Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].C([O-])([O-])=O.[Cs+].[Cs+].[C:15]([NH:22][CH2:23][CH2:24]Br)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CC#N.C(Cl)Cl>[C:18]([O:17][C:15](=[O:16])[NH:22][CH2:23][CH2:24][N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=[N+]([O-])c1cn[nH]c1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCn1cc([N+](=O)[O-])cn1
Temperature: 80 °C

Procedure:
To a solution of 4-nitro-1H-pyrazole (2.50 g, 21.45 mmol) in MeCN (30 mL), Cs2CO3 (8.39 g, 25.74 mmol) and 2-(boc-amino)ethyl bromide (5.45 g, 23.59 mmol) was added. The resulting mixture was refluxed (80° C.) for 1.5 h, then the reaction mixture was allowed to reach rt. The mixture was diluted with DCM, filtered, the filter cake was washed with DCM and the filtrate was concentrated in vacuo. The residue was partitionned between water and EtOAc, the org. layer was separated and the aq. layer was extracted with EtOAc (1×). The combined org. layers were washed with brine, dried (MgSO4) and concentrated in vacuo. Purification was performed by FC (EtOAc/hept 7:3 to EtOAc/MeOH 9:1) to obtain tert-butyl(2-(4-nitro-1H-pyrazol-1-yl)ethyl)carbamate as a slightly yellow solid which was used without further purification in the next step. LC-MS conditions A: tR=0.72 min, [M+H]+=257.08.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7]([O:9][CH2:10][CH2:11][OH:12])=[O:8])(=[O:4])=[O:3].C(Cl)Cl.[CH3:20][Si:21](Cl)([CH3:23])[CH3:22]>C(N(CC)CC)C>[NH2:1][S:2]([C:5]1[CH:16]=[CH:15][CH:14]=[CH:13][C:6]=1[C:7]([O:9][CH2:10][CH2:11][O:12][Si:21]([CH3:23])([CH3:22])[CH3:20])=[O:8])(=[O:3])=[O:4]
Reactant: C[Si](C)(C)Cl
Reactant: NS(=O)(=O)c1ccccc1C(=O)OCCO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[Si](C)(C)OCCOC(=O)c1ccccc1S(N)(=O)=O
Reaction time: 18 h

Procedure:
To a slurry of 12.25 g of 2-aminosulfonylbenzoic acid, 2-hydroxyethyl ester, 125 ml of dry methylene chloride, and 7.7 ml of triethylamine was added dropwise over 10 minutes 6.3 ml of trimethylsilyl chloride (exotherm to 36° C.). The resulting solution was allowed to stand at ambient temperature for 18 hours and then washed with saturated sodium chloride solution, dried (MgSO4), and the solvent removed under reduced pressure to give an oil which was chromatographed on silica gel eluting with 25% EtOAc:hexane to give a colorless oil which slowly crystallized. Trituration with hexane gave 8.0 g of white crystals, m.p. 72°-76° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[C:21]2[CH2:20][CH2:19][C@H:18]3[C@H:14]([CH2:15][C:16](=O)[N:17]3[CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1.C(OCC)(=O)C.[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:7][O:8][C:9]1[C:21]2[CH2:20][CH2:19][C@H:18]3[C@H:14]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1CCCc1ccccc1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCN1CCCc1ccccc1
Yield: 89.4 %

