Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][CH2:10][C:9](O)([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]2[CH:7]=[C:6]([N:19]=[N:20][C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:23][CH:22]=3)[CH:5]=[CH:4][C:3]1=2.C1CCC(N=C=NC2CCCCC2)CC1>C1C=CC=CC=1.Cl[Cu]>[CH3:32][C:2]1([CH3:1])[CH2:11][CH:10]=[C:9]([CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]2[CH:7]=[C:6]([N:19]=[N:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:30][CH:31]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)CC1(O)CCC(C)(C)c2ccc(N=Nc3ccc(C(=O)OCC)cc3)cc21
Agent: Cl[Cu]
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccccc1
Product: CCOC(=O)CC1=CCC(C)(C)c2ccc(N=Nc3ccc(C(=O)OCC)cc3)cc21
Temperature: 25 °C

Procedure:
A solution of (±) ethyl 4-[(5,5-dimethyl-8-hydroxy-8-carbethoxymethyl-5,6,7,8-tetrahydronaphth-2-yl)azo]benzoate (Compound D1, 108 mg, 0.25 mmol), DCC (55.9 mg, 0.271 mmol) and CuCl (36.6 mg, 0.37 mmol) in 8 ml of dry benzene was heated under reflux for 7 days. After cooling to room temperature, the solids were filtered out and the solution was extracted with ethyl acetate. The combined organic layer was washed with brine and dried over Na2 SO4. The solvent was removed under reduced pressure, the crude material was purified by flash chromatography (silicagel, 10 % ethyl acetate in hexane) to afford the pure title compounds as red oils.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([C:17]2([O:23][CH3:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[S:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][C:11]([C:14](=O)[CH3:15])=[CH:10][CH:9]=1.Cl.[NH2:26][OH:27]>>[Br:1][C:2]1[N:3]=[C:4]([C:17]2([O:23][CH3:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[S:5][C:6]=1[S:7][C:8]1[CH:13]=[CH:12][C:11](/[C:14](=[N:26]/[OH:27])/[CH3:15])=[CH:10][CH:9]=1
Reactant: NO
Reactant: COC1(c2nc(Br)c(Sc3ccc(C(C)=O)cc3)s2)CCOCC1
Agent: Cl
Product: COC1(c2nc(Br)c(Sc3ccc(/C(C)=N/O)cc3)s2)CCOCC1
Yield: 96 %

Procedure:
Using an analogous procedure to that described in Example 15, 4'-[4-bromo-2-(4-methoxytetrahydropyran-4-yl)thiazol-5-ylthio]acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-[4-bromo-2-(4-methoxytetrahydropyran-4-yl)thiazol-5-ylthio]acetophenone oxime in 96% yield, m.p. 130° C.;
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@H:4]([NH:15][C:16](=[O:31])[C:17]1[CH:22]=[CH:21][C:20]([C:23]([N:25]2[CH2:29][CH:28]=[CH:27][CH2:26]2)=[O:24])=[C:19]([CH3:30])[CH:18]=1)[C:5]1[NH:9][C:8]2[CH:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:7]=2[N:6]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:14][C:12]1[CH:11]=[CH:10][C:8]2[NH:9][C:5]([C@@H:4]([NH:15][C:16](=[O:31])[C:17]3[CH:22]=[CH:21][C:20]([C:23]([N:25]4[CH2:29][CH:28]=[CH:27][CH2:26]4)=[O:24])=[C:19]([CH3:30])[CH:18]=3)[CH2:3][CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])=[N:6][C:7]=2[CH:13]=1
Reactant: Cc1cc(C(=O)N[C@@H](CCN)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CC=CC1
Reactant: CS(=O)(=O)Cl
Agent: ClCl
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)N[C@@H](CCNS(C)(=O)=O)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CC=CC1
Yield: 58 %

