Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]C(OCC)=O)#[N:4].I[C:12]1[CH:13]=[CH:14][C:15]2[NH:21][C:20]3[N:22]=[C:23]([C:26]([F:29])([F:28])[F:27])[CH:24]=[CH:25][C:19]=3[CH2:18][N:17]([S:30]([C:33]3[CH:38]=[CH:37][C:36]([O:39][C:40]([F:43])([F:42])[F:41])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[C:16]=2[CH:44]=1.[OH-].[Na+]>CS(C)=O.[Cu]I.O.C(OCC)(=O)C>[F:41][C:40]([F:42])([F:43])[O:39][C:36]1[CH:37]=[CH:38][C:33]([S:30]([N:17]2[C:16]3[CH:44]=[C:12]([CH2:5][C:3]#[N:4])[CH:13]=[CH:14][C:15]=3[NH:21][C:20]3[N:22]=[C:23]([C:26]([F:28])([F:27])[F:29])[CH:24]=[CH:25][C:19]=3[CH2:18]2)(=[O:31])=[O:32])=[CH:34][CH:35]=1
Reactant: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1Cc2ccc(C(F)(F)F)nc2Nc2ccc(I)cc21
Reactant: CCOC(=O)CC#N
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Reaction time: 0.33 h

Procedure:
A sample of NaH (23.4 mg, 0.585 mmol) was put in a dried flask and 1.5 mL of DMSO (anhydrous) was added. Then ethyl cyanoacetate (0.062 ml, 0.585 mmol) was added slowly and stirred under N2 for 20 minutes. Then a solution of 8-iodo-6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (240 mg, 0.390 mmol, intermediate 61) in DMSO (2.0 ml) was added, followed by copper (I) iodide (111 mg, 0.585 mmol). The mixture was stirred for 2 hr at 90-95° C. Then 4 mL of water and 0.3 mL of 1N NaOH were added and the reaction mixture was stirred at 80-85° C. for 1 hr. The reaction mixture was poured into 50 mL of ethyl acetate and 10 mL of water, and the aqueous layer was extracted with ethyl acetate (20 mL×2). The combined organic layers were dried over Na2SO4 and concentrated. The resulting residue was purified by column chromatography on silica gel, eluting with hexane/acetone (6:1-4:1) to give the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([C:11]1[O:15][N:14]=[C:13]([NH2:16])[N:12]=1)([CH3:10])[CH3:9])(C)(C)C.[ClH:18].O1CCOCC1>C(O)C>[ClH:18].[NH2:7][C:8]([C:11]1[O:15][N:14]=[C:13]([NH2:16])[N:12]=1)([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NC(C)(C)c1nc(N)no1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(N)c1nc(N)no1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of [1-(3-amino-[1,2,4]oxadiazol-5-yl)-1-methyl-ethyl]carbamic acid tert-butyl ester (100 mg, 0.41 mmol) in ethanol (2 mL) was added HCl in dioxane (4 M, 0.41 ml, 1.65 mmol) and the reaction mixture was stirred 16 hours at room temperature. The reaction mixture was concentrated in vacuo and dried by applying high vacuum at 40° C. for 4 hours to give the title compound as white solid (75 mg, quant.); LC-MS (UV peak area/ESI) nd, 143.0928 (M+H)+.
Reaction SMILES: [C:1]1([C:12]([NH:14][CH:15]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:44])([F:43])[CH:40]([F:42])[F:41])[CH:33]=2)[CH:16]([C:18]2[CH:30]=[CH:29][C:21]([O:22][CH2:23][C:24]([O:26]CC)=[O:25])=[CH:20][CH:19]=2)[OH:17])=[O:13])[C:6]2[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl>CO>[C:1]1([C:12]([NH:14][CH:15]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][C:39]([F:43])([F:44])[CH:40]([F:41])[F:42])[CH:33]=2)[CH:16]([C:18]2[CH:30]=[CH:29][C:21]([O:22][CH2:23][C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)[OH:17])=[O:13])[C:6]2[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)COc1ccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)NC(=O)c2cccc3c2C=CCCC3)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)COc1ccc(C(O)C(Cc2cccc(OC(F)(F)C(F)F)c2)NC(=O)c2cccc3c2C=CCCC3)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of ethyl (4-{(1RS,2SR)-2-[(6,7-dihydro-5H-benzo[a][7]annulen-1-ylcarbonyl)amino]-1-hydroxy-3-[3-(1,1,2,2-tetrafluoroethoxy)phenyl]propyl}phenoxy)acetate (100 mg, 0.163 mmol) in methanol (20 ml) was added 2N aqueous sodium hydroxide solution (0.16 ml, 0.32 mmol), and the mixture was stirred overnight at room temperature. The reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (100 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-ethyl acetate-methanol=10:1). Recrystallization from ethyl acetate-hexane gave the objective substance (87 mg, 91%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[C:8]([C:26]#[C:27][C:28]2([CH3:32])[CH2:31][O:30][CH2:29]2)[CH:7]=1)([OH:5])[CH3:4].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3OP(O)(O)=O)C=2N=1>>[F:34][C:2]([F:1])([F:33])[C@@:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[C:8]([C:26]#[C:27][C:28]2([CH3:32])[CH2:31][O:30][CH2:29]2)[CH:7]=1)([OH:5])[CH3:4]
Reactant: CC1(C#Cc2cc([C@](C)(O)C(F)(F)F)ccc2N2CCN(S(=O)(=O)c3cccs3)CC2)COC1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Product: CC1(C#Cc2cc([C@@](C)(O)C(F)(F)F)ccc2N2CCN(S(=O)(=O)c3cccs3)CC2)COC1

