Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[C:17]3[C:12](=[C:13]([Cl:19])[CH:14]=[C:15]([Cl:18])[CH:16]=3)[CH2:11][N:10]([CH3:20])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[N:21]([CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][NH2:35])=[N+:22]=[N-:23].N1CCC[C@H]1C(O)=O.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.[Cu]I>[N:21]([CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][NH:35][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[C:17]3[C:12](=[C:13]([Cl:19])[CH:14]=[C:15]([Cl:18])[CH:16]=3)[CH2:11][N:10]([CH3:20])[CH2:9]2)[CH:3]=1)=[N+:22]=[N-:23]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(Br)c2)C1
Reactant: [N-]=[N+]=NCCOCCOCCOCCN
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(NCCOCCOCCOCCN=[N+]=[N-])c2)C1
Temperature: 90 °C

Procedure:
Into a 10-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of 4-(3-bromophenyl)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinoline (intermediate 1.4) (400 mg, 1.08 mmol, 1.00 equiv) in DMSO (6 mL), 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethanamine (236.11 mg, 1.08 mmol, 1.00 equiv), (S)-pyrrolidine-2-carboxylic acid (24.79 mg, 0.21 mmol, 0.20 equiv), copper(I) iodide (20.48 mg, 0.11 mmol, 0.10 equiv) and potassium carbonate (223.18 mg, 1.62 mmol, 1.50 equiv). The resulting solution was stirred at 90° C. in an oil bath and the reaction progress was monitored by LCMS. After stirring overnight the reaction mixture was cooled with a water/ice bath and then diluted with ice water. The resulting solution was extracted with 3×30 mL of ethyl acetate and the organic extracts were combined and washed with 2×20 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (2:1). This resulted in 130 mg (24%) of N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenamine as yellow oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[C:4](NCC2C=CC(OC)=CC=2)[N:3]=1.[H-].[Na+].I[CH:24]([CH3:26])[CH3:25].O>CN(C=O)C>[CH:24]([C:2]1[N:10]=[C:9]2[C:5]([NH:6][CH:7]=[N:8]2)=[CH:4][N:3]=1)([CH3:26])[CH3:25]
Reactant: COc1ccc(CNc2nc(Cl)nc3nc[nH]c23)cc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ncc2[nH]cnc2n1
Reaction time: 0.5 h

Procedure:
2-chloro-6-(4-methoxybenzylamino) purine was suspended in dry DMF (5 ml) and treated with sodium hydride, 60% dispersion (82 mg, 2.06 mmol). The suspension was stirred for 30 min over which time it became a clear yellow/green solution. 2-Iodopropane (0.280 mL, 1.7 eq.) was added over 5 min and the resultant solution stirred for 2 days. Water was added and the solution and extracted with ethyl acetate. The organic layer was evaporated to give the product isopropyl purine.
Reaction SMILES: [CH:1]([C:3]1[N:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[CH3:20])[CH:5]=[C:6]([C:10](=[O:12])[CH:11]=1)[C:7]([OH:9])=[O:8])=O.[CH2:21]([O:23][C:24]([CH:26]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:25])[CH3:22]>CO>[CH2:21]([O:23][C:24]([CH:26]=[CH:1][C:3]1[N:4]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]=2[CH3:20])[CH:5]=[C:6]([C:10](=[O:12])[CH:11]=1)[C:7]([OH:9])=[O:8])=[O:25])[CH3:22]
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1cc(O)ccc1-n1cc(C(=O)O)c(=O)cc1C=O
Solvent: CO
Product: CCOC(=O)C=Cc1cc(=O)c(C(=O)O)cn1-c1ccc(O)cc1C
Yield: 32 %

Procedure:
In 5 ml of methanol was dissolved 0.15 g of 6-formyl-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinic acid, and 0.19 g of ethoxycarbonylmethylenetriphenylphosphorane was added thereto. They were reacted at room temperature for one hour. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and the residue was purified by a column chromatography (Wako Silica Gel C-200; eluent: chloroform/ethanol (50:1 by volume) mixture) to obtain 0.06 g of 6-(2-ethoxycarbonylethenyl)-1-(4-hydroxy-2-methylphenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 185°-189° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[O:13]1[CH:17]=[CH:16][N:15]=[C:14]1[C:18]1[S:19][CH:20]=[CH:21][C:22]=1[NH2:23]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:23][C:22]2[CH:21]=[CH:20][S:19][C:18]=2[C:14]2[O:13][CH:17]=[CH:16][N:15]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: Nc1ccsc1-c1ncco1
Reactant: COc1ccc(CC(=O)O)cc1
Product: COc1ccc(CC(=O)Nc2ccsc2-c2ncco2)cc1

