Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:9](=[N:10][C:11](C#N)=[C:12]([C:15]#[N:16])[N:13]=2)[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH3:19][OH:20]>>[CH3:19][O:20][C:11]1[N:10]=[C:9]2[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:2](=[O:1])[C:14]2=[N:13][C:12]=1[C:15]#[N:16]
Reactant: CO
Reactant: N#Cc1nc2c(nc1C#N)-c1ccccc1C2=O
Product: COc1nc2c(nc1C#N)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 16 h
Yield: 126.5 %

Procedure:
To a suspension of 1 (1.10 g, 4.7 mmol) in MeOH (47 ml) sodium (110 mg) was added and the mixture was stirred at room temperature for 16 hours. The precipitate was filtered, washed with EtOH and dried under vacuum, yielding 3 (1.03 g, 93%) as yellow-green solid.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([C:7]1[N:12]=[C:11]2[NH:13][C:14](=[O:27])[N:15]([C:17]3[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=3[CH3:26])[CH2:16][C:10]2=[CH:9][N:8]=1)(=[O:6])=[O:5].I[CH3:29]>CN(C=O)C.C(OCC)(=O)C>[CH3:3][S:4]([C:7]1[N:12]=[C:11]2[N:13]([CH3:29])[C:14](=[O:27])[N:15]([C:17]3[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:18]=3[CH3:26])[CH2:16][C:10]2=[CH:9][N:8]=1)(=[O:5])=[O:6]
Reactant: Cc1ccc([N+](=O)[O-])cc1N1Cc2cnc(S(C)(=O)=O)nc2NC1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc([N+](=O)[O-])cc1N1Cc2cnc(S(C)(=O)=O)nc2N(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.4 %

Procedure:
To the suspension of NaH (60% dispersion in mineral oil, 139 mg, 3.5 mmol) in DMF is added 7-methanesulfonyl-3-(2-methyl-5-nitro-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (1.15 g, 3.2 mmol), prepared as in Reference 1, at 0° C. When H2 evolution has ceased, iodomethane (0.99 ml, 15.8 mmol) is added and the reaction mixture is stirred for 3 hours at room temperature. The mixture is diluted with ethyl acetate, and washed with 5% aqueous Na2S2O3 solution to remove DMF. The organic layer is dried over MgSO4 and concentrated under reduced pressure. The crude product is purified by flash column chromatography (SiO2, EtOAc/hexane=1/1) to give 7-methanesulfonyl-1-methyl-3-(2-methyl-5-nitro-phenyl)-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one (0.85 g, 70%) as a white solid.
Reaction SMILES: CC(OC([NH:8][C@H:9]([C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:11][C:12]([OH:14])=O)=O)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C1C=NC2N(O)N=NC=2C=1.[NH2:53][C:54]1[CH:55]=[C:56]([S:60]([OH:63])(=[O:62])=[O:61])[CH:57]=[CH:58][CH:59]=1>C(Cl)Cl.FC(F)(F)C(O)=O.C(N(CC)CC)C>[NH2:8][C@H:9]([C:15]([O:17][CH3:18])=[O:16])[CH2:10][CH2:11][C:12]([NH:53][C:54]1[CH:55]=[C:56]([S:60]([OH:63])(=[O:61])=[O:62])[CH:57]=[CH:58][CH:59]=1)=[O:14]
Reactant: Nc1cccc(S(=O)(=O)O)c1
Reactant: COC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@@H](N)CCC(=O)Nc1cccc(S(=O)(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Boc-Glu-OME, 130 mg (0.5 mmol), 190 mg (0.5 mmol) of 2-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), 70 mg (0.5 mmol) of 7-aza-1-hydroxybenzotriazole (HOAt) and 87 mg (0.5 mmol) of 3-aminobenzenesulfonic acid were suspended in 2.0 ml of methylene chloride, and 0.5 ml of triethylamine was added to the suspension. The mixture was stirred at room temperature overnight. After the solvent was removed by distillation, the purification step A was applied to give the intermediate. The crude product was dissolved in 4.0 ml of trifluoroacetic acid (TFA) and stirred at room temperature for an hour. After the solvent was removed by distillation, the purification step A was applied to give 7.4 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](Br)[CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[S:5][CH:6]=1.[F:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:23]3[CH:22]=[CH:21][CH:20]=[C:19]([F:18])[CH:24]=3)[CH:13]=[C:12]([CH3:17])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1cc(Br)cc(C(=O)Nc2nc(C)cs2)n1
Reactant: OB(O)c1cccc(F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1cc(-c2cccc(F)c2)cc(C(=O)Nc2nc(C)cs2)n1
Temperature: 90 °C
Reaction time: 24 h
Yield: 70.6 %