Procedure:
(2S)-1,1,1-trifluoro-2-(3-((3-methyl-3-oxetanyl)ethynyl)-4-(4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol. 1H NMR (400 MHz, CD3OD) δ 7.92 (dd, J=1.2, 5.1 Hz, 1H), 7.67 (dd, J=1.2, 3.7 Hz, 1H), 7.58 (d, J=2.0 Hz, 1H), 7.50 (s, 1H), 7.29 (dd, J=3.8, 5.0 Hz, 1H), 7.01 (d, J=8.6 Hz, 1H), 4.76 (d, J=5.5 Hz, 2H), 4.48 (d, J=5.5 Hz, 2H), 3.31-3.25 (m, 4H), 3.25-3.15 (m, 4H), 1.71-1.67 (m, 3H), 1.64 (s, 3H). m/z (ESI, +ve ion) 515.0 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=2.90 μM; GK-GKRP EC50 (LC MS/MS)=2.80 μM.
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.O.O.Cl[Sn]Cl.O.C([O-])(O)=O.[Na+]>CN(C=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:10]
Reactant: Cc1ccc([N+](=O)[O-])c(Br)c1C
Agent: Cl[Sn]Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(N)c(Br)c1C

Procedure:
To a solution of 2-bromo-3,4-dimethylnitrobenzene (1.0 g, 4.35 mmole) in 10 mL DMF was added SnCl2.2H2O (4.92 g, 21.8 mmole). This solution was stirred overnight at room temperature 50 mL of H2O was added and the pH was adjusted to 8 with the addition of sat. NaHCO3 and extracted with 150 mL of EtOAC. The organic layer was dried over Na2SO4, filtered and evaporated yielding 2-bromo-3,4-dimethylaniline which was used as is in the conversion to 2-bromo-3,4-dimethyliodobenzene in a similar manner to that of Example 86. Compound 102 was prepared from 2-bromo-3,4-dimethyliodo-benzene using procedures similar to those of Examples 25 and 40. MS (ion spray): m/z 314.0/316.1 (M−H); 316.1/318.0 (M+H). 1H NMR: (DMSO-d6, 400 MHz) δ 7.37 (d, 1H), 7.15 (d, 1H), 2.43 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Mg].[CH3:17][O:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([CH:27]=[O:28])=[CH:23][CH:22]=1)=[O:20].Cl>O1CCCC1.O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH:27]([OH:28])[C:24]1[CH:23]=[CH:22][C:21]([C:19]([O:18][CH3:17])=[O:20])=[CH:26][CH:25]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Brc1ccccc1OCc1ccccc1
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(O)c2ccccc2OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.1 %