Procedure:
2-(4-methoxyphenyl)-N-(2-(oxazol-2-yl)thiophen-3-yl)acetamide was prepared from 2-(4-methoxyphenyl)acetic acid 64 mg, 0.385 mmol) and 2-(oxazol-2-yl)thiophen-3-amine (64 mg, 0.385 mmol) according to protocol A. Retention time (min)=6.845, method [7], MS(ESI) 315.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 10.59 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.52 (s, 1H), 7.28-7.37 (m, 3H), 6.94-6.99 (m, 3H), 3.85 (s, 3H), 3.66 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2OS(C(F)(F)F)(=O)=O)=[CH:4][CH:3]=1.[Cl:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][N:24]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:22][C:23]1[CH:28]=[C:27]([C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=2[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:26]=[CH:25][N:24]=1
Reactant: O=S(=O)(OC1=C(c2ccc(F)cc2)CCCC1)C(F)(F)F
Reactant: CC1(C)OB(c2ccnc(Cl)c2)OC1(C)C
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(C2=C(c3ccnc(Cl)c3)CCCC2)cc1
Temperature: 100 °C
Yield: 58.3 %

Procedure:
Trifluoro-methanesulfonic acid 2-(4-fluoro-phenyl)-cyclohex-1-enyl ester (200 mg, 0.62 mmol), 2-Chloro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (162 mg, 0.68 mmol), Bis(triphenylphosphine)Palladium (II) dichloride (43 mg, 0.062 mmol), Sodium Carbonate solution (2.0 M, 1.54 mL, 3.1 mmol) and DMF (3 mL) are mixed in a 5 mL microwave tube with a stir bar and the mixture is heated to 100° C. in microwave reactor for 30 min. The mixture is poured to water (10 mL) and extracted with EtOAc (10 mL×3). The organic extracts are washed with water (20 mL×1), brine (20 mL×1) and dried over anhydrous sodium sulfate. After concentration, the crude is purified by silica flash column chromatography using EtOAc in Heptane (gradient from 0% to 20%) to give 104 mg of the desired product.
Reaction SMILES: CCN(C(C)C)C(C)C.[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[CH:20]=[C:19]([C:21]([OH:23])=O)[N:18]=[N:17]2)[CH:11]=1.NC1C=NC=CC=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:53][CH2:54][C:55]([N:57]1[CH2:62][CH2:61][CH:60]([O:63][C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=2[Cl:70])[CH2:59][CH2:58]1)=[O:56]>CN(C=O)C.O>[Cl:70][C:65]1[CH:66]=[CH:67][CH:68]=[CH:69][C:64]=1[O:63][CH:60]1[CH2:59][CH2:58][N:57]([C:55](=[O:56])[CH2:54][NH:53][C:21]([C:19]2[N:18]=[N:17][N:16]([C:12]3[CH:11]=[N:10][CH:15]=[CH:14][CH:13]=3)[CH:20]=2)=[O:23])[CH2:62][CH2:61]1
Reactant: NCC(=O)N1CCC(Oc2ccccc2Cl)CC1
Reactant: O=C(O)c1cn(-c2cccnc2)nn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Nc1cccnc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1cn(-c2cccnc2)nn1
Yield: 90.74 %

