Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[O:34]COCC[Si](C)(C)C)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[CH:4][CH:3]=1.Cl>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[O:14][CH2:15][C:16]2[CH:25]=[C:24]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[OH:34])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCOc1ccccc1COc1cc(COC2CNCCC2c2ccc(F)cc2)cc2ccccc12
Agent: Cl
Solvent: CO
Product: Oc1ccccc1COc1cc(COC2CNCCC2c2ccc(F)cc2)cc2ccccc12

Procedure:
Cleavage of the SEM group from (3RS,4RS)-4-(4-fluorophenyl)-3-[4-[2-(2-trimethylsilyl-ethoxymethoxy)-benzyloxy]-naphthalen-2-ylmethoxy]-piperidine using a 2N solution of hydrogen chloride in methanol analogously to the procedure described in Example 5(g) yielded (3RS,4RS)-4-(4-fluorophenyl)-3-[4-[2-hydroxy-benzyloxy]-naphthalen-2-ylmethoxy]-piperidine as a colourless resin; MS: 458 (M+H)+.
Reaction SMILES: [C:1]([O:6][CH3:7])(=[O:5])[C@@H:2]([CH3:4])[OH:3].C(N(CC)CC)C.Cl.C(N(CC)CC)C.[C:23]1([CH3:33])[CH:28]=[CH:27][C:26](S(Cl)(=O)=O)=[CH:25][CH:24]=1>C(#N)C>[CH3:33][C:23]1[CH:28]=[CH:27][C:26]([O:3][C@H:2]([CH3:4])[C:1]([O:6][CH3:7])=[O:5])=[CH:25][CH:24]=1
Reactant: COC(=O)[C@@H](C)O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](C)Oc1ccc(C)cc1
Temperature: -5 °C

Procedure:
Methyl (R)-(+)-lactate (3.33 g) and acetonitrile (16.7 ml) were charged to a flask and the resulting solution cooled to −5° C. Triethylamine (4.9 ml) was added. Triethylamine hydrochloride (0.31 g) was added. A solution of para-toluenesulfonyl chloride (5.8 g) dissolved in acetonitrile (16.7 ml) was added dropwise to the reaction mixture (over 40 mins), maintaining the temperature below 5° C. After complete addition a precipitate formed which was filtered. The filtrate was diluted further with acetonitrile (55 ml), to give (2R)-2-(4-methylphenoxy)-propanoic acid, methyl ester. The solution was treated with potassium carbonate (5 g) and 5-chloro-2-hydroxy benzaldehyde. The reaction mixture was heated at 50° C. for 32 h, then cooled to 20° C., diluted with water (100 ml) and extracted with tert-butyl methyl ether (250 ml). The organic phase was washed (brine), dried (MgSO4) and concentrated in vacuo. The residue was purified by chromatography (silica, 5-20% EtOAc/hexane as eluent) to give the sub-title compound (5.3 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl[C:12]1[C:21]2[C:16](=[C:17]([CH3:24])[C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[N+:15]([O-:25])=[CH:14][CH:13]=1.O>CN(C=O)C>[CH2:3]([O:10][C:12]1[C:21]2[C:16](=[C:17]([CH3:24])[C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[N+:15]([O-:25])=[CH:14][CH:13]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: OCc1ccccc1
Reactant: COc1ccc2c(Cl)cc[n+]([O-])c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(OCc3ccccc3)cc[n+]([O-])c2c1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 59.2 %