Procedure:
A Grignard reagent was prepared from 2-benzyloxybromobenzene (5.3 g), magnesium (0.49 g) and tetrahydrofuran (160 mL). The obtained Grignard reagent was added to a solution of methyl terephthalaldehydate (3.3 g) in tetrahydrofuran (60 mL), and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added water and dilute hydrochloric acid, and the mixture was extracted with ethylacetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on aminopropyl silica gel (eluent: hexane/ethyl acetate=4/1) to give methyl 4-[(2-benzyloxyphenyl)-hydroxymethyl]benzoate (2.6 g).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:22]([F:25])([F:24])[F:23])[C:18]([F:21])([F:20])[F:19])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.O=[Mn]=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:26])([C:18]([F:21])([F:19])[F:20])[C:22]([F:23])([F:24])[F:25])=[CH:14][CH:15]=2)[CH:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC(c1ccc2c(c1)CCN2Cc1ccccc1)(C(F)(F)F)C(F)(F)F
Agent: O=[Mn]=O
Solvent: Cc1ccccc1
Product: OC(c1ccc2c(ccn2Cc2ccccc2)c1)(C(F)(F)F)C(F)(F)F
Temperature: 60 °C
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A solution of 8.5 g (22.51 mmol) of 2-(1-benzyl-2,3-dihydro-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol in 60 mL toluene was treated with 9.8 g (112 mmol) of MnO2 powder. The mixture was stirred for 10 hrs at RT and 8 hrs at 60° C. Filtration and evaporation of the solvent yielded 8.0 g (95%) of 2-(1-benzyl-1H-indol-5-yl)-1,1,1,3,3,3-hexafluoro-propan-2-ol, yellow solid, MS: 374 (MH+).
Reaction SMILES: C(N(CC)CC)C.[Si:8]([O:15][CH2:16][C@H:17]1[CH2:26][C:25]2[C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=[CH:21][C:20]=2[C@H:19]([CH3:31])[NH:18]1)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.[Cl:65][C:66]1[C:71]([CH2:72][C:73](O)=[O:74])=[C:70]([F:76])[C:69]([O:77][CH3:78])=[CH:68][CH:67]=1.[Cl-].[NH4+]>CN(C)C=O>[Si:8]([O:15][CH2:16][C@H:17]1[CH2:26][C:25]2[C:24]([C:27]([O:29][CH3:30])=[O:28])=[CH:23][CH:22]=[CH:21][C:20]=2[C@H:19]([CH3:31])[N:18]1[C:73](=[O:74])[CH2:72][C:71]1[C:66]([Cl:65])=[CH:67][CH:68]=[C:69]([O:77][CH3:78])[C:70]=1[F:76])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:9])[CH3:10]
Reactant: COc1ccc(Cl)c(CC(=O)O)c1F
Reactant: COC(=O)c1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N[C@H]2C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1C[C@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)Cc1c(Cl)ccc(OC)c1F)[C@H]2C
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.1 %

