Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.Cl[CH2:21][C:22]1[CH:41]=[CH:40][C:25]([O:26][CH2:27][C:28]2[N:29]=[C:30]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[O:31][C:32]=2[CH3:33])=[C:24]([O:42][CH3:43])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:43][O:42][C:24]1[CH:23]=[C:22]([CH:41]=[CH:40][C:25]=1[O:26][CH2:27][C:28]1[N:29]=[C:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:31][C:32]=1[CH3:33])[CH2:21][O:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: COc1cc(CCl)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: CCOC(=O)CCc1cc(O)nn1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cc(OCc2ccc(OCc3nc(-c4ccccc4)oc3C)c(OC)c2)nn1-c1ccccc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 88.4 %

Procedure:
A mixture of ethyl 3-(3-hydroxy-1-phenyl-1H-pyrazol-5-yl)propionate (700 mg), 4-(4-chloromethyl-2-methoxyphenoxymethyl)-5-methyl-2-phenyloxazole (930 mg), potassium carbonate (750 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and ethyl 3-[3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1-phenyl-1H-pyrazol-5-yl]propionate (1.35 g, yield 88%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:14][OH:15])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].CCN(C(C)C)C(C)C.[Si:25](Cl)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>C(Cl)Cl>[C:28]([Si:25]([CH3:27])([CH3:26])[O:15][CH2:14][C:6]1[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: O=[N+]([O-])c1cc(CO)cc(C(F)(F)F)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 87.1 %

Procedure:
To a solution of [3-nitro-5-(trifluoromethyl)phenyl]methanol (2.80 g, 12.7 mmol) in DCM (20 mL) was added DIPEA (6.62 mL, 38.00 mmol). The reaction mixture was cooled to 0° C. tert-Butyldimethylsilyl chloride (3.82 g, 25.3 mmol) was added dropwise and the reaction mixture was allowed to stir at rt over the weekend. The reaction mixture was diluted with DCM and washed with water and brine. The organic solution was dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give tert-butyl(dimethyl)-{[3-nitro-5-(trifluoromethyl)benzyl]oxy}silane (3.71 g, 87%) as a white solid. 1H NMR (400 MHz,CDCl3, HCl salt) δ: 8.35-8.41 (m, 2H), 7.92 (s, 1H), 4.88 (s, 2H), 0.97 (s, 9H), and 0.15 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:13]([O:15][CH3:16])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC[N:19]([CH:23]([CH3:25])C)[CH:20]([CH3:22])C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.N1CCCC1>C(Cl)Cl>[CH3:16][O:15][C@H:13]([CH3:14])[C@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:10](=[O:12])[N:19]1[CH2:20][CH2:22][CH2:25][CH2:23]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: C1CCNC1
Product: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
(2S,3R)-2-(Tert-butoxycarbonylamino)-3-methoxybutanoic acid (643 mg, 2.76 mmol), which is commercially available, and DIPEA (1.440 mL, 8.27 mmol) was mixed in DCM (10 mL). The mixture was cooled to 0° C. TBTU (974 mg, 3.03 mmol) was added and the mixture stirred at rt for 10 min. Pyrrolidine (0.274 mL, 3.31 mmol) was added and the resultant mixture was stirred at rt for 16 h. The mixture was diluted with DCM (10 mL). The organic phase was washed with NaHCO3 (8% in aq. solution) and brine, filtered through a phase separator and concentrated under reduced pressure. The residue was purified via Biotage (gradient; DCM/iso-propanol, 99:1 to 95:5, KP-SIL 340 g column). The solvent was removed under reduced pressure to give the title compound (0.704 g, 95%). 1H NMR (400 MHz, CD3OD) δ 1.15, 1.44, 1.82-2.05, 3.33, 3.35-3.52, 3.54-3.65, 3.66-3.79, 4.36. Total no of protons: 25. LCMS (M+H)+: 287.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH:5](CC)[CH2:6][CH2:7][N:8]1[C:27](=[S:28])[N:11]2[C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=4)[O:15][C:16]=3[CH:17]=[C:10]2[C:9]1=[O:29])C.O>FC(F)(F)C(O)=O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([C:14]2[O:15][C:16]3[CH:17]=[C:10]4[C:9](=[O:29])[N:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:32])=[O:3])[C:27](=[S:28])[N:11]4[C:12]=3[CH:13]=2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: CCOC(=O)C(CC)CCN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(O)CCCN1C(=O)c2cc3oc(-c4ccc([N+](=O)[O-])cc4)cc3n2C1=S
Temperature: 70 °C
Yield: 92.5 %

