Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:14])=O>CN(C=O)C.ClCCl>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[C:3]=1[C:4]([Cl:14])=[O:5]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1c(F)cccc1F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1c(F)cccc1F
Yield: 76.9 %

Procedure:
A mixture of 2,6-difluorobenzoic acid (10 g, 63.3 mmol) and DMF (3 drops) in dichloromethane (150 ml) was treated with thionyl chloride (23 ml, 316.5 mmol). The mixture was heated at reflux overnight. The solvent was removed in vacuo and the residue azeotroped (toluene 3×50 ml) to give 2,6-difluorobenzoyl chloride as an oil (8.59 g, 77%). N Boc-L4-aminophenylalanine methyl ester (100.92 g, 40.6 mmol) and NMM (5.3 ml, 48.7 mmol) were added to a solution of the above acid chloride in DMF (50 nm). The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the residue partitioned between ethyl acetate and aqueous. The aqueous layer was extracted with ethyl acetate (3×100 ml). The combined organic layers were dried (MgSO4) and evaporated in vacuo to give a pale brown oily solid. Trituration with ether gave the title compound as a white solid (6.93 g). δH(d6 DMSO) 7.67-7.53 (3H, m), 7.27-7.20 (5H, m), 4.19-4.11 (1H, m), 3.62 (3H, s), 3.00-2.73 (2H, m), 1.33 (9H, s); m/z (ESI, 70V) 457 (M++Na).
Reaction SMILES: Cl.[CH:2]1([NH:5][C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@H:25]4[CH3:30])[C:18]4[CH2:23][NH:22][CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)=[O:7])[CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:40]([O:42][CH2:43][CH3:44])=[O:41]>CN(C=O)C>[CH:2]1([NH:5][C:6](=[O:7])[NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@H:25]4[CH3:30])[C:18]4[CH2:23][N:22]([C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:21][C:19]=4[N:20]=3)=[C:11]([F:31])[CH:10]=2)[CH2:3][CH2:4]1
Reactant: CCOC(=O)Cl
Reactant: C[C@@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2F)nc2c1CNC2
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)N1Cc2nc(-c3ccc(NC(=O)NC4CC4)cc3F)nc(N3CCOC[C@H]3C)c2C1
Reaction time: 8 h
Yield: 26.8 %

Procedure:
A solution of (R)-1-cyclopropyl-3-(3-fluoro-4-(4-(3-methylmorpholino)-6,7-dihydro-5H-pyrrolo[3,4-d]pyrimidin-2-yl)phenyl)urea hydrochloride (intermediate 33) (121 mg, 0.270 mmol) and triethylamine (75 μL, 0.534 mmol) in anhydrous DMF (2 ml) was stirred at RT for 40 minutes. After this time, ethyl chloroformate (30 μl, 0.322 mmol) was added and stirring was continued at RT overnight. The reaction was partitioned between H2O and EtOAc and the aqueous phase was extracted into EtOAc. The organic extracts were combined, dried over magnesium sulphate and concentrated in vacuo. The sample was then purified via preparative HPLC at low pH to yield the title compound (35 mg, 27%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7]([OH:17])=[C:6]([C:18](=[O:24])[CH:19]([CH3:23])[CH2:20][CH:21]=[O:22])[C:5]2=[O:25].[OH:26]OS([O-])=O.[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[C:8]1([CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[C:7]([OH:17])=[C:6]([C:18](=[O:24])[CH:19]([CH3:23])[CH2:20][C:21]([OH:26])=[O:22])[C:5]2=[O:25]
Reactant: O=S([O-])OO
Reactant: CC(CC=O)C(=O)C1=C(O)C2(CCOCC2)c2ccc(Cl)cc2C1=O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(CC(=O)O)C(=O)C1=C(O)C2(CCOCC2)c2ccc(Cl)cc2C1=O
Temperature: 25 °C
Yield: 88 %

