Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([CH3:15])[CH:9]=[C:8]2OC)(=O)C.[CH3:18][NH:19][CH3:20]>C(O)(=O)C>[CH3:18][N:19]([CH3:20])[C:8]1[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([NH2:4])[CH:6]=2)[N:11]=[C:10]([CH3:15])[CH:9]=1
Reactant: COc1cc(C)nc2ccc(NC(C)=O)cc12
Reactant: CNC
Solvent: CC(=O)O
Product: Cc1cc(N(C)C)c2cc(N)ccc2n1
Yield: 77 %

Procedure:
The procedure is carried out as in Step A of Example 6, but starting with 57.4 g (0.25 mol) of 6-acetamido-4-methoxyquinaldine, prepared according to J. Amer. Chem. Soc., 1948, 70, 4065, and 100 cm3 of a 40% aqueous dimethylamine solution in 250 cm3 of acetic acid heated at 100° C. for 2 hours in a 1-dm3 autoclave. 38.71 g (77%) of 4-dimethylamino-6-aminoquinaldine are then obtained, after acid-base purification, on carrying out the procedure as in Step A of Example 6.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C(=O)(O)[O-].[Na+].Cl[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]>O>[CH:21]([O:20][C:18]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([NH2:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)=[O:19])([CH3:23])[CH3:22]
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1ccc(N)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC(C)OC(=O)Nc1ccc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
A stirred suspension of 2,5-diaminonitrobenzene (60 g.) in a solution of sodium bicarbonate (49.4 g) in water (780 ml) at 10° C. was treated dropwise with isopropyl chloroformate (48 g) and the mixture was stirred at room temperature for 3 hours. The crude brown solid was filtered off, washed well with water and dried to give 4-isopropoxycarbonylamino-2-nitroaniline (90.0 g), m.p. 158°-160° C., which was used in the next stage of the synthesis without further purification being necessary. Recrystallisation of a sample from toluene gave pure 2-nitro-4-isopropoxycarbonylaminoaniline, m.p. 161°-163° C.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1.O>CN(C=O)C.C(OCC)(=O)C>[Br:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:12]1[CH:13]=[N:14][CH:15]=[N:16][CH:17]=1
Reactant: Oc1cccc(Br)c1
Reactant: Brc1cncnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Brc1cccc(Oc2cncnc2)c1
Yield: 47.5 %

Procedure:
NaH (166 mg, 6.92 mmol, 1.10 eq) in DMF (15 mL) in a flame-dried microwave vial was cooled to 0° C. and 3-bromophenol (982 μL, 6.29 mmol, 1.00 eq) was added dropwise. The reaction was stirred for 30 min. at 0° C. at which point 5-bromopyrimidine (1.0 g, 6.3 mmol, 1.0 eq) was added and the reaction microwaved at 200° C. for 60 minutes. The reaction was diluted with ethyl acetate (50 mL) and was with water (3×). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. Purification by flash chromatography on silica gel afforded 750 mg (52%) of the title compound as an orange oil: 1H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 8.67 (s, 2H), 7.43-7.36 (m, 3H), 7.16 (dt, J=7.7, 1.9 Hz, 1H); ES-MS [M+1]+: 251.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:37])[C@@H:9]([CH3:36])[C:10]([NH:12][C@@H:13]([CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[C:25]([O:27]CC)=[O:26])=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[Li+].[OH-].OS([O-])(=O)=O.[K+]>C(O)C>[C:1]([O:5][C:6]([N:8]([CH3:37])[C@@H:9]([CH3:36])[C:10]([NH:12][C@@H:13]([CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[C:25]([OH:27])=[O:26])=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)[C@@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C1CCOCC1
Agent: O=S(=O)([O-])O
Agent: [K+]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: C[C@@H](C(=O)N[C@H](C(=O)N1c2ncccc2C[C@H]1C(=O)O)C1CCOCC1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.8 %