Procedure:
Compound 1 (10 mg, 0.023 mmol) was dissolved in trifluoroacetic acid (TFA, 2 ml), to give a clear red solution. Water (0.5 ml) was added and the mixture was heated at 70° C. overnight. Additional water (2 ml) was then added and the solvents of the reaction mixture were evaporated to give Compound 2 as a yellow-brown solid (8.5 mg, 88% yield).
Reaction SMILES: [C:1]([C:3]1[CH:23]=[CH:22][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:5][CH:4]=1)#[N:2].[O:24]([CH2:31][CH2:32]O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N(C(OCC)=O)=NC(OCC)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][C:9](=[O:21])[CH:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:32][CH2:31][O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:15][C:14]=2[F:20])[O:11][CH3:12])=[CH:22][CH:23]=1)#[N:2]
Reactant: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(O)cc1F
Reactant: OCCOc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(C(=O)NCc1ccc(C#N)cc1)c1ccc(OCCOc2ccccc2)cc1F

Procedure:
In analogy to example 22.1, (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4-hydroxy-phenyl)-2-methoxy-acetamide (example 70.4) was reacted with 2-phenoxyethanol, diethyl azodicarboxylate and triphenyl-phosphine in THF to give (RS)-N-(4-cyano-benzyl)-2-[2-fluoro-4-(2-phenoxy-ethoxy)-phenyl]-2-methoxy-acetamide. Colorless oil. MS 435.3 ([M+H]+)
Reaction SMILES: [CH3:1][C:2]1[N:3]=[N:4][S:5][C:6]=1[C:7]([OH:9])=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClN1C(=O)CCC1=O.[CH:37]1([CH2:40][N:41]2[C:49]3[N:48]=[C:47]([CH2:50][C:51]4[CH:56]=[CH:55][C:54]([NH:57][CH3:58])=[CH:53][CH:52]=4)[NH:46][C:45]=3[C:44](=[O:59])[N:43]([CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[F:67])[C:42]2=[O:68])[CH2:39][CH2:38]1>ClCCl>[CH:37]1([CH2:40][N:41]2[C:49]3[N:48]=[C:47]([CH2:50][C:51]4[CH:52]=[CH:53][C:54]([N:57]([CH3:58])[C:7]([C:6]5[S:5][N:4]=[N:3][C:2]=5[CH3:1])=[O:9])=[CH:55][CH:56]=4)[NH:46][C:45]=3[C:44](=[O:59])[N:43]([CH2:60][C:61]3[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=3[F:67])[C:42]2=[O:68])[CH2:39][CH2:38]1
Reactant: CNc1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Reactant: Cc1nnsc1C(=O)O
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1nnsc1C(=O)N(C)c1ccc(Cc2nc3c([nH]2)c(=O)n(Cc2ccccc2F)c(=O)n3CC2CC2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 15.6 %

Procedure:
A mixture of 4-methyl-[l,2,3]thiadiazole-5-carboxylic acid (12 mg, 0.08 mmol) in dichloromethane (2.0 mL) cooled to 0° C. was treated with triphenylphosphine (27 mg , 0.10 mmol), and N-chlorosuccinimide (14 mg, 0.10 mmol). This mixture was stirred at 0° C. for 30 min and at 25° C. for 10 min. At this time, the reaction was treated with 3-cyclopropylmethyl-1-(2-fluoro-benzyl)-8-(4-methylamino-benzyl)-3,7-dihydro-purine-2,6-dione ( 75 mg, 0.17 mmol). The reaction was then stirred at 25° C. for 18 h. At this time, the reaction was diluted with dichloromethane. The organics were washed with a saturated aqueous sodium bicarbonate solution. This solution was extracted with a 90/10 dichloromethane/methanol solution. The organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by HPLC (15–60% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 40 min). Fractions with the desired product were combined and concentrated in vacuo. The resulting residue was diluted with dichloromethane (100 mL) and was washed with a saturated aqueous sodium bicarbonate solution (25 mL). The aqueous layer was re-extracted with dichloromethane (1×50 mL). The combined organics were dried over magnesium sulfate, filtered, and concentrated in vacuo. The resulting solid was dried in vacuo for 24 h to afford 4-methyl-[1,2,3]thiadiazole-5-carboxylic acid {4-[3-cyclopropylmethyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-methyl-amide (7.0 mg, 14.5%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ13.14 (broad s, 1H), 6.92–6.67 (m, 8H), 4.75 (s, 2H), 3.70 (s, 2H), 3.47 (d, J=7.32 Hz, 2H), 2.99 (s, 3H), 2.26 (s, 3H), 0.82 (m, 1H), 0.03 (m, 4H).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].C(#N)C.Br[CH2:24][CH2:25][O:26][CH3:27]>C(OCC)(=O)C>[CH3:13][O:12][C:3]1[C:2]([O:1][CH2:24][CH2:25][O:26][CH3:27])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCCBr
Reactant: COC(=O)c1cccc(O)c1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COCCOc1cccc(C(=O)OC)c1OC
Temperature: 25 °C
Yield: 88.5 %