Procedure:
NaH (973 mg, 60% in mineral oil, 24.3 mmol) was added at 0° C., under inert atmosphere, to benzylalcohol (2.96 mL, 28.6 mmol) in DMF (10 mL). After 5 min at 0° C., the solution was warmed up to room temperature. After 10 min at room temperature, 4-chloro-7-methoxy-8-methylquinoline N-oxide (61, 3.2 g, 14.3 mmol) was added in one potion. The resulting black solution was stirred at room temperature under inert atmosphere for another 30 min, then poured into ice-cooled water, and extracted 4 times with AcOEt. Combined organic layers were dried (Na2SO4) and evaporated. The residue was purified by column chromatography (gradient AcOEt/CH2Cl2, 1:1 to 1:0, then AcOEt/MeOH 9:1) to give 2.5 g (59%) of the target product 62 as a yellow powder: m/z=296 (M+H)+.
Reaction SMILES: [CH2:1]1[CH:5]2[C:6]3[C:11]([CH:3]([CH2:4]2)[CH2:2]1)=[N:10][C:9](Cl)=[N:8][CH:7]=3.[NH2:13][NH2:14]>N1C=CC=CC=1>[CH2:1]1[CH:5]2[C:6]3[C:11]([CH:3]([CH2:4]2)[CH2:2]1)=[N:10][C:9]([NH:13][NH2:14])=[N:8][CH:7]=3
Reactant: Clc1ncc2c(n1)C1CCC2C1
Reactant: NN
Solvent: c1ccncc1
Product: NNc1ncc2c(n1)C1CCC2C1

Procedure:
2-Chloro-5,8-methano-5,6,7,8-tetrahydroquinazoline was dissolved in anhydrous pyridine (30 mL) and treated with anhydrous hydrazine (15 mL) at 120° C. for 5 h. The solvent was removed under vacuum. The residue was partitioned between chloroform and 1M aqueous potassium carbonate solution. The organic layer was dried over anhydrous sodium sulfate and concentrated to give 2-hydrazino-5,8-methano-5,6,7,8-tetrahydroquinazoline as a tan solid, 2.68 g; 1H NMR (CDCl3, 300 MHz) 7.99 (s, 1H), 7.93 (br s, 1H), 3.90 (br s, 2H), 3.48 (s, 1H), 3.23 (s, 1H), 1.97 (m, 2H), 1.76 (d, 1H), 1.55 (d, 1H), 1.20-1.35 (m, 2H) ppm; 13C NMR (CDCl3, 75 MHz ) 179.48, 163.48, 147.10, 129.57, 47.58, 45.45, 39.86, 27.82, 25.46; MS(ES) 177 (M+H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11].[C:12]([CH2:15][C:16](=O)[CH3:17])(=O)[CH3:13].O.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:16]([CH3:17])=[CH:15][C:12]([CH3:13])=[N:11]1
Reactant: COc1ccccc1NN
Reactant: CC(=O)CC(C)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccccc1-n1nc(C)cc1C

Procedure:
3.50 g of 2-methoxyphenyl hydrazine hydrochloride was dissolved in 60 ml of ethanol, and 2.06 ml of acetyl acetone was added and heated at reflux for 1 hour. To the reaction mixture was added 150 ml of water, neutralized with saturated aqueous solution of sodium carbonate, and extracted with 150 ml of ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure and purified by silica gel column chromatography (n-hexane:ethyl acetate=2:1) to yield 3.88 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7](Cl)(=[O:9])=[O:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:13][CH:14]([CH3:26])[C:15]([O:17][NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:16]>>[CH3:13][CH:14]([CH3:26])[C:15]([O:17][N:18]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[S:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8])=[O:16]
Reactant: O=S(=O)(Cl)c1ccc(Cl)s1
Reactant: CC(C)C(=O)ONC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Product: CC(C)C(=O)ON(C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)s1

Procedure:
N-[(tert-Butoxy)carbonyl]5-chlorothiophene-2-sulfonamido 2-methylpropanoate (108) is synthesised from 5-chlorothiophene sulfonyl chloride, sodium hydride and [(tert-butoxy)carbonyl]amino 2-methylpropanoate according to Scheme 2. δH (500 MHz, CHLOROFORM-d) 7.65 (1H, d, 4.1 Hz), 6.99 (1H, d, 4.1 Hz), 2.81 (1H, sept, 7.0 Hz), 1.49 (9H, s), 1.31 (6H, d, 7.0 Hz).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl[CH2:17][CH:18]([OH:22])[CH2:19][CH2:20][Cl:21]>O>[Cl:21][CH2:20][CH2:19][CH:18]([OH:22])[CH2:17][O:13][C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][CH:11]=1
Reactant: OC(CCl)CCCl
Reactant: Oc1ccc(-c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OC(CCCl)COc1ccc(-c2ccccc2)cc1
Temperature: 40 °C

