Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([OH:6])[CH2:4]Cl.[C:13]1(=[O:23])[NH:17][C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12.[K]>CN(C)C=O>[C:13]1(=[O:23])[N:17]([CH2:2][C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)([OH:6])[CH2:4][N:17]2[C:16](=[O:18])[C:15]3=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]3[C:13]2=[O:23])[C:16](=[O:18])[C:15]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:14]12
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OC(CCl)(CCl)c1ccccc1
Agent: [K]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CC(O)(CN1C(=O)c2ccccc2C1=O)c1ccccc1
Temperature: 100 °C
Yield: 63 %

Procedure:
A mixture of 30.6 g (0.149 mol) of 1,3-dichloro-2-phenylpropan-2-ol, 55.5 g (0.300 mol) of potassium phthalimide and 300 ml of dimethylformamide is heated in a water bath at 100° C. for 4 h. The resulting reaction medium is cooled and evaporated until the volume has been halved, and the insoluble material formed is filtered off, washed with CH3OH and then dried to give 40 g (yield: 63%) of 1,3-diphthalimido-2-phenylpropan-2-ol.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][N:7]([CH3:9])[CH2:6][N:5]([C:10]2[S:11][C:12]3[C:18]([CH:19]=[O:20])=[CH:17][C:16]([C:21]4[CH:22]=[N:23][C:24]([N:27]5[CH2:32][CH2:31][C:30]([CH3:38])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:29][CH2:28]5)=[N:25][CH:26]=4)=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:39])[CH3:2].[BH4-].[Na+]>CCO.C(Cl)Cl.CCOC(C)=O>[CH2:1]([N:3]1[CH2:8][N:7]([CH3:9])[CH2:6][N:5]([C:10]2[S:11][C:12]3[C:18]([CH2:19][OH:20])=[CH:17][C:16]([C:21]4[CH:22]=[N:23][C:24]([N:27]5[CH2:28][CH2:29][C:30]([CH3:38])([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:31][CH2:32]5)=[N:25][CH:26]=4)=[CH:15][C:13]=3[N:14]=2)[C:4]1=[O:39])[CH3:2]
Reactant: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(C=O)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C1(C)CCN(c2ncc(-c3cc(CO)c4sc(N5CN(C)CN(CC)C5=O)nc4c3)cn2)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
Ethyl 1-[5-[2-(3-ethyl-5-methyl-2-oxo-1,3,5-triazinan-1-yl)-7-formyl-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (560 mg, 1.02 mmol) was dissolved in 1:1 EtOH/CH2Cl2 (40 mL) and cooled to 0° C. NaBH4 (77 mg, 2.03 mmol) was added and the mixture allowed to warm to rt with stirring for 2 h. The mixture was diluted with EtOAc (200 mL), washed with water, brine and separated. The organic fraction was dried (Na2SO4) and concentrated under reduced pressure to afford the desired compound (484 mg, 86%) as a white solid. MS: 554.12 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=[CH2:17])[CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[CH3:2].ClC1C=CC=C(C(OO)=[O:27])C=1>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:5]1([CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]2)[CH2:17][O:27]1)=[O:18])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(CCCCOC1CCCCC1)C(=O)OCC
Solvent: ClCCl
Product: CCOC(=O)C1(CCCCOC2CCCCC2)CO1

Procedure:
2.4 g of the title compound, in the form of a colourless oil, which is purified by chromatography on silica gel (migrating agent: 90:10 petroleum ether/ethyl acetate), are obtained by the procedure described in Example 1a) from 4.9 g of 6-cyclohexyloxy-2-methylenehexanoic acid ethyl ester and 7 g of m-chloroperbenzoic acid in 50 ml of methylene chloride.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][C:3]=1[NH:10][C:11](=O)[CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.[H-].[Na+].I[CH2:26][CH2:27][CH3:28]>CN(C=O)C>[N:16]1([CH2:15][CH2:14][CH2:13][CH2:12][C:11]2[N:10]([CH2:26][CH2:27][CH3:28])[C:3]3[CH:4]=[C:5]([C:8]#[N:9])[CH:6]=[CH:7][C:2]=3[N:1]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: N#Cc1ccc(N)c(NC(=O)CCCCN2CCCCC2)c1
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCn1c(CCCCN2CCCCC2)nc2ccc(C#N)cc21
Temperature: 25 °C

