Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][CH2:10][CH:11]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)[C:12]1[C:20]2[C:15](=[C:16]([CH2:22][S:23][CH3:24])[C:17]([F:21])=[CH:18][CH:19]=2)[NH:14][CH:13]=1)(=O)=O.C(OCC)(=O)C>CN(C=O)C>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([CH:11]([C:12]2[C:20]3[C:15](=[C:16]([CH2:22][S:23][CH3:24])[C:17]([F:21])=[CH:18][CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:9][C:1]#[N:2])=[CH:30][CH:29]=1
Reactant: [C-]#N
Reactant: CSCc1c(F)ccc2c(C(CCOS(C)(=O)=O)c3ccc(Cl)cc3)c[nH]c12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSCc1c(F)ccc2c(C(CCC#N)c3ccc(Cl)cc3)c[nH]c12
Temperature: 80 °C
Reaction time: 3 h

Procedure:
0.46 g (7.01 mmol) of potassium cyanide were added to 1.55 g (3.50 mmol) of the compound from Example 66A in 32 ml of DMF. The mixture was stirred at 80° C. for 3 h, ethyl acetate was added to the reaction solution, and the mixture was washed twice with water and once with saturated aqueous sodium chloride solution. The combined organic phases were dried over sodium sulfate, the solid was filtered off, and the solvents were removed. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient). 1.00 g (77% of theory) of the target compound was obtained.
Reaction SMILES: CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[F:22][C:23]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:24]=1[NH2:25].[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41](O)=[O:42]>CN(C=O)C>[Br:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][C:41]([NH:25][C:24]1[CH:26]=[CH:27][C:28]([F:30])=[CH:29][C:23]=1[F:22])=[O:42]
Reactant: O=C(O)CCCCCCCCCBr
Reactant: Nc1ccc(F)cc1F
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(CCCCCCCCCBr)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 15 h
Yield: 44.8 %

Procedure:
WSC (990 mg, 5.2 mmols) and HOBt (698 mg, 5.2 mmols) were added to a DMF (10 ml) solution of 2,4-difluoroaniline (1.29 g, 10 mmols) and 10-bromodecanoic acid (1.18 g, 4.7 mmols), and stirred at room temperature for 15 hours. The reaction mixture was extracted with ether. The organic layer was washed with water, 1 N HCl an aqueous saturated solution of sodium hydrogencarbonate and saturated saline in that order, and dried with anhydrous magnesium sulfate, and the solvent was evaporated. Then, the residue was purified through silica gel column chromatography (developer:hexane/acetone=10/1) aid the resulting crystals were recrystallized from ether-hexane to obtain 763 mg (yield, 45%) of 10-bromo-N-(2,4-difluorophenyl) decanamide as colorless needle-like crystals.
Reaction SMILES: [CH2:1]([CH2:8][NH2:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.[CH3:14][OH:15]>>[CH2:1]([CH2:8][NH:9][CH:1]1[CH2:2][CH2:3][O:15][CH2:14][CH2:8]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCc1ccccc1
Reactant: CO
Solvent: ClC(Cl)Cl
Product: c1ccc(CCNC2CCOCC2)cc1
Yield: 70 %

Procedure:
Into a similar device to that used in Example 7 were charged 1.38 g (5.0 mmol) of tetrahydropyranyl-4-p-toluenesulfonate synthesized in Example 6 and having a purity of 93% and 3.18 g (26.0 mmol) of benzylmethylamine, and the mixture was reacted at 70° C. for 4 hours and further at 90° C. for 5 hours. After completion of the reaction, the resulting reaction mixture was concentrated under reduced pressure and purified by silica gel column chromatography (Filler: Wako gel C-200 (available from Wako Junyaku Co.), Eluent: chloroform/methanol (=9/1 (volume ratio)) to obtain 0.72 g (yield: 70%) of 4-benzylmethylaminotetrahydropyrane having a purity of 90% (areal percentage according to high performance liquid chromatography) as a pale yellowish liquid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][S:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:12][C:11]=3[N:22]([CH3:32])[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:25])=[O:24])=[N:4]1.[CH3:33][S:34](Cl)(=[O:36])=[O:35].C(N(CC)CC)C>O1CCCC1>[CH3:33][S:34]([O:1][CH2:2][C@@H:3]1[CH2:7][S:6][C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:12][C:11]=3[N:22]([CH3:32])[S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)(=[O:24])=[O:25])=[N:4]1)(=[O:36])=[O:35]
Reactant: CS(=O)(=O)Cl
Reactant: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@H](CO)CS3)cc2c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCOc1cc(N(C)S(=O)(=O)c2ccccn2)c2[nH]c(C3=N[C@H](COS(C)(=O)=O)CS3)cc2c1
Yield: 76.7 %