Procedure:
Prepared analogously to Example 125 from N-[(1S)-3-amino-1-(5-chloro-1H-benzimidazol-2-yl)propyl]-4-(2,5-dihydropyrrol-1-ylcarbonyl)-3-methylbenzamide, methanesulfonic acid chloride and triethylamine in tetrahydrofuran. Yield: 58%; Rf value: 0.40 (silica gel: dichloromethane/ethanol=9:1); C24H26ClN5O4 (516.019); mass spectrum: (M+H)+=516/518 (chlorine isotope).
Reaction SMILES: [CH3:1][Al](C)C.Cl[C:6]1[N:7]=[CH:8][CH:9]=[C:10]2[CH:14]=[N:13][NH:12][C:11]=12.[NH4+].[Cl-]>C1COCC1.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>[CH3:1][C:6]1[N:7]=[CH:8][CH:9]=[C:10]2[CH:14]=[N:13][NH:12][C:11]=12
Reactant: Clc1nccc2cn[nH]c12
Reactant: C[Al](C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1nccc2cn[nH]c12
Temperature: 65 °C
Reaction time: 16 h

Procedure:
Trimethylaluminum (23.9 mL, 47.8 mmol, 2M sol. in toluene) was added to a vigorously stirred solution of 7-chloro-1H-pyrazolo[3,4-c]pyridine (3.67 g, 23.9 mmol) and Pd(PPh3)4 (1.38 g, 1.19 mmol) in THF (109 mL) under argon. The reaction mixture was stirred at 65° C. for 16 h. The mixture was cooled to RT and poured into sat. aq. NH4Cl. The resulting suspension was filtered, the solid washed with water and discarded. The filtrate and the combined washings were extracted with EtOAc (3×). The combined organic extracts were washed with brine then dried (Phase separator) and concentrated under reduced pressure to give 7-methyl-1H-pyrazolo[3,4-c]pyridine as a solid. MS (LC-MS): 134 [M+H]+, tR (HPLC conditions k): 0.25 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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]>[Cl:1][C:2]1[C:3]2[C:10]([C:26]3[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=3)[C:20]#[N:21])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: C[Si](C)(C)CCOCn1cc(-c2cccc(C#N)c2)c2c(Cl)ncnc21
Temperature: 25 °C

Procedure:
To a stirred mixture of 4-chloro-5-iodo-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (C1) (8.2 g, 20 mmol), (3-cyanophenyl)boronic acid (3.2 g, 22 mmol) and potassium carbonate (8.3 g, 60 mmol) in a mixture of 1,2-dimethoxyethane and water (4:1 ratio, 250 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (731 mg, 1.00 mmol). The reaction mixture was degassed and then charged with nitrogen; this procedure was carried out a total of three times. The reaction mixture was heated at reflux for 3 hours, then cooled to room temperature and diluted with saturated aqueous sodium chloride solution (100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. Purification via silica gel column chromatography (Eluent: 10:1 petroleum ether/ethyl acetate) provided the product as a yellow oil. Yield: 5.0 g, 12 mmol, 60%. 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 8.13 (s, 1H), 8.00-8.02 (m, 1H), 7.84-7.92 (m, 2H), 7.68 (dd, J=7.8, 7.8 Hz, 1H), 5.70 (s, 2H), 3.60 (dd, J=8.0, 8.0 Hz, 2H), 0.86 (dd, J=8.0, 8.0 Hz, 2H), −0.08 (s, 9H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH2:16][CH2:17][CH3:18])[C:6]=2[O:5][C:4]([C:24]([O:26]CC)=[O:25])=[CH:3]1)[N:13]=[C:12]([C:19]([O:21]CC)=[O:20])[CH:11]=[CH:10]3.[OH-].[Na+]>CO>[O:1]=[C:2]1[C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([CH2:16][CH2:17][CH3:18])[C:6]=2[O:5][C:4]([C:24]([OH:26])=[O:25])=[CH:3]1)[N:13]=[C:12]([C:19]([OH:21])=[O:20])[CH:11]=[CH:10]3
Reactant: CCCc1c2nc(C(=O)OCC)ccc2cc2c(=O)cc(C(=O)OCC)oc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCc1c2nc(C(=O)O)ccc2cc2c(=O)cc(C(=O)O)oc12