Procedure:
To a suspension of 150 mg (0.48 mmol) of 4-Bromo-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide, 71 mg (0.5 mmol, 1.05 equiv.) of 3-Fluorophenyl-boronic acid in 2 ml of dioxane were added 0.5 ml of 2M sodium carbonate solution and the mixture was purged with Argon for 10 min. Then 25 mg (0.096 mmol, 0.2 equiv.) of Triphenylphosphine and 10.8 mg (0.048 mmol, 0.1 equiv.) of Palladium acetate were added and the mixture was stirred under Argon atmosphere for 24 h at 90° C. The reaction was allowed to cool to r.t., taken up in two times in ethyl acetate and evaporated to dryness. The residue was separated by flash chromatography on silicagel (heptane/ethyl acetate 4:1) to yield the title compound (111 mg, 71%) as a yellow solid, MS (ISP): m/e=328.0 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[CH2:24]([O:31][C:32]([NH:34][CH2:35][CH2:36][CH2:37][CH2:38][NH2:39])=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[NH:3]1[CH:4]=[CH:5][N:1]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:39][CH2:38][CH2:37][CH2:36][CH2:35][NH:34][C:32]([O:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:33])=[O:20])=[CH:22][CH:23]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: O=C(O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Reactant: NCCCCNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The compound (413 mg) obtained in Example 2-2 and N-benzyloxycarbonyl-1,4-diaminobutane (247 mg) were dissolved in anhydrous DMF (8.0 ml) and added with WSCI hydrochloride (234 mg) and HOBt (165 mg), followed by stirring at room temperature for 14 hours. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform, washed with 1 mol/l hydrochloric acid, a 1 mol/l sodium hydroxide aqueous solution, and saturated saline solution, and dried with anhydrous magnesium sulfate, followed by distilling the solvent off. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water) and treated with hydrochloric acid, thereby obtaining hydrochloride (23.0 mg) of the subject compound as a white solid.
Reaction SMILES: I[C:2]1[C:3](=[O:21])[C:4]2[C:9]([O:10][C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[C:8]1[NH:18][N:19]=[CH:20][C:7]1=[CH:6][CH:5]=2.[C:22]([O:26][C:27](=[O:48])[NH:28][C:29]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31][CH2:30]1)([CH3:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[C:22]([O:26][C:27](=[O:48])[NH:28][C:29]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[C:3](=[O:21])[C:4]4[C:9]([O:10][C:11]=3[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:8]3[NH:18][N:19]=[CH:20][C:7]3=[CH:6][CH:5]=4)=[CH:35][CH:34]=2)[CH2:30][CH2:31][CH2:32]1)([CH3:24])([CH3:25])[CH3:23]
Reactant: O=c1c(I)c(-c2ccccc2)oc2c1ccc1cn[nH]c12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(ccc5cn[nH]c54)c3=O)cc2)CCC1
Temperature: 125 °C
Yield: 42.2 %

