Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].COC1C=C(C=CC=1OC)C[NH:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[C:12]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:11]([CH3:27])[NH+:10]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:20][O:19][C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[C:9]([NH2:8])=[N:10][C:11]([CH3:27])=[C:12]2[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc2c(NCc3ccc(OC)c(OC)c3)[nH+]c(C)c(-c3ccccc3)c2c1
Agent: [Cl-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc2c(N)nc(C)c(-c3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The free base of 1-[(3,4-dimethoxybenzyl)amino]-6-methoxy-3-methyl-4-phenylisoquinolinium chloride was treated with 5 mL of CH2Cl2 and 10 mL of trifluoroacetic acid. The reaction was stirred at room temp for 2 h, then concentrated to dryness. The residue was combined with saturated aqueous sodium carbonate, and the mixture was extracted with EtOAc (3×). The combined organic solutions were dried (Na2SO4) and concentrated. Recrystallization from EtOAc/hexanes gave a solid which was further purified by flash chromatography (0-1% MeOH/ammonia-saturated CHCl3). The solid thus obtained was triturated with hexanes to give the titled compound.
Reaction SMILES: [C:1]1([C:7](=[N:14][CH2:15][C:16]#[N:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Br)=[CH:21][CH:20]=1.[OH-].[Na+]>C(Cl)Cl.[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[C:1]1([C:7](=[N:14][CH:15]([CH2:23][C:22]2[CH:25]=[CH:26][C:19]([F:18])=[CH:20][CH:21]=2)[C:16]#[N:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: N#CCN=C(c1ccccc1)c1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: N#CC(Cc1ccc(F)cc1)N=C(c1ccccc1)c1ccccc1
Reaction time: 18 h
Yield: 91.9 %

Procedure:
To a solution of 2-(diphenylmethyleneamino)acetonitrile (1.21 g, 5.47 mmol, 1.0 equiv) in CH2Cl2 (9.12 mL) was added 4-fluorobenzyl bromide (0.75 mL, 6.02 mmol, 1.1 equiv), benzyltrimethylammonium chloride (0.10 g, 0.547 mmol, 0.1 equiv), and NaOH (0.99 mL of a 10 M aqueous solution, 9.85 mmol, 1.8 equiv). The reaction was stirred vigorously for 18 h, at which time TLC analysis indicated complete consumption of the starting nitrile. The reaction was added to water and extracted with CH2Cl2 (×3). The combined CH2Cl2 extracts were dried (Na2SO4) and concentrated in vacuo. The crude product was purified by silica gel chromatography (5-30% ethyl acetate/hexane) to provide the title compound (1.65 g, 92% yield) as a viscous yellow oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.54-7.65 (m, 2H), 7.38-7.48 (m, 4H), 7.31-7.38 (m, 2H), 7.00-7.09 (m, 2H), 6.89-6.97 (m, 2H), 6.84 (d, J=6.30 Hz, 2H), 4.35 (dd, J=7.81, 6.04 Hz, 1H), 3.10-3.29 (m, 2H); LCMS (ES+, (M+H)+) m/z 329.25.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=2)=[CH:4][CH:3]=1.Br[CH2:33][CH2:34][OH:35].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:33][CH2:34][OH:35])[C:12](=[O:17])[N:11]([CH3:18])[C:10]=3[N:9]=[C:8]2[O:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:27])[F:28])[CH:21]=2)=[CH:30][CH:31]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1nc(Oc1cccc(C(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reactant: OCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(CCO)c(=O)c2c1nc(Oc1cccc(C(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Yield: 28.9 %

