenyl]-2,7-diaza-spiro[4.4]nonane-2-carboxylic acid tert-butyl ester was treated with hydrogen bromide. In this way the product was obtained with molecular weight 361.45 (C22H23N3O2); MS (ESI): 362 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13](Cl)[C:12]=2[F:18])[CH2:4][CH2:3]1.C(=[NH:32])(C1C=CC=CC=1)C1C=CC=CC=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].Cl>C1(C)C=CC=CC=1.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH2:32])[C:12]=2[F:18])[CH2:4][CH2:3]1
Reactant: CN1CCC(NCCc2cccc(Cl)c2F)CC1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CN1CCC(NCCc2cccc(N)c2F)CC1
Yield: 11.4 %

Procedure:
Mix 1-methyl-4-(N-(2-fluoro-3-chlorophenyl)ethylamino)piperidine (Preparation 26) (0.367 g), benzophenone imine (0.295 g), Pd2(dba)3 (50 mg), 2-(di-t-butylphosphino)biphenyl (32 mg), and sodium t-butoxide (0.182 g) in toluene (10 mL) and heat at reflux for three days. Dilute with methanol (5 mL), 30 minutes after adding 2 mL of 5N HCl, load on a SCX column (10 g), wash with methanol, elute the product with 2M NH3 in methanol, evaporate and purify on a silica gel column (35 g), using a gradient of dichloromethane-2M NH3 in methanol to give 39 mg of the title compound: mass spectrum (electric spray) m/z=252 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][C@H:13]3[CH2:18][CH2:17][C@H:16]([C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:8]=2)[CH:3]=1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1C)(C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC.[N+:57]([CH2:60][CH3:61])([O-:59])=[O:58]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:19]([C@H:16]1[CH2:15][CH2:14][C@H:13]([O:12][C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([CH:60]([N+:57]([O-:59])=[O:58])[CH3:61])[CH:3]=3)[CH:8]=2)[CH2:18][CH2:17]1)([CH3:22])([CH3:21])[CH3:20]
Reactant: CC[N+](=O)[O-]
Reactant: CC(C)(C)[C@H]1CC[C@H](Oc2ccc3cc(Br)ccc3c2)CC1
Agent: [Pd]
Agent: Cc1ccccc1-c1ccccc1P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: COCCOC
Product: CC(c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
A 40 mL vial equipped with a magnetic stir bar was charged with 2-bromo-6-(trans-4-tert-butylcyclohexyloxy)naphthalene (0.6695 g, 1.853 mmol), tris(dibenzylideneacetone)dipalladium(O) (0.06363 g, 0.06948 mmol), 2-(di-t-butylphosphino)-2′-methylbiphenyl (0.08684 g, 0.2779 mmol), and cesium carbonate (0.7245 g, 2.224 mmol). The reaction vessel was capped, evacuated, and backfilled with argon three times then 1,2-dimethoxyethane (20.00 mL, 192.4 mmol) was added via syringe under argon. After the mixture was stirred vigorously for 2 min at room temperature, nitroethane (0.2795 mL, 3.891 mmol) was added and the reaction was heated overnight at 50° C. The reaction was allowed to cool to ambient temperature. The mixture was quenched with a solution of sat. aqueous ammonium chloride. The layers were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phase was washed with water then dried with magnesium sulfate, filtered and concentrated under reduced pressure. The residue was taken up in methylene chloride and silica gel was added. The solvent was removed and the residue was purified by flash column chromatography using 0-20% ethylacetate in hexanes to give the title compound in 58% yield.
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][CH2:8][C@@H:9]2[CH2:11][C@@H:10]2[CH:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([CH2:24][CH3:25])=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[CH:4][CH:3]=1.CC(P(C(C)(C)C)C1C(C2C=CC=CC=2)=CC=CC=1)(C)C.CC([O-])(C)C.[Na+].C(=[NH:68])(C1C=CC=CC=1)C1C=CC=CC=1.C([O-])(=O)C.[Na+].Cl.NO>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:24]([C:21]1[CH:20]=[N:19][C:18]([N:15]2[CH2:16][CH2:17][CH:12]([C@H:10]3[CH2:11][C@H:9]3[CH2:8][O:7][CH2:6][C:5]3[CH:26]=[CH:27][C:2]([NH2:68])=[CH:3][CH:4]=3)[CH2:13][CH2:14]2)=[N:23][CH:22]=1)[CH3:25]
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(Br)cc3)CC2)nc1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: Cc1ccccc1
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(N)cc3)CC2)nc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The product of example 54 (step A) (100 mg, 0.2 mmol), Pd2(dba)3 (21 mg, 0.023 mmol), (2-biphenyl)di-tert-butylphosphine (14 mg, 0.046 mmol), NaOtBu (48 mg, 0.5 mmol), and benzophenone imine (50 mg, 0.28 mmol) were dissolved in toluene (1.5 mL), and the solution was heated under N2 at 60° C. for 6 hours. The mixture was filtered and the filtrate concentrated in vacuo. The residue was dissolved in MeOH (3 mL), and sodium acetate (38 mg, 0.46 mmol) and hydroxylamine hydrochloride (32 mg, 0.46 mmol) were added. The solution was stirred at RT for 1 h. The solution was partitioned between sat. NaHCO3 (aq.) and EtOAc. The aqueous layer was extracted with EtOAc. The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified via silica gel column chromatography (2/1 hexanes/EtOAc) which provided the title compound.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([C:12]([NH:14][CH2:15][C:16]([OH:18])=O)=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.FC(F)(F)C(O)=O.[Br:57][C:58]1[CH:70]=[CH:69][CH:68]=[CH:67][C:59]=1[O:60][CH:61]1[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]1>CN(C=O)C.O>[Br:57][C:58]1[CH:70]=[CH:69][CH:68]=[CH:67][C:59]=1[O:60][CH:61]1[CH2:66][CH2:65][N:64]([C:16](=[O:18])[CH2:15][NH:14][C:12]([C:9]2[CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[O:11][N:10]=2)=[O:13])[CH2:63][CH2:62]1
Reactant: Brc1ccccc1OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1cc(-c2ccccc2)on1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Br)CC1)c1cc(-c2ccccc2)on1
Reaction time: 8 h
Yield: 34.9 %