Procedure:
To a solution of 1 mole (158 g.) of 4-phenylphenol 100 g. of sodium hydroxide and 500 ml. of water was added 1 mole (143.02 g.) of 1,4-dichloro-2-butanol with stirring at 40° C. The resulting mixture was heated at 68° C. in a steam bath for 6 hr., cooled and extracted with 300 ml. of chloroform. The chloroform extract was washed with water to neutrality, dried over sodium sulfate and concentrated to dryness. The solid residue was recrystallized with isopropanol and yielded 180 g. of a white crystalline solid which melted at 123°-124° C.
Reaction SMILES: C([O:3][C:4]([CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)C(OCC)=O)=[O:5])C>[OH-].[Na+]>[O:19]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:6][C:4]([OH:5])=[O:3])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(CCCCCCCOc1ccccc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)CCCCCCCCOc1ccccc1
Temperature: 190 °C
Yield: 85.9 %

Procedure:
A solution of ethyl 2-ethoxycarbonyl-9-phenoxynonanoate (1.84 g, 5.3 mmol) in 20% NaOH (20 mL) was refluxed for 10 h. The solution was acidified with HCl(pH=2) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with water (2×30 mL), and brine (30 mL), and dried over Na2SO4. After removal of the solvent in vacuo, the residue was heated on an oil bath at 180-200° C. for 10 min. The crude product was distilled (Kugelrohr) followed by crystallization (hexane) to give the product (1.14 g, 85%), mp 66.5-67.5° C. (lit.3 68-69° C.). IR: 3450-2500, 1720 cm-1 ; 1H-NMR: 1.26-1.39 (m, 8H), 1.61 (q, 2H), 1.75 (q, 2H), 2.34 (t, 2H), 3.93 (t, 2H), 6.83-6.96 (m, 3H), 7.28 (t, 2H), 10.8 (bs, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][N:10]=[C:11]3[CH:16]=[CH:15][C:14]([C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[O:18])=[CH:13][C:12]=23)[CH:5]=[CH:6][CH:7]=1>C1COCC1.O>[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:18])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:13][C:12]=1[C:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[O:9]
Reactant: O=C(c1ccc(F)cc1)c1ccc2noc(-c3cccc(Cl)c3)c2c1
Solvent: C1CCOC1
Solvent: O
Product: Nc1ccc(C(=O)c2ccc(F)cc2)cc1C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
A mixture of intermediate 2 (0.0514 mol) in THF (180 ml) was cooled on an ice bath. TiCl3 15% in water (180 ml) was added dropwise slowly. The mixture was stirred at room temperature overnight, then poured out into ice water and extracted with DCM. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated till dryness, yielding 18.2 g (100%) of [2-amino-5-(4-fluorobenzoyl)phenyl](3-chlorophenyl)-methanone (intermediate 3).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C)C=O>[CH2:15]([N:4]1[N:3]=[C:2]([Br:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]1=[O:12])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]nc(Br)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ccccc2c(Br)nn1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.3 %

Procedure:
4-Bromo-2H-phthalazin-1-one (10.38 g, 46 mmol) was dissolved in dimethylformamide (DMF) (60 ml). To this was added NaH (60%, 1.55 g, 46.2 mmol) as a DMF suspension (20 ml). The mixture was stirred at room temperature for 30 mins then benzyl bromide (13.82 g, 50.8 mmol) was added in one portion as a solution in DMF (20 ml). The reaction mixture was stirred for 2 hours then the DMF was removed under reduced pressure and the resulting crude material purified by column chromatography (gradient elution: 100% heptane to 20% ethyl acetate: heptane) to give the title compound (8.16 g, 56% yield) as a white solid. 1H-NMR: (400 MHz, D6-DMSO), 8.30 (1H, dd), 8.03 (1H, ddd), 7.97–7.91 (2H, m), 7.34–7.27 (5H, m), 5.31 (2H, s); MS (ESI+)=(M+H)+ 315 & 317
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([CH:11]=[O:12])=[N:9][N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][O:14]3)[C:5]2=[N:6][CH:7]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>CN(C=O)C.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>[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([C:2]2[CH:3]=[C:4]3[C:10]([CH:11]=[O:12])=[N:9][N:8]([CH:13]4[CH2:18][CH2:17][CH2:16][CH2:15][O:14]4)[C:5]3=[N:6][CH:7]=2)[CH:28]=1
Reactant: O=Cc1nn(C2CCCCO2)c2ncc(Br)cc12
Reactant: OB(O)c1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1nn(C2CCCCO2)c2ncc(-c3cccnc3)cc12
Temperature: 90 °C