Procedure:
To a solution of 7-(4-chlorobenzyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione (60 mg, 0.133 mmol, example 1) in DMF (1 mL) was added 2-bromoethanol (16.5 mg, 0.133 mmol) and cesium carbonate (86.6 mg, 0.266 mmol). The resulting mixture was subjected to microwave irradiation at 120 for 20 min in a sealed tube. The mixture was diluted with ethyl acetate (5 mL) and extracted with saturated aqueous ammonium chloride solution. The organic phase was dried and concentrated to give crude product which was purified preparative HPLC to give 7-(4-chlorobenzyl)-1-(2-hydroxyethyl)-3-methyl-8-(3-(trifluoromethyl)phenoxy)-1H-purine-2,6(3H,7H)-dione (19 mg, 28.8% yield) as white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]2[CH:9](O)[CH2:8][S:7][C:6]=2[C:11]=1[Cl:12].B(F)(F)F.CCOCC.[OH-].[Na+]>C(O)(=O)C>[Cl:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]2[CH:9]=[CH:8][S:7][C:6]=2[C:11]=1[Cl:12]
Reactant: COc1cc2c(c(Cl)c1Cl)SCC2O
Agent: FB(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(=O)O
Product: COc1cc2ccsc2c(Cl)c1Cl
Yield: 100 %

Procedure:
A mixture of 0.7 g of 6,7-dichloro-2,3-dihydro-3-hydroxy-5-methoxybenzo[b]thiophene, 1 ml of boron trifluoride etherate and 4 ml of glacial acetic acid is heated at 100° for 5 min. Ice is added and the mixture is basified with dilute sodium hydroxide solution. The off-white solid is collected on a filter, air-dried and recrystallized from ether-hexane to give 0.65 g of 6,7-dichloro-5-methoxybenzo[b]thiophene as prisms, mp 103°-104.5°.
Reaction SMILES: [CH3:1][O-:2].[Na+].CO.Cl[CH2:7][N:8]([CH2:13][CH2:14][CH3:15])[S:9]([Cl:12])(=[O:11])=[O:10]>C1CCCCC1>[CH3:1][O:2][CH2:7][N:8]([CH2:13][CH2:14][CH3:15])[S:9]([Cl:12])(=[O:11])=[O:10]
Reactant: CCCN(CCl)S(=O)(=O)Cl
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: CO
Product: CCCN(COC)S(=O)(=O)Cl
Reaction time: 1 h
Yield: 68 %

Procedure:
26 parts of sodium methylate in 160 parts of methanol are added in the course of 20 minutes, at from 0° to 5° C., to a mixture of 106 parts of N-chloromethyl-N-propylsulfamic acid chloride in 200 parts of cyclohexane. The reaction mixture is then stirred for one hour at from 40° to 45° C., after which the sodium chloride which has precipitated is separated off. On subsequent distillation, the solvent is removed first and 70.5 parts (68% of theory) of N-methoxymethyl-N-propylsulfamic acid chloride of boiling point 59°-65° C./0.1 mbar and nD25 =1.4543 are then obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].[Br:12]Br>C(O)(=O)C.C(OCC)C>[Br:12][C:8]1[CH:7]=[C:6]([CH2:10][CH3:11])[C:4]([NH2:5])=[C:3]([CH2:1][CH3:2])[CH:9]=1
Reactant: CCc1cccc(CC)c1N
Reactant: BrBr
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCc1cc(Br)cc(CC)c1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
To a stirred solution of 2,6-diethylaniline (10.0 g, 67.0 mmol) in acetic acid (50 mL) at ambient temperature was added bromine (10.4 mL, 201 mmol). The reaction was stirred overnight at ambient temperature. The reaction mixture was diluted with diethyl ether (200 mL) and washed with 5% sodium bisulfite (4×50 mL) and brine. The organic phase was dried with sodium sulfate and the solvents were removed in vacuo. The residue was chromatographed on silica gel, eluting with 9:1 hexane-ethyl acetate to give the title compound (3.28 g, 21 % yield).
Reaction SMILES: C([O:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])=[C:6]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH:5]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[Si:20]([O:19][C:6]1[CH:5]=[C:4]([OH:3])[CH:9]=[C:8]([Cl:10])[C:7]=1[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(OC=O)cc(Cl)c1O[Si](C)(C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cc(O)cc(Cl)c1O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
To a solution of 1.236 g (2.97 mmol) of 3,4-bis-(t-butyldimethylsilyloxy)-5-chlorophenyl formate in 10 mL of methanol was added 2.05 g (15.0 mmol) of potassium carbonate at 25° C. The solution was stirred for 30 min., diluted with 35 mL of water, and extracted three times with diethyl ether (50 mL each). The combined extracts were washed with brine, dried (MgSO4), and concentrated to give 1.028 g (90% yield) of 3,4-bis-(t-butyldimethylsilyloxy)-5-chlorophenol. 1H NMR (CDCl3) d 6.45 (d, J=2.8 Hz, 1H), 6.31 (d, J=2.8 Hz, 1H), 1.00 (s, 9H, t-Bu), 0.93 (s, 9H, t-Bu), 0.18 (s, 6H, Me), 0.15 (s, 6H, Me); 13C NMR (CDCl3) d 149.7 (s), 148.9 (s), 137.7 (s), 126.9 (s), 109.8 (d), 107.8 (d), 26.3 (q, 3C), 26.2 (q, 3C), −3.6 (q, 2C, Me), −3.4 (q, 2C, Me). Anal. Calcd for C18H33ClO3Si2: C, 55.57; H, 8.55. Found: C, 55.39; H, 8.87.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si](Cl)(C)C.CC1(C)[O:19][C:18](=O)[CH2:17][C:16](=[O:21])[O:15]1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[O:19]=[C:18]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:17][C:16]([OH:21])=[O:15]
Reactant: Nc1ccccc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(O)CC(=O)Nc1ccccc1
Reaction time: 1 h
Yield: 65.6 %