Procedure:
0.457 g (0.01204 mol) of lithium aluminum hydride was suspended in 40 ml of THF under argon. A solution of 4.04 g (0.01204 mol) of rac-cis-1,3,3a,4,5,9b-hexahydro-6-methoxy-3-(3-phenyl-propyl)-2H-benzo[e]indol-2-one in 40 ml of THF was added dropwise thereto and the mixture was boiled under reflux for 2 hours. 10 ml of ethyl acetate and a saturated aqueous Na2SO4 solution were cautiously added dropwise thereto in succession until a complete white precipitate had resulted. After filtration and concentration there was obtained an oil which was chromatographed over silica gel with cyclohexane/ethyl acetate 3:1. There were obtained 3.46 g (89%) of oily rac-cis-2,3,3a,4,5,9b-hexahydro-6-methoxy-3-(3-phenyl-propyl)-1H-benzo[e]indole.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[N:4][O:5][C:6]=1[N:7]([C:16]([O:18]CC(Cl)(Cl)Cl)=O)C(OCC(Cl)(Cl)Cl)=O.[C:25]1([C:31]2[N:35]=[C:34]([N:36]3[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]3)[S:33][N:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[Cl:1][C:2]1[C:3]([CH3:24])=[N:4][O:5][C:6]=1[NH:7][C:16]([N:39]1[CH2:40][CH2:41][N:36]([C:34]2[S:33][N:32]=[C:31]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:35]=2)[CH2:37][CH2:38]1)=[O:18]
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cc1noc(N(C(=O)OCC(Cl)(Cl)Cl)C(=O)OCC(Cl)(Cl)Cl)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CS(C)=O
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)c1Cl

Procedure:
A solution of bis(2,2,2-trichloroethyl) (4-chloro-3-methylisoxazol-5-yl)imidodicarbonate (200 mg, 0.418 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (203 mg, 0.836 mmol), diisopropylethylamine (0.144 ml, 0.836 mmol) and dimethylsulfoxide (4 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain the desired product as a solid. This was recrystallized from a mixed solvent of ethyl acetate and hexane to obtain the desired product (111 mg, 66.1%) as a solid.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].CCN=C=NCCCN(C)C.[CH3:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:30][CH2:31][CH2:32][CH2:33][C:34](O)=[O:35]>C(Cl)Cl>[O:8]=[C:3]1[CH2:4][CH2:5][C:6](=[O:7])[N:2]1[O:1][C:34](=[O:35])[CH2:33][CH2:32][CH2:31][O:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH3:20]
Reactant: O=C1CCC(=O)N1O
Reactant: COCCOCCOCCOCCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: COCCOCCOCCOCCCC(=O)ON1C(=O)CCC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
N-hydroxysuccinimide (0.55 g, 4.8 mmol) and EDCI (1.15 g, 6.0 mmol) were dissolved in CH2Cl2 (7 mL). Then 4-{2-[2-(2-Methoxy-ethoxy)-ethoxy]-ethoxy}-butyric acid (0.940 g, 3.8 mmol), dissolved in CH2Cl2 (2 mL), was added. Reaction stirred overnight at room temperature. Crude reaction was diluted with CH2Cl2 (21 mL), washed 1M HCl (30 mL), H2O (30 mL), dried MgSO4, and evaporated to dryness. Column chromatography (Silica, ethyl acetate) afforded 4, a clear oil (0.556 g, 43% yield).
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.Br>I>[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1
Reactant: COc1ccc(CN)cc1
Agent: Br
Agent: I
Product: NCc1ccc(O)cc1
Yield: 130.9 %

Procedure:
10 g 4-methoxy benzylamine chlorohydrate of formula (IV) are reflux boiled for 4 hours with 16 ml hydrobromic acid 48% (d=1.47) (or 20 ml aqueous hydroiodic acid). The obtained solution is vacuum concentrated to dryness. The residue, treated with acetonitrile, provides 11.75 g (theorical yield, m.p. 175°-180° C.) 4-hydroxy benzylamine bromohydrate of formula (V) when HBr is used.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([F:15])=[C:13](F)[C:12]([F:17])=[C:11]2[C:6]=1[C:7](=[O:24])[C:8]([C:21]([OH:23])=[O:22])=[CH:9][N:10]2[CH:18]1[CH2:20][CH2:19]1)(=[O:3])[CH3:2].[CH:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:26]>>[C:1]([NH:4][C:5]1[C:14]([F:15])=[C:13]([N:30]2[CH2:31][CH2:32][N:27]([CH:25]=[O:26])[CH2:28][CH2:29]2)[C:12]([F:17])=[C:11]2[C:6]=1[C:7](=[O:24])[C:8]([C:21]([OH:23])=[O:22])=[CH:9][N:10]2[CH:18]1[CH2:20][CH2:19]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Reactant: O=CN1CCNCC1
Product: CC(=O)Nc1c(F)c(N2CCN(C=O)CC2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1