Procedure:
DIPEA (215 mg, 1.66 mmol) was added to a stirred solution of 1-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid (70 mg, 0.37 mmol) (prepared by the method used for the synthesis of Intermediate 64, starting from 3-aminopyridine) in DMF (5 mL) followed by HOBt (55 mg, 0.41 mmol) and EDCI (177 mg, 0.92 mmol) and stirring was continued at ambient temperature. After 2 minutes of stirring, 2-amino-1-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (prepared according to Step 1 and 5 of the General Scheme) (124 mg, 0.4 mmol) was added and the resulting mixture was stirred at ambient temperature overnight. Cold water was then added and filtered the precipitate was filtered to afford 147 mg (90.74% Yield) of 1-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid {2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2-oxo-ethyl}-amide. LC/MS [M+H]+: 441, 98.31%. 1H NMR (300 MHz, DMSO-d6): δ 9.5 (s, 1H), 9.24 (d, 1H), 8.76 (d, 1H), 8.56 (t, 1H), 8.46 (d, 1H), 7.74 (d, 1H), 7.48 (d, 1H), 7.36 (q, 2H), 7.02 (t, 1H), 4.8 (m, 1H), 4.4 (d, 2H), 3.8 (t, 2H), 3.6 (t, 2H), 2.1 (d, 2H), 1.8 (d, 2H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([F:23])[CH:17]=1.O>CC(C)=O.CCOC(C)=O>[CH2:2]([O:22][C:19]1[CH:20]=[CH:21][C:16]([Br:15])=[CH:17][C:18]=1[F:23])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Oc1ccc(Br)cc1F
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.6 %

Procedure:
1-(Bromomethyl)benzene (4.92 g, 28.8 mmol) and K2CO3 (3.98 g, 28.8 mmol) were added to a solution of 4-bromo-2-fluorophenol (5.0 g, 26 mmol) in acetone. The reaction mixture was stirred at room temperature for 18 hours. Water (100 mL) and EtOAc (100 mL) were added, the organic layer was separated and dried over MgSO4 and concentrated to give 1-(benzyloxy)-4-bromo-2-fluorobenzene as a yellow solid 7.06 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(N(C)C)=O.O>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([O:8][C:4]2[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=2)[NH2:1])=[CH:11][CH:12]=1
Reactant: Nc1cccc(O)c1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1cccc(Oc2ccc(C(F)(F)F)cc2)c1
Temperature: 85 °C
Reaction time: 16 h
Yield: 58.6 %

Procedure:
3-Aminophenol (5.0 g, 45.8 mmol) and 4-bromo-α,α,α-trifluorotoluene (14.0 g, 62.2 mmol) were dissolved in anhydrous dimethylacetamide (20 mL), then anhydrous cesium carbonate (30 g, 92.3 mmol) and copper triflate benzene complex (200 mg) were added. The mixture was stirred and heated to 85° C. using a reflux condenser under an argon atmosphere. After 16 h, the mixture was diluted with water (120 mL), and the aqueous layer was extracted with diethyl ether (4×60 mL). The combined ether layers were washed with 3% HCl, 5% NaOH and water, then dried over anhydrous MgSO4. The ether was removed in vacuo, and the recovered oil purified by flash column chromatography on silica gel eluting with ethyl acetate in hexane (1:8) to give 6.8 g (59%) of the desired 3-(4-trifluoromethylphenoxy)aniline product as a yellow oil, which solidified to a yellow powder, 98% pure by HPLC analysis. HRMS calcd. for C13H10F3NO: 254.0792 [M+Hπ30, found: 254.0798.
Reaction SMILES: [Mg].II.[CH:4]([C:7]1[CH:8]=[C:9](Br)[CH:10]=[CH:11][CH:12]=1)([CH3:6])[CH3:5].BrCCBr.[C:18](=[O:20])=[O:19].Cl>O1CCCC1.O>[CH:4]([C:7]1[CH:8]=[C:9]([CH:10]=[CH:11][CH:12]=1)[C:18]([OH:20])=[O:19])([CH3:6])[CH3:5]
Reactant: CC(C)c1cccc(Br)c1
Reactant: O=C=O
Agent: Cl
Agent: II
Agent: [Mg]
Solvent: O
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC(C)c1cccc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
While stirring a solution of powdery magnesium (3.33 g, 137 mmol) and iodine (one crumb) in tetrahydrofuran (10 ml), a solution of 3-isopropylbromobenzene (10.91 g, 54.80 mmol) and 1,2-dibromoethane (10.3 g, 54.8 mmol) in tetrahydrofuran (100 ml) was dropwise added slowly. After completion of the dropwise addition, the mixture was stirred at 70° C. for 1 hr. The reaction solution was cooled to −78° C., and pulverized dry ice (10 g) was carefully added. The reaction solution was gradually warmed to room temperature with stirring. The reaction solution was diluted with water, acidified with conc. hydrochloric acid, and extracted twice with ethyl acetate. The solvent of the recovered organic layer was evaporated under reduced pressure to give a crude product of 3-isopropylbenzoic acid as a yellow liquid.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:8]=[C:9]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:10][N:11]1[C:15]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=2[N:13]([C@H:22]2[CH2:26][CH2:25][NH:24][CH2:23]2)[C:12]1=[O:27].C(N(CC)CC)C>C(Cl)(Cl)Cl.CN1CCN(C)C1=O>[Cl:6][C:7]1[CH:8]=[C:9]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:10][N:11]1[C:15]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=2[N:13]([C@H:22]2[CH2:26][CH2:25][N:24]([C:2]([O:4][CH3:5])=[O:3])[CH2:23]2)[C:12]1=[O:27]
Reactant: COC(=O)Cl
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CCNC3)c3ccc(C#N)cc32)cc1Cl
Solvent: ClC(Cl)Cl
Solvent: CN1CCN(C)C1=O
Solvent: CCN(CC)CC
Product: COC(=O)N1CC[C@H](n2c(=O)n(Cc3ccc(OC)c(Cl)c3)c3cc(C#N)ccc32)C1
Reaction time: 2 h
Yield: 59.7 %

