Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=O)[C:2]1=O.[OH-].[K+].[C:14]1(=O)[CH2:19][CH2:18]C[CH2:16][CH2:15]1>C(O)C>[CH2:7]1[C:6]2[C:11](=[N:1][C:16]3[C:2]([CH:4]=2)=[CH:18][CH:19]=[CH:14][CH:15]=3)[CH2:10][CH2:9][CH2:8]1
Reactant: O=C1CCCCC1
Reactant: O=C1Nc2ccccc2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: c1ccc2nc3c(cc2c1)CCCC3
Temperature: 310 °C
Reaction time: 10 h

Procedure:
A solution of isatin (40 g. 0.272 mol) in 30% aqueous potassium hydroxide (160 ml., 1.5 mol.) was added to a solution of cyclohexanone (69.7 g. 0.712 mol.) in ethanol (300 ml.) and the mixture heated at reflux with stirring for 10 hours. The ethanol was removed in vacuo and the residue dissolved in water (400 ml.) and extracted with ether (3 × 50 ml.). The aqueous phase was acidified with acetic acid and the resultant solid was washed with water, dried and heated at 310° C in a Wood's metal bath for 35 minutes. The cooled melt was diluted with 2N HCl (200 ml.) and extracted with chloroform (2 × 200 ml.) and the extracts discarded. The aqueous phase was adjusted to pH 9.0 with sodium carbonate and extracted with ethyl acetate (4 × 100 ml.) The combined extracts were washed with brine, dried and the solvent removed and the residual oily solid recrystallised from (bp 40°-60°) petrolum ether to give 1,2,3,4-tetrahydroacridine as colourless needles (38 g.). A sample (1 g.) was dissolved in anhydrous ether and treated with ethereal hydrogen chloride. The resultant solid was removed and recrystallised from isopropanol to give 1,2,3,4-tetrahydroacridine hydrochloride quarter hydrate as colourless needles m.p. 232° C. (Found C,70.2; H,6.5; N,5.9, C13H13N.HCl. 1/4H2O requires: C,69.7; H, 6.5; N, 6.2%).
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]2[C:10](I)=[CH:9][N:8]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1.[CH3:31][C:32]1[CH:40]=[C:39]2[C:35]([CH:36]=[C:37](B3OC(C)(C)C(C)(C)O3)[NH:38]2)=[CH:34][CH:33]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.C(Cl)Cl>[Br:1][C:2]1[N:3]=[C:4]2[C:10]([C:37]3[NH:38][C:39]4[C:35]([CH:36]=3)=[CH:34][CH:33]=[C:32]([CH3:31])[CH:40]=4)=[CH:9][N:8]([C:12]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc2cc(B3OC(C)(C)C(C)(C)O3)[nH]c2c1
Reactant: Brc1cnc2c(n1)c(I)cn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc2cc(-c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)c4ncc(Br)nc34)[nH]c2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 29.8 %

Procedure:
A solution of 2-bromo-7-iodo-5-trityl-5H-pyrrolo[2,3-b]pyrazine (6) (100 mg, 0.1766 mmol), 6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (7) (47 mg, 0.1766 mmol) in acetonitrile (5 mL) was added cesium carbonate (115.74 mg, 0.3532 mmol). The resulting reaction mixture was degassed, purged with nitrogen for 10 min followed by the addition of Pd(PPh3) Cl2.DCM (7.06 mg, 0.0088 mmol) to the reaction mixture, which was again degassed, purged with nitrogen for another 15 min. The final reaction mixture was stirred for 2 h at 90° C. in a seal tube. After completion of the reaction, the contents were allowed to cool to RT and was diluted with DCM (25 mL) and filtered through Celite bed. The organic layer was concentrated to get the crude. The resulting oil was purified by flash chromatography by using 100-200 mesh silica gel. The compound was eluted at 27% ethyl acetate in hexane to afford pale yellow solid (30 mg) of compound 2-bromo-7-(6-methyl-1H-indol-2-yl)-5-trityl-5H-pyrrolo[2,3-b]pyrazine (8).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=1)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].[OH:20][C:21]1[CH:22]=[C:23]([C:27]#[CH:28])[CH:24]=[CH:25][CH:26]=1>>[OH:20][C:21]1[CH:22]=[C:23]([C:27]#[C:28][C:2]2[CH:3]=[N:4][CH:5]=[C:6]([CH:19]=2)[C:7]([N:9]=[S@@:10]([CH3:18])(=[O:17])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH:24]=[CH:25][CH:26]=1
Reactant: C#Cc1cccc(O)c1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2cccc(O)c2)c1)c1ccccc1
Yield: 17 %