Procedure:
A solution of N-[2-[(4R)-4-(hydroxymethyl)-4,5-dihydro-1,3-thiazol-2-yl]-5-(2-methoxyethoxy)-1H-indol-7-yl]-N-methylpyridine-2-sulfonamide (0.28 g), methanesulfonyl chloride (0.10 g) and triethylamine (0.16 mL) in tetrahydrofuran (5.0 mL) was stirred at room temperature for 2 hr, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:4, volume ratio) to give the title compound (0.25 g, yield 77%) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][N:7]([CH2:9][C:10]([OH:12])=O)[CH3:8])=[O:5])[CH3:2].[NH2:13][C@@H:14]([CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[CH:41][CH:40]=1)[C:15]([N:17]([C@@H:29]([CH3:37])[CH:30]([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])[CH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)=[O:16]>>[C:46]([O:45][C:42]1[CH:41]=[CH:40][C:39]([CH2:38][C@H:14]([NH:13][C:10](=[O:12])[CH2:9][N:7]([CH3:8])[NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])[C:15]([N:17]([C@@H:29]([CH3:37])[CH:30]([O:34][CH2:35][CH3:36])[O:31][CH2:32][CH3:33])[CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[O:16])=[CH:44][CH:43]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)Cc1ccc(OC(C)(C)C)cc1
Reactant: CCNC(=O)NN(C)CC(=O)O
Product: CCNC(=O)NN(C)CC(=O)N[C@@H](Cc1ccc(OC(C)(C)C)cc1)C(=O)N(Cc1cccc2ccccc12)[C@@H](C)C(OCC)OCC

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(ethylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-9) 52 mg (0.30 mmol) was coupled with (S)-2-amino-3-(4-tert-butoxyphenyl)-N—((S)-1,1-diethoxy-propan-2-yl)-N-(naphthalen-1-ylmethyl)propanamide (Compound IV-2) 100 mg (0.20 mmol) to obtain the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[SH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27](F)=[C:26]([Cl:31])[CH:25]=1)(=[O:23])=[O:22]>>[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([S:19][C:10]2[CH:11]=[C:12]([C:15]([F:16])([F:17])[F:18])[CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:26]([Cl:31])[CH:25]=1)(=[O:23])=[O:22]
Reactant: CS(=O)(=O)c1ccc(F)c(Cl)c1
Reactant: FC(F)(F)c1ccc(OCc2ccccc2)c(S)c1
Product: CS(=O)(=O)c1ccc(Sc2cc(C(F)(F)F)ccc2OCc2ccccc2)c(Cl)c1

Procedure:
The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and the product from example 7 step (ii), yield 0.43 g.
Reaction SMILES: FC1C([O:8][C:9](=O)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([C:17]#[N:18])[CH:11]=2)=C(F)C(F)=C(F)C=1F.[CH3:24][C:25]1[C:47]([CH3:48])=[CH:46][C:45]([CH3:49])=[C:44]([CH3:50])[C:26]=1[CH2:27][O:28][C:29]1[CH:30]=[C:31]([C:35]2[CH:39]=[CH:38][O:37][C:36]=2[C:40]([NH:42][NH2:43])=[O:41])[CH:32]=[CH:33][CH:34]=1>CN(C=O)C.C(OCC)(=O)C>[C:17]([C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[OH:16])[C:9]([NH:43][NH:42][C:40]([C:36]1[O:37][CH:38]=[CH:39][C:35]=1[C:31]1[CH:32]=[CH:33][CH:34]=[C:29]([O:28][CH2:27][C:26]2[C:44]([CH3:50])=[C:45]([CH3:49])[CH:46]=[C:47]([CH3:48])[C:25]=2[CH3:24])[CH:30]=1)=[O:41])=[O:8])#[N:18]
Reactant: N#Cc1cc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1O
Reactant: Cc1cc(C)c(C)c(COc2cccc(-c3ccoc3C(=O)NN)c2)c1C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C)c(C)c(COc2cccc(-c3ccoc3C(=O)NNC(=O)c3ccc(O)c(C#N)c3)c2)c1C
Temperature: 70 °C
Reaction time: 8 h
Yield: 44.5 %