Procedure:
To a solution of aniline (13 mL, 143 mmol) in DCM (290 mL) was added TMSCl (18.2 mL, 143 mmol) at room temperature and the reaction mixture was stirred for 1 hour. [Rigo, B.; Fasseur, D.; Cauliez, P. and Couturier, D. Tetrahedron Lett.; 30; 23; 1989; 3073-3076.]. 2,2-Dimethyl-1,3-dioxane-4,6-dione (20.6 g, 143 mmol) was added and combined reaction mixture was stirred overnight at room temperature, poured into saturated NaHCO3 solution and extracted with EtOAc. The aqueous phase was collected, acidified with cone. HCl to pH˜3 by addition of 2N HCl and extracted with DCM. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure affording 3-oxo-3-(phenylamino)propanoic acid (1, 16.82 g, 65% yield) as a white solid. MS (m/z): 180.0 (25%) (M+H), 202.0 (100%) (M+Na).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[C:13](S(C)=O)[N:12]=[C:11]([C:18]([NH2:20])=[O:19])[CH:10]=1.C[CH2:22][N:23](C(C)C)[CH:24](C)C.Cl.CNC>O1CCOCC1>[CH3:22][N:23]([CH3:24])[C:13]1[N:12]=[C:11]([C:18]([NH2:20])=[O:19])[CH:10]=[C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:14]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COc1ccccc1-c1cc(C(N)=O)nc(S(C)=O)n1
Agent: CNC
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccccc1-c1cc(C(N)=O)nc(N(C)C)n1
Temperature: 85 °C

Procedure:
6-(2-Methoxyphenyl)-2-(methylsulfinyl)pyrimidine-4-carboxamide (46 mg, 0.15 mmol), 1,4-dioxane (2 mL), DIPEA (80 μL, 0.45 mmol), and dimethylamine hydrochloride (26 mg, 0.3 mmol) were added to a vial (8 mL). The vial was sealed and heated at 85° C. for two days. After the reaction solution cooled to room temperature, the solvent was removed under vacuum in a Savant SpeedVac. The resulting residue was purified by Prep. HPLC. 1H NMR (300 MHz, CDCl3) δ 7.95 (q, J=7.8, 1.8 Hz, 1H), 7.88 (s, 1H), 7.77 (bs, 1H), 7.40 (m, 1H), 7.04 (t, J=9.0 Hz, 1H), 6.98 (d, J=6.0 Hz, 1H), 5.78 (bs, 1H), 3.92 (s, 3H), 3.26 (s, 6H). HPLC ret. time 2.76 min, 10-100% CH3CN, 5 min gradient; ESI-MS m/z 273.1 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:25]#[N:26])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)=[O:4].[NH2:27][CH2:28][C:29]([OH:31])=[O:30]>>[C:25]([C:7]1[C:8]2[C:13](=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:27][CH2:28][C:29]([OH:31])=[O:30])=[O:4])[N:6]=1)#[N:26]
Reactant: COC(=O)c1nc(C#N)c2c(Oc3ccc(OC)cc3)cccc2c1O
Reactant: NCC(=O)O
Product: COc1ccc(Oc2cccc3c(O)c(C(=O)NCC(=O)O)nc(C#N)c23)cc1