Procedure:
In a manner similar to that describe in Example 425, a mixture of (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide and 3-hydroxy-1-ethynylbenzene were reacted to give the title compound as an off-white solid (19 mg, 17%).
Reaction SMILES: I(Cl)(=O)=O.I([Cl:8])(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.[CH:20]1([O:25][C:26]2[CH:27]=[C:28]([C:34](=[O:36])[CH3:35])[CH:29]=[CH:30][C:31]=2[O:32][CH3:33])[CH2:24][CH2:23][CH2:22][CH2:21]1>C1COCC1>[Cl:8][CH2:35][C:34]([C:28]1[CH:29]=[CH:30][C:31]([O:32][CH3:33])=[C:26]([O:25][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[CH:27]=1)=[O:36]
Reactant: O=I(=O)Cl
Reactant: COc1ccc(C(C)=O)cc1OC1CCCC1
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)CCl)cc1OC1CCCC1
Yield: 36.5 %

Procedure:
Under a N2 flow, a solution of benzyltrimethylammonium dichloroiodate (78 g) in THF (250 ml) was added to a mixture of 1-[3-(cyclopentyloxy)-4-methoxyphenyl]ethanone (26.3 g) in THF (250 ml) while stirring. The resulting reaction mixture was stirred for 16 hours at RT. The solvent was evaporated and the residue was redissolved in diethyl ether (300 ml). The mixture was added dropwise to a 5% Na2S2O4 solution (400 ml). The aqueous layer was extracted twice with diethyl ether (100 ml). The combined organic layers were washed twice with water (500 ml), dried (MgSO4), filtered and the solvent evaporated. The crude oil was crystallized from hexane. The precipitate was filtered off, washed with hexane and dried, yielding 11 g of 2-chloro-1-[3-(cyclopentyloxy)-4-methoxyphenyl]ethanone. The filtrate was evaporated and the residue was crystallized from hexane. The precipitate was filtered off and dried, yielding 7.4 g (24.6%) of 2-chloro-1-[3-(cyclopentyloxy)-4-methoxyphenyl]ethanone (interm. 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[Br:10]Br.O>CCOCC.C1(SC2C=CC=CC=2)C=CC=CC=1.[Cl-].[Al+3].[Cl-].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[C:7]=1[Br:10]
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: BrBr
Agent: [Al+3]
Agent: [Cl-]
Agent: c1ccc(Sc2ccccc2)cc1
Solvent: CCOCC
Solvent: O
Product: Oc1cc(Cl)c(Br)c(Cl)c1
Reaction time: 15 h
Yield: 60 %

Procedure:
81.5 g of 3,5-dichlorophenol and 2.5 g of diphenyl sulfide are dissolved in 1 liter of anhydrous ether. Then 2.5 g of anhydrous aluminium chloride are added and 80 g of bromine are added dropwise at room temperature in the course of 10 minutes. The reaction mixture is then stirred for 15 hours at reflux temperature and subsequently poured into water. The organic phase is separated, washed neutral with water, dried and concentrated. The solid residue is recrystallised from cyclohexane, affording 72.6 g of 3,5-dichloro-4-bromophenol in the form of colourless crystals with a melting point of 118°-120° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([Cl:11])[C:3]=1[CH:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:13]#[N:14].S1C=CC=C1.[H][H]>CO.[Pt]>[NH2:8][C:6]1[CH:5]=[C:4]([Cl:11])[C:3]([CH:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[C:13]#[N:14])=[C:2]([Cl:1])[CH:7]=1
Reactant: [H][H]
Reactant: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Agent: [Pt]
Solvent: CO
Solvent: c1ccsc1
Product: N#CC(c1ccc(Cl)cc1)c1c(Cl)cc(N)cc1Cl