Procedure:
A mixture of 3-cyano-4-hydroxybenzoic acid pentafluorophenyl ester (compound of Reference Example 63; 0.45 g) and 3-[3-(2,3,5,6-tetramethylbenzyloxy)phenyl]-2-furancarboxylic acid hydrazide (compound of Reference Example 4; 0.50 g) in DMF (5 ml) was stirred at 70° C. overnight. The reaction solution was then diluted with ethyl acetate, washed with 1 M hydrochloric acid and water, and dried over MgSO4. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: 0%→10% methanol/chloroform gradient) and recrystallized from ethyl acetate, thereby giving 0.31 g of the desired compound. Melting point: 210-211° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](Br)[CH3:9])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]2=[O:17])[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(Br)c1ccc(Br)cc1
Reactant: Oc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(c1ccc(Br)cc1)n1ccccc1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.2 %

Procedure:
To a solution of 1-bromo-4-(1-bromoethyl)benzene (200 mg, 0.76 mmol) and pyridin-2-ol (87 mg, 0.91 mmol) in N,N-dimethylformamide (30 mL) was added cesium carbonate (496 mg, 1.52 mmol). The mixture was stirred at room temperature for 12 hours. And then solvent was removed to give a residue. The residue was purified by column chromatography (silica gel, ethyl acetate/petroleum ether=1:10) to give 1-(1-(4-bromophenyl)ethyl)pyridin-2(1H)-one (161 mg, 76%) LRMS (M+H+) m/z: calcd 277.0. found 277.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[C:9]([C:14]([OH:16])=O)=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:19])=O.CN(C=O)C>C(Cl)Cl>[CH2:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([Cl:19])=[O:16])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1Cc1ccccc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)c1ccccc1Cc1ccccc1

Procedure:
To a solution of α-phenyl-o-toluic acid (4 g, 18.28 mmol) in dry CH2Cl2 (30 mL) was added thionyl chloride (5 mL, 68.50 mmol), followed by a drop of dry DMF. The reaction mixture was refluxed for 5 hr. The solvent and excess SOCl2 was removed in vacuo to give 2-benzyl-benzoyl chloride 18 as a pale yellow oil which was used directly in next step.
Reaction SMILES: Cl[CH2:2][C:3]1[S:7][C:6]([NH2:8])=[N:5][C:4]=1[C:9]([F:12])([F:11])[F:10].BrCC1CCCCO1.[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]2([C:33]3=[CH:34][C:35]4[O:39][CH2:38][O:37][C:36]=4[CH:40]=[C:32]3[O:31][CH2:30]2)[C:22]1=[O:41]>>[NH2:8][C:6]1[S:7][C:3]([CH2:2][N:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]3([C:33]4=[CH:34][C:35]5[O:39][CH2:38][O:37][C:36]=5[CH:40]=[C:32]4[O:31][CH2:30]3)[C:22]2=[O:41])=[C:4]([C:9]([F:12])([F:11])[F:10])[N:5]=1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Reactant: Nc1nc(C(F)(F)F)c(CCl)s1
Agent: BrCC1CCCCO1
Product: Nc1nc(C(F)(F)F)c(CN2C(=O)C3(COc4cc5c(cc43)OCO5)c3ccccc32)s1