Procedure:
A solution of methyl chloroformate (25.7 mg) in chloroform (1 ml) was added dropwise to a mixture of 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-[(S)-pyrrolidin-3-yl]-2,3-dihydro-1H-benzimidazole-2-one (80 mg) and triethylamine (31.7 mg) in a mixture of chloroform (1.6 ml) and 1,3-dimethyl-2-imidazolidinone (0.8 ml) under cooling on an ice bath. The reaction mixture was stirred at same temperature for 2 hours and quenched by addition of 3-(N,N-diethylamino)propylamine (0.1 ml). The mixture was poured into water and extracted with chloroform. The organic layer was washed with 1N-hydrochloric acid, water, an aqueous saturated sodium bicarbonate solution and brine, dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by a preparative thin layer chromatography (10% methanol in chloroform) to give 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-[(S)-1-methoxycarbonylpyrrolidin-3-yl]-2,3-dihydro-1H-benzimidazole-2-one (55 mg).
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:13]=[CH:12][N:11]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:17])[CH3:16])[C:8]=3[N:9]=[CH:10][C:5]2=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([OH:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[N:3]=1.C1C(=O)N([Br:41])C(=O)C1>C(Cl)Cl>[Br:41][C:13]1[C:7]2[N:6]3[C:2]([CH3:1])=[N:3][C:4]([C:24]4[CH:25]=[CH:26][C:27]([C:30]([OH:33])([CH3:31])[CH3:32])=[CH:28][CH:29]=4)=[C:5]3[CH:10]=[N:9][C:8]=2[N:11]([Si:14]([CH:21]([CH3:23])[CH3:22])([CH:18]([CH3:20])[CH3:19])[CH:15]([CH3:16])[CH3:17])[CH:12]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1nc(-c2ccc(C(C)(C)O)cc2)c2cnc3c(ccn3[Si](C(C)C)(C(C)C)C(C)C)n12
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(C)(C)O)cc2)c2cnc3c(c(Br)cn3[Si](C(C)C)(C(C)C)C(C)C)n12
Temperature: -20 °C
Reaction time: 0.67 h
Yield: 36.9 %