Procedure:
In a 100 mL round-bottomed flask, (S)-ethyl 1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylate (188 mg, 363 μmol, Eq: 1.00) was combined with THF (3 mL) and ethanol (1 mL) to give a colorless solution. Aqueous 1 M LiOH (1.1 mL, 1.1 mmol, Eq: 3) was added and the reaction was stirred at rt for 1 h. Aqueous 0.1 M KHSO4 (10 mL) was added and the resulting mixture was extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated in vacuo to give (S)-1-((S)-2-((S)-2-(tert-butoxycarbonyl(methyl)amino)propanamido)-2-(tetrahydro-2H-pyran-4-yl)acetyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (135 mg), m/z=491 (M+H).
Reaction SMILES: FC(F)(F)C([N:5]([CH2:16][CH:17]=[CH2:18])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](Cl)=[O:14])=[CH:8][CH:7]=1)=O.C(N(CC)CC)C.[C:28]([CH:33]([CH:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[OH:36])[OH:34])([O:30][CH2:31][CH3:32])=[O:29]>CCOCC>[CH2:16]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([O:36][CH:35]([CH:33]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[OH:34])[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[O:14])=[CH:8][CH:7]=1)[CH:17]=[CH2:18]
Reactant: CCOC(=O)C(O)C(O)C(=O)OCC
Reactant: C=CCN(C(=O)C(F)(F)F)c1ccc(CC(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CCNc1ccc(CC(=O)OC(C(=O)OCC)C(O)C(=O)OCC)cc1

Procedure:
A mixture of 4-[N-trifluoroacetyl-(allylamino)]phenylacetyl chloride and 1.2 g. triethylamine in 100 ml. warm ether is treated with 2.5 g. diethyl tartrate and refluxed for 24 hours. The hot solution is filtered, the residue is washed with hot ether, and the solution is evaporated. After treatment with aqueous methanolic potassium carbonate, the product is precipitated by acidification, filtered, and dried. Crystallization from acetone yields diethyl O-[4-(allylamino)phenylacetyl]tartrate as a white, crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]([N:6]=[C:7]=[O:8])=O.[F:21][C:22]([F:39])([F:38])[C:23]1[CH:24]=[C:25]([NH:29][NH:30]C(OC(C)(C)C)=O)[CH:26]=[CH:27][CH:28]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([CH2:13][NH:14][C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:9][C:3]=1[C:4]1[NH:6][C:7](=[O:8])[N:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([C:22]([F:21])([F:39])[F:38])[CH:24]=2)[N:30]=1
Reactant: CC(C)(C)OC(=O)NNc1cccc(C(F)(F)F)c1
Reactant: O=C=NC(=O)c1cc(CNC(=O)C(F)(F)F)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCc1ccc(Cl)c(-c2nn(-c3cccc(C(F)(F)F)c3)c(=O)[nH]2)c1)C(F)(F)F
Yield: 55.5 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 2-chloro-5-((2,2,2-trifluoroacetamido)methyl)benzoyl isocyanate (step-3 of Intermediate-26, 0.500 g, 1.55 mmol), tert-butyl 2-[3-(trifluoromethyl)phenyl]hydrazinecarboxylate (0.428 g, 1.55 mmol), DCM (20 mL) and trifluoro acetic acid (5.0 mL) to afford 0.400 g of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[C:24]3[C:19](=[C:20]([CH2:25][S:26][CH3:27])[CH:21]=[CH:22][CH:23]=3)[N:18](C(OC(C)(C)C)=O)[CH:17]=2)[CH:9]([CH3:15])[C:10](OCC)=[O:11])=[C:4]([F:35])[CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].Cl>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:16]2[C:24]3[C:19](=[C:20]([CH2:25][S:26][CH3:27])[CH:21]=[CH:22][CH:23]=3)[NH:18][CH:17]=2)[CH:9]([CH3:15])[CH2:10][OH:11])=[C:4]([F:35])[CH:3]=1
Reactant: CCOC(=O)C(C)C(c1ccc(Cl)cc1F)c1cn(C(=O)OC(C)(C)C)c2c(CSC)cccc12
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CSCc1cccc2c(C(c3ccc(Cl)cc3F)C(C)CO)c[nH]c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 200 mg of the compound from Example 36A with a purity of 90% (0.35 mmol) in 4 ml of tetrahydrofuran was added dropwise to 1.2 ml (1.2 mmol) of a 1N solution of lithium aluminum hydride in tetrahydrofuran in 2 ml of tetrahydrofuran at RT under argon. The mixture was stirred at RT for 15 min and then 1N hydrochloric acid was added. The mixture was extracted with dichloromethane, and the organic phase was dried over magnesium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 66 mg (51% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:14])=[C:7]([CH:13]=1)[C:8]([O:10][CH2:11][CH3:12])=[O:9])#[CH:2].I[C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]2[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1>O1CCCC1.C(N(CC)CC)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.[Cu]I>[OH:14][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[C:2][C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][C:26]3[C:31]([CH3:32])=[CH:30][CH:29]=[CH:28][N:27]=3)(=[O:24])=[O:23])=[CH:18][CH:17]=2)=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: C#Cc1ccc(O)c(C(=O)OCC)c1
Reactant: Cc1cccnc1NS(=O)(=O)c1ccc(I)cc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Nc3ncccc3C)cc2)ccc1O
Reaction time: 0.25 h