Procedure:
A mixture of 4-(6-chloro-2-hydroxy-4-oxo-2′,3′,5′,6′-tetrahydro-4H-spiro[naphthalene-1,4′-pyran]-3-yl)-3-methyl-4-oxobutanal (0.1 g, 0.3 mmol) in 2 mL DMF was stirred at room temperature and treated with oxone (0.2 mL, 0.3 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was quenched with 20 mL H2O, and the pH was adjusted to pH=5 with concentrated HCl. The precipitate that formed was collected by filtration and washed with 20 mL water. The product was dried under high vacuum to give 0.1 g of the product as an off-white solid. MS m/z 379 (M+H)+. Calculated for C19H19ClO6: 378.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:3]=1.[CH3:29]OC>>[CH3:29][O:1][C:2]1[C:7]2[O:8][C:9]3[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C:10]=3[C:6]=2[CH:5]=[C:4]([O:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCc2oc3c(O)cc(Oc4ccccc4)cc3c2C1
Reactant: COC
Product: COc1cc(Oc2ccccc2)cc2c3c(oc12)CCN(C(=O)OC(C)(C)C)C3
Yield: 78 %

Procedure:
The product of step C was converted to the methyl ether derivative following the procedure of Example 54, step B. Purification by flash column chromatography (SiO2, 17:3 hexane/ethyl acetate) provided tert-butyl 6-methoxy-8-phenoxy-3,4-dihydrobenzofuro[3,2-c]pyridine-2(1H)-carboxylate (20 mg, 78%) as a colorless oil: 1H NMR (CDCl3, 400 MHz) δ 7.36-7.29 (m, 2H), 7.11-7.04 (m, 1H), 7.02-6.95 (m, 2H), 6.63 (s, 1H), 6.56 (d, J=2.0 Hz, 1H), 4.46 (s, 2H), 4.00 (s, 3H), 3.82 (s, 2H), 2.86 (s, 2H), 1.50 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([Mg]Br)=[CH:5][CH:4]=1.[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2=[O:22]>O1CCCC1>[Cl:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16](=[O:21])[C:15]2([OH:22])[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc([Mg]Br)cc1
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Solvent: C1CCOC1
Product: COc1ccc(C2(O)C(=O)Nc3ccc(Cl)cc32)cc1
Temperature: -25 °C

Procedure:
A solution of 4-methoxyphenyl magnesium bromide in tetrahydrofuran (0.5 M, 50 mL, 25 mmol) (Aldrich) was added dropwise to a suspension of 5-chloroisatin (1.82 g, 10 mmol) (Avocado) in tetrahydrofuran (20 mL) under argon with cooling in a −25° C. bath and magnetic stirring at such a rate that reaction temperature was kept below −10° C. (approximately 30 minutes). Cooling bath was then removed and mixture allowed to warm to room temperature. After stirring for an additional 1 hour, 15% aqueous ammonium chloride solution (50 mL) was added and mixture extracted with ethyl acetate (2×75 mL). Ethyl acetate layers were then washed with water (75 mL), brine (75 mL), combined, dried (MgSO4), filtered and concentrated. Residue was stirred in dichloromethane (100 mL) at room temperature for 30 minutes and filtered to give crude rac-5-chloro-3-hydroxy-3-(4-methoxy-phenyl)-1,3-dihydro-indol-2-one as a white powder. (Yield 2.57 g, 88.7%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:23]CO)[N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:3]=12.[CH2:26]([OH:29])[C:27]#[CH:28].C(N(CC)CC)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.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>[Cl:1][C:2]1[C:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:6][N:5]=[C:4]2[N:14]([CH3:23])[N:15]=[C:16]([C:17]3[CH:22]=[C:21]([C:28]#[C:27][CH2:26][OH:29])[CH:20]=[CH:19][CH:18]=3)[C:3]=12
Reactant: C#CCO
Reactant: OCCn1nc(-c2ccccc2)c2c(Cl)c(-c3ccccc3)nnc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: Cn1nc(-c2cccc(C#CCO)c2)c2c(Cl)c(-c3ccccc3)nnc21
Temperature: 100 °C
Yield: 38.5 %