Procedure:
The product of step (b) (1.118 g) was suspended in methanol (100 mls) and heated and stirred under reflux with the dropwise addition of N/10 sodium hydroxide solution (58.37 mls). The reaction mixture was stirred and heated under reflux for a further 15 mins, cooled, filtered and acidified. The precipitated product was collected by filtration, washed with water and dried to give 0.852 g, mp 252° dec.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][CH2:14][N:15]1[C:19](=[O:20])[CH2:18][S:17][C:16]1=[O:21].N1C=CC=CC=1>C1(C)C=CC=CC=1>[Cl:1][CH2:2][C:3]([N:13]([CH2:14][N:15]1[C:19](=[O:20])[CH2:18][S:17][C:16]1=[O:21])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[CH3:6])=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccccc1NCN1C(=O)CSC1=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1ccccc1N(CN1C(=O)CSC1=O)C(=O)CCl
Reaction time: 3 h

Procedure:
A solution of 4.5 g of chloroacetyl chloride in 10 ml of toluene was added dropwise to a suspension of 7.8 g of N-(2-methylphenylaminomethyl)-2,4-thiazolidinedione and 3 g of pyridine in 80 ml of toluene at -5° C with stirring and kept on an ice bath for 3 hrs. The resulting precipitate was filtered and washed with water to give 2-chloro-N-(2,4-dioxothiazolidin-3-ylmethyl)-N-(2-methylphenyl)acetamide, mp 133°-136° C. The toluene filtrate was extracted with two 50 ml portions of 5% hydrochloric acid, 50 ml of water, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated on a rotary evaporator to give the product which was crystallized from benzene-ether, mp 134°-137° C. The total yield was 6.0 g [M+ = 312 (molecular ion by mass spec.)].
Reaction SMILES: C[O:2][C:3]([C:5]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:17]([C:24]3[N:25]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=4)[N:26]=[C:27]4[C:32]=3[CH:31]=[CH:30][CH:29]=[CH:28]4)[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)=[CH:11][CH:10]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Li+]>C1COCC1.CO>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([N:25]2[C:24]([CH:17]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][C:5]4([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]4)=[CH:14][CH:13]=3)=[C:32]3[C:27]([CH2:28][CH2:29][CH2:30][CH2:31]3)=[N:26]2)=[CH:34][CH:35]=1
Reactant: COC(=O)C1(Oc2ccc(OCC(c3c4ccccc4nn3-c3ccc(Cl)cc3)C3CCCCC3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1(Oc2ccc(OCC(c3c4c(nn3-c3ccc(Cl)cc3)CCCC4)C3CCCCC3)cc2)CC1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-1-(4-{2-[2-(4-chloro-phenyl)-2H-indazol-3-yl]-2-cyclohexyl-ethoxy}-phenoxy)-cyclopropanecarboxylic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as yellow oil. MS: m/e=533.2 [M−H−].
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]([NH:8][C:9]1[C:17](OC)=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([NH2:13])=[O:12])=O)[CH3:2].[C:24](=O)([O-])[O-].[K+].[K+].OO.C(O)C>ClCCl.O>[CH2:1]([O:3][C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6]1[NH:13][C:11](=[O:12])[C:10]2[C:9](=[C:17]([CH3:24])[CH:16]=[CH:15][CH:14]=2)[N:8]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOc1ccccc1C(=O)Nc1c(OC)cccc1C(N)=O
Agent: OO
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: CCOc1ccccc1-c1nc2c(C)cccc2c(=O)[nH]1