Procedure:
To a microwave vial were added 7-iodo-8-phenyl-1H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one (100 mg, 0.257 mmol), {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (115 mg, 0.308 mmol), sodium carbonate solution (2 M in water, 1 mL), tetrakis(triphenylphosphine)palladium(0) (44.5 mg, 0.039 mmol) and DME (3 mL). The reaction mixture was purged using nitrogen and heated in a microwave reactor at 125° C. for 1 hour. Further portions of {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester (50 mg, 0.134 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol) were added and the mixture was heated in a microwave reactor at 125° C. for a further 1 hour. The reaction mixture was partitioned between EtOAc and water and the resulting biphasic mixture was separated. The aqueous phase was extracted with EtOAc and the combined organic phase was washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 30 to 70% EtOAc in cyclohexane) to afford the title compound (55.1 mg, 42%) as a yellow gum. LCMS (Method H): RT=3.95 min, [M+H]+=508.
Reaction SMILES: [BH4-].[Na+].[CH2:3]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([CH:17]=[O:18])[O:16][C:10]=2[CH2:9]1)=[O:7])[CH3:4]>CO.[Cl-].[Na+].O>[CH2:3]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[C:15]([CH2:17][OH:18])[O:16][C:10]=2[CH2:9]1)=[O:7])[CH3:4]
Reactant: CCOC(=O)N1CCc2nc(C=O)oc2C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)N1CCc2nc(CO)oc2C1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 63.1 %

Procedure:
Sodium borohydride (0.71 g, 18.8 mmol) was added to a stirred solution of 2-formyl-6,7-dihydro-oxazolo[5,4-c]pyridine-5(4H)-carboxylic acid ethyl ester (2.82 g, 12.6 mmol) in MeOH (140 mL) at 0° C. The mixture was stirred at room temperature for 20 minutes, diluted with brine and extracted with DCM. The organic layer was separated, dried (Na2SO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica; AcOEt in DCM 0/100 to 100/0 and then MeOH in AcOEt 15/85). The desired fractions were collected and evaporated in vacuo to yield 6,7-dihydro-2-(hydroxymethyl)-oxazolo[5,4-c]pyridine-5(4H)-carboxylic acid ethyl ester (1.8 g, 63% yield) as a colorless oil. C10H14N2O4 LCMS: Rt 0.72, m/z 227 [M+H]+ (using method, LC-MS Method 6).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]=O.[CH2:13]([N:20]1[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[BH4-].[Na+]>CO.O>[CH2:13]([N:20]1[CH2:24][CH2:23][C@H:22]([NH:25][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH2:21]1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N[C@H]1CCN(Cc2ccccc2)C1
Reactant: O=Cc1ccc2ccccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: c1ccc(CN2CC[C@H](NCc3ccc4ccccc4c3)C2)cc1
Reaction time: 18 h

Procedure:
A solution of 2-naphthaldehyde (2.0 g, 12.8 mmol) and (3S)-1-benzyl-3-amino-pyrrolidine (2.37 g, 13.4 mmol) in methanol (30 mL) was stirred under nitrogen at room temperature for 6 hours. Sodium borohydride (969 mg, 25.6 mmol) was added and the reaction mixture left at room temperature for 18 hours. The reaction mixture was diluted with water and extracted into ethyl acetate (×3) and the organics were combined, dried over magnesium sulphate, and concentrated in vacuo. The crude product was purified by column chromatography on silica gel eluting with dichloromethane:methanol 100:0 to 97:3 to yield the title product, 4.01 g.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]2=[C:4]([Cl:11])[CH:3]=1.[Cl:12][C:13]1[S:17][C:16](B(O)O)=[CH:15][CH:14]=1>>[Cl:11][C:4]1[CH:3]=[C:2]([C:16]2[S:17][C:13]([Cl:12])=[CH:14][CH:15]=2)[N:7]=[C:6]2[CH2:8][CH2:9][CH2:10][C:5]=12
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Reactant: OB(O)c1ccc(Cl)s1
Product: Clc1ccc(-c2cc(Cl)c3c(n2)CCC3)s1
Yield: 14.3 %

Procedure:
Following general procedure F, 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.150 g, 0.80 mmol) was reacted with (5-chlorothiophen-2-yl)boronic acid (0.142 g, 0.88 mmol) to afford the title compound (0.031 g, 14%) as a white solid. MW=270.18. 1H NMR (CDCl3, 500 MHz) δ 7.32 (s, 1H), 7.27 (d, J=4.0 Hz, 1H), 6.89 (d, J=4.0 Hz, 1H), 3.08 (t, J=7.5 Hz, 2H), 2.98 (t, J=7.5 Hz, 2H), 2.16 (quin, J=7.5 Hz, 2H); APCI MS m/z 270 [M+H]+.
Reaction SMILES: [Si]([O:8][C@@H:9]([CH3:26])[CH2:10][CH2:11][N:12]1[CH:16]=[C:15]([B:17]2[O:21][C:20]([CH3:23])([CH3:22])[C:19]([CH3:25])([CH3:24])[O:18]2)[CH:14]=[N:13]1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:25][C:19]1([CH3:24])[C:20]([CH3:22])([CH3:23])[O:21][B:17]([C:15]2[CH:14]=[N:13][N:12]([CH2:11][CH2:10][C@@H:9]([OH:8])[CH3:26])[CH:16]=2)[O:18]1
Reactant: C[C@@H](CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H](O)CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 18.6 %