Procedure:
In the same manner as described in Example 1 (1), 5-acetylamino-1-cycloproply-6,7,8-trifluoro-1,4-dihydro-4- oxoquinoline-3-carboxylic acid (m.p. 247°-248° C.) was allowed to react with 1-formylpiperazine to give 5-acetylamino-1-cyclopropyl-6,8-difluoro-7-(4-formyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]([C:9](=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])([CH3:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CO>O>[Cl:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH:9]([OH:17])[C:2]([CH3:8])([CH3:1])[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(C)(C)C(=O)c1ccccc1Cl
Solvent: O
Solvent: CO
Product: CCOC(=O)C(C)(C)C(O)c1ccccc1Cl
Temperature: 70 °C
Reaction time: 24 h
Yield: 81.8 %

Procedure:
tBuBisP*-RuBr2 (5 mg) was placed in a pressurized hydrogenation reactor equipped with a stirrer chip, and after deaeration, substituted with argon. Thereto was poured a mixture of deaerated ethyl 2,2-dimethyl(2-chlorobenzoyl)acetate (515 mg) (2.0 mmol), methanol (4 ml) and water (0.4 ml). The mixture was stirred under a hydrogen pressure (6 atm) at 70° C. for 24 h. According to the high performance liquid chromatography analysis of the mixture after completion of the reaction, the yield was 97% and enantioselectivity was 90% ee. After the analysis, the reaction mixture was concentrated to dryness and purified by column chromatography (hexane:ethyl acetate=3:1, silica gel: 50 g) to give the title compound (420 mg, 81.8%) as a colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.CO[CH:10]1[CH2:14][CH2:13][CH:12](OC)O1>C(O)(=O)C>[N:5]1[CH:6]=[CH:7][C:2]([N:1]2[CH:10]=[CH:14][CH:13]=[CH:12]2)=[CH:3][CH:4]=1
Reactant: COC1CCC(OC)O1
Reactant: Nc1ccncc1
Solvent: CC(=O)O
Product: c1ccn(-c2ccncc2)c1

Procedure:
A 1-liter 3-neck flask equipped with stirrer, condenser, heating mantle, addition funnel and thermometer is charged with 47 g (0.5 mole) of 4-aminopyridine and 66 g (0.5 mole) of 2,5-dimethoxytetrahydrofuran. These materials are mixed together and 210 ml of glacial acetic acid is added dropwise with stirring over ten minutes while maintaining the temperature at less than 20°C.
Reaction SMILES: [K].[Cl:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[C:5]([Cl:13])[C:4]=1[N:14]1[C:18]([NH:19][C:20](=[O:25])[CH2:21][O:22][CH2:23][CH3:24])=[C:17]([S:26]([C:28]([F:31])([F:30])[F:29])=[O:27])[C:16]([C:32]#[N:33])=[N:15]1.[CH3:34]Br>C(#N)C>[Cl:13][C:5]1[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:3]([Cl:2])[C:4]=1[N:14]1[C:18]([N:19]([CH3:34])[C:20](=[O:25])[CH2:21][O:22][CH2:23][CH3:24])=[C:17]([S:26]([C:28]([F:31])([F:29])[F:30])=[O:27])[C:16]([C:32]#[N:33])=[N:15]1
Reactant: CCOCC(=O)Nc1c(S(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: CBr
Agent: [K]
Solvent: CC#N
Product: CCOCC(=O)N(C)c1c(S(=O)C(F)(F)F)c(C#N)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 60 °C
Reaction time: 6 h
Yield: 64 %

Procedure:
To a suspension of the potassium salt of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-cyano-4-trifluoromethylsulfinyl-5-(ethoxyacetamido)pyrazole, prepared in Step 1 above, (18.9 g, assay=75.6%, 0.026 mol) in 56.8 g of acetonitrile, a solution of methyl bromide in acetonitrile (86.5 g, conc=28%, 0.255 mol) was added. The mixture was stirred during 6 hours at 60° C. and then concentrated to dryness. The residue was solubilized in a mixture of toluene (100 g) and water (100 g). The organic layer was washed with 100 g of water and concentrated to a 38% solution, heated to 80° C. and product was recrystallized in a 40/60 toluene/n-heptane solution to afford 10.3 g of a white solid (yield=64%, assay=85%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=[O:6].[CH3:11]CCCC.C(OCC)C>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]2[O:6][CH2:11]2)[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: O=Cc1cc(F)cc(F)c1
Reactant: CCCCC
Solvent: CCOCC
Product: Fc1cc(F)cc(C2CO2)c1

