Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([N:6]([C@H:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:34]=2[O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH2:29]1)[C:7](=[O:27])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([O:25]C)=[O:24])=[CH:19][CH:18]=1)=[O:13])[CH2:4][CH3:5]>CO>[CH2:3]([N:6]([C@H:28]1[CH2:37][CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:46][CH2:47][C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:34]=2[O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH2:29]1)[C:7](=[O:27])[CH2:8][CH2:9][CH2:10][CH2:11][C:12]([NH:14][CH2:15][CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][CH:22]=1)=[O:13])[CH2:4][CH3:5]
Reactant: CCCN(C(=O)CCCCC(=O)NCCc1ccc(C(=O)OC)cc1)[C@H]1CCc2c(ccc(OCc3ccccc3)c2OCc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCN(C(=O)CCCCC(=O)NCCc1ccc(C(=O)O)cc1)[C@H]1CCc2c(ccc(OCc3ccccc3)c2OCc2ccccc2)C1

Procedure:
An aqueous solution of NaOH 4N (2 ml) was added dropwise at room temperature to a stirred solution of Intermediate 56 (2.0 g; 2.9 mmoles), prepared as described in example 26, in methanol (10 ml).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH2:5]O.S(Cl)([Cl:15])=O>C1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[C:4]=1[CH2:5][Cl:15]
Reactant: COc1cccc(OC)c1CO
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1cccc(OC)c1CCl
Reaction time: 1.17 h

Procedure:
1.86 g (11.1 mmol) of 2,6-dimethoxybenzyl alcohol was dissolved in 15 ml of benzene, and the resultant solution was cooled to 5° C. The solution was then added with 1.55 g (13.0mmol) of thionyl chloride at the same temperature. The mixture was subjected to temperature elevation up to a room temperature, then stirred for 70 min. to complete a reaction. The reacted solution was condensed under reduced pressure to thereby obtain a crude product of 2,6-dimethoxybenzyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[C:4]([C:9]([F:12])([F:11])[F:10])[CH:3]=1.[OH:13][CH:14]1[CH2:18][CH2:17][NH:16][CH2:15]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([N:16]2[CH2:17][CH2:18][CH:14]([OH:13])[CH2:15]2)=[CH:3][C:4]=1[C:9]([F:12])([F:11])[F:10]
Reactant: OC1CCNC1
Reactant: FC(F)(F)c1cc(Br)ccc1Cl
Product: OC1CCN(c2ccc(Cl)c(C(F)(F)F)c2)C1
Yield: 90 %

Procedure:
The title compound (8.56 g, yield 90%) was obtained from bromo-4-chloro-3-(trifluoromethyl)benzene and 3-hydroxypyrrolidine by a method similar to that in Reference Example 1.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[NH2:19][C:20]1([CH2:26][C:27]([NH2:29])=[O:28])[CH2:23][S:22](=[O:25])(=[O:24])[CH2:21]1>>[NH2:29][C:27](=[O:28])[CH2:26][C:20]1([NH:19][C:10]([C:7]2[CH:6]=[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:4]([CH:1]3[CH2:2][CH2:3]3)=[CH:9][N:8]=2)=[O:12])[CH2:21][S:22](=[O:24])(=[O:25])[CH2:23]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: NC(=O)CC1(N)CS(=O)(=O)C1
Product: NC(=O)CC1(NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)CS(=O)(=O)C1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 48c) and 2-(3-amino-1,1-dioxo-thietan-3-yl)acetamide (example 160d) as starting materials and isolated (130 mg, 43%); MS (ESI, m/z): 422.2 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][C:9]3([CH:15]4[CH2:16][CH2:17][N:12]([CH2:13][CH2:14]4)[CH2:11]3)[O:10][C:6]=2[CH:5]=[CH:4][N:3]=1>CO.[Pd]>[O:10]1[C:6]2[CH:5]=[CH:4][N:3]=[CH:2][C:7]=2[CH2:8][C:9]21[CH:15]1[CH2:14][CH2:13][N:12]([CH2:17][CH2:16]1)[CH2:11]2
Reactant: Clc1nccc2c1CC1(CN3CCC1CC3)O2
Agent: [Pd]
Solvent: CO
Product: c1cc2c(cn1)CC1(CN3CCC1CC3)O2
Reaction time: 2.5 h
Yield: 10.4 %