Procedure:
Tetrakis(triphenylphosphine)palladium (0.29 g, 0.25 mmol) and copper(I)iodide (0.095 g, 0.5 mmol) were added to a solution of ethyl 5-ethynyl-2-hydroxybenzoate (10.5 g, 55 mmol) and 4-iodo-N-(3-methyl-2-pyridinyl)benzenesulfonamide (18.7 g, 50 mmol) in tetrahydrofuran (7:5 ml) and triethylamine (75 ml) at 55° C. After 2 h the solid product was collected with filtration and washed with hydrochloric acid (1M). The material was boiled in formic acid (300 ml ) for 15 min. and filtered. Water (200 ml) was added and the product crystallized upon cooling. Yield 17.3 g (79%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([CH3:19])=[CH:10][C:9]=1[N+:20]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:18])[CH2:15][CH2:16][CH3:17])[C:11]([CH3:19])=[CH:10][C:9]=1[NH2:20])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C
Agent: [Pd]
Product: CCCN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C

Procedure:
The title compound was prepared from [4-methyl-5-(methyl-propyl-amino)-2-nitro-phenyl]-carbamic acid tert-butyl ester (Example C21) (3.59 g, 11.1 mmol) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a purple solid (3.23 g, 99%).
Reaction SMILES: [N:1]([C@@H:4]([CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)[CH2:5][O:6][Si:7]([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8])=[N+]=[N-]>CO.[Pd]>[Si:7]([O:6][CH2:5][C@H:4]([CH:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)[NH2:1])([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H](N=[N+]=[N-])C1CCOCC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@@H](N)C1CCOCC1
Reaction time: 18 h
Yield: 97.4 %

Procedure:
{[(2S)-2-Azido-2-tetrahydro-2H-pyran-4-ylethyl]oxy}(tert-butyl)dimethylsilane (2.19 g, 7.68 mmol) was dissolved in 25 mL of methanol and the solution was placed in a pressure bottle. Palladium on carbon (10%, 250 mg) was then added and the reaction mixture was shaken under H2 at 50 PSI (3.4×105 Pa). After 18 hours, the reaction mixture was filtered through a pad of CELITE filter agent. The pad was rinsed with methanol and the combined filtrates were concentrated under reduced pressure to give 1.94 g of (1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-tetrahydro-2H-pyran-4-ylethanamine as a colorless syrup.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:19])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]([O:24][CH3:25])=[O:23].C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:19][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2cc(Cl)ccc2c(O)c1-c1ccccc1
Reactant: COC(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1c(-c2ccccc2)c(=O)[nH]c2cc(Cl)ccc12