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-(chloromethyl)-4-(trifluoromethyl)thiazol-2-amine to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-{[2-amino-4-(trifluoromethyl)-1,3-thiazol-5-yl]methyl}spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one was obtained (4.0%) as a colorless solid: mp 165-167° C.; 1H NMR (300 MHz, DMSO-d6) δ7.39 (br, 2H), 7.32 (dd, J=7.7, 7.7 Hz, 1H), 7.18 (d, J=6.7 Hz, 1H), 7.05 (dd, J=7.5, 7.5 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.69 (s, 1H), 6.12 (s, 1H), 5.91 (s, 2H), 5.02 (ABq, 2H), 4.70 (ABq, 2H); 13C NMR (75 MHz, DMSO-d6) δ176.8, 167.9, 155.9, 148.9, 142.2, 141.8, 134.7 (q, 1JCF=135 Hz), 132.1, 129.5, 124.5, 123.9, 123.8 (m), 119.9, 109.2, 103.2, 101.9, 93.9, 80.2, 57.8, 40.9; MS (ES+) m/z 462.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:9]([OH:10])=[C:8]([F:11])[C:7]([Br:12])=[C:6]([CH3:13])[C:3]=1[C:4]#[N:5].[C:14](Cl)(=O)[CH3:15].[Cl-].[NH4+]>C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>[Br:12][C:7]1[C:8]([F:11])=[C:9]2[O:10][C:14]([CH3:15])=[N:1][C:2]2=[C:3]([C:4]#[N:5])[C:6]=1[CH3:13]
Reactant: Cc1c(Br)c(F)c(O)c(N)c1C#N
Reactant: CC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1nc2c(C#N)c(C)c(Br)c(F)c2o1
Temperature: 25 °C
Reaction time: 14 h
Yield: 72.8 %

Procedure:
Diisopropylethylamine (22 ml, 0.126 mmol) was added to an ethyl acetate (400 ml) solution of 2-amino-5-bromo-4-fluoro-3-hydroxy-6-methylbenzonitrile (I-75) (8.85 g, 36.1 mmol), cooled with ice, then acetyl chloride (3.85 ml, 54.2 mmol) was dropwise added, followed by stirring as such for 14 hours with gradually heating up to room temperature. With cooling with ice, aqueous saturated ammonium chloride solution was added, and the organic layer was collected. This was washed with saturated brine, dried over anhydrous sodium sulfate, then the solvent was evaporated away under reduced pressure. The resulting residue was suspended in toluene (500 ml), a catalytic amount of p-toluenesulfonic acid was added, followed by heating under reflux for 3 hours with a Dean-Stark device. After cooling, the solvent was evaporated away, the resulting residue was dissolved in ethyl acetate, washed with water. After drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, the precipitated crystal was washed with isopropyl ether, then collected by filtration to obtain the entitled compound (7.07 g, 73%) as a colorless solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[CH:10][CH:9]=1.[CH3:22][C:23]1[CH:37]=[CH:36][C:26]([CH:27](O)[C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)=[CH:25][CH:24]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:22][C:23]1[CH:37]=[CH:36][C:26]([CH:27]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)[O:1][CH2:2][CH2:3][S:4][CH2:5][CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16](=[O:21])[C:17]([F:18])([F:19])[F:20])=[CH:10][CH:9]=2)=[CH:25][CH:24]=1
Reactant: O=C(CCc1ccc(OCCSCCO)cc1)C(F)(F)F
Reactant: Cc1ccc(C(O)c2ccc(C)cc2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1ccc(C(OCCSCCOc2ccc(CCC(=O)C(F)(F)F)cc2)c2ccc(C)cc2)cc1
Yield: 94.2 %

Procedure:
A solution of 4-[4-[2-(2-hydroxyethylthio)ethoxy]phenyl]-1,1,1-trifluoro-2-butanone (1.20 g, 3.72 mmol), 4,4′-dimethylbenzhydrol (0.95 g, 4.47 mmol) and p-toluenesulfonic acid (0.035 g) in toluene (20 ml) was heated under reflux for 15 min. The cooled reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent in vacuo and chromatography of the residue on silica gel (elution with a gradient of ethyl acetate 20-40% in hexane) gave 1.81 g (94%) of the title material as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[C:22]([O:25][CH2:26][CH2:27]Br)(=[O:24])[CH3:23]>CN(C)C=O.O>[C:22]([O:25][CH2:26][CH2:27][O:8][C:4]1[C:3]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[C:2]([NH2:1])[N:6]([CH3:7])[N:5]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)OCCBr
Reactant: Cc1ccc(-c2c(O)nn(C)c2N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1nn(C)c(N)c1-c1ccc(C)cc1
Reaction time: 16 h
Yield: 42.5 %