Procedure:
A mixture of 4-chloro-3-(3-iodophenyl)-1-methyl-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (Compound 7, Example 32) (80 mg, 0.18 mmol), propargyl alcohol (41 mg, 0.74 mmol), triethylamine (87 μl, 0.63 mmol), Cut (3.5 mg, 0.018 mmol), triphenylphosphine (5 mg, 0.018 mmol) and Pd(PPh3)4 (20 mg, 0.018 mmol) in 1,4-dioxane (1.5 mL) was heated at 100° C. for 4 h in a sealed tube. The reaction mixture was partitioned between CH2Cl2 and water. The organic phase was separated and dried using a phase separating cartridge then concentrated in vacuo. The crude residue was purified by column chromatography (silica gel, 20-30% ethyl acetate/isohexane), yielding Compound 30 as a solid (26 mg).
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28].C(N(CC)CC)C>C(O)C>[C:19]1(=[O:28])[N:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][S:1][C:2]2[N:7]3[CH:8]=[CH:9][N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]12
Reactant: Sc1cccc2nccn12
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCBr
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1CCCCCCSc1cccc2nccn12
Temperature: 25 °C
Reaction time: 12 h
Yield: 75.4 %

Procedure:
To a suspension of 5-mercaptoimidazo[1,2-a]pyridine (1.50g, 10 mmoles) and N-[6-(bromo)hexyl]phthalimide (3.10 g, 10 mmoles) in ethanol (100 ml) was added triethylamine (2.1 ml, 15 mmoles) and the mixture was stirred at room temperature for 12 hours. After the solvent was distilled off, chloroform was added to the residue, which was washed with water, dried over anhydrous magnesium sulfate and the solvent was distilled off. Then the residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.86 g of the desired product (75.5%, light tan solid).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([N+:23]([O-:25])=[O:24])=[C:11]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:28](I)[CH3:29].O>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10]([N+:23]([O-:25])=[O:24])=[C:11]([N:15]([CH2:28][CH3:29])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)(C)C)c1cccc(OCc2ccccc2)c1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 103.6 %

Procedure:
To a solution of tert-butyl N-(3-benzyloxy-2-nitrophenyl)carbamate (3 g) in dimethylformamide (30 ml) was added sodium hydride (60% in oil, 575 mg) under ice-cooling, and the mixture was stirred for 15 minutes. To the mixture was added ethyl iodide (1.49 g), and the mixture was stirred for 2 hours at ambient temperature. To the reaction mixture was added water (150 ml), and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1, v/v) and crystallized with hexane to give tert-butyl N-(3-benzyloxy-2-nitrophenyl)-N-ethylcarbamate (3.36 g).
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16](O)=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:21][NH2:22]>>[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([NH:22][CH3:21])=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)C=Cc1ccc(OCc2ccc(F)cc2)cc1
Reactant: CN
Product: CNC(=O)C=Cc1ccc(OCc2ccc(F)cc2)cc1
Yield: 21 %

Procedure:
The title compound is prepared in analogy to example 12 b) from 3-[4-(4-fluoro-benzyloxy)-phenyl]-acrylic acid and methylamine. Yield=21%. Colorless solid. MS: m/e=286.0 (M++H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]([C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)=[N:8][O:9][C:10]=2[CH3:11])[N:3]=[CH:2]1.[C:19]([C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1)#[N:20]>>[F:18][C:15]1[CH:16]=[CH:17][C:12]([C:7]2[C:6]([C:4]3[N:3]=[CH:2][N:1]([C:24]4[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=4)[CH:5]=3)=[C:10]([CH3:11])[O:9][N:8]=2)=[CH:13][CH:14]=1
Reactant: Cc1onc(-c2ccc(F)cc2)c1-c1c[nH]cn1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: Cc1onc(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C#N)cc2)cn1
Yield: 13 %