Procedure:
The compound (1.04 g) obtained in Example 61-2 was dissolved in DMF (31.2 ml) and added with 60% sodium hydride (0.166 g) and 1-iodopropane (0.405 ml) while the whole was being stirred under ice-cooling. The solution was warmed to room temperature and stirred for 15 hours. The reaction solution was poured in ice-cold water and subjected to separation/extraction with chloroform. The organic layer was washed with a saturated saline solution and then dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was again dissolved in a 4 mol/l hydrogen chloride/dioxane solution (10 ml) and the whole was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and a saturated saline solution. Then, the resultant was dried with anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified′through silica gel column chromatography (chloroform), thereby obtaining the subject compound (451.8 mg) as a yellow oily substance.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)=[N:9][NH:10][C:11]=2[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:3][CH:2]=1.OS(O)(=O)=O.[CH3:30]O>>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[C:8]([C:18]3[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=3)=[N:9][NH:10][C:11]=2[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:30])=[O:16])=[CH:3][CH:2]=1
Reactant: CO
Reactant: O=C(O)CCCc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Agent: O=S(=O)(O)O
Product: COC(=O)CCCc1[nH]nc(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(4-(4-pyridyl)-3-(4-fluorophenyl)pyrazolyl)butyric acid (Example C-130) (40 g, 123 mmol) in 650 mL of MeOH was added 20 mL of concentrated H2SO4. The solution was stirred overnight at room temperature. The solution was concentrated and diluted with 200 mL of water. The solution was cooled with an ice/water bath and to the solution was added 150 mL of saturated NaHCO3. The solution was neutralized further with 50% NaOH to pH 7. The resulting slurry was extracted with CH2Cl2 (3×250 mL). The combined extracts were washed with water (1×300 mL) and saturated NaHCO3 (1×500 mL). The organic phase was dried over Na2SO4, filtered and concentrated to afford methyl 4-(4-(4-pyridyl)-3-(4-fluorophenyl)pyrazolyl)butyrate: MS (M+H): 340 (base peak).
Reaction SMILES: [CH3:1][C:2]([CH3:36])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18](B3OC(C)(C)C(C)(C)O3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4].Cl[C:38]1[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=1>>[CH3:36][C:2]([CH3:1])([CH2:5][C@@:6]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[O:11][C:10](=[O:12])[N:9]([C@H:13]([C:15]2[CH:20]=[CH:19][C:18]([C:38]3[N:39]=[N:40][C:41]([CH3:44])=[CH:42][CH:43]=3)=[CH:17][CH:16]=2)[CH3:14])[CH2:8][CH2:7]1)[C:3]#[N:4]
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)C#N)(c2ccccc2)OC1=O
Reactant: Cc1ccc(Cl)nn1
Product: Cc1ccc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)C#N)(c4ccccc4)OC3=O)cc2)nn1

Procedure:
The title compound was prepared from 2,2-dimethyl-3-((R)-2-oxo-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-6-yl)propanenitrile and 3-chloro-6-methylpyridazine following a procedure analogous to that described in Example 14. LC-MS Method 1 tR=1.41 min, m/z=455; 1H NMR (CDCl3) 8.20 (d, 1H), 7.92 (d, 1H), 7.74 (d, 2H), 7.37 (dt, 6H), 7.05 (d, 2H), 5.66 (q, 1H), 3.00 (dm, 1H), 2.93 (s, 3H), 2.49 (m, 2H), 2.34 (m, 1H), 2.17 (d, 2H), 1.58 (d, 3H), 1.39 (s, 3H), 1.33 (s, 3H).
Reaction SMILES: CC1(C)[O:7][C:6](=[O:8])[C:5](=[C:9]([OH:15])[CH:10]=[C:11]([NH:13][CH3:14])[CH3:12])[C:4](=O)[O:3]1.[F:18][B-](F)(F)F.F[B-](F)(F)F.F[N+]1C=CC=CC=1C1C=CC=C[N+]=1F>C(#N)C>[F:18][C:10]1[C:9]([OH:15])=[C:5]([C:6]([OH:7])=[O:8])[C:4](=[O:3])[N:13]([CH3:14])[C:11]=1[CH3:12]
Reactant: F[B-](F)(F)F
Reactant: CNC(C)=CC(O)=C1C(=O)OC(C)(C)OC1=O
Agent: F[n+]1ccccc1-c1cccc[n+]1F
Solvent: CC#N
Product: Cc1c(F)c(O)c(C(=O)O)c(=O)n1C
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 108.9 %