Procedure:
A mixture of 31.1 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-nitrobenzeneacetonitrile (intermediate 1), 2 parts of a solution of 4% thiophene in methanol and 480 parts of methanol is hydrogenated in the Parr apparatus at 50 degrees C with 3 parts of 5% platinum-on-charcoal catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off, washed with tetrahydrofuran and the filtrate is evaporated in vacuo. The residue is crystallized from 160 parts of 2-propanol. The product is filtered off, washed with 2,2'-oxybispropane and dried, yielding 4-amino-2,6-dichloro-α-(4-chlorophenyl)benzeneacetonitrile. (intermediate 2).
Reaction SMILES: [C:1]1([CH2:7][C@@H:8]2[CH2:12][O:11][C:10](=[O:13])[NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[CH:19]1([CH2:24][CH2:25][C:26](Cl)=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH:19]1([CH2:24][CH2:25][C:26]([N:9]2[C@H:8]([CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:12][O:11][C:10]2=[O:13])=[O:27])[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: O=C(Cl)CCC1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(CCC1CCCC1)N1C(=O)OC[C@H]1Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
A dry round bottom flask was charged with of (R)-4-(phenylmethyl)-2-oxazolidinone (1, 17.7 g, 0.100 mol). Anhydrous tetrahydrofuran (300 mL) was then added, and the solution was cooled to −78° C. A solution of butyllithium (42.0 mL, 0.105 mol, 2.50 M in hexane) was added to the reaction flask over a 10-min period. After a few minutes, 3-Cyclopentylpropionyl chloride (16.8 mL, 0.110 mol) was added. The resulting solution was stirred for 30 min at −78° C., then allowed to warm to ambient temperature over a 30-min period. Excess 3-cyclopentylpropionyl chloride was quenched by the addition of 60 mL of saturated aqueous ammonium chloride. The bulk of the tetrahydrofuran and hexane was removed on a rotary evaporator, and the slurry was extricated with two 80 mL portion of dichloromethane. The combined organic layers were washed with 75 mL of 1 M sodium hydroxide and 75 mL of brine, dried over anhydrous magnesium sulfate, and filtered. The solvent was removed under reduced pressure. The residue was triturated with hexane to provide 16.5 g of desired product 2 as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.18-7.40 (5 H, m), 4.67 (1 H, m), 4.12-4.22 (2 H, m), 3.30 (1 H, dd, J=13.4, 3.1 Hz), 2.84-3.06 (2 H, m), 2.76 (1 H, dd, J=13.4, 9.6 Hz), 1.42-1.96 (9 H, m), 1.15 (2 H, br, m).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9](Br)=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2].[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([O:19][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:8][C:7]=1[CH3:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(Oc2ccccc2)nc1C
Temperature: 95 °C
Yield: 66.2 %

Procedure:
A mixture of 2-bromo-4-methyl-thiazole-5-carboxylic acid ethyl ester (1.89 g, 7.57 mmol), phenol (855 mg, 9.09 mmol) and potassium carbonate (1.36 g, 9.84 mmol) in dimethylformamide (18 mL) was heated at 95° C. for 15 h before it was cooled to room temperature and partitioned between ethyl acetate and water, the organic layer was washed with water, aqueous sodium hydroxide (2×), brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (1.32 g): MS: (+) m/z 264.0 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[SH:11][CH2:12][CH2:13][S:14]([O-:17])(=[O:16])=[O:15].[Na+:18].CO.[Na]>CO>[N:10]1[CH:9]=[CH:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([S:11][CH2:12][CH2:13][S:14]([O-:17])(=[O:16])=[O:15])=[N:7]2.[Na+:18]
Reactant: O=S(=O)([O-])CCS
Reactant: Clc1ccc2nccn2n1
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: O=S(=O)([O-])CCSc1ccc2nccn2n1
Yield: 80.1 %

Procedure:
To a solution of 1.35 g of 6-chloroimidazo[1,2-b]pyridazine in 30 ml of methanol were added 1.45 g of sodium 2-mercaptoethanesulfonate and 1.80 ml of 28 W/W % sodium-methanol solution, followed by refluxing for 5 hours. The precipitated crystals were collected by filtration and washed with methanol to obtain 1.98 g of sodium 2-[(imidazo[1,2-b]pyridazin-6-yl)thio]ethanesulfonate.
Reaction SMILES: [CH:1]([C:3]1[S:7][C:6]([N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:9](=[O:11])[CH3:10])=[CH:5][CH:4]=1)=[O:2].N1C=CC=CC=1.[Mn]([O-])(=O)(=O)=[O:35].[K+]>O>[C:9]([N:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6]1[S:7][C:3]([C:1]([OH:35])=[O:2])=[CH:4][CH:5]=1)(=[O:11])[CH3:10]
Reactant: CCCCCCCCCCCCCCCCN(C(C)=O)c1ccc(C=O)s1
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Product: CCCCCCCCCCCCCCCCN(C(C)=O)c1ccc(C(=O)O)s1