Procedure:
A solution of 7-chloro-4-hydroxy-3-phenyl-2(1H)-quinolone (0.5 g) in DMF was stirred for 14 h with methyl bromoacetate (206 μl) and sodium bicarbonate (1.55 g). The reaction mixture was then partitioned between water and ethyl acetate. The aqueous phase was extracted with two further portions of ethyl acetate. The combined organic phases were washed with brine (3×), dried (MgSO4) and the solvent was removed in vacuo to give the crude product which was recrystallised from ethyl acetate-hexane to give the title compound, 208 mg; mp 188°-191° C. (ethyl acetate-hexanes); Found: C, 63.27; H, 4.24; N, 4.07. C18H14ClNO4 requires C, 62.89; H, 4.11; N, 4.07%; δ (360 MHz, DMSO-d6) 3.55 (3H, s, CO2CH3), 4.19 (2H, s, CH2CO2), 7.28 (1H, dd, J=2.6, 8.7 Hz, 6-H), 7.35-7.40 (6H, m, aromatics), 8.01 (1H, d, J=8.7 Hz, 5-H), 11.92 (1H, s, NH); m/z CI+ 344 (M+).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]=O)[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([O:26][CH2:27][CH2:28]P(OCC)(OCC)=O)(=[O:25])[CH3:24].CN(C)C=O.[H-]>O>[CH2:1]([N:8]1[CH:12]=[C:11](/[CH:13]=[CH:24]/[C:23]([O:26][CH2:27][CH3:28])=[O:25])[C:10]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1cn(Cc2ccccc2)nc1OCc1ccccc1
Reactant: CCOP(=O)(CCOC(C)=O)OCC
Agent: [H-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(Cc2ccccc2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
To a mixture of 1-benzyl-3-benzyloxy-1H-pyrazole-4-carbaldehyde (12.90 g), diethylphosphonoethyl acetate (9.60 ml) and N,N-dimethylformamide (200 ml) was added hydride (60% in oil, 1.94 g) at 0° C., and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dilute hydrochloric acid, washed successively with saturated brine, dried (MgSO4) and concentrated. The obtained crystals were collected by filtration to give ethyl (E)-3-(1-benzyl-3-benzyloxy-1H-pyrazol-4-yl)propenoate (14.50 g, yield 91%). The crystals were recrystallized from ethyl acetate-hexane. melting point: 88–89° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][CH:8]=[N:7][C:6]=2[C:5]([CH3:11])=[CH:4][CH:3]=1.[N+:12]([O-])([OH:14])=[O:13].[OH-].[NH4+]>S(=O)(=O)(O)O>[CH3:11][C:5]1[C:6]2[NH:7][CH:8]=[N:9][C:10]=2[C:2]([CH3:1])=[CH:3][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: Cc1ccc(C)c2[nH]cnc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1cc([N+](=O)[O-])c(C)c2[nH]cnc12
Temperature: 0 °C
Reaction time: 0.83 h