Procedure:
The title compound was synthesized from 1-cyano-4-hydroxy-8-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid methyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=392.4.
Reaction SMILES: [I:1]/[CH:2]=[CH:3]\[C:4]([OH:6])=O.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[F:41][C:42]1([F:46])[CH2:45][NH:44][CH2:43]1>C(Cl)Cl.CCCCCC.C(OCC)(=O)C>[F:41][C:42]1([F:46])[CH2:45][N:44]([C:4](=[O:6])/[CH:3]=[CH:2]\[I:1])[CH2:43]1
Reactant: FC1(F)CNC1
Reactant: O=C(O)/C=C\I
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCC
Product: O=C(/C=C\I)N1CC(F)(F)C1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 52.2 %

Procedure:
In a 25-mL, three-necked, round-bottomed flask equipped with nitrogen inlet and a rubber septum, (Z)-3-iodoacrylic acid (0.250 g, 1.0 eq.) was dissolved in DCM (10 mL, 40 V). The reaction mixture was cooled to 0° C., and DIPEA (0.168 g, 1.1 eq), HATU (0.494 g, 1.1 eq) and 3,3-difluoroazetidine hydrochloride (0.179 g, 1.1) were added. The reaction mixture was stirred at 0° C. for 2-3 hr. The progress of the reaction was followed by TLC analysis on silica gel with 40% ethyl acetate in hexane. The reaction mixture was filtered and concentrated by rotary evaporation (25° C., 20 mmHg) to afford 0.3 g of crude compound which was purified by column chromatography using silica 60/120 using 40% ethyl acetate in hexane as mobile phase. The column (5×10 cm) was packed in 5% ethyl acetate in hexane and started eluting in ethyl acetate in gradient manner starting with fraction collection (50-mL fractions) from 20% to 30% ethyl acetate in hexane. Compound started eluting with 20% ethyl acetate in hexane. Fractions containing such TLC profile were combined to obtain 0.18 g of desired compound (yield 52.33%). Mass: [M+H]+: 273.8.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16](O)=[O:17])=[C:11]([N+:19]([O-])=O)[CH:10]=2)=[CH:5][CH:4]=1>C(O)(=O)C.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]3[C:12]([CH2:15][C:16](=[O:17])[NH:19]3)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(CC(=O)O)c([N+](=O)[O-])c2)cc1
Agent: [Fe]
Solvent: CC(=O)O
Product: COc1ccc(-c2ccc3c(c2)NC(=O)C3)cc1
Temperature: 100 °C
Yield: 45 %

Procedure:
Iron chips (3.6 g) were added in one portion to 7.2 g of 4′-methoxy-3-nitrobiphenyl-4-acetic acid in 50 mL of glacial acetic acid and heated at 100° C. overnight. The reaction mixture was concentrated to dryness, sonicated in ethyl acetate and filtered to remove the insolubles. The filtrate was washed twice with 1 N hydrochloric acid, brine, dried over anhydrous sodium sulfate and concentrated to give 2.7 g (54% yield based on 5-bromo-2-fluoronitrobenzene) of 6-(4-methoxyphenyl)-2-oxindole as a rose colored solid.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4].[C:21]([CH2:29][NH:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][NH:34]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C>[C:21]([CH2:29][NH:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][N:34]1[CH2:2][C:3]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C:9](=[O:16])[NH:8][C:7]2[CH:17]=[CH:18][CH:19]=[N:20][C:6]1=2)=[O:4])(=[O:28])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(CNCCC1CCCCN1)c1ccccc1
Reactant: O=C1Nc2cccnc2N(C(=O)CCl)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C(CNCCC1CCCCN1CC(=O)N1c2ccccc2C(=O)Nc2cccnc21)c1ccccc1