Procedure:
1.0 g of 2,2-dimethyl-5-(1-hydroxy-3-methylamino-2-butenylidene)-1,3-dioxane-4,6-dione was suspended in 20 ml of acetonitrile, 806 mg of N,N′-difluoro-2,2′-bipyridinium bis(tetrafluoroborate) was added thereto, and this was stirred at room temperature for 1 hour and at 50° C. for 30 minutes. The reaction mixture was added to 100 ml of ice water and extracted with 100 ml of chloroform twice. The organic layer was dried with anhydrous magnesium sulfate and concentrated, and the residue was subjected to silica gel column chromatography (eluent:ethyl acetate) to obtain 480 mg of 5-fluoro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylic acid represented by the formula:
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]([O:31]C)=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH3:4]>C(O)C>[CH2:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[C:24]([C:29]([OH:31])=[O:30])=[CH:25][CH:26]=[CH:27][CH:28]=3)=[CH:19][CH:18]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1)[CH3:4]
Reactant: CCc1cc(OCc2ccc(-c3ccccc3C(=O)OC)cc2)c2ccccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCc1cc(OCc2ccc(-c3ccccc3C(=O)O)cc2)c2ccccc2n1
Yield: 69.3 %

Procedure:
1.25M sodium hydroxide solution (2.4 ml) was added to a solution of methyl 4'-[(2-ethylquinolin-4-yloxy)methyl]biphenyl-2- carboxylate (A) (380 mg) in ethanol (5 ml). The solution was heated under reflux for 2 hours and then volatile material was removed by evaporation. The residue was dissolved in water (30 ml) and the solution acidified to pH 4 with 2M hydrochloric acid. The precipitated solid was a collected, dried under high vacuum and recrystallised from ethanol to give 4'-[(2-ethylquinolin-4-yloxy)methyl]biphenyl-2-carboxylic acid (254 mg), as white crystals, m.p. 204°-205° C.; NMR (d6 -dimethylsulphoxide (d6 -DMSO)): 1.34(t,3H), 2.9(q,2H), 5.42(s,2H), 7.1(s,1H), 7.38-7.78(complex m,10H), 7.88(d,1H), 8.15(dd,1H), 12.74(br,1H); mass spectrum (negative fast atom bombardment [-ve FAB], DMSO/glycerol (GLY): 382 (M-H)-, 172; microanalysis found: C,78.0; H,5.4; N,4.05; C25H21NO3 requires: C,78.3; H,5.5; N,3.7%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1F)[N:8]([CH2:14][CH2:15][F:16])[CH:7]=[C:6]([C:17]([OH:19])=[O:18])[C:5]2=[O:20].[CH:21]1([NH:24][CH2:25][C@@H:26]2[C@H:30]([F:31])[CH2:29][NH:28][CH2:27]2)[CH2:23][CH2:22]1>>[CH:21]1([NH:24][CH2:25][C@@H:26]2[C@H:30]([F:31])[CH2:29][N:28]([C:11]3[C:10]([F:13])=[C:9]4[C:4]([C:5](=[O:20])[C:6]([C:17]([OH:19])=[O:18])=[CH:7][N:8]4[CH2:14][CH2:15][F:16])=[CH:3][C:2]=3[F:1])[CH2:27]2)[CH2:23][CH2:22]1
Reactant: O=C(O)c1cn(CCF)c2c(F)c(F)c(F)cc2c1=O
Reactant: F[C@@H]1CNC[C@@H]1CNC1CC1
Product: O=C(O)c1cn(CCF)c2c(F)c(N3C[C@H](CNC4CC4)[C@H](F)C3)c(F)cc2c1=O
Yield: 33.2 %