Procedure:
The 4′-chlorospiro[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[3,2-c]pyridine] (125 mg or 5.0 mmol) from Example 33 was dissolved in 50 mL of anhydrous methanol, and 25 mg of 10% palladium on carbon was added. The bottle was placed on the Parr apparatus under hydrogen atmosphere and shaken for 2.5 hours. The Pd/C was removed by filtration and washed with methanol. The solvent was removed in vacuo and the residue was taken up in chloroform and methanol and transferred to a vial. The solvent was removed in vacuo and chased with two portions of ether. After drying with high vacuum obtained 112 mg of off-white powder (104% with residual solvent.) Electrospray MS 217 [MH]+.
Reaction SMILES: [N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][F:19])=[CH:12][C:11]=3[O:20]C)[CH:8]=[CH:9][C:2]=12.Br>C(O)(=O)C>[N:1]1[O:5][N:4]=[C:3]2[CH:6]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([NH:16][CH2:17][CH2:18][F:19])=[CH:12][C:11]=3[OH:20])[CH:8]=[CH:9][C:2]=12
Reactant: COc1cc(NCCF)ccc1-c1ccc2nonc2c1
Agent: Br
Solvent: CC(=O)O
Product: Oc1cc(NCCF)ccc1-c1ccc2nonc2c1

Procedure:
10 mg (0.03 mmol) of (4-benzo[1,2,5]oxadiazol-5-yl-3-methoxy-phenyl)-(2-fluoro-ethyl)-amine are dissolved in 0.3 mL acetic acid and 0.3 mL hydrobromic acid (33% in acetic acid) and stirred at 80 QC for 72 h. Then the solvents are removed. The mixture of starting material and desired product can be separated by HPLC (20 to 100% CH3CN/H2O (6′), 100% CH3CN (1.5°), 100 to 20% CH3CN/H2O (0.5°): product elutes after 4.5°). MS(ES+): 274 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:30][O:31][CH2:32]Cl>C1COCC1>[Br:1][C:2]1[C:7]([N:8]([CH2:30][O:31][CH3:32])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1
Reactant: COCCl
Reactant: O=S(=O)(Nc1cc(Cl)cnc1Br)c1ccc(Cl)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(Cl)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of N-(2-bromo-5-chloro-pyridin-3-yl)-4-chloro-3-trifluoromethyl-benzenesulfonamide (100 mg, 0.22 mmol) and K2CO3 (91 mg, 0.66 mmol) in THF (5 mL) was added chloromethyl methyl ether (0.054 mL, 0.66 mmol) at room temperature. The resulting mixture was stirred for 3 h at room temperature then filtered. The filter cake was washed with THF and the combined filtrate was concentrated under reduced pressure. The resulting residue was purified by flash column chromatography to provide desired product. Mass spectrum m/z: 494.9 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH2:31]([C:33]([NH2:42])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][CH3:35])[CH3:32]>>[CH2:31]([C:33]([NH:42][C:22]([C@H:12]1[CH2:11][CH2:10][C@H:9]2[C@H:8]3[C@H:17]([CH2:16][CH2:15][C@:13]12[CH3:14])[C@:18]1([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]1)=[CH:6][CH2:7]3)=[O:30])([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[CH2:34][CH3:35])[CH3:32]
Reactant: CCC(N)(CC)c1ccccc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: CCC(CC)(NC(=O)[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(C#N)CC[C@]4(C)[C@H]3CC[C@]12C)c1ccccc1
Yield: 79 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1-ethyl-1-phenylpropylamine as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 79%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>N1C=CC=CC=1>[C:12]([O:1][CH2:2][CH2:3][N:4]([CH3:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: CN(CCO)c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)OCCN(C)c1ccccc1
Temperature: 0 °C