Procedure:
To a mixture of methyl 3-hydroxy-2-(methyloxy)benzoate (0.48 g, 2.6 mmol), potassium carbonate (0.73 g, 5.3 mmol) and acetonitrile (30 mL) was added 1-bromo-2-(methyloxy)ethane (0.37 mL, 4.0 mmol). The resulting mixture was heated at reflux 18 hours. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate (100 mL), filtered and concentrated. The residue was then diluted with ethyl acetate (100 mL) and washed with 5% sodium hydroxide solution, water and brine (100 mL each), dried over sodium sulfate, filtered and concentrated to give an oily residue which was purified by flash chromatography (silica gel, 30% ethyl acetate-hexane) to provide methyl 2-(methyloxy)-3-{[2-(methyloxy)ethyl]oxy}benzoate, (0.54 g, 2.3 mmol, 85% yield). 1H NMR (400 MHz, CDCl3): 7.35-7.33 (m, 1H), 7.11-7.04 (m, 2H), 4.18-4.17 (m, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.80-3.77 (m, 2H), 3.46 (s, 3H).
Reaction SMILES: Cl.Cl.[CH:3]([N:6]([CH3:13])[CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)([CH3:5])[CH3:4].Cl[C:15]([O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)=[CH:20][CH:19]=1)=[O:16]>CN(C)C=O>[F:33][C:31]([F:32])([F:34])[C:28]1[CH:29]=[CH:30][C:25]([O:24][C:21]2[CH:22]=[CH:23][C:18]([O:17][C:15]([N:10]3[CH2:9][CH2:8][CH:7]([N:6]([CH:3]([CH3:5])[CH3:4])[CH3:13])[CH2:12][CH2:11]3)=[O:16])=[CH:19][CH:20]=2)=[N:26][CH:27]=1
Reactant: CC(C)N(C)C1CCNCC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)N(C)C1CCN(C(=O)Oc2ccc(Oc3ccc(C(F)(F)F)cn3)cc2)CC1

Procedure:
The title product was prepared from isopropyl-methyl-piperidin-4-yl-amine, dihydrochloride and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate; dimethylformamide as solvent, preparative HPLC (method C) (77%, light yellow oil). HPLC-MS m/z=438.3 (M+1), Rt: 2.77 min.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[CH2:18]([CH:20]1[O:22][CH2:21]1)Cl>CS(C)=O.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([O:15][CH2:18][CH:20]2[CH2:21][O:22]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCC1CO1
Reactant: O=C(OCc1ccccc1)N1CC(O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CC(OCC2CO2)C1
Temperature: 22.5 °C
Reaction time: 24 h
Yield: 81.3 %

Procedure:
To a solution of 8 (30 g, 0.15 mol) in DMSO (250 mL) was slowly added a solution of NaOH (9.9 g, 0.25 mol) in water (195 mL) at 15-25° C. Epichlorohydrin (93.8 g, 1.01 mol) was added and the mixture was stirred at 20-25° C. for 24 h. The mixture was diluted with water (300 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layer was washed with water (2×50 mL), dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate-heptanes 3:2, yielding 9 as a clear oil (32.1 g, 84%). 1H NMR (300 MHz, CDCl3): δ 2.60 (1H, dd, J=4.8, 2.6 Hz), 2.81 (1H, dd, J=4.9, 4.2 Hz), 3.09-3.16 (1H, m), 3.25 (1H, dd, J=11.4, 6.2 Hz), 3.68 (1H, dd, J=11.5, 2.5 Hz), 3.89-3.97 (2H, m), 4.15-4.24 (2H, m), 4.29-4.37 (1H, m), 5.09 (2H, s), 7.28-7.36 (5H, m); 13C NMR (75 MHz, CDCl3): δ 44.2, 50.4, 56.7, 56.9, 66.7, 68.6, 70.0, 128.0, 128.1, 128.5, 136.6, 156.5; IR: (film) 2951, 1709, 1420 cm−1; ES-HRMS m/z: (M++1H) calcd. for C14H18NO4 264.1230. found 264.1230.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)=[CH:3][CH:2]=1.[CH3:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][C:19]=1[CH:24]=O>>[CH3:17][C:18]1[CH:22]=[C:21]([CH3:23])[NH:20][C:19]=1[CH:24]=[C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)[NH:11][C:10]1=[O:16]
Reactant: O=C1Cc2c(cccc2-c2ccncc2)N1
Reactant: Cc1cc(C)c(C=O)[nH]1
Product: Cc1cc(C)c(C=C2C(=O)Nc3cccc(-c4ccncc4)c32)[nH]1