Procedure:
Using 6,7,8-trifluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (200 mg) and (3R,4S)-3-cyclopropylaminomethyl-4-fluoropyrrolidine (120 mg), the same procedure was followed as in Example 23 to give 7-[(3S,4S)-3-cyclopropylaminomethyl-4-fluoro-1-pyrrolidinyl]-6,8-difluoro-1-(2-fluoroethyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid as pale yellow crystals (98.0 mg).
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21]1[O:23][C@H:22]1[CH2:24][OH:25].C(N(CC)CC)C>C(Cl)Cl>[C:2]1([C:1]([O:25][CH2:24][C@H:22]2[O:23][CH2:21]2)([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC[C@H]1CO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: c1ccc(C(OC[C@@H]2CO2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 2 h
Yield: 130.9 %

Procedure:
A solution of trityl chloride (48.25 g, 173 mmol) in anhydrous CH2Cl2 (150 mL) was added to a stirred solution of (S)-(−)-glycidol (12.21 g, 164 mmol) and triethylamine (34.5 mL, 247 mmol) in anhydrous CH2Cl2 (250 mL) at −20° C. under a N2 atmosphere. After 2 h, CH2Cl2 was removed under vacuum. The mixture was taken up in EtOAc (500 mL) before it was washed with H2O (2×200 mL). The organic layer was dried, filtered and concentrated to give the crude title compound (67.9 g) contaminated with trityl alcohol, which can be removed by chromatography.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[O:9])=[C:4]([Cl:18])[CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-].O>C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[O:9])=[C:4]([Cl:18])[CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Br)cc2Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O
Product: O=C(c1ccc(O)cc1)c1ccc(Br)cc1Cl
Temperature: 25 °C
Yield: 74.2 %

Procedure:
A mixture of 70 (2.00 g, 6.14 mmol) and AlCl3 (3.50 g, 26.2 mmol) were refluxed in benzene (50 mL) for 3 h and then cooled to RT. Water (100 mL) was cautiously added dropwise, and the mixture was extracted with Et2O (3×100 mL). The combined ethereal extracts were washed with water (200 mL), brine (200 mL), and dried over MgSO4. Concentration followed by flash chromatography (20:1 to 5:1 hexanes:EtOAc) afforded 1.42 g (74%) of 71. 1H NMR (400 MHz, CDCl3): δ 5.97 (br s, 1H), 6.89 (d, J=8.8 Hz, 2H), 7.23 (d, J=8.1 Hz, 1H), 7.50 (dd, J=8.1 Hz, 1.7 Hz, 1H), 7.64 (d, J=1.7 Hz, 1H), 7.73 (d, J=8.8 Hz, 2H).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[OH:31])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[O:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[C:36]([C:43](=[O:46])[CH2:44]Br)=[CH:35]1>CN(C=O)C.O>[O:34]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[C:36]([C:43](=[O:46])[CH2:44][O:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:24]=2)=[CH:35]1
Reactant: Oc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C(CBr)c1coc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(COc1ccccc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1coc2ccccc12
Reaction time: 0.17 h
Yield: 60 %