Procedure:
Add triethylamine (0.36 mL, 2.57 mmol) to a stirred solution of methyl (1S,3R)-3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-methyl-1,2,3,4-tetrahydroisoquinoline-5-carboxylate (500 mg, 1.29 mmol), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.02 g, 1.93 mmol) and 2-(6-chloro-2-fluoro-3-methoxy-phenyl)acetic acid (356 mg, 1.54 mmol) in dimethylformamide (6.4 mL). Stir at room temperature for 16 h. Add saturated aqueous ammonium chloride (60 mL). Extract with ethyl acetate (3×50 mL). Wash the combined organic layers with brine. Dry over magnesium sulfate, filter and concentrate under reduced pressure. Purify by flash chromatography to yield the title compound as an amorphous yellow solid (703 mg, 1.15 mmol): MS (m/z): 550.0 (M+1).
Reaction SMILES: [Cl:1]C([O-])=O.[N:5]([CH2:12][CH2:13][OH:14])([CH2:9][CH2:10][OH:11])[CH2:6][CH2:7][OH:8]>C(OCC)(=O)C>[CH2:6]([N:5]([CH2:12][CH2:13][OH:14])[CH2:9][CH2:10][OH:11])[CH2:7][OH:8].[ClH:1]
Reactant: O=C([O-])Cl
Solvent: OCCN(CCO)CCO
Solvent: CCOC(C)=O
Product: Cl
Reaction time: 2 h

Procedure:
100 g of a polyether acrylate (Laromer® LR 8812) were admixed with 5.75 g of chloroformate of the formula III and 3.3 g of triethanolamine at room temperature. 300 ml of ethyl acetate were then added. After 2 hours, the triethanolammonium chloride formed was washed out using distilled water in a separating funnel. After removal of the aqueous phase, the ethyl acetate was distilled off. (Viscosity of the end product: 928 mPas).
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6])[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: C=CCCCCCBr
Agent: [K]
Solvent: CN(C)C=O
Product: C=CCCCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A solution of potassium phthalimide (627 mg, 3.38 mmol) and 7-bromohept-1-ene in dry DMF (10 mL) was stirred at 100° C. under nitrogen for 1 h. Then, the reaction mixture was successively cooled to room temperature, filtered, diluted with ether, and filtered again. The filtrate was concentrated under reduced pressure to give the target product 75 as an oil, which was used without further purifications in the next step: m/z=244 (M+H)+.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[CH3:12][C:13]1[C:14](B(O)O)=[CH:15][C:16]2[C:17]([CH3:26])([CH3:25])[CH2:18][CH2:19][C:20]([CH3:24])([CH3:23])[C:21]=2[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:12][C:13]1[C:14]([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][C:3]=2[O:10][CH3:11])=[CH:15][C:16]2[C:17]([CH3:26])([CH3:25])[CH2:18][CH2:19][C:20]([CH3:24])([CH3:23])[C:21]=2[CH:22]=1
Reactant: COc1ccc(C=O)nc1Br
Reactant: Cc1cc2c(cc1B(O)O)C(C)(C)CCC2(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(C=O)nc1-c1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 75.4 %

Procedure:
A mixture of 6-bromo-5-methoxypyridine-2-carboxaldehyde (512 mg, 2.37 mmol), (3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphthalen-2-yl) boronic acid (700 mg, 2.84 mmol) and potassium carbonate (1.31 g, 9.5 mmol) in 1,2-dimethoxyethane (22 mL) and water (2 mL) was degassed with argon. Tetrakis(triphenylphosphine) palladium(0) (550 mg, 0.48 mmol) was added and the mixture heated under reflux under argon for 24 hours. The solution was cooled to room temperature, diluted with ethyl acetate and washed successively with water and brine, dried over anhydrous magnesium sulfate, filtered and evaporated. The residue was chromatographed on silica gel (Biotage hexane:EtOAc 9:1) to give 603 mg (75% yield) of 6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphth-2-yl)-5-methoxy-pyridine-2-carboxaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]([OH:15])=[C:13]2[C:8]([CH:9]=[CH:10][CH:11]=[N:12]2)=[C:7](Br)[N:6]=1)=[O:4].[CH3:17][NH:18][S:19]([C:22]1[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=1)(=[O:21])=[O:20]>N1C=CC=CC=1>[OH:15][C:14]1[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:6][C:7]([N:18]([CH3:17])[S:19]([C:22]2[N:23]=[CH:24][N:25]([CH3:27])[CH:26]=2)(=[O:20])=[O:21])=[C:8]2[C:13]=1[N:12]=[CH:11][CH:10]=[CH:9]2
Reactant: CNS(=O)(=O)c1cn(C)cn1
Reactant: COC(=O)c1nc(Br)c2cccnc2c1O
Solvent: c1ccncc1
Product: COC(=O)c1nc(N(C)S(=O)(=O)c2cn(C)cn2)c2cccnc2c1O
Reaction time: 1 h