Procedure:
To 5-amino-1-methyl-4-(4-methylphenyl)-1H-pyrazol-3-ol (Preparation 3a) (250 mg) in dimethyl formamide (5 ml) at room temperature was added potassium carbonate (510 mg) and 2-bromoethyl acetate (205 mg), the mixture was stirred for 16 hrs. The reaction was diluted with water (60 ml) and extracted with ethyl acetate (3×30 ml). The organic fractions were combined, washed with water (2×30 ml) and brine (30 ml) and dried over magnesium sulfate, filtered concentrated under reduced pressure. The residue was purified by column chromatography (silica, 30 g) eluted with ethyl acetate:hexane (1:1) to yield the title compound as a white solid (151 mg).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[Al+3].[Cl-].[Cl-].[Cl-].[C:12]1([CH2:18][C:19]([O:21][CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])=[O:20])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:15]1[CH:16]=[CH:17][C:12]([CH2:18][C:19]([O:21][CH2:22][CH:23]([CH2:28][CH3:29])[CH2:24][CH2:25][CH2:26][CH3:27])=[O:20])=[CH:13][CH:14]=1)=[O:6]
Reactant: CCCCC(CC)COC(=O)Cc1ccccc1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCC(CC)COC(=O)Cc1ccc(C(=O)CCCCl)cc1
Temperature: 35 °C
Reaction time: 2.5 h

Procedure:
Mix chlorobutyryl chloride (16.9 g) and AlCl3 (29.3 g) at room temperature. Add 2-phenylacetic acid, 2-ethylhexyl ester (27.6 g), keeping the temperature below 10° C. Heat at 35° C. for 24 hours, quench in ice water (200 g). Separate the organic phase, dry (MgSO4) and evaporate the solvent in vacuo. Dilute the residue with ethanol (150 mL), add hydrogen chloride (5 g) and heat to 75° C. After 2.5 hours, add another 5 g of hydrogen chloride and stir at 75° C. for 24 hours. Evaporate the solvent in vacuo to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[C:14]([CH2:16][C:17]3[C:18](=[O:29])[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21](=[O:24])[C:22]=3[CH3:23])[CH:13]=[CH:12][C:11]=2[O:30]C(=O)C)=[CH:4][CH:3]=1.C(=O)([O-])O.[Na+]>CO.O>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][C:9](=[O:34])[C:10]2[CH:15]=[C:14]([CH2:16][C:17]3[C:18](=[O:29])[C:19]([O:27][CH3:28])=[C:20]([O:25][CH3:26])[C:21](=[O:24])[C:22]=3[CH3:23])[CH:13]=[CH:12][C:11]=2[OH:30])=[CH:4][CH:3]=1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3ccc(Cl)nc3)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)Nc3ccc(Cl)nc3)c2)=C(C)C1=O
Yield: 87.5 %

Procedure:
N-(6-Chloropyridin-3-yl)-5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzamide (0.070 g, 0.144 mmol) was dissolved in methanol (3 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (1.5 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.056 g, 0.126 mmol, 88%).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([OH:23])=[C:8]2[CH:14]=[CH:13][N:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])C.[NH2:24][CH2:25][C:26]([OH:28])=[O:27].C[O-].[Na+].CO>>[F:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][N:12]1[C:9]2=[CH:10][N:11]=[C:6]([C:4]([NH:24][CH2:25][C:26]([OH:28])=[O:27])=[O:5])[C:7]([OH:23])=[C:8]2[CH:14]=[CH:13]1
Reactant: CCOC(=O)c1ncc2c(ccn2Cc2cccc(F)c2)c1O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2c(ccn2Cc2cccc(F)c2)c1O

Procedure:
Prepared in analogy to that of Example 1(e) from 1-(3-fluoro-benzyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 344 (M+H)+.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:11]=[C:10](Cl)[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH2:20]([OH:23])[CH2:21][OH:22]>>[NH2:2][C:3]1[N:11]=[C:10]([O:22][CH2:21][CH2:20][OH:23])[N:9]=[C:8]2[C:4]=1[N:5]=[CH:6][N:7]2[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCCO
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1ccccc1
Agent: [Na]
Product: Nc1nc(OCCO)nc2c1ncn2Cc1ccccc1
Temperature: 100 °C
Yield: 70 %