Procedure:
25 g of N-(5-formyl-thien-2-yl)-N-hexadecylacetamide are dissolved in 20 cc. of pyridine. A solution of 6.7 g of potassium permanganate in 90 cc. of pyridine and 40 cc. of water is added with stirring and cooling such that the temperature of the reaction mixture does not rise above -3° C. Stirring is continued until all of KMnO4 has been reacted. Thereafter, the solvents are distilled off, the residue is triturated with dilute hydrochloric acid and the mixture is extracted with chloroform. The chloroform layer is separated, washed with water and dried over Na2SO4. The solvent is evaporated and the resulting crude product is purified chromatographically on a column of silicic acid gel using chloroform as eluant.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][CH2:5][N:4]=[C:3]1[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:22][CH2:23][CH2:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]1>CN(C)C=O>[O:2]1[CH2:7][CH2:6][CH2:5][N:4]=[C:3]1[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:22][CH2:23][CH2:24][CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH2:27][CH2:26]2)=[CH:10][CH:9]=1
Reactant: CCOC(=O)N1CCC(CCCCl)CC1
Reactant: Oc1ccc(C2=NCCCO2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCC(CCCOc2ccc(C3=NCCCO3)cc2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
A mixture of 15 parts of 4-(5,6-dihydro-4H-1,3-oxazin-2-yl)phenol hydrochloride, 29 parts of potassium carbonate and 180 parts of N,N-dimethylformamide was stirred for 1 hour at about 80° C. Then there were added 16.4 parts of ethyl 4-(3-chloropropyl)-1-piperidinecarboxylate and stirring was continued overnight at about 95° C. The reaction mixture was poured into ice water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (98.5:1.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated, yielding 18.8 parts (71.7%) of ethyl 4-[3-[4-(5,6-dihydro-4H-1,3-oxazin-2-yl)phenoxy]propyl]-1-piperidinecarboxylate; mp. 128.5° C. (int. 59).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[N+:11]([O-])([O-:13])=[O:12].[K+].O.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])[O-]
Reactant: NC(=O)c1ccc(N)nc1
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: NC(=O)c1cnc(N)c([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 23 %

Procedure:
To a solution of 6-aminonicotinamide (524 mg, 3.82 mmol) in TFA (10 mL) was added KNO3 (524 mg, 5.18 mmol) at room temperature with stirring. The resulting solution was stirred at 80° C. for 18 h, cooled to room temperature, then cooled water (100 mL) was added (no precipitate was formed). The resulting acidic aqueous solution was basified to pH 9 with 40% aq NaOH. The precipitate was filtered, washed with cooled water (2×5 mL), and dried to give 160 mg (23%) of 65 as a yellow powder, mp 289°-90° C. 1H NMR (DMSO-d6), 7.430 (s, 1H), 8.078 (s, 1H), 8.285 (bs, 2H, easily exchanged with D20), 8.840 (s, 2H).
Reaction SMILES: [CH2:1]([C:8]1[S:9][C:10]([CH3:27])=[C:11]([CH3:26])[C:12]=1[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21]C)=[C:17](C(C)C)[CH:16]=1)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B(Br)(Br)Br.C(=O)=O.[CH3:35][C:36]([CH3:38])=O>C(Cl)Cl>[CH3:27][C:10]1[S:9][C:8]2[CH:1]=[C:2]3[C:3](=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([CH:36]([CH3:38])[CH3:35])[CH:16]=4)[C:12]=2[C:11]=1[CH3:26])[CH:4]=[CH:5][CH:6]=[CH:7]3
Reactant: COc1ccc(C(=O)c2c(Cc3ccccc3)sc(C)c2C)cc1C(C)C
Reactant: CC(C)=O
Agent: BrB(Br)Br
Agent: O=C=O
Solvent: ClCCl
Product: Cc1sc2cc3ccccc3c(-c3ccc(O)c(C(C)C)c3)c2c1C
Reaction time: 2 h
Yield: 27 %