Procedure:
A mixture of 9.5 g (0.033 mol) of 11-(chloroacetyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, 9.8 g (0.04 mol) of 2-[2-[(benzoyl)methylamino]ethyl]-piperidine, 4.2 g (0.04 mol) of sodium carbonate and 300 ml of acetonitrile is refluxed for 10 hours. Then the reaction mixture is filtered and the filtrate is evaporated to dryness in vacuo. The crude product obtained is purified by chromatography on silica gel (Baker, 30-60 μm) with a mixture of methylene chloride/methanol/cyclohexane/ammonia/ethyl acetate=68:15:15:2:500 as eluant.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[C:14]([CH3:19])=[CH:15][C:16]([CH3:18])=[N:17][C:10]=3[NH:9][C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25]Br.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:1]1([N:7]2[C:12](=[O:13])[C:11]3[C:14]([CH3:19])=[CH:15][C:16]([CH3:18])=[N:17][C:10]=3[N:9]([CH2:25][CH2:24][CH2:23][CH2:22][Br:21])[C:8]2=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCCCBr
Reactant: Cc1cc(C)c2c(=O)n(-c3ccccc3)c(=O)[nH]c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(C)c2c(=O)n(-c3ccccc3)c(=O)n(CCCCBr)c2n1
Yield: 64.9 %

Procedure:
A mixture comprising of 13.36 g 3-phenyl-5,7-dimethylpyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione, 43.18 g of 1,4-dibromobutane, 10.37 g of anhydrous potassium carbonate and 150 ml of N,N-dimethyl-formamide was heated at 80° C. for 3 hours. After the completion of the reaction, the reaction mixture was poured into 600 ml of water. The resulting mixture was extracted with ethyl acetate and further with a small amount of dichloromethane. These extracts were combined, dried over anhydrous potassium carbonate and distilled under a reduced pressure to remove the solvent. The obtained residue was dissolved in a small amount of dichloromethane, columnchromatographed over silica gel column and eluted with dichloromethane. The eluate was concentrated under a reduced pressure and the residue was recrystallized from a dichloromethaneisopropyl ether solvent to give 13.06 g of 3-phenyl-5,7-dimethyl-1-(4-bromobutyl)pyrido[2,3-d]-pyrimidin-2,4(1H,3H)-dione having a melting point of 153.5° to 154.5° C., which serves as an intermediate (yield: 65%).
Reaction SMILES: [CH2:1]([C:8]1[CH:24]=[CH:23][C:11]2[NH:12][C:13]([CH:15](Cl)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[N:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:25]1([C:31]2[N:36]=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(CC)CC)C.O>CN(C=O)C>[CH2:1]([C:8]1[CH:24]=[CH:23][C:11]2[NH:12][C:13]([CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:28]3[CH2:29][CH2:30][N:25]([C:31]4[N:32]=[CH:33][CH:34]=[CH:35][N:36]=4)[CH2:26][CH2:27]3)=[N:14][C:10]=2[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(c1ccccc1)c1nc2cc(Cc3ccccc3)ccc2[nH]1
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: c1ccc(Cc2ccc3[nH]c(C(c4ccccc4)N4CCN(c5ncccn5)CC4)nc3c2)cc1
Temperature: 25 °C
Yield: 86.7 %

Procedure:
300 mg of 5-benzyl-2-(chloro(phenyl)methyl)-1H-benzo[d]imidazole and 300 mg 2-(piperazin-1-yl)pyrimidine were dissolved in 5 ml of DMF at room temperature. After a few seconds, 0.5 ml of triethylamine was added, and the reaction mixture was stirred at room temperature, while being monitored by TLC. Once the starting material was no longer detected (overnight), additional 0.2 ml of triethylamine was added, followed by 3 ml of water, and the reaction mixture was cooled to 0° C. The precipitated solid was collected by vacuum filtration, washed with cold water and dried for 2 hours at 50° C., to give 360 mg (80% yield) of the product (BPRM-VR-2′ b).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18]3[S:19][C:20]([C:23](O)=[O:24])=[CH:21][N:22]=3)=[O:16])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:26][CH2:27][CH2:28][OH:29].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][N:10]2[CH:14]=[C:13]([C:15]([NH:17][C:18]3[S:19][C:20]([C:23]([NH:26][CH2:27][CH2:28][OH:29])=[O:24])=[CH:21][N:22]=3)=[O:16])[N:12]=[N:11]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(Nc1ncc(C(=O)O)s1)c1cn(Cc2ccc(Cl)c(Cl)c2)nn1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1ncc(C(=O)NCCO)s1)c1cn(Cc2ccc(Cl)c(Cl)c2)nn1
Temperature: 40 °C
Reaction time: 48 h
Yield: 30 %