Procedure:
To a stirred solution of 2-(1-trityl-1H-imidazol-4-yl)phenol (0.5 mmol) in anhydrous DMF (3 mL) at 0° C. was added NaH (36.0 mg, 0.75 mmol). The resulting suspension was allowed to stir for 10 min. To the resulting solution was added 1-(benzofuran-3-yl)-2-bromoethanone (0.50 mmol). After stirring overnight, the reaction mixture was carefully diluted, with water and extracted with ethyl acetate (2×10 mL). The combined organic layers were washed with water, brine and dried (Na2SO4). The solvent was removed under reduced pressure and the crude product was purified by column chromatography. Yield 60%. 1H NMR: 5.16 (s, 2H), 6.88 (d, 1H, J=8.10 Hz), 7.06-7.47 (m, 20H), 7.54 (d, 2H, J=7.92 Hz), 8.22 (dd, 2H, J=7.60 Hz, 1.35 Hz), 8.33 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH:12]([F:14])[F:13].S(Cl)(Cl)=O.[Si](C=[N+]=[N-])(C)(C)[CH3:20].[BrH:26]>C(Cl)Cl.CN(C=O)C>[Br:26][CH2:20][C:6]([C:5]1[CH:9]=[CH:10][C:2]([Br:1])=[C:3]([O:11][CH:12]([F:14])[F:13])[CH:4]=1)=[O:8]
Reactant: Br
Reactant: O=C(O)c1ccc(Br)c(OC(F)F)c1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(CBr)c1ccc(Br)c(OC(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-Bromo-3-(difluoromethoxy)benzoic acid (6.65 mmol) was suspended in DCM (33 mL) and thionyl chloride (2.9 mL, 33 mmol) was added, followed by DMF (5 drops). After stirring at RT for 2 h, the reaction mixture was concentrated under reduced pressure. The crude residue was dissolved in DCM (17 mL) and treated with TMS-diazomethane (2.0 M in hexane, 8.3 mL, 16.6 mmol). After stirring at RT for 2 h, HBr (33% w/w in AcOH) (5.8 mL, 33 mmol) was added dropwise. After stirring for 1 h more at RT, the reaction mixture was concentrated under reduced pressure. The crude residue was diluted with EtOAc. The organic solution was washed with saturated aqueous NaHCO3 and brine, then dried over MgSO4, filtered and concentrated to afford 2-Bromo-1-(4-bromo-3-(difluoromethoxy)phenyl)ethanone (yield undetermined, material carried on crude assuming total conversion).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:17][C:16]3[C:15](O)=[N:14][CH:13]=[N:12][C:11]=3[CH:10]=2)=[CH:5][CH:4]=1.[Cl:19]CCCl.P(Cl)(Cl)(Cl)=O.N>C(N(CC)C1C=CC=CC=1)C.O1CCCC1>[Cl:19][C:15]1[C:16]2[NH:17][C:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[CH:10][C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: COc1ccc(-c2cc3ncnc(O)c3[nH]2)cc1
Reactant: ClCCCl
Agent: N
Solvent: CCN(CC)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2cc3ncnc(Cl)c3[nH]2)cc1
Temperature: 110 °C

Procedure:
6-(4-Methoxyphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol (500 mg) was suspended in N,N-diethylaniline (1.11 mL)/1,2-dichloroethane (3.73 mL), phosphorus oxychloride (2.29 mL) was added, and the mixture was stirred with heating at 110° C. for 2 hrs. After cooling to room temperature, the reaction mixture was treated with ice water (20 mL), and adjusted to pH 7 or above with aqueous ammonia. After diluting with tetrahydrofuran (500 mL), the mixture was washed with saturated brine (50 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=80:20→20:80) to give the title compound (25 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[S:11]([N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)(=[O:13])=[O:12]
Reactant: C1CCNCC1
Reactant: O=C(O)c1ccc(Br)c(S(=O)(=O)Cl)c1
Product: O=C(O)c1ccc(Br)c(S(=O)(=O)N2CCCCC2)c1
Yield: 88 %

Procedure:
Compound 3.1 was prepared from 4-bromo-3-chlorosulfonyl-benzoic acid 2.1 and piperidine a1 in 88% yield according to general method B. MS (M−1)=346.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[CH2:7][CH2:8][N:9]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[O:12])[CH2:10][C:5]2=[N:4][CH:3]=1.C1C(=O)N([Cl:28])C(=O)C1>CN(C)C=O>[Cl:28][C:3]1[N:4]=[C:5]2[CH2:10][N:9]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])=[O:12])[CH2:8][CH2:7][N:6]2[C:2]=1[Cl:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(c1ccc(Cl)cc1Cl)N1CCn2c(Cl)cnc2C1
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1Cl)N1CCn2c(nc(Cl)c2Cl)C1

Procedure:
3-Chloro-7-[(2,4-dichlorophenyl)carbonyl]-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (E44) (300 mg, 0.907 mmol) and NCS (133 mg, 0.998 mmol) were stirred at RT for 16 h in N,N-dimethylformamide (DMF) (2 mL). Solvents were removed in vacuo and the residue was purified by MDAP to afford desired product in 218 mg.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]2[CH:30]=[CH:29][C:11]([CH2:12][N:13]3[CH:21]=[C:20]4[C:15]([N:16]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:17](=[O:24])[N:18]([CH3:23])[C:19]4=[O:22])=[CH:14]3)=[CH:10][CH:9]=2)[CH:5]=[CH:4][CH:3]=1.[Cl:31]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[Cl:31][C:14]1[N:13]([CH2:12][C:11]2[CH:29]=[CH:30][C:8]([C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=3)=[CH:9][CH:10]=2)[CH:21]=[C:20]2[C:19](=[O:22])[N:18]([CH3:23])[C:17](=[O:24])[N:16]([CH2:25][CH:26]([CH3:28])[CH3:27])[C:15]=12
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)cc21
Solvent: CN(C)C=O
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)Cn1c(=O)n(C)c(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)c(Cl)c21
Temperature: 100 °C
Yield: 56.7 %