Procedure:
A solution of methyl-5-bromo-8-hydroxy-1,6-naphthyridine-7-carboxylate (0.969 g, 3.42 mmol), N,1-dimethyl-1H-imidazole-4-sulfonamide (0.60 g, 3.42 mmol) and Cu2O (0.49 g, 3.42 mmol) in pyridine (15 mL) was heated at reflux for 16 hr. The reaction was filtered and the solids washed with CHCl3 (100 mL). The filtrate was stirred for 1 hr with disodium ethylenediamine tetraacetate (1.0 g) in water (20 mL) in the presence of air. The organic extracts were stirred for 1 hr with disodium ethylenediamine tetraacetate (1.0 g in water 20 mL) in the presence of air. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo. The residue was suspended in acetonitrile (10 mL) and the resulting solid collected by filtration. The solids were washed with diethyl ether (5 mL) and dried in vacuo to afford the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)=[C:6](Cl)[N:5]2[N:14]=[CH:15][N:16]=[C:4]2[N:3]=1.[CH:17]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[C:7]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)=[C:6]([NH:22][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[N:5]2[N:14]=[CH:15][N:16]=[C:4]2[N:3]=1
Reactant: NC1CCCC1
Reactant: Clc1nc2ncnn2c(Cl)c1-c1ccsc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Clc1nc2ncnn2c(NC2CCCC2)c1-c1ccsc1
Yield: 70.4 %

Procedure:
5,7-Dichloro-6-thien-3-yl-1,2,4-triazolo[1,5-a]pyrimidine (0.54 g, 0.002 mol) was dissolved in tetrahydrofuran (20 ml). A mixture of cyclopentylamine (0.2 g, 0.002 mol), tetrahydrofuran (2 ml) and triethylamine (0.25 g, 0.002 mol) was then added with stirring and the stirring continued for a further hour after the addition was complete. The solvent was then distilled off in vacuo and the residue treated with ethyl acetate and water (50 ml each). The organic phase was separated, dried with sodium sulphate, filtered and the solvent removed in vacuo. The residue was purified by chromatography on silica gel using 8:2 ethyl acetate: petroleum ether (300 ml) as eluant to give 0.45 g 5-chloro-6-thien-3yl-7-cyclopentylamino-1,2,4-triazolo[1,5-a]-pyrimidine as colourless crystals, m.pt. 78° C. Yield: 71% of theoretical.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6](=[O:8])[CH3:7]>CS(C)=O.C([O-])(=O)C.[Ag+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[S:1]1[C:5]([C:5]2[S:1][C:2]([C:6](=[O:8])[CH3:7])=[N:3][CH:4]=2)=[CH:4][N:3]=[C:2]1[C:6](=[O:8])[CH3:7]
Reactant: CC(=O)c1nccs1
Agent: Cl[Pd]Cl
Agent: [Ag+]
Agent: [Fe+2]
Solvent: CS(C)=O
Product: CC(=O)c1ncc(-c2cnc(C(C)=O)s2)s1
Temperature: 60 °C
Yield: 24.4 %