Procedure:
Following General Procedure EC and using 3,5-difluorobenzaldehyde (Aldrich), the title compound was isolated after flash chromatography with 20:1 pentane/diethylether.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C@H:3]([OH:25])[CH2:4][CH:5]([O:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[S:6]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[N:12]2)(=[O:8])=[O:7].[C:33](=O)([O:42][C@H:43]1[CH2:47][CH2:46][O:45][CH2:44]1)[O:34]N1C(=O)CCC1=O.C(N(CC)C(C)C)(C)C>C(#N)C>[CH2:26]([C@H:2]([NH:1][C:33](=[O:34])[O:42][C@H:43]1[CH2:47][CH2:46][O:45][CH2:44]1)[C@H:3]([OH:25])[CH2:4][CH:5]([O:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24]1)[S:6]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[N:12]2)(=[O:7])=[O:8])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CC(OC1CCCC1)S(=O)(=O)c1ccc2nccnc2c1
Reactant: O=C(O[C@H]1CCOC1)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccccc1)[C@H](O)CC(OC1CCCC1)S(=O)(=O)c1ccc2nccnc2c1)O[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
A mixture of (3R,4S)-4-amino-1-(cyclopentyloxy)-5-phenyl-1-(6-quinoxalinylsulfonyl)-3-pentanol (50 mg, 0.110 mmoL), 2,5-dioxo-1-pyrrolidinyl [(3S)tetrahydro-3-furanyl] carbonate (28 mg, 0.121 mmol, WO 94/05639) and N,N-diisopropylethylamine (47.8 μL, 0.274 mmol) were combined under Argon at ambient temperature in approximately 1.5 mL of acetonitrile. After stirring for approximately 16 hours at ambient temperature, the reaction mixture was evaporated in vacuo and partitioned between ethyl acetate and aqueous potassium carbonate (5% w/v). The layers were separated and the aqueous layer was back extracted with ethyl acetate. The combined organic layers were washed twice with 1N sodium hydrogen sulfate. The acid layers were combined and back extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The residue was purified on a preparative TLC plate (20×20 cm, 1000 μM) eluting with 93:7 dichloromethane:methanol. The product band was removed, eluted with 3:1 methylene chloride:methanol, filtered, and evaporated in vacuo. The residue was crystallized with several drops of methanol. The residual solid was dried under high vacuum to provide (3S)tetrahydro-3-furanyl N-[(1S,2R)-1-benzyl-4-(cyclopentyloxy)-2-hydroxy-4-(6-quinoxalinyl sulfonyl)butyl]carbamate (54 mg, 86%) as a white solid. H1-NMR (chloroform-D3): 1.61 (m, 5H), 1.86 (m, 4H), 2.09 (m, 1H), 2.97 (m, 3H), 3.20 (m, 2H), 3.80 (m, 6H), 4.83 (m, 1H), 4.93 (m, 1H), 5.14 (m, 1H), 7.28 (m, 5H), 8.13 (m, 1H), 8.31 (d, 1H), 8.69 (d, 1H), 9.05 (s, 2H). MS(ESI): 571(M+H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]1[C:10]([N+:11]([O-])=O)=[CH:9][CH:8]=[CH:7][C:6]=1[S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15].S(S([O-])=O)([O-])=O.[Na+].[Na+]>CO.O>[NH2:11][C:10]1[C:5]([NH:4][CH2:3][CH2:2][OH:1])=[C:6]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:15])=[O:16])[CH:7]=[CH:8][CH:9]=1
Reactant: CN(C)S(=O)(=O)c1cccc([N+](=O)[O-])c1NCCO
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)S(=O)(=O)c1cccc(N)c1NCCO
Temperature: 60 °C