Procedure:
A solution of 74.0 g (0.489 mol) of N-(2-hydroxyethyl)-N-methylaniline in 100 mL of pyridine was treated dropwise with 55 g (0.54 mol) of acetic anhydride. The resulting mixture was heated at reflux for 10 hr, then cooled and poured onto 500 g of ice. The mixture was extracted three times with dichloromethane (3×100 mL), the combined extracts were dried using magnesium sulfate (MgSO4) and the solvent was evaporated. The residue was distilled at reduced pressure, producing 84.2 g of a slightly yellow oil, b.p. 107°-116° C. (0.4 mm).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:4]([CH2:15][CH:16](OC)OC)[CH:3]=1>Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][CH:7]=1)[N:8]([CH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[CH:16]=[CH:15]2
Reactant: COC(Cc1cc(Br)ccc1NC1CCOCC1)OC
Agent: Cl
Solvent: CO
Product: Brc1ccc2c(ccn2C2CCOCC2)c1
Yield: 106.1 %

Procedure:
Compound 87 (168 mg, 0.488 mmol) was dissolved in anhydrous 1M HCl/methanol (10 mL) in a dry argon purged flask, refluxed for 1 hour, concentrated under reduced pressure to yield compound 88 as a pale brown solid (145 mg, 100%). 1H NMR (DMSO-d6) δ 1.77-2.06 (m, 4H), 3.57 (dt, 2H, J=11.4, 2.1 Hz), 3.99 (dd, 2H, J=11.2, 4.0 Hz), 4.59-4.69 (m, 1H), 6.46 (d, 1H, J=3.2 Hz), 7.23 (dd, 1H, J=8.9, 2.1 Hz), 7.57-7.60 (m, 2H), 7.73 (d, 1H, J=1.8 Hz). ESI-MS (m/z, %): 280/282 (MH+, 100%).
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:21])[NH:6][C:7](=[O:20])[NH:8][C:9]=1[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Br[CH2:23][C:24]1[O:25][CH:26]=[CH:27][C:28]=1[C:29]([O:31][CH3:32])=[O:30]>>[CH3:32][O:31][C:29]([C:28]1[CH:27]=[CH:26][O:25][C:24]=1[CH2:23][N:8]1[C:9]([C:10](=[O:19])[C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:21])[NH:6][C:7]1=[O:20])=[O:30]
Reactant: Cc1cc(C)cc(C(=O)c2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: COC(=O)c1ccoc1CBr
Product: COC(=O)c1ccoc1Cn1c(C(=O)c2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Yield: 39.7 %