Procedure:
To a heterogeneous solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (III) (328 mg, 1.05 mmol) and K3PO4 (334 mg, 1.57 mmol) in DMF (10 mL) and water (2 mL) was added pyridin-3-ylboronic acid (143 mg, 1.16 mmol). The solution was purged with argon by using argon/vacuum cycle (3×). Pd(PPh3)4 (36 mg, 0.03 mmol) was added to the solution and again purged with argon. The solution was heated at 90° C. for 4 h under argon. The DMF was removed under vacuum. The residue was partitioned between EtOAc and water. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined EtOAc was dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was purified through a silica gel column (10:90 EtOAc:hexane→50:50 EtOAc:hexane) to produce 5-(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-3-carbaldehyde (CXXXI) as an off-white waxy solid (283 mg, 0.92 mmol, 91% yield). 1H NMR (DMSO-d6) δ ppm 1.57-1.68 (m, 3H), 1.75-1.89 (m, 1H), 2.01-2.13 (m, 2H), 2.49-2.56 (m, 1H), 3.78 (dt, J=11 Hz, J=4 Hz, 1H), 3.94-4.03 (m, 1H), 6.25 (dd, J=10 Hz, J=2 Hz, 1H), 7.58-7.64 (m, 1H), 8.25 (td, J=8 Hz, J=2 Hz, 1H), 8.66 (dd, J=5 Hz, J=2 Hz, 1H), 8.77 (d, J=2 Hz, 1H), 9.02 (d, J=2 Hz, 1H), 9.09 (d, J=2 Hz, 1H), 10.21 (s, 1H); ESIMS found for C17H16N4O2 m/z 309.4 (M+H).
Reaction SMILES: [CH2:1]([N:5]1[C:11](=[O:12])[O:10][C:8](=O)[C:7]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:6]12)[CH:2]([CH3:4])[CH3:3].[H-].[Na+].C(OCC)(=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[OH:10][C:8]1[C:7]2[C:6](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]([CH2:1][CH:2]([CH3:3])[CH3:4])[C:11](=[O:12])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CC(C)Cn1c(=O)oc(=O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)c1c(O)c2ccccc2n(CC(C)C)c1=O

Procedure:
Reagents: Comp 19 (1.36 mmols, 0.3 g); Sodium hydride (5.75 mmols, 0.138 g); Diethyl malonate (6.84 mmols, 1.1 g). Yield: 0.15 g (38%), yellow oil.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1.[CH2:19](Br)[CH:20]=[CH2:21]>>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][CH:7]=1)[CH:20]=[CH2:19]
Reactant: COC(=O)c1ccc(Oc2cccc(O)c2)cc1
Reactant: C=CCBr
Product: C=CCOc1cccc(Oc2ccc(C(=O)OC)cc2)c1
Yield: 96 %

Procedure:
The title compound was prepared in 96% yield as an oil from methyl 4-(3-hydroxyphenoxy)benzoate and allyl bromide by the procedure of Preparation 36. NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9](=[N:11][OH:12])[CH3:10])=[CH:4][CH:3]=1.[NH2:14][NH:15][C:16]([NH2:18])=[S:17].CO>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:14][NH:15][C:16]([NH2:18])=[S:17])[C:9](=[N:11][OH:12])[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(=NO)C(=O)c1ccc(Cl)cc1
Reactant: NNC(N)=S
Solvent: CO
Solvent: CC(=O)O
Product: CC(=NO)C(=NNC(N)=S)c1ccc(Cl)cc1
Yield: 86.5 %