Procedure:
A stirred mixture of 2-(2-ethoxybenzamido)-3-methoxybenzamide (2.6 g, 0.0083 mol), anhydrous potassium carbonate (2.33 g, 0.017 mol), hydrogen peroxide (30%, 4 ml), ethanol (40 ml) and water (80 ml) was heated under reflux for 1 hour. The mixture was allowed to cool and poured into a mixture of water (200 ml) and dichloromethane (100 ml), then the aqueous phase separated, acidified to pH 4 by the addition of 2N hydrochloric acid and extracted with dichloromethane (2×100 ml). The organic solutions were combined, dried (MgSO4) and evaporated under vacuum to give the title compound, which crystallized from ethyl acetate as a colorless solid (2.8 g, 83%), m.p. 198°-199° C. Found: C,68.88; H,5.50; N,9.30. C17H16N2O3 requires C,68.91; H,5.44; N,9.45%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)[CH:5]=[CH:6][CH:7]=1.[CH2:18]([N:20]([CH2:34][CH3:35])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=O)=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:19]>C(O)C.N1CCCCC1>[CH2:34]([N:20]([CH2:18][CH3:19])[CH2:21][CH2:22][NH:23][C:24]([C:26]1[NH:27][C:28]([CH:32]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=3)[NH:12][C:11]2=[O:17])=[C:29]([CH3:31])[CH:30]=1)=[O:25])[CH3:35]
Reactant: CCN(CC)CCNC(=O)c1cc(C)c(C=O)[nH]1
Reactant: O=C1Cc2c(cccc2-c2cccc(Br)c2)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1cc(C)c(C=C2C(=O)Nc3cccc(-c4cccc(Br)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 34.5 %

Procedure:
To a solution of 4-(3-bromo-phenyl)-1,3-dihydro-indol-2-one (72 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The reaction solution was evaporated, and purified on a silica gel column eluting with MeOH—CH2Cl2 5:95 to provide pure product 5-[4-(3-bromo-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-2-carboxylic acid (2-diethylamino-ethyl)-amide as a yellow solid (45 mg, 35%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][CH:9]=1)[CH2:4][CH2:5][OH:6].C(N(CC)C(C)C)(C)C.[C:24]([C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[O:35][CH:36]([CH3:38])[CH3:37])[C:29](O)=[O:30])#[N:25].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:14][C:11]1[CH:10]=[CH:9][C:8]([CH2:7][C@H:3]([NH:2][C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:34]([O:35][CH:36]([CH3:38])[CH3:37])=[C:26]([C:24]#[N:25])[CH:27]=2)[CH2:4][CH2:5][OH:6])=[CH:13][CH:12]=1
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: N[C@H](CCO)Cc1ccc(Br)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1ccc(C(=O)N[C@H](CCO)Cc2ccc(Br)cc2)cc1C#N
Reaction time: 0.05 h
Yield: 78.7 %

Procedure:
To a suspension of (3S)-3-Amino-4-(4-bromophenyl)-1-butanol hydrochloride (1.80 g, 6.42 mmol) in dry DMF (32 mL) was added N,N-diisopropylethyl amine (2.49 g, 19.3 mmol) and the resultant clear solution was stirred for 3 min. 3-Cyano-4-[(1-methylethyl)oxy]benzoic acid (1.45 g, 7.06 mmol) and HBTU (2.68 g, 7.06 mmol) were added and the reaction was stirred at rt under nitrogen. After 1.5 h, the reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3×30 mL). The extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography (75% EtOAc/hexanes) to give 2.18 g (78%) of the title compound as a white solid. LC/MS (ES) m/e 431.2 (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH:10]=[C:11]([C:17]([OH:19])=O)[NH:12]2.Cl.Cl.Cl.[N:23]1([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[N:23]1([CH2:30][CH2:31][N:32]2[CH2:33][CH2:34][CH:35]([NH:38][C:17]([C:11]3[NH:12][C:13]4[C:9]([CH:10]=3)=[C:8]([O:7][CH2:6][C:2]3[O:1][CH:5]=[CH:4][CH:3]=3)[CH:16]=[CH:15][CH:14]=4)=[O:19])[CH2:36][CH2:37]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(O)c1cc2c(OCc3ccco3)cccc2[nH]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(OCc3ccco3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-(furan-2-ylmethoxy)-1H-indole-2-carboxylic acid 93 (preparation see below) and amine 5.
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][C:4]([C:7]2([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[Br:15]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:15][CH2:14][C:1]1[CH:2]=[CH:3][C:4]([C:7]2([C:10]([O:12][CH3:13])=[O:11])[CH2:9][CH2:8]2)=[CH:5][CH:6]=1
Reactant: COC(=O)C1(c2ccc(C)cc2)CC1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C1(c2ccc(CBr)cc2)CC1
Yield: 97.7 %