Procedure:
4-Pyridin-4-yl-1,3-dihydroindol-2-one was condensed with 3,5-dimethyl-1H-pyrrole-2-carbaldehyde to give the title compound.
Reaction SMILES: SC1N(C)C(=O)C2C(=CC=C(C)C=2)[N:3]=1.ClC1N=C(O)C2C(=CC=C(C)C=2)N=1.[NH:28]([C:30]1[N:39]=[C:38]([OH:40])[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([CH3:41])[CH:36]=2)[N:31]=1)[NH2:29].SC1N=C(O)C2C(=CC=C(C)C=2)N=1.O.NN>O>[NH2:3][N:39]1[C:38](=[O:40])[C:37]2[C:32](=[CH:33][CH:34]=[C:35]([CH3:41])[CH:36]=2)[N:31]=[C:30]1[NH:28][NH2:29]
Reactant: Cc1ccc2nc(NN)nc(O)c2c1
Reactant: Cc1ccc2nc(S)n(C)c(=O)c2c1
Agent: Cc1ccc2nc(Cl)nc(O)c2c1
Agent: Cc1ccc2nc(S)nc(O)c2c1
Agent: NN
Solvent: O
Product: Cc1ccc2nc(NN)n(N)c(=O)c2c1
Temperature: 25 °C
Yield: 95 %

Procedure:
2-mercapto-3,6-dimethylquinazolin-4(3H)-one, 2-chloro-6-methylquinazolin-4-ol, 2-hydrazino-6-methylquinazolin-4-ol or 2-mercapto-6-methylquinazolin-4-ol was stirred in 5 volumes of hydrazine hydrate at reflux for 24 hours and the mixture was diluted with 5 volumes of water. The mixture was cooled to room temperature and was filtered. The product was washed with water and then methanol and dried to obtain a 95% yield of 3-amino-2-hydrazino-6-methylquinazolin-4(3H)-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][CH2:5][SH:6].CC([O-])(C)C.[K+].Cl[C:15]1[C:24]([C:25]([NH:27][CH2:28][C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[O:26])=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1.CCCCCC>CN(C=O)C>[CH3:1][O:2][C:3](=[O:7])[CH2:4][CH2:5][S:6][C:15]1[C:24]([C:25](=[O:26])[NH:27][CH2:28][C:29]2[S:30][CH:31]=[CH:32][CH:33]=2)=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: COC(=O)CCS
Reactant: O=C(NCc1cccs1)c1cc2ccccc2nc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)CCSc1nc2ccccc2cc1C(=O)NCc1cccs1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 53.3 %

Procedure:
A solution of 361 mg (3.0 mmol) 3-mercaptopropionic acid methyl ester in DMF (18 ml) was cooled to 0° C. and mixed with 336.6 mg (3.0 mmol) potassium tert-butylate and stirred for 10 min. Then 908 mg (3.0 mmol) 2-chloro-N-(thiophen-2-ylmethyl)quinoline-3-carboxamide (precursor VVV01) were added and the reaction solution was then heated slowly to 50° C. and stirred for 16 h at this temperature. It was then diluted with EE and washed with a saturated aqueous NH4Cl solution. The aqueous phase was extracted with EE. The combined organic phases were washed with water and brine, dried over Na2SO4, filtered and concentrated to small volume under vacuum. Column chromatography (hexane/EE 4:1) with the residue yielded 614 mg (1.6 mmol, 53%) 3-[[3-[oxo-(2-thienylmethylamino)methyl]-2-quinolyl]thio]propanoic acid methyl ester. MS: m/z 387.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].C(N(CC)CC)C>ClCCl>[CH3:29][S:30]([N:1]([S:30]([CH3:29])(=[O:32])=[O:31])[C:2]1[CH:7]=[C:6]([CH2:8][NH:9][C:10]2[CH:28]=[CH:27][CH:26]=[CH:25][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:22])([F:24])[F:23])[CH:16]=2)=[O:13])[CH:5]=[CH:4][N:3]=1)(=[O:32])=[O:31]
Reactant: Nc1cc(CNc2ccccc2C(=O)Nc2cccc(C(F)(F)F)c2)ccn1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N(c1cc(CNc2ccccc2C(=O)Nc2cccc(C(F)(F)F)c2)ccn1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 49.2 %