Procedure:
A mixture of 4'-chloro-2-hydroxyiminopropiophenone (252.3 g), thiosemicarbazide (151.3 g), methanol (650 ml) water (300 ml), and acetic acid (9 ml) was refluxed for 31 hours with stirring. After cooling, the resulting precipitates were collected by filtration, washed successively with methanol, water and methanol, and then dried to give 4'-chloro-2-hydroxyiminopropiophenone thiosemicarbazone (298.88 g).
Reaction SMILES: [CH2:1]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[N+:18]([C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1)([O-:20])=[O:19].O>COCCOC.C(=O)([O-])[O-].[Na+].[Na+].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>[N+:18]([C:21]1[CH:26]=[CH:25][C:24]([C:12]2[CH:11]=[CH:10][C:9]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])=[CH:14][CH:13]=2)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: CCCCCCCCc1ccc(B(O)O)cc1
Reactant: O=[N+]([O-])c1ccc(I)cc1
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: COCCOC
Solvent: O
Product: CCCCCCCCc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Yield: 95 %

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (0.30 g, 0.26 mmol) and p-n-octylphenylboronic acid (1.0 g, 4.3 mmol) were sequentially added to a stirred solution of 4-nitroiodobenzene (0.87 g, 3.5 mmol) in 1,2-dimethoxyethane (13 mL) and aqueous sodium carbonate (2 M, 13 mL) under dry nitrogen. The stirred mixture was heated under reflux overnight and cooled. Water was added and the product was extracted into ether (30 3 mL) and the combined ethereal extracts were washed with brine and dried with MgSO4. The solvent was removed in vacuo and the residue was purified by chromatography using a short silica gel column (hexane:ethyl acetate—5:1 to 2:1] to provide 4′-nitro-4-n-octyl-biphenyl as a yellow oil, which solidified upon standing (1.04 g, 95% yield). The solid was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[H-].[Na+].Br[CH2:22][C:23]([O:25][CH3:26])=[O:24]>CN(C=O)C.O>[CH3:26][O:25][C:23](=[O:24])[CH2:22][O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:18])[N:6]2[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1cc2c(O)cccc2n1Cc1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1cc(C)n2Cc1ccccc1
Reaction time: 0.67 h
Yield: 87.7 %

Procedure:
4-Hydroxy-2-methyl-1-(phenylmethyl)-1H-indole (530 mg, 2.2 mmol) was added to 88 mg (2.2 mmol) of 60% NaH/mineral oil in 20 mL of DMF and the mixture stirred for 0.67 hours. Then, 0.21 mL (2.2 mmol) of methyl bromoacetate was added and stirring maintained for 17 hours. The mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate solution was washed with brine, dried (MgSO4), and concentrated at reduced pressure. The residue was chromatographed on silica gel eluting with 20% EtOAc/hexane to give 597 mg (88% yield) of [[2-methyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester, 140°-143° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH:29]([C:32]([NH2:34])=[O:33])[CH2:28][CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:34][C:32]([CH:29]3[CH2:30][CH2:31][NH:26][CH2:27][CH2:28]3)=[O:33])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: NC(=O)C1CCNCC1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC(=O)C3CCNCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and piperidine-4-carboxamide. MS obsd. (ESI+) [(M+H)+] 465, 1H NMR (400 MHz, CD3OD) δ ppm 8.50 (s, 1 H), 8.14 (s, 1 H), 8.01-7.98 (d, J=1.2 Hz, 1 H), 7.95-7.93 (d, J=7.2 Hz, 1 H), 7.84-7.82 (d, J=8.8 Hz, 1 H), 7.66-7.61 (m, 2 H), 7.52-7.51 (m, 1 H), 5.23 (s, 1 H), 4.59 (s, 2 H), 3.74 (s, 2 H), 3.57-3.54 (m, 2 H), 3.22-3.10 (m, 4 H), 2.50 (s, 3 H), 2.26-2.22 (m, 2 H), 2.14-2.08 (m, 2 H).
Reaction SMILES: [CH2:1]([CH:5]([C:7]1[N:8]([CH2:20][CH:21]([CH3:23])[CH3:22])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[OH:6])[CH2:2][CH2:3][CH3:4].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([O:6][CH:5]([C:7]1[N:8]([CH2:20][CH:21]([CH3:22])[CH3:23])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:1][CH2:2][CH2:3][CH3:4])(=[O:26])[CH3:25]
Reactant: CCCCC(O)c1nc2cnc3ccccc3c2n1CC(C)C
Reactant: CC(=O)OC(C)=O
Product: CCCCC(OC(C)=O)c1nc2cnc3ccccc3c2n1CC(C)C