Procedure:
5-Isopropyl-6-(3,5-dimethylbenzoyl)-2,4-pyrimidinedione and 2-bromomethyl-3-methoxycarbonylfurane were reacted by the same way with the example 1 to obtain the titled compound (162 mg, yield: 39.7%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:14]3[N:15]=[C:16]([NH:19][C@H:20]4[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]4)[CH:17]=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1.CCN(C(C)C)C(C)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>CS(C)=O>[F:28][C:2]([F:1])([F:27])[O:3][C:4]1[CH:5]=[C:6]([C:10]2[N:14]3[N:15]=[C:16]([NH:19][C@H:20]4[CH2:21][CH2:22][C@H:23]([NH:26][S:39]([CH3:38])(=[O:41])=[O:40])[CH2:24][CH2:25]4)[CH:17]=[CH:18][C:13]3=[N:12][CH:11]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CS(=O)(=O)N[C@H]1CC[C@H](Nc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a 0° C. solution of trans-N1-(3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)cyclohexane-1,4-diamine (180 mg, 0.46 mmol) and DIPEA (178 mg, 1.38 mol) in DMSO (2.0 mL) was added dropwise MeSO2Cl (53 mg, 0.46 mmol). The resulting mixture was stirred at room temperature overnight. LCMS showed most of starting material was converted. The mixture was partitioned between brine (100 mL) and EtOAc (50 mL) and separated. The aqueous layer was extracted with EtOAc (50 mL*3). The combined extracts were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by prep-HPLC to give EX. 8-91 (57.1 mg, 26.4%) as a white solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].CI.C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19](C)=O>>[CH2:18]([O:9][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])[CH3:19]
Reactant: CC(C)=O
Reactant: Oc1cccc(F)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Product: CCOc1cccc(F)c1F
Temperature: 70 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
To a solution of 2,3-difluorophenol 21a (2.04 g, 14.5 mmol) in acetone (50 mL) were added methyl iodide (1.62 mL, 9.98 mmol) and potassium carbonate (3.18 g, 23.06 mmol) in turn at room temperature. The mixture was warmed up to 70° C. and stirred for 3 hours, and then filtered. To the mixture was added ethyl acetate (40 mL). The resulting mixture was washed with water (40 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound 23b as yellow oil (2.42g, 100%). This material was not further purified. The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ (ppm): 7.01-6.95 (m, 1H), 6.80-6.72 (m, 2H), 4.14 (q, 2H), 1.48 (t, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([CH2:13][S:14][C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)[C:8]=1[CH3:24].CC1C([O:43]CC(F)(F)F)=CC=NC=1CSC1NC2C=CC=CC=2N=1>>[CH3:24][C:8]1[C:9]([CH2:13][S+:14]([O-:43])[C:15]2[NH:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[N:16]=2)=[N:10][CH:11]=[CH:12][C:7]=1[O:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1]
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2ccccc2[nH]1
Reactant: COCCCOc1ccnc(CSc2nc3ccccc3[nH]2)c1C
Product: COCCCOc1ccnc(C[S+]([O-])c2nc3ccccc3[nH]2)c1C
Yield: 75 %

Procedure:
The experiment described in example 2 was repeated using 48.8 g of 2-[[[4-(3-methoxypropoxy)-3-methyl-2-pyridinyl]methyl]thio]-1H-benzimidazole as substrate instead of Lansoprazole sulfide. 38.3 g of crystallized Rabeprazole are isolated after crystallization and drying (yield 75%).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:22]=[C:21]([Cl:23])[C:20]([F:24])=[CH:19][C:5]=1[C:6]([C:8](=[CH:14][NH:15][CH:16]1[CH2:18][CH2:17]1)[C:9]([O:11]CC)=[O:10])=[O:7]>O1CCOCC1>[Cl:23][C:21]1[CH:22]=[C:4]2[C:5]([C:6](=[O:7])[C:8]([C:9]([OH:11])=[O:10])=[CH:14][N:15]2[CH:16]2[CH2:18][CH2:17]2)=[CH:19][C:20]=1[F:24]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=C(O)c1cn(C2CC2)c2cc(Cl)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.7 %