Procedure:
At -78° C., to a stirred solution of (2-benzyl-4,5-dimethylthiophen-3-yl)-(4-methoxy-3-isopropyl-phenyl)-methanone (6.48 g, 0.0178 mol) in CH2Cl2 (75 mL) was added dropwise boron tribromide (9.4 mL, 0.099 mol). After the addition was complete the dry ice/acetone bath was removed and the reaction was stirred for 2 h. The reaction was quenched into KH2PO4 (100 mL), extracted with CH2Cl2 and concentrated. Purification on silica gel, eluting with 5% EtOAc/pet. ether, gave 1.67 g (27%) of the title compound as a yellow solid. 1H NMR (DMSO-d6) β 9.49 (s, 1 H), 8.42 (s, 1 H), 7.94 (d, 1 H), 7.47-7.32 (m, 3 H), 7.01 (s, 1 H), 6.93 (s, 2 H), 3.32 (m, 1 H), 2.39 (s, 3 H), 1.59 (s, 3 H), 1.19 (d, 6 H).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH:13]([CH3:18])[CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.Cl.[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:16][CH2:15][CH2:14][CH:13]([CH3:18])[O:12][C:8]2[N:9]=[C:10]3[C:5]([CH2:4][CH2:3][C:2](=[O:1])[NH:11]3)=[CH:6][CH:7]=2)[CH2:30][CH2:29]1
Reactant: CC(CCC=O)Oc1ccc2c(n1)NC(=O)CC2
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(CCCN1CCN(c2cccc(Cl)c2Cl)CC1)Oc1ccc2c(n1)NC(=O)CC2
Reaction time: 0.17 h
Yield: 60.1 %

Procedure:
To a solution of 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-pentanal (450 mg, crude) in DCE (10 mL) was added 2,3-dichlorophenyl-piperazine hydrochloride (495 mg, 1.85 mmol) followed by Et3N (0.55 mL, 3.96 mmol). The mixture was stirred for 10 min and then powdered NaBH(OAc)3 (534 mg, 2.52 mmol) was added. The reaction was stirred at room temperature for 2 h and then quenched with saturated NaHCO3. The mixture was extracted with EtOAc (2×). The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated to give a foam. Purification by liquid chromatography (4% MeOH/CH2Cl2) gave the title compound as a white foam (507 mg, 1.09 mmol, 61%). MS: APCI: M+1: 463.1 (Exact Mass: 462.16). The enantiomers were separated by chiral HPLC (Chiralcel OD).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:7][C:6]([F:9])([F:8])[CH2:5][CH:4]1[NH:10][C:11](=[O:23])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[N:22]=[CH:21][CH:20]=[N:19]1.Cl[C:25]1[CH:30]=[N:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1.CCN(C(C)C)C(C)C>CS(C)=O>[F:8][C:6]1([F:9])[CH2:5][CH:4]([NH:10][C:11](=[O:23])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[N:19]=[CH:20][CH:21]=[N:22]2)[CH:3]([NH:2][C:25]2[CH:30]=[N:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=2)[CH2:7]1
Reactant: NC1CC(F)(F)CC1NC(=O)c1ccccc1-n1nccn1
Reactant: FC(F)(F)c1cnc(Cl)cn1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(NC1CC(F)(F)CC1Nc1cnc(C(F)(F)F)cn1)c1ccccc1-n1nccn1

Procedure:
A microwave vial was charged with N-(2-amino-4,4-difluorocyclopentyl)-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 42; 65 mg, 0.19 mmol), 2-chloro-5-(trifluoromethyl)pyrazine (CAS number 799557-87-2; 38 mg, 0.21 mmol) and DIPEA (99 μl, 0.57 mmol) in dry DMSO (630 μl). The reaction was subjected to microwave irradiation at 140° C. for 30 minutes. The reaction was partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude material was purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [OH-].[Na+].[OH:3][CH:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:11]=[C:12]([C:20]([NH:22][C:23]3[C:24]([CH3:34])=[C:25]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:26]([O:28]C)=[O:27])=[O:21])[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:6][CH2:5]1.CO>C1COCC1>[OH:3][CH:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:11]=[C:12]([C:20]([NH:22][C:23]3[C:24]([CH3:34])=[C:25]([CH:30]=[CH:31][C:32]=3[CH3:33])[C:26]([OH:28])=[O:27])=[O:21])[C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][CH2:9]1
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCC(O)CC3)cc3ccccc23)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)O)c(C)c1NC(=O)c1cc(N2CCC(O)CC2)cc2ccccc12
Reaction time: 12 h
Yield: 29.1 %