Procedure:
To sodium (74 mg, 3.2 mmol) in 5 ml of ethylene glycol were added 6-amino-9-benzyl-2-chloropurine (157 mg, 0.58 mmol). The mixture was heated at 100° C. for 4 hours and concentrated in vacuo to dryness. To the residue was added water and the mixture was extracted with chloroform. The organic layer was dried on magnesium sulfate and the solvent was removed in vacuo. The residue was purified with silica gel chromatography (3% methanol/chloroform) to give the subject compound (121 mg, yield 70%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:31][C:30]([CH:32]=O)=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:34][NH:35][CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39]>>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[C:24]([C:27]4[O:31][C:30]([CH2:32][N:35]([CH2:36][CH2:37][S:38]([CH3:41])(=[O:40])=[O:39])[CH3:34])=[CH:29][CH:28]=4)[CH:25]=3)[N:20]=[CH:19][N:18]=2)=[CH:14][CH:15]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CNCCS(C)(=O)=O
Reactant: O=Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Agent: Cl
Product: CN(CCS(C)(=O)=O)Cc1ccc(-c2ccc3ncnc(Nc4ccc(OCc5ccccc5)cc4)c3c2)o1
Yield: 38.8 %

Procedure:
In an analogous manner to Example 10, 5-(4-(4-Benzyloxy-phenylamino)-quinazolin-6-yl)-furan-2-carbaldehyde hydrochloride (0.217 g, 0.474 mmol) was reacted with N-methyl-N-(2-methanesulphonyl-ethyl)amine (0.41 1g, 3.0 mmol). Purification by silica gel chromatography, eluting with 2-3% MeOH/CHCl3, followed by trituration with ether, gave the title compound as a pale yellow solid (0.100 g, 0.184 mmol, 39%); δH [2H6]DMSO 9.84 (1H,s), 8.63 (1H,s), 8.48 (1H,s), 8.12 (1H,d), 7.78 (1H,d), 7.68 (2H,d), 7.13-7.52 (5H,m), 7.02-7.10 (3H,m), 6.55 (1H,d), 5.14 (2H,s), 3.70 (2H,s), 3.35-3.44 (2H, obscured by water), 3.05 (3H,s), 2.84 (2H,t), 2.28 (3H,s).
Reaction SMILES: C([O:8][CH2:9][C:10]#[C:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[CH2:27][CH2:26][C@@:20]3([NH:24][C:23](=[O:25])[O:22][CH2:21]3)[CH2:19]2)=[CH:14][CH:13]=1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[OH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C@@H:18]2[CH2:27][CH2:26][C@@:20]3([NH:24][C:23](=[O:25])[O:22][CH2:21]3)[CH2:19]2)=[CH:16][CH:17]=1
Reactant: O=C1N[C@@]2(CC[C@@H](c3ccc(C#CCOCc4ccccc4)cc3)C2)CO1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=C1N[C@@]2(CC[C@@H](c3ccc(CCCO)cc3)C2)CO1
Yield: 45.5 %

Procedure:
To a suspension of palladium hydroxide on carbon (0.583 g, 0.830 mmol) in MeOH (250 mL) was added a solution of (5R,7R)-7-(4-(3-(benzyloxy)prop-1-ynyl)phenyl)-3-oxa-1-azaspiro[4.4]nonan-2-one (20 g, 41.5 mmol) in MeOH (10 mL). Hydrogen was bubbled through the solution for about 10 minutes and an atmosphere of hydrogen was maintained via balloon. After about 15 hours the reaction mixture was filtered through Celite® and concentrated in vacuo. The crude product was purified by chromatography on silica gel (EtOAc/DCM) to provide (5R,7R)-7-(4-(3-hydroxypropyl)phenyl)-3-oxa-1-azaspiro[4.4]nonan-2-one (5.2 g, 18.89 mmol, 45.5% yield) as a colorless solid.