Procedure:
To a solution of methyl 1-(p-tolyl)cyclopropanecarboxylate (622 mg, 3.27 mmol) in carbon tetrachloride (16 mL) was added N-bromosuccinimide (611 mg) followed by benzoyl peroxide (40 mg). The resulting solution was heated at reflux overnight, and then diluted with methylene chloride. The mixture was washed with brine, dried on MgSO4, and concentrated to afford a colorless oil (860 mg, 97%).
Reaction SMILES: C([O:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]=3[C:17](=[O:37])[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1)(=O)C1C=CC=CC=1.Cl(O)(=O)(=O)=O.[OH-].[K+].CO.[OH-].[Na+]>C(O)CC.C(O)C>[OH:9][C@H:10]1[CH2:34][CH2:33][C@@:32]2([CH3:35])[C@@H:12]([CH2:13][CH2:14][C:15]3[C@@H:31]2[CH2:30][CH2:29][C@@:28]2([CH3:36])[C:16]=3[C:17](=[O:37])[CH2:18][C@@H:19]2[C@H:20]([CH3:27])[CH2:21][CH2:22][CH2:23][CH:24]([CH3:26])[CH3:25])[CH2:11]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H](OC(=O)c5ccccc5)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: [K+]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CCCO
Solvent: CO
Solvent: CCO
Product: CC(C)CCC[C@@H](C)[C@H]1CC(=O)C2=C3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
Then a stirred mixture of the precursor (6) in a protic solvent, preferably methanol, is treated with potassium carbonate and heated at reflux for 3 hours to give the desired product (3β,5α)-3-hydroxycholest-8(14)en-15-one (7). This conversion was based upon the procedures of E. J. Parish and G. J. Schroepfer and J. Org. Chem., 45, 4034-4037 (1980) and R. E. Dolle and L. Kruse, J. Org. Chem., 51, 4047-4053 (1986). Alternatively, the precursor (6) is treated with perchloric acid in n-propanol or ethanol at reflux or treated with potassium hydroxide or sodium hydroxide methanol at room temperature to give the desired product (7).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C:15]1[CH:20]=[CH:19][C:18](OS(C(F)(F)F)(=O)=O)=[CH:17][C:16]=1[O:29][CH3:30])[NH:4][C:5]([C@H:7]1[CH2:9][C@@H:8]1[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=[O:6].[C:31]1([CH3:40])[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CCOC(C)=O>COCCOC.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>[OH:1][CH2:2][C@H:3]([NH:4][C:5]([C@H:7]1[CH2:9][C@@H:8]1[C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=[O:6])[C:15]1[CH:20]=[CH:19][C:18]([C:34]2[CH:35]=[CH:36][C:31]([CH3:40])=[CH:32][CH:33]=2)=[CH:17][C:16]=1[O:29][CH3:30]
Reactant: Cc1ccccc1B(O)O
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)ccc1[C@H](CO)NC(=O)[C@H]1C[C@@H]1c1cccs1
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: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cc(-c2ccc(C)cc2)ccc1[C@H](CO)NC(=O)[C@H]1C[C@@H]1c1cccs1
Temperature: 80 °C
Yield: 21.3 %