Procedure:
6-(4-(6-fluoropyridin-2-yl)benzyl)-1-isobutyl-3-methyl-1H-pyrrolo [3,4-d]pyrimidine-2,4(3H,6H)-dione (81 mg, 0.2 mmol) is dissolved in a mixture of CCl4 and DMF (3/1, v/v), and then N-chlorosuccinimide (27 mg, 0.2 mmol) is added. The reaction mixture is heated in a Biotage microwave at 100° C. for 30 minutes. Solvents are removed under vacuum, and the residue is purified by a semi-preparative HPLC to give pure product as off white solids (50 mg, yield 70%). MS (ESI) m/z 441.2 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1.[NH:19]1[C:27]2[C:22](=[C:23]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C@H:12]1[CH2:17][CH2:16][C@@H:15]([N:31]2[CH2:32][CH2:33][N:28]([C:23]3[CH:24]=[CH:25][CH:26]=[C:27]4[C:22]=3[CH:21]=[CH:20][NH:19]4)[CH2:29][CH2:30]2)[CH2:14][CH2:13]1
Reactant: COc1ccc2[nH]cc(C3CCC(=O)CC3)c2c1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc2[nH]cc([C@H]3CC[C@@H](N4CCN(c5cccc6[nH]ccc56)CC4)CC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
A solution of 4-(5-methoxy-1H-indol-3-yl)-cyclohexanone (1.2 g, 5 mmol), 1-(indol-4-yl)piperazine (1 g, 5 mmol), sodium triacetoxyborohydride (1.47 g, 6.2 mmol) and acetic acid (0.28 ml, 4 mmol) in 1,2-dichloroethane (20 ml) was allowed to stir at room temperature overnight. The reaction was quenched with 1N sodium hydroxide (10 ml), extracted with methylene chloride (3×60 ml) and washed with brine (3×60 ml). The organic layer was dried over anhydrous sodium sulfate and filtered. Chromatography (2.5% methanol-ethyl acetate) afforded 1.18 g (55%) of product as a white solid: mp 105-108° C.
Reaction SMILES: [CH3:1][S:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)(=[N:4][CH3:5])=[O:3].C1(C(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C([Li])CCC.CCCCCC.[C:42]1([C:47]([CH2:49][S:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)=[O:48])[CH2:46][CH2:45][CH2:44][CH:43]=1.[Cl-].[NH4+]>C1COCC1>[C:51]1([S:50][CH2:49][C:47]([OH:48])([C:42]2[CH2:46][CH2:45][CH2:44][CH:43]=2)[CH2:1][S:2]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)(=[N:4][CH3:5])=[O:3])[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: CN=S(C)(=O)c1ccccc1
Reactant: O=C(CSc1ccccc1)C1=CCCC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: c1ccc(C(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN=S(=O)(CC(O)(CSc1ccccc1)C1=CCCC1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of S-methyl-N-methyl-S-phenyl-sulfoximine (2.04 g, 12 mmol) and triphenylmethane (5 mg) in dry THF (20mL) is added dropwise to a solution of n-butyllithium (1.6 mol) in hexane (7.5 mL, 12 mmol) at 0° C. A solution of phenylthio-methyl cyclopent-1-enyl ketone (2.18 g, 10mmol) in dry THF (10 mL) is then added slowly during a period of 10 minutes. After stirring at 0° C. for 30 minutes, the mixture is poured into a 5% ammonium chloride aqueous solution (50 mL) and extracted with dichloromethane (40 mL×3). The combined extracts are washed with H2O, dried (Na2SO4), and evaporated in vacuo to dryness. The thin layer chromatography (TLC, SiO2, toluene/EtOAc, 9:1 v/v) of the mixture showed that it contains a mixture of diastereomers in a syrup, 2.70 g (70%) (Rf=0.43 and 0.37), which are isolated by liquid chromatography (SiO2, touene/EtOAc, 9:1 v/v) and used directly in the next step without further separation.