Procedure:
A mixture of 2-[({1-[(3,4-dichlorophenyl)methyl]-1H-1,2,3-triazol-4-yl}carbonyl)amino]-1,3-thiazole-5-carboxylic acid (Intermediate 14) (0.18 g, 0.45 mmol), 2-aminoethanol (32 μL, 1.2 eq), HATU (0.22 g, 1.3 eq) and DIPEA (100 μL, 1.3 eq) in DMF (20 mL) was stirred at 40° C. for 48 hours. The solvent was evaporated and the residue was washed with water and extracted with DCM. The insoluble compound was filtered and washed with a mixture of acetonitrile/methanol 80/20 and then purified by flash chromatography eluting with DCM/MeOH (95/5) to give the title compound as a white solid (60 mg, 30%). HRMS calculated for C16H14Cl2N6O3S (M+H)+441.0303, found: 441.0339, Rt: 2.39 min. MP: 274.8° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:18].[C:29](OCC)(=[O:31])[CH3:30]>>[C:29]([NH:1][C:2]1[C:10]2[C:5](=[CH:6][C:7]([Cl:11])=[CH:8][CH:9]=2)[N:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:3]=1[C:17]([C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1)=[O:18])(=[O:31])[CH3:30]
Reactant: CCOC(=O)n1c(C(=O)c2ccc3ccccc3c2)c(N)c2ccc(Cl)cc21
Reactant: CCOC(C)=O
Product: CCOC(=O)n1c(C(=O)c2ccc3ccccc3c2)c(NC(C)=O)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 2 (Method A) from 3-amino-6-chloro-1-(ethoxycarbonyl)-2-(2-naphthoyl)indole (step 1). tlc: Rf =0.6 (50% ethyl acetate in hexanes)
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.[ClH:26].O1CCOCC1>>[ClH:26].[ClH:26].[NH2:7][C@@H:8]([CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]1)=[O:10]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cccnc1)C(=O)N1CCC(O)CC1
Agent: Cl
Solvent: C1COCCO1
Product: N[C@@H](Cc1cccnc1)C(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
(S)-[2-(4-Hydroxy-piperidin-1-yl)-2-oxo-1-pyridin-3-ylmethyl-ethyl]-carbamic acid-tert-butyl ester (367 mg, 1.05 mmol) was dissolved in 4M HCl-dioxane at 0° C. The resulting suspension was stirred for 1.5 hours at 25° C., concentrated and the residue triturated with ether. Yield, 450 mg, 100%.
Reaction SMILES: [C:1]([O:22]CC)(=[O:21])/[CH:2]=[CH:3]\[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].[OH-].[Na+].O.Cl>CO>[C:1]([OH:22])(=[O:21])/[CH:2]=[CH:3]\[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCCC=CC=CC=CC=C/C=C\C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCCCCC=CC=CC=CC=C/C=C\C(=O)O
Reaction time: 1.5 h
Yield: 96 %

Procedure:
To a solution of ethyl cis-eicosapentaenoate (5 g, 15.15 mmol) in methanol (100 mL) was added an aqueous solution of sodium hydroxide (6 g, 150 mmol, in 20 mL of water) at rt and stirred for 1.5 h. The reaction mixture was poured into ice cooled water and acidified with dil. HCl. The solution was extracted with dichloromethane (3×50 mL) and the combined layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the acid (4.4 g, 96%) as an oil; LCMS (ESI, negative ion mode): m/z 301 (M-H)−.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.BrCC1[CH:50]=[C:49]([F:51])[C:48]([F:52])=[CH:47][C:46]=1[Cl:53]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[CH:50]=[C:49]([F:51])[C:48]([F:52])=[CH:47][C:46]=3[Cl:53])[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Fc1cc(Cl)c(CBr)cc1F
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn(Cc3cc(F)c(F)cc3Cl)nc2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(bromomethyl)-2-chloro-4,5-difluorobenzene and isolated as colorless gum (6.2 mg, 34%). MS (m/e): 443.4 (MH+).