Procedure:
Silver acetate (4.0 mL, 79 mmol) was added to a stirred solution of [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (0.970 g, 1.18 mmol), and 1-(thiazol-2-yl)ethanone (5.0 g, 39 mmol) in dimethylsulfoxide (235 mL). The reaction was purged with nitrogen and heated at 60° C. for 8 h. The reaction mixture was cooled, filtered through CELITE®, and washed with dichloromethane and water. The layers were separated and the organic was concentrated to dryness. The crude material was dry loaded onto silica gel and purified by flash chromatography (eluted with a gradient of 0 to 10% methanol in dichloromethane) to yield 1,1′-(5,5′-bithiazole-2,2′-diyl)diethanone (1.2 g) as a brown solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH:14]=[O:15])=[CH:12][N:11]=[CH:10]2)=[CH:5][CH:4]=1)[CH3:2].[Cl:16][C:17]1[C:22](C(C2C=NN(C)C=2C2C=CC(C)=CC=2)O)=[C:21]([Cl:38])[N:20]=[CH:19][N:18]=1>>[Cl:16][C:17]1[C:22]([CH:14]([C:13]2[N:9]([C:6]3[CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH:7]=3)[CH:10]=[N:11][CH:12]=2)[OH:15])=[C:21]([Cl:38])[N:20]=[CH:19][N:18]=1
Reactant: Cc1ccc(-c2c(C(O)c3c(Cl)ncnc3Cl)cnn2C)cc1
Reactant: CCc1ccc(-n2cncc2C=O)cc1
Product: CCc1ccc(-n2cncc2C(O)c2c(Cl)ncnc2Cl)cc1

Procedure:
1-(4-Ethylphenyl)-1H-imidazole-5-carbaldehyde (C19) was converted to the product using a procedure analogous to that described for the synthesis of (4,6-dichloropyrimidin-5-yl)[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]methanol (C4) in Example 1, step 4. The crude product, a yellow solid, was washed with a 1:1 mixture of heptane and ethyl acetate to afford the product. Yield: 473 mg, 1.35 mmol, 74%. LCMS m/z 348.9 (M+1). 1H NMR (500 MHz, CDCl3) δ 1.29 (t, J=7.6 Hz, 3H), 2.73 (q, J=7.6 Hz, 2H), 6.27 (br s, 1H), 7.14-7.15 (m, 1H), 7.28-7.33 (m, 4H), 7.69 (d, J=0.7 Hz, 1H), 8.68 (s, 1H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:4](=O)[O:5][C:6](=[O:8])[CH:7]=1.Cl.Cl.[NH2:14][NH2:15]>O>[F:1][C:2]([F:11])([F:10])[C:3]1[C:4](=[O:5])[NH:14][NH:15][C:6](=[O:8])[CH:7]=1
Reactant: NN
Reactant: O=C1C=C(C(F)(F)F)C(=O)O1
Agent: Cl
Solvent: O
Product: O=c1cc(C(F)(F)F)c(=O)[nH][nH]1
Reaction time: 4 h
Yield: 4.6 %

Procedure:
3-Trifluoromethylfuran-2,5-dione (5 g) was introduced in portions into an already boiling solution of hydrazine dihydrochloride (3.2 g) in water (50 ml). After stirring for 4 h, the mixture was left to stand overnight; the next day, the mixture was refluxed for a further 8 h and left to stand overnight. Then it was dried and the residue was purified by means of preparative chromatography (met. C). The clean fractions were combined, the ACN was drawn off and the residue was freeze-dried. 250 mg of the title compound were obtained. LC-MS rt: 0.23 min [M+H]+: 181.1 (met.b)
Reaction SMILES: N1C=CC=C(CN)C=1.[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][NH2:14].[F:19][C:20]1[CH:42]=[CH:41][C:23]([CH2:24][N:25]2[C@@H:29]([CH3:30])[CH2:28][N:27]([C:31]3[S:32][C:33]([C:37](O)=[O:38])=[C:34]([CH3:36])[N:35]=3)[C:26]2=[O:40])=[CH:22][CH:21]=1>>[F:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH2:13][NH:14][C:37]([C:33]1[S:32][C:31]([N:27]2[CH2:28][C@H:29]([CH3:30])[N:25]([CH2:24][C:23]3[CH:41]=[CH:42][C:20]([F:19])=[CH:21][CH:22]=3)[C:26]2=[O:40])=[N:35][C:34]=1[CH3:36])=[O:38]
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Reactant: NCc1ccc(F)c(F)c1
Agent: NCc1cccnc1
Product: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1ccc(F)c(F)c1
Yield: 74 %