Procedure:
As described for Example 3, 4-(1H-imidazol-4-yl)-5-methyl-3-(4-fluorophenyl)-isoxazole (73 mg, 0.3 mmol) was converted, using 4-cyanophenylboronic acid instead of 4-fluorophenylboronic acid, to the title compound (13 mg, 13%) which was obtained as an off-white solid. MS: m/e=345.3[M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH3:14])[O:13][CH2:12][CH2:11][O:10]1.C(N(CC)CC)C.[CH3:22][Si:23](Cl)([CH3:25])[CH3:24]>O1CCCC1>[Br:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2([CH3:14])[O:10][CH2:11][CH2:12][O:13]2)=[C:2]([O:1][Si:23]([CH3:25])([CH3:24])[CH3:22])[CH:7]=1
Reactant: C[Si](C)(C)Cl
Reactant: CC1(c2ccc(Br)cc2O)OCCO1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC1(c2ccc(Br)cc2O[Si](C)(C)C)OCCO1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.6 %

Procedure:
Under ice-cooling, to a solutin of 3.11 g (12 mmol) of 2-(2-hydroxy-4-bromophenyl)-2-methyl-1,3-dioxolane in 24 ml of tetrahydrofuran were added dropwise successively, 1.84 ml (13.2 mmol) of triethylamine and 1.68 ml (13.2 mmol) of trimethylsilyl chloride with stirring. The mixture was stirred at room temperature for 3 hours and filtered. The filtrate was concentrated under reduced pressure to give 4.0 g of the crude product.
Reaction SMILES: [NH3:1].CS([C:6]1[N:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C:9]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:8]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[N:7]=1)(=O)=O>C1COCC1>[NH2:1][C:6]1[N:11]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[C:9]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)=[C:8]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=2[Cl:35])[N:7]=1
Reactant: N
Reactant: CS(=O)(=O)c1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Solvent: C1CCOC1
Product: Nc1nc(Oc2ccc(F)c(F)c2)c(-c2ccc(Cl)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 5 mL round bottom flask fitted with a magnetic stir bar and rubber septum was added 1 mL THF and excess ammonia gas. The flask was cooled to 0°. 2-(methylsulfonyl)-4-(3,4-difluorophenoxy)-5-[4-chlorophenyl]-6-[2,4-dichlorophenyl]pyrimidine (Example 20, 270 mg, 0.5 mmol) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was washed with saturated NaHCO3, dried over MgSO4, filtered and the solvent removed under reduced pressure. Flash column chromatography on silica gel (eluted with 60/40 hexanes/ethyl acetate) afforded 2-(amino)-4-(3,4-difluorophenoxy)-5-(4-chlorophenyl)-6-(2,4-dichlorophenyl)pyrimidine. HPLC/MS: m/e=480 (M+1); Rt=4.2 min; 1H-NMR 500 MHz (CD3OD): δ 6.95 (m, 1H), 7.20 (m, 4H), 7.28 (m, 4H), 7.41 (d, J=2 Hz, 1H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]([CH3:15])[N:13]=[C:12]([C:16](=O)[CH3:17])[C:11]=3[OH:19])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[NH:20]([C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:25]1)=[S:23])[NH2:21].Cl.C(OCC)(=O)C>CN(C)C=O>[CH2:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[N:14]([CH3:15])[N:13]=[C:12]([C:16](=[N:21][NH:20][C:22]([N:24]4[CH2:29][CH2:28][CH:27]([C:30]([O:32][CH3:33])=[O:31])[CH2:26][CH2:25]4)=[S:23])[CH3:17])[C:11]=3[OH:19])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(=O)c1nn(C)c(-c2ccc3c(c2)CCC3)c1O
Reactant: COC(=O)C1CCN(C(=S)NN)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1CCN(C(=S)NN=C(C)c2nn(C)c(-c3ccc4c(c3)CCC4)c2O)CC1
Yield: 76.5 %