Procedure:
A solution of (S)-1-(3-[(tert-butyldimethylsilyl)oxy]butyl]-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (Compound 70C, 7.7 g, 20.2 mmol) in THF (30 mL) was treated with tetrabutylammonium fluoride (30 mL, 1M solution in THF) and stirred for 24 hrs at RT under nitrogen atmosphere. Tetrahydrofuran was evaporated under reduced pressure and the residue was purified by column chromatography (SiO2, 1% methanol in dichloromethane) to give colorless gum (1 g, 20%). 1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 7.64 (s, 1H), 4.15-4.23 (m, 2H), 3.60-3.3.71 (m, 1H), 1.7-1.98 (m, 2H), 1.23 (s, 12H), 1.12 (s, d, 3H).
Reaction SMILES: C[N:2]([CH3:12])[CH:3]=[CH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)=O.Cl.NC1[N:16]=[CH:17][NH:18][C:19]=1[C:20]([NH2:22])=[O:21].C([O-])(=O)C.[Na+]>C(O)(=O)C>[S:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[C:5]1[N:16]2[CH:17]=[N:18][C:19]([C:20]([NH2:22])=[O:21])=[C:12]2[N:2]=[CH:3][CH:4]=1
Reactant: CN(C)C=CC(=O)c1cccs1
Reactant: NC(=O)c1[nH]cnc1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Product: NC(=O)c1ncn2c(-c3cccs3)ccnc12

Procedure:
A mixture of 0.01 mol of 3-dimethylamino-1-(2-thienyl)-2-propen-1-one (prepared as described in Example 1, Part A), 0.01 mol of 4amino-5-imidazolecarboxamide hydrochloride and 0.01 mol of anhydrous sodium acetate in 25 ml. of glacial acetic acid can be refluxed for 16 hours. The reaction mixture can be cooled and the crystalline precipitate collected by filtration and washed with water to produce 4-(2-thienyl)imidazo[1,5-a]pyrimidine-8-carboxamide.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:35]1[CH:46]=[CH:45][C:38]([C:39]([NH:41][CH:42]2[CH2:44][CH2:43]2)=[O:40])=[CH:37][CH:36]=1.CN(C=O)C>CO.C([O-])(O)=O.[Na+]>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[C:16](=[O:33])[NH:17][C:18]1[CH:19]=[C:20]([C:35]2[CH:36]=[CH:37][C:38]([C:39](=[O:40])[NH:41][CH:42]3[CH2:44][CH2:43]3)=[CH:45][CH:46]=2)[CH:21]=[CH:22][CH:23]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)OC1(C)C
Reactant: O=C(NC1CC1)c1ccc(Br)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(-c2cccc(NC(=O)[C@@H]3CCCN3C(=O)OCc3ccccc3)c2)cc1
Temperature: 70 °C