Procedure:
To a solution of 2-[(2-hydroxyethyl)amino]-N,N-dimethyl-3-nitrobenzenesulfonamide (107 mg, 0.37 mmol) in methanol (2 mL) a solution of 85% sodium hydrosulfite (0.30 g, 1.5 mmol) in water (1.2 mL) was added. The obtained suspension was heated at 60° C. for 10 min. The volatiles were removed in vacuo, and the residue was partitioned between a saturated solution of sodium bicarbonate and ethyl acetate. The organic phase was dried over magnesium sulfate and concentrated in vacuo affording 3-amino-2-[(2-hydroxyethyl)amino]-N,N-dimethylbenzenesulfonamide, 69 mg (72 %) as an oil: MS (ESI) m/z 260 [M+H].
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][C:9]([OH:11])=[O:10])=[C:6](C(C)(C)C)[C:5]([OH:16])=[C:4]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:3]=1.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:3]=[C:4]([C:17]([CH3:20])([CH3:18])[CH3:19])[C:5]([OH:16])=[CH:6][C:7]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1CC(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1cc(C(C)(C)C)c(O)cc1CC(=O)O
Yield: 96.9 %

Procedure:
Into a 300-ml four-necked flask, were charged 27.8 g of 6-methyl-2,4-di-t-butyl-3-hydroxyphenylacetic acid, 150 ml of toluene and 3 ml of concentrated sulfuric acid. The mixture was heated under reflux for about 5 hours under a nitrogen stream. After completion of the reaction, the reaction mixture was neutralized with an aqueous sodium carbonate solution, washed with water, then dehydrated and freed from the solvent under reduced pressure to obtain 21.5 g (97% yield) of pale yellow 2-methyl-4-t-butyl-5-hydroxyphenylacetic acid which was recrystallized from a chloroform-hexane mixture to yield white crystals melting at 132° to 134° C.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][N:14]1[C:18]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=2[F:26])=[CH:17][C:16]([C:27](=[O:35])[NH:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)=[C:15]1[CH3:36])=O)(C)(C)C.[C:37]([OH:43])([C:39]([F:42])([F:41])[F:40])=[O:38]>C(Cl)Cl>[F:40][C:39]([F:42])([F:41])[C:37]([OH:43])=[O:38].[CH:29]1([NH:28][C:27]([C:16]2[CH:17]=[C:18]([C:19]3[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:20]=3[F:26])[N:14]([CH2:13][CH:9]3[CH2:10][CH2:11][CH2:12][NH:8]3)[C:15]=2[CH3:36])=[O:35])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: Cc1c(C(=O)NC2CCCCC2)cc(-c2cc(Cl)ccc2F)n1CC1CCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(C(=O)NC2CCCCC2)cc(-c2cc(Cl)ccc2F)n1CC1CCCN1
Yield: 95 %

Procedure:
To a solution of 2-[5-(5-chloro-2-fluoro-phenyl)-3-cyclohexylcarbamoyl-2-methyl-pyrrol-1-ylmethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (51 mg) in methylene chloride (1 mL) was added at 0° C. TFA (0.5 mL). After 3 hours the volatiles were evacuated in vacuo and the residue was azeotroped with ethyl acetate (3×) and dried on high vacuum overnight to afford the desired title compound (50 mg, 95%) as a pale yellow solid, MS (ISP) 418.1 (M+H)+.
Reaction SMILES: F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C.[F:19][C:20]1[CH:25]=[C:24](B(O)O)[CH:23]=[CH:22][N:21]=1.[Br:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][C:35]=1[O:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:47]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)=[N:46][N:45]=2)=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[F:19][C:20]1[CH:25]=[C:24]([C:34]2[CH:33]=[N:32][CH:31]=[CH:30][C:35]=2[O:36][C:37]2[CH:38]=[CH:39][C:40]([NH:43][C:44]3[C:53]4[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=4)[C:47]([C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=4)=[N:46][N:45]=3)=[CH:41][CH:42]=2)[CH:23]=[CH:22][N:21]=1.[Br:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][C:35]=1[O:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:44]2[C:53]3[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=3)[C:47]([C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)=[N:46][N:45]=2)=[CH:39][CH:38]=1
Reactant: OB(O)c1ccnc(F)c1
Agent: [Pd+2]
Agent: Brc1cnccc1Oc1ccc(Nc2nnc(-c3ccccc3)c3ccccc23)cc1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Fc1cc(-c2cnccc2Oc2ccc(Nc3nnc(-c4ccccc4)c4ccccc34)cc2)ccn1
Temperature: 100 °C