Procedure:
Following the procedure as described in Example 2, making variations as required to replace pyridin-3-ylmethanamine with 3,4-difluorobenzylamine to react with (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as an off-white solid in 74% yield: mp 62-65° C. (diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 8.54 (t, J=5.9 Hz, 1H), 7.44-7.30 (m, 4H), 7.21-7.12 (m, 3H), 4.60 (d, J=15.6 Hz, 1H), 4.35 (d, J=5.9 Hz, 2H), 4.30 (d, J=15.6 Hz, 1H), 4.19 (dd, J=10.0, 9.1 Hz, 1H), 3.80-3.69 (m, 1H), 3.55 (dd, J=10.0, 6.2 Hz, 1H), 2.47 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ 161.8, 161.5 (d, 1JC-F=244 Hz), 157.2, 154.9, 151.3, 150.4 (dd, JC-F=66, 13 Hz), 147.1 (dd, JC-F=66, 13 Hz), 137.6 (dd, JC-F=5, 4 Hz), 133.1 (d, 4JC-F=3 Hz), 130.0 (d, 3JC-F=8 Hz), 124.0 (dd, JC-F=7, 3 Hz), 117.6, 117.3 (d, JC-F=17 Hz), 116.3 (d, JC-F=17 Hz), 115.4 (d, 2JC-F=21 Hz), 49.4, 48.6, 43.7, 41.7, 18.4, 17.1; MS (ES+) m/z 474.8 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][C:3]=1[CH2:4][NH:5][CH2:6][CH3:7].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18]>>[CH2:20]([O:19][C:17](=[O:18])[N:5]([CH2:4][C:3]1[CH:8]=[C:9]([C:12]([F:13])([F:14])[F:15])[CH:10]=[CH:11][C:2]=1[Br:1])[CH2:6][CH3:7])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Br
Product: CCN(Cc1cc(C(F)(F)F)ccc1Br)C(=O)OCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 1, Step 6, using the following starting materials: (2-bromo-5-trifluoromethyl-benzyl)-ethyl-amine and benzyl chloroformate.
Reaction SMILES: [CH2:1]([N:8](CC)[C:9]1[N:13]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([CH2:24][N:25]4[CH2:30][CH2:29][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]4)[N:20]3[CH3:23])=[C:16]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:15]=2)[C:12]2[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=2[N:10]=1)[C:2]1C=CC=CC=1.C(O)(=O)C>[Pd].C(O)C>[CH2:1]([NH:8][C:9]1[N:13]([C:14]2[N:22]=[C:21]3[C:17]([N:18]=[C:19]([CH2:24][N:25]4[CH2:26][CH2:27][CH:28]([C:31]([OH:34])([CH3:33])[CH3:32])[CH2:29][CH2:30]4)[N:20]3[CH3:23])=[C:16]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)[N:15]=2)[C:12]2[CH:41]=[CH:42][CH:43]=[CH:44][C:11]=2[N:10]=1)[CH3:2]
Reactant: CCN(Cc1ccccc1)c1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCNc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)n(C)c2n1
Temperature: 65 °C
Reaction time: 18 h
Yield: 8.9 %

Procedure:
A mixture of 2-(1-((2-(2-(benzyl(ethyl)amino)-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)methyl)piperidin-4-yl)propan-2-ol (0.6 mmol) and palladium on carbon (10 wt %, 0.3 g) and acetic acid (0.1 mL) in ethanol (20 mL) was stirred under a hydrogen atmosphere at 65° C. for 18 hours. The reaction mixture was then filtered though celite and concentrated. The crude product was purified by RP-HPLC to give 255 (28.5 mg, 17%). LCMS m/z: 534.3 (MH+)