Procedure:
To a solution of 2-(4-(1-methyl-6-(triisopropylsilyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (1.5 g, 3.2 mmol, Preparation #AX.1) in DCM (32.4 ml) at about −20° C. was added NBS (0.46 g, 2.6 mmol). The mixture was stirred at about −20° C. for about 40 min. The mixture was diluted with DCM (100 mL) and washed with saturated aqueous NaHCO3 (75 mL). The organic phase was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (120 g silica gel column; 0 to 50% EtOAc/heptane) to give 2-(4-(8-bromo-1-methyl-6-(triisopropylsilyl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-3-yl)phenyl)propan-2-ol (0.52 g, 29%). LC/MS (Table 2, Method h) Rt=2.51 min; MS m/z 543 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C@H:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[CH2:13][CH2:12]1)[CH3:10])=[O:5].C(O[C:35]([N:37]([CH2:39][C:40](O)=[O:41])C)=O)(C)(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:1][C:2]1[N:27]=[C:26]([Cl:28])[CH:25]=[C:24]([CH3:29])[C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C@H:9]([N:11]1[CH2:16][CH2:15][CH:14]([N:17]([C:40](=[O:41])[CH2:39][NH:37][CH3:35])[CH2:18][C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[CH2:13][CH2:12]1)[CH3:10])=[O:5]
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Reactant: Cc1cc(Cl)nc(Cl)c1C(=O)NCC[C@@H](C)N1CCC(NCc2ccsc2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNCC(=O)N(Cc1ccsc1)C1CCN([C@H](C)CCNC(=O)c2c(C)cc(Cl)nc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Following general procedure E: to a stirred solution of 2,6-dichloro-4-methyl-N—((R)-3-{4-[(thiophen-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-nicotinamide (62 mg, 0.137 mmol), (tert-butoxycarbonyl-methyl-amino)-acetic acid (28 mg, 0.159 mmol), HOBt (24 mg, 0.177 mmol) and DIPEA (59 μL, 0.34 mmol) in DMF (3 ml) was added EDCI (34 mg, 0.177 mmol). The reaction was stirred at rt overnight under N2 pressure. The resultant crude product (88 mg) was used in the next step.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.O[C:16]1[CH:17]=[C:18]([S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23])[CH:19]=[CH:20][CH:21]=1.[Cl:28][C:29]1[C:30]([C:55]([F:58])([F:57])[F:56])=[C:31]([CH:52]=[CH:53][CH:54]=1)[CH2:32][N:33]([CH2:38][CH:39]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:34][CH2:35][CH2:36][OH:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl>C(Cl)Cl.C(OCC)C>[ClH:28].[Cl:28][C:29]1[C:30]([C:55]([F:56])([F:57])[F:58])=[C:31]([CH:52]=[CH:53][CH:54]=1)[CH2:32][N:33]([CH2:38][CH:39]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[CH2:34][CH2:35][CH2:36][O:37][C:19]1[CH:20]=[CH:21][CH:16]=[CH:17][C:18]=1[S:22]([N:25]([CH3:27])[CH3:26])(=[O:24])=[O:23]
Reactant: CN(C)S(=O)(=O)c1cccc(O)c1
Reactant: OCCCN(Cc1cccc(Cl)c1C(F)(F)F)CC(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CN(C)S(=O)(=O)c1ccccc1OCCCN(Cc1cccc(Cl)c1C(F)(F)F)CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
DIAD (48 uL, 0.24 mmol) was added dropwise to a RT solution of 3-hydroxy-N,N,-dimethyl-benzenesulfonamide (0.040 g, 0.2 mmol), 3-[(3-chloro-2-trifluoromethyl-benzyl)-diphenylethyl-amino]-propan-1-ol (0.088 g, 0.2 mmol) and triphenylphosphine (0.063 g, 0.24 mmol). The mixture was stirred for 48 at rt than was concentrated and purified by reverse phase HPLC to provide a solid which was dissolved in CH2Cl2 and treated with excess 4M HCl in diethyl ether. The mixture was concentrated to provide 35 mg (25%) of the title compound. MS (ESI) 632 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)[NH2:5].C(=O)(O)[O-].[Na+].Cl[C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]>CC(C)=O.O>[C:21]([NH:5][C:4]1[CH:6]=[CH:7][C:8]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[C:2]([F:1])[CH:3]=1)([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22]