Procedure:
193 mg (0.5 mmol) of 2-[(2-amino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide is mixed in 3 ml of dichloromethane with 69 mg (0.6 mmol) of methanesulfonic acid chloride and 61 mg (0.6 mmol) of triethylamine and stirred together for 1.5 hours at room temperature. Then, it is washed once with dilute sodium bicarbonate solution, dried, filtered and concentrated by evaporation. The residue is chromatographed via flash chromatography (5 g of Isolute) with a gradient of cyclohexane:ethyl acetate=100:0 to 50:50 as an eluant. 80 mg (30% of theory) of 2-[(2-bismethanesulfonylamino-pyridin-4-ylmethyl)-amino]-N-(3-trifluoromethyl-phenyl)-benzamide is obtained as a resin.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]([C:5]1[CH:16]=[CH:15][C:8]2[O:9][C:10]([CH3:14])([CH3:13])[O:11][CH2:12][C:7]=2[CH:6]=1)[OH:4].[C:17](N1C=CN=C1)(N1C=CN=C1)=[O:18].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:14][C:10]1([CH3:13])[O:9][C:8]2[CH:15]=[CH:16][C:5]([C@H:3]3[O:4][C:17](=[O:18])[NH:1][CH2:2]3)=[CH:6][C:7]=2[CH2:12][O:11]1
Reactant: CC1(C)OCc2cc([C@@H](O)CN)ccc2O1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC1(C)OCc2cc([C@@H]3CNC(=O)O3)ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.9 %

Procedure:
To a solution of (R)-2-amino-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanol (2.53 g, 11.3 mmol) in chloroform (12 mL) was added carbonyldiimidazol (2.75 g, 17 mmol) and triethylamine (2.37 mL, 17 mmol). The mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue diluted with ethyl acetate (25 mL). The organic layer was washed with water (2×10 mL), brine (10 mL), dried (Na2SO4), and the solvent reduced under reduced pressure. Purification by column chromatography with silica gel and n-hexane/ethyl acetate (1:2) as eluent yielded the title compound (1.63 g, 51%).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[C:12]([NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][C:28]([NH:31][C:32](=[O:34])[CH3:33])=[CH:27][CH:26]=2)=[N:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:16]=1)C1C=CC=CC=1.CO.[H][H]>[Pd].CCOC(C)=O>[C:32]([NH:31][C:28]1[CH:29]=[CH:30][C:25]([C:24]([NH:23][C:12]2[C:11]([NH2:10])=[CH:16][CH:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:13]=2)=[O:35])=[CH:26][CH:27]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Nc1ccc(C(=O)Nc2nc(-c3ccccc3)ccc2NC(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(=O)Nc1ccc(C(=O)Nc2nc(-c3ccccc3)ccc2N)cc1

Procedure:
A solution of benzyl(2-{[4-(acetylamino)benzoyl]amino}-6-phenylpyridin-3-yl)carbamate from the previous step (30 mg theoretical, 0.0626 mmol) and MeOH (100 uL) were treated with 10% palladium on carbon (cat) and the reaction was fitted with a hydrogen balloon. After one hour the reaction was diluted with EtOAc, filtered through celite and concentrated to a residue purified via reversed phase HPLC (30-70% MeCN in water with 0.05% TFA) to afford fractions concentrated via sublimation to afford the title compound as a light yellow solid and a TFA salt. 1H NMR (MeOH-d4, 600 MHz) δ 8.04 (d, J=8.8 Hz, 2H), 7.87 (d, J=7.3 Hz, 2H), 7.76 (t, 8.2 Hz, 3H), 7.62 (d, J=8.5 Hz, 1H), 7.51 (t, J=7.6 Hz, 2H), 7.45 (d, J=7.3 Hz, 1H), 2.18 (s, 3H); MS cal'd (M+H)+, exp 347 (M+H)+. The in vitro HDAC1 IC50 of this compound is 86 nM. The IC50 of this compound in HCT-116 cells is 2050 nM.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].C[CH:18]([C:22](=O)[CH3:23])[C:19](=[O:21])C>>[CH3:23][C:22]1[CH:18]=[C:19]([OH:21])[C:12]2[C:11](=[C:10]([C:3]3[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=3[CH3:1])[CH:15]=[CH:14][CH:13]=2)[N:16]=1
Reactant: Cc1cc(C)c(-c2ccccc2N)c(C)c1
Reactant: CC(=O)C(C)C(C)=O
Product: Cc1cc(C)c(-c2cccc3c(O)cc(C)nc23)c(C)c1
Temperature: 170 °C