Procedure:
To a cold (ice bath) solution of 4,7-dimethylbenzimidazole (1 g) in concentrated sulfuric acid (8 mL) is added dropwise concentrated nitric acid (0.37 mL), over 50 minutes. The mixture is stirred an additional 30 minutes in the ice bath, then poured into a mixture of crushed ice (30 mL) and ammonium hydroxide (30 mL). The resulting mixture is extracted with ethyl acetate. The extract is dried over MgSO4 and rotary evaporated to afford 4,7-dimethyl-5-nitrobenzimidazole as a dark tan solid.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(=O)([O-])[O-].[K+].[K+].[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][C:21]=1[O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(COC)OC.CS(C)=O>[F:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][O:1][N:2]2[C:3](=[O:12])[C:4]3=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]3[C:6]2=[O:7])=[CH:22][C:21]=1[O:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Fc1ccc(CBr)cc1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CS(C)=O
Product: O=C1c2ccccc2C(=O)N1OCc1ccc(F)c(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
N-hydroxyphthalimide (2.19, 0.018 mole) was dissolved in a mixture of dry dimethoxyethane (15 ml) and dry dimethyl sulphoxide (4 ml). The clear yellow solution was cooled to 25° and potassium carbonate (1.24 g, 0.009 mol) was added. A red suspension resulted. 4-Fluoro-3-phenoxybenzyl bromide (5 g, 0.018 mol) was added dropwise over 5h at 22°-28°. The reaction mixture was stirred at room temperature overnight, after which most of the dimethoxyethane was removed in vacuo, and the solution then quenched by pouring into dilute hydrochloric acid (100 ml 1%). The resulting slurry was filtered, and the crystals washed with distilled water and dried in vacuo to give N-(4-fluoro-3-phenoxybenzyloxy)phthalimide as white crystals (6.4 g), (98%), m.p. 88.2°.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[C:8]([CH3:21])[CH:7]=1.[CH3:23]I>CN(C)C=O>[CH3:3][O:4][C:5](=[O:22])[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH3:23])=[C:8]([CH3:21])[CH:7]=1
Reactant: COC(=O)c1ccc(CNC(=O)OC(C)(C)C)c(C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN(C)C(=O)OC(C)(C)C)c(C)c1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Add in portions of 60% sodium hydride dispersion in oil (472 mg, 11.81 mmol) to 4-(tert-butoxycarbonylamino-methyl)-3-methyl-benzoic acid methyl ester (3.0 g, 10.74 mmol) in anhydrous dimethylformamide (50 mL) at 0° C. under argon gas. After complete addition, stir the reaction mixture for 15 min at 0° C. Add methyl iodide (735 μL, 11.8 mmol) to the reaction mixture. Allow the reaction mixture to warm-up to room temperature and stir overnight. Quench the reaction mixture with saturated aqueous ammonium chloride and extract with ethyl acetate (3×). Combine the organic layers, wash with brine, dry over sodium sulfate, and concentrate. Purify the residue by chromatography (silica gel) eluting with 25% ethyl acetate/hexane to give the title compound. MS (m/z): 316 (M+23).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[NH:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=3)=[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)[N:16]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.C1C=CC2N(O)N=NC=2C=1.[NH2:44][CH2:45][CH2:46][OH:47].C(Cl)CCl>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.O>[F:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]2[NH:13][C:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH3:33])[N:28]=3)=[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[N:23]=[CH:22][CH:21]=[CH:20]4)[N:16]=2)=[CH:7][C:3]=1[C:4]([NH:44][CH2:45][CH2:46][OH:47])=[O:6]
Reactant: NCCO
Reactant: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(C(=O)O)c3)nc2-c2ccc3ncccc3c2)n1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCCl
Solvent: c1ccncc1
Product: Cc1cccc(-c2[nH]c(Cc3ccc(F)c(C(=O)NCCO)c3)nc2-c2ccc3ncccc3c2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 61 %