Procedure:
1-[5-(2,3-dihydro-1H-inden-5-yl)-4-hydroxyl-1-methyl-1H-pyrazol-3-yl]ethanone (50 mg, 0.195 mmol) and methyl 1-(hydrazinecarbonothioyl)piperidine-4-carboxylate (51 mg, 0.234 mmol, synthesized in accordance with WO2006062240) in N,N-dimethylformamide was stirred with concentrated hydrochloric acid (24 μL, 0.293 mmol) at room temperature for 1 day. After the reaction, ethyl acetate was added, and the reaction solution was washed with saturated aqueous ammonium chloride and saturated aqueous sodium chloride. The resulting organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure. The resulting residue was purified by medium pressure silica gel column chromatography (hexane/ethyl acetate=1/1 (v/v)→ethyl acetate) to obtain the desired product (68 mg, 77% yield).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1F.O.[NH2:16][NH2:17]>C(O)C>[N+:10]([C:7]1[CH:6]=[C:5]2[C:4]([C:3]([OH:2])=[N:16][NH:17]2)=[CH:9][CH:8]=1)([O-:12])=[O:11]
Reactant: NN
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1F
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc2c(O)n[nH]c2c1
Yield: 30.9 %

Procedure:
2-Fluoro-4-nitrobenzoic acid methyl ester (5 g, 25.11 mmol) and hydrazine hydrate (1.34 ml, 27.62 mmol) were dissolved in 250 ml of ethanol and heated under reflux for 11 h. A further 0.26 ml of hydrazine hydrate were added and heated under reflux for a further 6 h, and the mixture was concentrated and ethyl acetate and water were added. The precipitated residue was filtered off with suction and dried. Purification by preparative HPLC (PR18, acetonitrile/water 0.1% TFA) resulted in 1.39 g of product, M+H+: 180.05.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C([Sn](CCCC)(CCCC)[C:37]1[N:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]2=[N:39][CH:38]=1)CCC>CN(C=O)C.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>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:37]4[N:41]5[CH:42]=[CH:43][CH:44]=[CH:45][C:40]5=[N:39][CH:38]=4)[N:20]=3)[N:15]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2ccccn12
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cnc4ccccn34)nc12)C(=O)N1CC(C#N)C1
Temperature: 75 °C

Procedure:
2-Bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]amide (110 mg, 0.22 mmol) was combined with 3-tributylstannanyl-imidazo[1,2-a]pyridine (159 mg, 0.39 mmol) in DMF that had been sparged with nitrogen for 10 min. To this was added tetrakis(triphenylphosphine)palladium(0) (25 mg, 0.022 mmol) and the mixture heated to 70-80° C. for 3 h. All solvent was removed by high vacuum evaporation and the product purified by silica gel chromatography to give 2-imidazo[1,2-a]pyridin-3-yl-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide. LCMS: (M+H)+=544.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C@@H:5]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[CH:20]=1)[C@@H:6]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1.Br[C:27]1[S:28][CH:29]=[CH:30][N:31]=1>CC(O)C>[Cl:25][C:21]1[CH:20]=[C:19]([C@H:5]([O:4][CH2:3][CH2:2][NH:1][C:27]2[S:28][CH:29]=[CH:30][N:31]=2)[C@@H:6]2[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:7]2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCN)c2cccc(Cl)c2)C1
Reactant: Brc1nccs1
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]([C@@H](OCCNc2nccs2)c2cccc(Cl)c2)C1
Reaction time: 96 h
Yield: 49.2 %