Procedure:
A mixture of 2′,4′,6′-trimethyl-biphenyl-2-ylamine(607 mg, 2.88 mmol) and methyl acetylacetone (607 mg, 5.75 mmol) in polyphosphoric acid (3 ml) was heated in 170° C. oil bath for 2.5 hours. The mixture was quenched with water and extracted twice with chloroform. The organic layer was washed with brine, dried and concentrated to give the title compound as an oil. The oil was pumped in vacuo, then trituated with a mixture of ether and hexane to give 642 mg (81%) of the title compound as a beige solid. The solid was recrystallized from ethyl acetate to give a beige solid, mp>250° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([S:8][CH3:9])[S:5][C:4]=1[C:10]1[NH:11][C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2.[OH:19]O>>[CH3:1][O:2][C:3]1[CH:7]=[C:6]([S:8]([CH3:9])=[O:19])[S:5][C:4]=1[C:10]1[NH:11][C:12]2[C:13]([N:18]=1)=[N:14][CH:15]=[CH:16][CH:17]=2
Reactant: OO
Reactant: COc1cc(SC)sc1-c1nc2ncccc2[nH]1
Product: COc1cc(S(C)=O)sc1-c1nc2ncccc2[nH]1
Temperature: 25 °C
Reaction time: 30 h

Procedure:
3.80 g (13.7 mmoles) of the 2-(3-methoxy-5-methylthio-2-thienyl)-1H-imidazo[4,5-b]pyridine, obtained in Example 1, are dissolved in 80 ml of glacial acid, 1.63 g (14.4 mmoles) of 30% aqueous solution of hydrogen peroxide are added and stirred at room temperature for 30 hours. The solution is concentrated in vacuo, the residue is dissolved in a small amount of water, neutralized with a saturated solution of sodium hydrogen carbonate, and the precipitating crystals are aspirated and dried. Yield: 3.95 g (98%), m.p. (ethanol) 233°-235° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([C:17](=[NH:19])[NH2:18])=[N:9]2)=[CH:5][CH:4]=1.C[N:23](C)[CH:24](N(C)C)[CH:25]([O:28][CH3:29])[C:26]#N.N1CCCCC1>CC(C)CCO>[CH3:29][O:28][C:25]1[C:24]([NH2:23])=[N:19][C:17]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:21][CH:20]=3)[N:9]=2)=[N:18][CH:26]=1
Reactant: COC(C#N)C(N(C)C)N(C)C
Reactant: COc1ccc(Cn2nc(C(=N)N)c3ccccc32)cc1
Solvent: CC(C)CCO
Solvent: C1CCNCC1
Product: COc1ccc(Cn2nc(-c3ncc(OC)c(N)n3)c3ccccc32)cc1
Temperature: 100 °C
Reaction time: 72 h

Procedure:
6.45 g of 1-(4-methoxybenzyl)-1H-indazole-3-carboximidamide (23.0 mmol, 1 eq.), 5.40 g of 3,3-bis(dimethylamino)-2-methoxypropanenitrile (1-2-1, 31.5 mmol, 1.37 eq.) and 0.455 ml of piperidine (4.60 mmol, 0.2 eq.) were dissolved in 82.7 ml of dry 3-methylbutan-1-ol, put under a nitrogen atmosphere and stirred at 100° C. for 3 days. The mixture was cooled down at room temperature and stirred for 18 hours for crystallization. The resulting suspension was filtered off. The crystals were washed with cold methanol and dried in vacuo at 50° C. The crystallization was repeated twice with cold methanol to receive 2 further filter cakes and a combined yield of 6.87 g (19 mmol, 82.5%) of the analytically pure target compound.