Procedure:
A resealable reaction tube was charged with tri-tert-butylphosphonium tetrafluoroborate (0.024 g, 0.082 mmol), palladium (II) acetate (0.009 g, 0.041 mmol), 2-fluoropyridine-4-boronic acid (0.086 g, 0.614 mmol) and N-(4-(3-bromopyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine (0.192 mg, 0.409 mmol) and was purged with nitrogen for several minutes. 1.2 mL of dioxane and 2.0 M aqueous sodium carbonate (0.614 mL, 0.123 mmol) were added, the tube was sealed, and the reaction mixture was heated to 100° C. for 48 h. The mixture was diluted with EtOAc and washed with water. The organic portion was dried with MgSO4 and concentrated. Purification by Gilson reverse phase liquid chromatography (5-70% ACN/water/0.1% TFA over 14 min) provided N-(4-(3-(2-fluoropyridin-4-yl)pyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine as a mixture with the hydrodehalogenation product of N-(4-(3-bromopyridin-4-yloxy)phenyl)-4-phenylphthalazin-1-amine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[OH:21])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:23][C:24]([O:26][CH3:27])=[O:25])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ccccc2O)CC1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1ccccc1NC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 83 %

Procedure:
1-(tert-Butoxycarbonyl)-4-[(2-hydroxyphenyl)amino]piperidine (50 mg) was dissolved in N,N-dimethylformamide (1 ml), added with methyl bromoacetate (17 μl) and potassium carbonate (25 mg) and stirred at room temperature for 17 hours. The reaction mixture was added with water (3 ml) and extracted twice with ethyl acetate (3 ml). The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer silica gel column chromatography (developing solvent: hexane:ethyl acetate=1:1) to obtain 51.8 mg of the title compound. Yield: 83%.
Reaction SMILES: [C:1]1([CH:7](O)[CH2:8][NH:9][CH2:10][C:11]2[CH:15]=[CH:14][S:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[NH4+]>>[C:1]1([CH:7]2[CH2:8][NH:9][CH2:10][C:11]3[CH:15]=[CH:14][S:13][C:12]2=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC(CNCc1ccsc1)c1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: c1ccc(C2CNCc3ccsc32)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
1-Phenyl-2-(thiophen-3-ylmethylamino)ethanol (4.5 g, 19.2 mmol) was added to a flask containing polyphosphoric acid (20 g) and the mixture was heated to 80° C. After 1 h, the reaction was cooled down to room temperature and treated with crushed ice. The mixture was then rendered basic using ammonium hydroxide. The aqueous mixture was extracted twice with dichloromethane. The organic layers were combined and washed with water and brine. The organic portion was dried with sodium sulfate, reduced in vacuo and placed on a vacuum line to give an oil. Yield=3.5 g. MS (M+H)+ 216.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[C:7]([O:13][CH3:14])[CH:8]=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:28][CH2:29][CH:30]([OH:32])[CH3:31]>C1(C)C=CC=CC=1>[CH3:14][O:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:6]=1[C:5]1[N:28]([CH2:29][CH:30]([OH:32])[CH3:31])[CH:2]=[CH:3][C:4]=1[CH2:12]2
Reactant: CC(O)CN
Reactant: COc1cccc2c1C(=O)C(CC=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cccc2c1-c1c(ccn1CC(C)O)C2
Reaction time: 0.58 h
Yield: 45.3 %

Procedure:
A solution of 2.04 g of (RS)-2-(2-oxoethyl)-7-methoxy-1-indanone and 80 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 35 minutes, during which the solvent was reduced to a volume of 25 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 2:3). There was obtained 1.1 g (45%) of (RS)-1-(8-methoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol as a brown oil which was used directly in the next reaction.