Procedure:
A 25 mL flask was charged with (R)-tert-butyl 3-((R)-(2-aminoethoxy)(3-chlorophenyl)methyl)piperidine-1-carboxylate (100 mg, 0.27 mmol) and 2-bromo-thiazole (22 mg, 0.135 mmol) dissolved in propan-2-ol (5 mL) and stirred for 96 hr under reflux. The solvent and excess reagent was removed in vacuo to afford a residue purified by chromatography to give the pure (R)-tert-butyl 3-((R)-(3-chlorophenyl)(2-(thiazol-2-ylamino)ethoxy)methyl)piperidine-1-carboxylate (30 mg, 25%)
Reaction SMILES: C(CCC1C=CC([C:12]2[C:13]([CH3:43])([CH3:42])[C@H:14]3[C@:27]([CH3:30])([CH2:28][CH:29]=2)[C@@H:26]2[C@:17]([CH3:41])([C@@:18]4([CH3:40])[C@H:23]([CH2:24][CH2:25]2)[C@H:22]2[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]2([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=CC=1)(O)=O.[CH3:44][NH:45][S:46]([C:49]1[CH:50]=[C:51](B(O)O)[CH:52]=[CH:53][CH:54]=1)(=[O:48])=[O:47].B(O)O>>[CH3:40][C@:18]12[C@@:17]3([CH3:41])[C@@H:26]([C@:27]4([CH3:30])[C@@H:14]([CH2:15][CH2:16]3)[C:13]([CH3:42])([CH3:43])[C:12]([C:51]3[CH:52]=[CH:53][CH:54]=[C:49]([S:46](=[O:48])(=[O:47])[NH:45][CH3:44])[CH:50]=3)=[CH:29][CH2:28]4)[CH2:25][CH2:24][C@@H:23]1[C@H:22]1[C@H:31]([C:34]([CH3:36])=[CH2:35])[CH2:32][CH2:33][C@:21]1([C:37]([OH:39])=[O:38])[CH2:20][CH2:19]2
Reactant: CNS(=O)(=O)c1cccc(B(O)O)c1
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(CCC(=O)O)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: OBO
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6cccc(S(=O)(=O)NC)c6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12

Procedure:
The title compound was prepared following the method described above for compound (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-9-(4-(2-carboxyethyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylic acid (example 4a) using 3-(N-methylsulfamoyl)phenylboronic acid as the reactant boronic acid. The product was isolated as a white solid (32.47 mg, 62%). LCMS: m/e 606.58 (M−H)−, 4.47 min (method 2). 1H NMR (599 MHz, DMSO-D6_CDCl3) δ ppm 0.94 (s, 3H), 0.95 (s., 3H), 1.00 (br. s., 6H), 1.03 (s, 3H), 1.04-1.78 (m, 17H), 1.71 (s, 3H), 1.88 (t, J=7.03 Hz, 2H), 2.14 (dd, J=17.28, 6.15 Hz, 1H), 2.20 (d, J=12.30 Hz, 1H), 2.31-2.39 (m, 1H), 2.46 (d, J=4.69 Hz, 3H), 2.99-3.08 (m, 1H), 4.61 (s., 1H), 4.74 (s, 1H), 5.34 (d, J=5.86 Hz, 1H), 7.39 (d, J=8.20 Hz, 1H), 7.46 (q, J=5.27 Hz, 1H), 7.51-7.58 (m, 2H), 7.71 (d, J=7.62 Hz, 1H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:16]([C:17]2C=CN[N:18]=2)=[CH:15][N:14]=[C:13]([NH:22][CH2:23][CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)[N:12]=1.[Cl:35]C1C=C(Cl)C=CC=1C(=O)[C:44](C1N=C(C)NC=1)=[CH:45][N:46](C)[CH3:47]>>[ClH:3].[ClH:35].[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:16]([C:17]2[N:18]=[C:45]([CH3:44])[NH:46][CH:47]=2)=[CH:15][N:14]=[C:13]([NH:22][CH2:23][CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)[N:12]=1
Reactant: Cc1nc(C(=CN(C)C)C(=O)c2ccc(Cl)cc2Cl)c[nH]1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3cc[nH]n3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Agent: Cl
Product: Cc1nc(-c2cnc(NCCNc3ccc([N+](=O)[O-])cn3)nc2-c2ccc(Cl)cc2Cl)c[nH]1

Procedure:
Made using the same procedure as for [4-(2,4-dichlorophenyl)-5-pyrazolylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine dihydrochloride except that 1-(2,4-dichlorophenyl)-3-(dimethylamino)-2-(2-methylimidazolyl)prop-2-en-1-one (XV, 421 mg, 1.3 mmol) was used.