Procedure:
A mixture of trifluoro-methanesulfonic acid 4-{(R)-2-hydroxy-1-[((1S,2S)-2-thiophen-2-yl-cyclopropanecarbonyl)amino]-ethyl}-3-methoxy-phenyl ester (66 mg, 0.142 mmol), tolylboronic acid (38.1 mg, 0.284 mmol), Pd(PPh3)4 (16.4 mg, 0.014 mmol) and Na2CO3 (45.2 mg, 0.426 mmol) in DME/H2O (1.2/0.4 mL) was heated at 80° C. for 3 h. The reaction mixture was passed through a short silica pad (EtOAc) and concentrated. The residue was subjected to preparative HPLC to give the titled compound (12.3 mg). 1H NMR (400 MHz, MeOD) δ ppm 7.7 (d, J=8.3 Hz, 2H), 7.6 (d, J=8.3 Hz, 1H), 7.5 (d, J=7.8 Hz, 2H), 7.4 (t, J=5.4 Hz, 2H), 7.1-7.2 (m, 1H), 7.1 (d, J=3.5 Hz, 1H), 5.6 (dd, J=7.8, 4.5 Hz, 1H), 4.8 (s, 1H), 4.2 (s, 3H), 4.0 (dd, J=11.1, 4.5 Hz, 1H), 3.9 (dd, J=11.4, 7.8 Hz, 1H), 2.8 (dd, J=6.3, 2.5 Hz, 1H), 2.6 (s, 3H), 2.3 (dd, J=8.0, 4.7 Hz, 1H), 1.8 (ddd, J=9.2, 4.8, 4.7 Hz, 1H), 1.5 (ddd, 1H). LRMS (ESI)=408, [(M+1)+ calcd for C24H26NO3S 407.5].
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[N:4]([CH:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[N:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[CH:24]=[CH:23][C:22]=1[NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]3)[N:3]=[C:2]([C:25]3[CH:24]=[CH:23][C:22]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:40])([CH3:41])[CH3:42])=[C:21]([O:20][CH3:19])[CH:26]=3)[C:10]=12
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Reactant: CN1CCC(n2nc(I)c3c(N)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COc1cc(-c2nn(C3CCN(C)CC3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Yield: 73.1 %

Procedure:
3-Iodo-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (270 mg, 0.754 mmol), tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (290 mg, 0.829 mmol), palladium tetrakistriphenyphosphine (52 mg, 0.045 mmol) and sodium carbonate (192 mg, 1.81 mmol) were mixed in ethylene glycol dimethyl ether (8 mL) and water (4 mL). The reaction mixture was heated at reflux overnight under nitrogen. Organic solvent was removed under reduced pressure and the aqueous layer was extracted with dichloromethane. The combined organic layer was washed with water then brine, dried over MgSO4, filtered and evaporated. The residue was purified by flash column chromatography using dichloromethane/methanol (90:10 to 70:30) as mobile phase to give tert-butyl N-{4-[4-amino-1-(1-methyl-4-piperidyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-2-methoxyphenyl}carbamate (250 mg, 73%). 1H NMR (DMSO-d6) δ 1.48 (s, 9H), 1.88 (m, 2H), 2.10 (m, 2H), 2.24 (m, 5H), 2.92 (m, 2H), 3.69 (s, 3H), 4.64 (m, 1H), 7.21 (m, 2H), 7.91 (d, J=8.16 Hz, 1H), 8.04 (s, 1H), 8.23 (s, 1H). LCMS (Thermoquest AQA single Quad MS, Finnigan HPLC-Column: Genesis, C18, 3 um, 33×4.6 mm. Eluents: 30% B/A to 95% B/A in 4.5 min. (B: acetonitrile, A: 50 mM ammonia acetate buffer, pH 4.5), 0.8 mL/min.): MH+=454.2, Rt=1.67 min.