Procedure:
Using the general method of Example 46, α-butyl-1-(2-methylpropyl)-1H-imidazo[4,5-c]quinoline-2-methanol (11.6 g; 37 mmol, Example 56) was reacted with acetic anhydride to provide the desired product.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([C@@H:20]([NH:22][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][N:27]4[CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH3:21])=[N:10][C:9]=2[CH:8]=[CH:7][C:6]=1[F:38])=[O:4].O[Li].O.Cl>CO.O>[F:38][C:6]1[CH:7]=[CH:8][C:9]2[N:10]=[C:11]([C@@H:20]([NH:22][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][N:27]4[CH:32]3[CH2:37][CH2:36][CH2:35][CH2:34][O:33]3)[CH3:21])[N:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]=2[C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1c(F)ccc2nc([C@H](C)Nc3ncnc4c3ncn4C3CCCCO3)n(-c3ccccc3)c12
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c(C(=O)O)c2n1-c1ccccc1
Temperature: 80 °C
Reaction time: 18 h
Yield: 72.7 %

Procedure:
A solution of 5-fluoro-3-phenyl-2-{(S)-1-[9-(tetrahydropyran-2-yl)-9H-purin-6-ylamino]ethyl}-3H-benzoimidazole-4-carboxylic acid methyl ester (580 mg, 1.13 mmol) and LiOH.H2O (94 mg, 2.25 mmol) in MeOH (20 mL) and water (2 mL) was heated at 45° C. for 3 h. Additional LiOH.H2O (94 mg) was added and the mixture heated at 80° C. for 16 h. After further addition of LiOH.H2O (94 mg), stirring at 75° C. was continued for 18 h. After cooling to RT, the pH of the mixture was adjusted to 4 by addition of 1N HCl. The organic solvent was removed under reduced pressure and EtOAc was added to the crude mixture. After sonication of the suspension, the organic solvent was removed in vacuo. The solid was collected by filtration and dried in vacuo to afford the title compound (412 mg, 73%). LCMS (Method C): RT 2.40 min [M+H]+ 502.0.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)=[O:4].[NH:13]1[CH2:16][CH:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:14]1>C1(C)C=CC=CC=1>[C:9]([C:8]1[CH:11]=[CH:12][C:5]([C:3](=[O:4])[CH2:2][N:13]2[CH2:14][CH:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16]2)=[CH:6][CH:7]=1)#[N:10]
Reactant: N#Cc1ccc(C(=O)CBr)cc1
Reactant: CC(C)(C)OC(=O)C1CNC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)C1CN(CC(=O)c2ccc(C#N)cc2)C1
Reaction time: 8 h
Yield: 28.3 %

Procedure:
To a mixture of 4-(2-bromoacetyl)benzonitrile (448 mg, 2 mmol) in toluene (10 mL) was added tert-butyl azetidine-3-carboxylate (346 mg, 2.2 mmol). The reaction mixture was stirred overnight and then, solvent was removed. The solids were triturated with EtOAC. The solids were collected and dried in vacuo to yield 170 mg of tert-butyl 1-(2-(4-cyanophenyl)-2-oxoethyl)azetidine-3-carboxylate as an off white solid. MS (m+1)=301. HPLC Peak RT=0.97 minutes (Analytical Method B).