Procedure:
To a stirred solution of [(5-phenyl-isoxazole-3-carbonyl)-amino]-acetic acid (72.5 mg, 0.00026 mol) in DMF (1.5 mL) was added DIPEA (0.166 g, 0.00128 mol), HOBt (43.3 mg, 0.00032 mol) and EDCI.HCl (61.5 mg, 0.00032 mol) at ambient temperature. After 2 minutes 4-(2bromo-phenoxy)-piperidine trifluoroacetate (0.1 g, 0.00027 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by column chromatography using silica gel, 60-120 mesh (40% ethyl acetate in hexane) to afford 0.044 g (35%) of 5-phenyl-isoxazole-3-carboxylic acid {2-[4-(2-bromo-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LCMS: 484.08 (M+1)+, 77.84%, 1H NMR (DMSO-d6): δ 8.63 (t, 1H), 7.98 (m, 2H), 7.6 (m, 4H), 7.4 (m, 2H), 7.2 (m, 1H), 6.9 (t, 1H), 4.8 (s, 1H), 4.3 (m, 2H), 3.5 (m, 4H), 1.5 (m, 4H).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]#[N:29])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])[CH:19]=3)[NH:14][N:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[OH-:30].[K+]>CC(O)(C)C>[CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:28]([NH2:29])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[F:27])[CH:19]=3)[NH:14][N:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C#N)cc(-c4ccccc4F)cc23)CC1
Reactant: [OH-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccccc4F)cc23)CC1
Yield: 25.1 %

Procedure:
The mixture of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(2-fluorophenyl)-1H-indazole-7-carbonitrile (Intermediate 12) (0.102 mmols) and potassium hydroxide (26 mg, 0.51 mmol) in 2-methyl-2-propanol (4 mL) was heated overnight. The reaction mixture was concentrated. The residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to afford the title compound (11 mg, 25% for 2 steps)
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH3:8])[S:5][C:6]=1[CH3:7].[CH3:9][O:10][C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14](B(O)O)=[CH:13][N:12]=1.C(=O)(O)[O-].[Na+]>COCCOC.C(Cl)Cl.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>[CH3:8][C:4]1[S:5][C:6]([CH3:7])=[C:2]([C:14]2[C:15]([O:17][CH3:18])=[N:16][C:11]([O:10][CH3:9])=[N:12][CH:13]=2)[N:3]=1
Reactant: COc1ncc(B(O)O)c(OC)n1
Reactant: Cc1nc(Br)c(C)s1
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: ClCCl
Solvent: COCCOC
Product: COc1ncc(-c2nc(C)sc2C)c(OC)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-bromo-2,5-dimethyl-1,3-thiazole (commercially available from Apollo Scientific Ltd, 410 mg, 2.135 mmol) in 1,2-Dimethoxyethane (DME) (6.5 mL), Tetrakis(triphenylphosphine)palladium (123 mg, 0.107 mmol) was added and the mixture was stirred at rt for 30 minutes. Then [2,4-bis(methyloxy)-5-pyrimidinyl]boronic acid (commercially available from Aldrich, 916 mg, 4.48 mmol) and 1M Sodium bicarbonate aqueous solution (5.83 mL, 5.83 mmol) were added. The reaction mixture was then stirred at 90° C. for 2.5 h and left stirring at rt overnight. The day after the mixture was diluted with DCM and washed with water. Organic layer was dried and concentrated under vacuum. Crude product was first purified by flash chromatography (eluent: Cy/AcOEt 65:35) and further purified by SCX cartridge affording 5-(2,5-dimethyl-1,3-thiazol-4-yl)-2,4-bis(methyloxy)pyrimidine with minor unknown impurities that was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][CH:11]=[N:10][C:9]=2[C:13](OCC)=[O:14])=[CH:4][CH:3]=1.CC(C[AlH]CC(C)C)C.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][CH:11]=[N:10][C:9]=2[CH:13]=[O:14])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ncoc1-c1ccc(Cl)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1ncoc1-c1ccc(Cl)cc1
Temperature: -20 °C

Procedure:
To a solution of 33C (1.25 g, 5 mmol) in THF was added DIBAL-H (1.0 M in toluene, 10 mmol) dropwise at −70° C. The resulting solution was allowed to warm to −20° C. over 3 h. Upon completion of the reaction, saturated aqueous NH4Cl was added to the flask and the mixture was partitioned between EtOAc and water. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude product was used in the next step without further purification. MS (m/z) 208.1 [M+H]+.