Procedure:
A solution of aqueous 2N NaOH (3.00 ml) is added to a stirred solution of methyl 3-(3-(4-hydroxypiperidin-1-yl)-1-naphthamido)-2,4-dimethylbenzoate (0.10 g, 0.23 mmol) in THF:MeOH (3 ml:1 ml). After 12 hours at room temperature, the organic solvent is removed under reduced pressure and the residue is diluted with water, acidified to pH 4 with aqueous 1N HCl and extracted with dichloromethane (2×20 ml). The organic layers are combined and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure and the resulting precipitate is triturated with diethyl ether and filtered to afford the title compound as a white solid (0.028 g, 29%). Mass spectrum (m/z): 419.2 (M+1).
Reaction SMILES: [CH:1]12[CH2:24][CH2:23][CH:4]([C:5]([C:7]3[N:12]=[C:11]4[N:13]([CH3:22])[C:14](=[O:21])[N:15]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:10]4=[CH:9][CH:8]=3)=[CH:6]1)[CH2:3][NH:2]2.CCN(C(C)C)C(C)C.[C:34](Cl)(=[O:36])[CH3:35]>C(Cl)Cl>[C:34]([N:2]1[CH2:3][CH:4]2[CH2:23][CH2:24][CH:1]1[CH:6]=[C:5]2[C:7]1[N:12]=[C:11]2[N:13]([CH3:22])[C:14](=[O:21])[N:15]([CH2:16][C:17]([CH3:19])([CH3:20])[CH3:18])[C:10]2=[CH:9][CH:8]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Cn1c(=O)n(CC(C)(C)C)c2ccc(C3=CC4CCC3CN4)nc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CC2CCC1C=C2c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
5-(2-Azabicyclo[2.2.2]oct-5-en-5-yl)-1-(2,2-dimethylpropyl)-3-methyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (2-5, 25 mg, 0.08 mmol, 1.0 equiv) was added to anhydrous DCM (0.80 mL). To this solution was added DIPEA (40 μL, 0.23 mmol, 3.0 equiv) and acetyl chloride (11 μL, 0.15 mmol, 2.0 equiv) and the resulting mixture was allowed to stir at room temperature for 10 min. Following this duration, LCMS showed consumption of starting material. Saturated NaHCO3 (3 mL) and ethyl acetate (3 mL) were then added and the layers were separated. The aqueous layer was back-extracted with ethyl acetate (3×3 mL) and the combined organics were dried over Na2SO4, filtered and concentrated in vacuo to give a yellow oil. Purification by reverse-phase HPLC (10-100% CH3CN:0.1% TFA in H2O) afforded 3-1 as a white solid. MS m/z (M+H): calculated=369.2285; observed=369.2284.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][CH:10]=[C:6]2[CH2:5][CH2:4][NH:3]1.[H-].[Na+].I[CH2:14][CH3:15]>CN(C=O)C>[CH2:14]([N:3]1[CH2:4][CH2:5][C:6]2=[CH:10][N:9]=[CH:8][N:7]2[C:2]1=[O:1])[CH3:15]
Reactant: O=C1NCCc2cncn21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCc2cncn2C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 500 mg (3.6 mmol) of 5,6,7,8-tetrahydro-5-oxoimidazo[1,5-c]pyrimidine dissolved in 5 mL of DMF are added cautiously at room temperature 173 mg (4.32 mmol) of sodium hydride. The reaction medium is stirred for 1 hour at room temperature, and 0.35 mL (4.32 mmol) of iodoethane is then added dropwise. The reaction medium is stirred for 2 hours at room temperature and the solvents are then evaporated off. The residue is treated with 1N NaHCO3 solution and extracted with chloroform. The combined organic phases are dried with MgSO4, filtered and evaporated. The oil obtained is used directly in the following step.