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(Nc1ccc(N2CCOCC2)c(F)c1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 28.91 g of 3-fluoro-4-morpholinyl-aniline and 27.88 g of sodium bicarbonate in 500 mL of acetone and 250 mL of water at 0° C. was added 28.68 g of benzyl chloroformate. After stirring the mixture for 1.5 hours, the mixture was poured onto 1000 cc of ice and water, and the ice allowed to melt. The precipitated solid was collected by filtration and washed with 3×250 ml of water, and then dried in a vacuum oven at 750° C. to give a gray-purple solid. This was recrystallized from acetone-water to give a cream-colored solid, mp=123°-124° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[CH:21]([NH:22][CH3:23])[CH2:20][CH2:19][CH2:18][N:13]3[C:14](=[O:17])[C:15]=2[OH:16])=[O:9])=[CH:4][CH:3]=1.O1CCCC1.[OH-].[Na+].[CH3:33][N:34]([CH3:39])[S:35](Cl)(=[O:37])=[O:36]>O.C(#N)C>[CH3:33][N:34]([CH3:39])[S:35]([N:22]([CH3:23])[CH:21]1[C:12]2=[N:11][C:10]([C:8]([NH:7][CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:25][CH:24]=3)=[O:9])=[C:15]([OH:16])[C:14](=[O:17])[N:13]2[CH2:18][CH2:19][CH2:20]1)(=[O:37])=[O:36]
Reactant: CNC1CCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Reactant: CN(C)S(=O)(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: CN(C)S(=O)(=O)N(C)C1CCCn2c1nc(C(=O)NCc1ccc(F)cc1)c(O)c2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of crude compound obtained in Step 3 in a 2:1 mixture of tetrahydrofuran and 2 M aq. sodium hydroxide was added N,N-dimethylsulfamoyl chloride (4.6 eq.). The mixture was stirred at room temperature for 16 h. The mixture was concentrated under reduced pressure and the product was isolated by preparative RP-HPLC, using water (0.1% TFA) and acetonitrile (0.1% TEA) as eluents (column: C18). The pooled product fractions were lyophilized to afford the title compound as a fluffy, slightly pink material.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[CH:3]=1.Cl[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[C:27]#[N:28])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[N:7]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]#[N:28])=[CH:19][CH:20]=2)[C:6](=[O:8])[N:5]([CH2:9][CH2:10][CH3:11])[C:4](=[O:12])[CH:3]=1
Reactant: CCCn1c(=O)cc(Cl)[nH]c1=O
Reactant: N#Cc1ccccc1-c1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCn1c(=O)cc(Cl)n(Cc2ccc(-c3ccccc3C#N)cc2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
A mixture of 6-chloro-3-propylpyrimidine-2,4(1H,3H)-dione (3 g), 4-chloromethyl-2'-cyanobiphenyl (4.76 g) and potassium carbonate (2.64 g) in DMF (50 ml) was stirred at room temperature for 3 hours and then at 60° C. for 2 hours. The reaction mixture was concentrated to dryness in vacuo and then the residue was dissolved in methylene chloride. The insoluble material was removed from the reaction mixture by filtration and the filtrate was concentrated to dryness. The resulting residue was purified by column chromatography on silica gel to give colorless crystals (5.9 g, 98%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=O.[O:15]=[C:16]([CH3:22])[CH2:17][C:18]([O:20][CH3:21])=[O:19].C(O)(=O)C.N1CCCCC1>ClCCl>[CH3:1][C:2]1[O:3][C:4]2[C:9]([C:10](=[O:12])[CH:11]=1)=[CH:8][CH:7]=[CH:6][C:5]=2[CH:13]=[C:17]([C:16](=[O:15])[CH3:22])[C:18]([O:20][CH3:21])=[O:19]
Reactant: Cc1cc(=O)c2cccc(C=O)c2o1
Reactant: COC(=O)CC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: C1CCNCC1
Product: COC(=O)C(=Cc1cccc2c(=O)cc(C)oc12)C(C)=O

Procedure:
1 g (5.31 mmol) of 2-methyl-4-oxo-4H-chromene-8-carbaldehyde, 680 mg (5.84 mmol) of methyl 3-oxobutanoate, 456 μl (7.97 mmol) of acetic acid and 105 μl (1.06 mmol) of piperidine in 50 ml of anhydrous dichloromethane are stirred under reflux with a water trap for 24 h. After cooling, the reaction solution is diluted with dichloromethane (100 ml) and washed successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phase is dried over magnesium sulfate and concentrated. The residue is recrystallized from isopropanol. 1.43 g (94% of theory) of the title compound are obtained as an E/Z mixture.