Procedure:
3.44 g of 80% sodium hydride are added in portions, with cooling in ice and stirring, to a solution of 31.9 g of ethyl 2-(2,4-dichloro-5-fluorobenzoyl)-3-cyclopropylaminoacrylate (6) in 100 ml of anhydrous dioxane. The mixture is then stirred at room temperature for 30 minutes and under reflux for 2 hours and the dioxane is removed in vacuo. The residue (40.3 g) is suspended in 150 ml of water, 6.65 g of potassium hydroxide are added and the mixture is refluxed for 1.5 h. The warm solution is filtered and washed with H2O. The solution is then acidified to pH 1 to 2 with half-concentrated hydrochloric acid, with cooling in ice, the precipitate is filtered off with suction, washed with water and dried in vacuo at 100° C. In this manner, 27.7 g of 7-chloro-1-cyclo-propyl-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid II, of melting point 234°-237° C., are obtained.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[N:10]=[C:9]([CH:12]([CH3:14])[CH3:13])[C:8]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([N:22]4[CH:26]=[CH:25][CH:24]=[N:23]4)=[CH:18][CH:17]=3)=[C:7]([CH3:27])[C:6]=2[C:5]([OH:28])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:35][O:36][C:37](=[O:40])[CH2:38]Br>CC(C)=O>[CH3:35][O:36][C:37](=[O:40])[CH2:38][O:28][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[C:11]2[C:6]=1[C:7]([CH3:27])=[C:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]3[CH:26]=[CH:25][CH:24]=[N:23]3)=[CH:18][CH:17]=1)[C:9]([CH:12]([CH3:13])[CH3:14])=[N:10]2
Reactant: COC(=O)CBr
Reactant: Cc1c(Cc2ccc(-n3cccn3)cc2)c(C(C)C)nc2c(Cl)ccc(O)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(Cl)c2nc(C(C)C)c(Cc3ccc(-n4cccn4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 8-chloro-2-isopropyl-4-methyl-3-(4-pyrazol-1-ylbenzyl)quinolin-5-ol (0.10 g), acetone (3.0 mL), potassium carbonate (0.035 g) and bromoacetic acid methyl ester (0.025 mL) was stirred at room temperature for 20 hours. The mixture was concentrated under reduced pressure and the residue partitioned between ethyl acetate and water. The organic phase was dried over magnesium sulfate and concentrated under reduced pressure. Purification of the residue by column chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate (10:0 to 8:2 by volume) gave title compound as colourless oil (0.087 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[C:8](=[O:25])[NH:9][C:10]3[C:15]([C:16]=2[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:14][C:13]([CH:23]=[O:24])=[CH:12][CH:11]=3)[O:4][N:3]=1.[BH4-].[Na+]>C(Cl)Cl.CO>[OH:24][CH2:23][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:25])[C:7]([C:5]1[O:4][N:3]=[C:2]([CH3:1])[CH:6]=1)=[C:16]2[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cc(-c2c(-c3ccccc3)c3cc(C=O)ccc3[nH]c2=O)on1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(-c2c(-c3ccccc3)c3cc(CO)ccc3[nH]c2=O)on1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90.3 %

Procedure:
A mixture of 3-(3-methyl-isoxazol-5-yl)-2-oxo-4-phenyl-1,2-dihydro-quinoline-6-carboxaldehyde (a) (33 mg, 0.11 mmol), sodium borohydride (NaBH4) (4 mg, 0.1 mmol) in DCM (1 mL) and methanol (1 mL) was stirred at room temperature for 1.5 h, and then concentrated. To the residue was added DCM (10 mL) and water (1 mL). The organic layer was separated from the aqueous layer, dried (MgSO4), filtered, and concentrated. The residue was purified by flash chromatography on silica gel to give 6-hydroxymethyl-3-(3-methylisoxazol-5-yl)-4-phenyl-1H-quinolin-2-one (c) (33 mg, 90%). 1H NMR (300 MHz, CD3OD) δ 7.65-7.58 (m, 1H), 7.49-7.38 (m, 4H), 7.30-7.20 (m, 3H), 6.30 (s, 1H), 4.51 (s, 2H), 2.17 (s, 3H). MS: 333.2 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[NH:22][C:23](=[O:31])[CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12](OC(C)(C)C)=O)[CH2:8][CH2:7]1.FC(F)(F)C(O)=O.[C:39]1(=O)[CH2:42]C[CH2:40]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(Cl)CCl>[CH:12]1([N:9]2[CH2:10][CH2:11][CH:6]([O:5][C:4]3[CH:19]=[CH:20][C:21]([NH:22][C:23](=[O:31])[CH2:24][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[C:2]([F:1])[CH:3]=3)[CH2:7][CH2:8]2)[CH2:42][CH2:39][CH2:40]1
Reactant: O=C1CCC1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)CN3CCOCC3)c(F)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCOCC1)Nc1ccc(OC2CCN(C3CCC3)CC2)cc1F
Yield: 55.5 %