Procedure:
A mixture of 2-fluoro-5-((5-(6-methylpyridin-2-yl)-4-(quinolin-6-yl)-1H-imidazol-2-yl)methyl)benzoic acid (Example 104) (50 mg, 0.114 mmol), HOBt (23 mg, 0.171 mmol), DMAP (3 mg, 0.023 mmol), and 2-aminoethanol in pyridine (1 mL) was added EDC (33 mg, 0.171 mmol) and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into H2O and extracted with CH2Cl2 (5 mL, 3 times). The organic layer was dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by MPLC (MeOH:CH2Cl2=1:100 (v/v) to 1:20 (v/v)) to afford the title compound (34.7 mg, 61%). (300 MHz, CDCl3) δ 2.37 (3H, s), 3.57 (2H, q), 3.79 (2H, t), 4.15 (2H, s), 6.91 (1H, dd), 6.96 (1H, d), 7.04-7.15 (1H, m), 7.20-7.30 (1H, m), 7.37-7.43 (2H, m), 7.80 (1H, dd), 7.85 (1H, dd), 8.04 (1H, d), 8.10 (1H, d), 8.14 (1H, dd), 8.90 (1H, dd), MS (ESI) m/z 482 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].[C:13](#N)CC>>[NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[C:10](=[O:12])[CH2:11][CH3:13]
Reactant: CCC#N
Reactant: CC(=O)c1cc(C)cc(C)c1N
Product: CCC(=O)c1cc(C)cc(C)c1N

Procedure:
2′-Amino-3′,5′-dimethylpropiophenone was synthesized in the same fashion as for 2′-amino-3′,5′-dimethylacetophenone (Example 39) except that propionitrile was used instead of acetonitrile.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl[CH2:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH3:20][C:21]1[C:29]2[CH2:28][C:27]3([O:33][CH2:32][CH2:31][O:30]3)[CH2:26][CH2:25][C:24]=2[NH:23][N:22]=1.ClCCl>C(OCC)(=O)C>[CH2:13]([O:12][CH2:11][N:23]1[C:24]2[CH2:25][CH2:26][C:27]3([O:30][CH2:31][CH2:32][O:33]3)[CH2:28][C:29]=2[C:21]([CH3:20])=[N:22]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCOCc1ccccc1
Reactant: Cc1n[nH]c2c1CC1(CC2)OCCO1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nn(COCc2ccccc2)c2c1CC1(CC2)OCCO1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
N-ethyl-N-isopropylpropan-2-amine (4.08 mL) and benzyl chloromethyl ether (0.792 mL) were added to a mixture of 3′-methyl-1′,4′,6′,7′-tetrahydrospiro[1,3-dioxolane-2,5′-indazole] (925 mg) and dichloromethane (20 mL) under ice cooling under an argon gas atmosphere, followed by stirring for 4.5 hours at room temperature. The reaction liquid was diluted with ethyl acetate and then washed with water, saturated aqueous sodium bicarbonate, and saturated brine in this order, followed by drying, and concentrating under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate), thereby obtaining a mixture (1.11 g) of l′-[(benzyloxy)methyl]-3′-methyl-1′,4′,6′,7′-tetrahydrospiro[1,3-dioxolane-2,5′-indazole] and a regioisomer thereof.
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:44])([C:22]([F:43])([F:42])[C:23]([F:41])([F:40])[C:24]([F:39])([F:38])[C:25]([F:37])([F:36])[C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]C1C=C(C)C=CC=1S([O-])(=O)=O>O1CCCC1>[F:3][C:4]([F:44])([C:22]([F:43])([F:42])[C:23]([F:41])([F:40])[C:24]([F:39])([F:38])[C:25]([F:37])([F:36])[C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][NH:2][CH3:1]
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)c1
Reactant: CN
Solvent: C1CCOC1
Product: CNCCCCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.7 %

Procedure:
3.78 g of methylamine is condensed in a solution of 5.72 g of 7,7,8,8,9,9,10,10,11,11,12,12,13,13,14,14,14-heptadecafluoro-tetradecyl-tosylate in 10 ml of absolute tetrahydrofuran at −20° C., and it is stirred overnight in a pressure vessel at room temperature. After the pressure vessel was opened at −20° C., it is allowed to come to room temperature to allow excess methylamine to evaporate off. The reaction solution is taken up in dichloromethane, washed with water, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 4.29 g of (7,7,8,8,9,9,10,10,11,11,12,12,13,13,14,14,14-heptadecafluoro-tetradecyl)-methyl-amine is obtained as a crude product.