Procedure:
To a stirred solution of tert-Butyl 4-[3-fluoro-4-(2-(morpholin-4-yl)acetylamino) phenoxy]piperidine-1-carboxylate (3.1 g, 0.007 moles, obtained in above step) in dichloromethane (25 mL) was added trifluoroacetic acid (8.1 g, 0.071 moles) and stirred reaction mass overnight at room temperature. After completion of reaction, solvent was evaporated under vacuum and the residue, thus obtained, was basified with 10% caustic lye solution. Extracted the reaction mass with ethyl acetate twice, the combined organic layer dried over sodium sulphate and evaporated under reduced pressure. The crude product, thus obtained, was treated with cyclobutanone (0.6 g, 0.008 moles), in ethylene dichloride (30 mL), and stirred for 4 hours at room temperature. Sodium triacetoxyborohydride (3 g, 0.014 moles) was added to reaction mass in a single lot and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched in water and basified with lye solution. The layers were separated and the aqueous layer was extracted with dichloromethane twice. The combined organic layers were dried over sodium sulfate, concentrated under vacuum and the residual mass was further purified by flash chromatography (dichloromethane: triethylamine, 9.5:0.5) to obtain the title compound 1.52 g (Yield: 55%).
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH2:32]([C:34]1[CH:39]=[CH:38][C:37]([S:40](Cl)(=[O:42])=[O:41])=[CH:36][CH:35]=1)[CH3:33]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:40]([C:37]4[CH:38]=[CH:39][C:34]([CH2:32][CH3:33])=[CH:35][CH:36]=4)(=[O:42])=[O:41])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: CCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccc(CC)cc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 4-ethyl-benzenesulfonyl chloride. Purity (ELSD, based on MW=589.7)=90%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[I:14]Cl>CO>[I:14][C:10]1[C:11]([CH3:13])=[CH:12][C:3]([O:2][CH3:1])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C)cc1OC
Reactant: ClI
Solvent: CO
Product: COC(=O)c1cc(I)c(C)cc1OC
Temperature: 50 °C

Procedure:
To a solution of methyl 2-methoxy-4-methylbenzoate (2.6 g, 14.43 mmol) in methanol (25 ml) at room temperature in a 100 ml round bottomed (RB) flask was added iodine monochloride (3.62 ml, 72.1 mmol) in methanol dropwise. The reaction mixture was heated at 50° C. for 15 hours. The methanol was concentrated, diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic extracts were washed with 0.1N HCl, water and brine solution. The organic layer was dried over Na2SO4, filtered and concentrated. The crude material was used for the next step without further purification (3.2 g, 73%). LCMS: (ES+) m/z=307 (M+H)+; Column: ZORBAX SB C18 (4.6×50) mm, 5 μm; Moblie (M) phase A: 10% MeOH-90% H2O-0.1% TFA; Moblie (M) phase B: 90% MeOH-10% H2O-0.1% TFA; Flow: 5 ml/min; Time (min.): 0 2 3; % B: 0 100 0; Retention Time (RT): 1.87 min.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=2)[C:9](OCC)=[O:10])[N:3]=[CH:2]1.CC(C[AlH]CC(C)C)C.[OH-].[Na+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.O>[S:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[C:8]([CH2:9][OH:10])[CH:14]=[CH:15][CH:16]=2)[N:3]=[CH:2]1
Reactant: CCOC(=O)c1cccc(-c2cscn2)c1
Agent: CC(C)C[AlH]CC(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: OCc1cccc(-c2cscn2)c1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A cooled (−78° C.) solution of ethyl 3-(thiazol-4-yl)benzoate (501 mg; 2.14 mmol) in anh. toluene (7 ml) was treated with a solution of 1 M DIBAH in toluene (6.44 ml; 6.44 mmol), and the resulting mixture was further stirred at −78° C., under nitrogen, for 5 min., and then at 0° C. for 30 min. The mixture was then treated successively with water (35 ml), 1 M aq. NaOH (11 ml), and aq. sat. NaHCO3 (30 ml). The separated aq. layer was further extracted with AcOEt (2×50 ml). The mixed organic layers were then dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=20/1) afforded (3-(thiazol-4-yl)phenyl)methanol as a pale yellow oil. LC-MS (conditions A): tR=0.50 min.; [M+H]+: 192.04 g/mol.