Procedure:
A solution of (S)-2-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylcarbamoyl]-pyrrolidine-1-carboxylic acid benzyl ester (74 mg, 0.16 mmol), 4-bromo-N-cyclopropyl-benzamide (39.7 mg, 0.17 mmol), and Pd[P(Ph)3]4 (13.7 mg, 7.2 mol %) in methanol (2 mL), NaHCO3 (sat. aq., 300 μL), and DMF (400 μL) was degassed and heated to 70° C. overnight in a sealed vial. The reaction was cooled, filtered, and purified by reverse phase HPLC to give the desired product. Yield 5.3 mg. MS: 484.2 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 0.51-0.70 (m, 4H), 1.76-1.98 (m, 3H), 2.08-2.30 (m, 1H), 2.77-2.86 (m, 1H), 3.38-3.52 (m, 2H), 4.27-4.37 (m, 1H), 4.86-5.08 (m, 2H), 6.96-7.65 (m, 7
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:29])([C:25]([F:28])([F:27])[F:26])[C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[C:32]1([CH2:38][C:39](Cl)=[O:40])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>ClCCl>[F:24][C:21]([F:22])([F:23])[C:20]([C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:10]2[CH2:9][CH2:8][CH:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:39](=[O:40])[CH2:38][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:31][CH:30]=3)[CH2:12][CH2:11]2)=[CH:15][CH:16]=1)([OH:29])[C:25]([F:28])([F:26])[F:27]
Reactant: Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Cc1ccccc1)Nc1ccc(CC2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.6 %

Procedure:
2-(4-((4-(4-Aminobenzyl)piperidin-1-yl)methyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (0.336 mmol, 150 mg) and 2-phenylacetyl chloride (0.504 mmol, 0.067 mL, 78 mg) were combined in dichloromethane (3 mL) and cooled to 0° C. Triethylamine (0.672 mmol, 0.093 mL, 68.0 mg) was added and the mixture allowed to stir at 0° C. for 2 hours before allowing to warm to room temperature and stirring overnight. The reaction was diluted with dichloromethane and washed with water. The mixture was filtered through a hydrophobic frit and concentrated under vacuum. The residue was purified by flash chromatography on silica gel (eluent: dichloromethane-10% methanol/dichloromethane gradient) to afford the title compound (124.4 mg).
Reaction SMILES: [BH4-].[Li+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[Br:14])[C:7](OC)=[O:8].[Cl-].[NH4+]>O1CCCC1>[Br:14][C:13]1[CH:12]=[CH:11][C:6]([CH2:7][OH:8])=[CH:5][C:4]=1[CH3:3]
Reactant: COC(=O)c1ccc(Br)c(C)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(CO)ccc1Br
Temperature: 60 °C
Reaction time: 12 h
Yield: 104.1 %

Procedure:
284 mg (12.9 mmol, 3 eq) of lithium borohydride are added to a solution of 1.0 g (4.3 mmol, 1 eq) of methyl 3-methyl-4-bromobenzoate in 10 ml of tetrahydrofuran. The reaction mixture is stirred at 60° C. for 12 hours. The reaction medium is hydrolyzed with ammonium chloride solution and extracted with ethyl acetate. The organic phases are combined, washed with sodium chloride solution and dried over sodium sulfate. 900 mg of (4-bromo-3-methylphenyl)methanol are obtained in oil form and used in the following reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.Cl[CH2:27][C:28]#[N:29]>>[C:28]([CH2:27][N:5]1[CH2:6][CH2:7][C:3]([O:2][CH3:1])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:4]1)#[N:29]
Reactant: N#CCCl
Reactant: COC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCNC1
Product: COC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCN(CC#N)C1
Yield: 45 %

Procedure:
Using an analogous procedure to that described in Example 3, 3-methoxy-3-[3-(naphth-2-ylmethoxy)phenyl]pyrrolidine was reacted with 2-chloroacetonitrile to give 1-(cyanomethyl)-3-methoxy-3-[3-(naphth-2-ylmethoxy)phenyl]pyrrolidine in 45% yield, m.p. 76°-77° C. (recrystallised from methanol).
Reaction SMILES: BrBr.[Br:3][C:4]1[C:9]([Br:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH3:11].S(=O)(=O)(O)[OH:13]>>[Br:3][C:4]1[C:9]([Br:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:11]=[O:13]
Reactant: O=S(=O)(O)O
Reactant: Cc1cccc(Br)c1Br
Agent: BrBr
Product: O=Cc1cccc(Br)c1Br
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Bromine (168 g., 1.05 mole) is added over about one hour, with vigorous stirring, to 117.5 g. (0.47 mole) of 2,3-dibromotoluene at 190° C. After the addition is complete, the mixture is cooled to 100° C., then 120 cc. of concentrated sulfuric acid is added and the mixture is stirred for one hour at 100° C. Temperature is raised to 140° C. for five minutes, then the mixture is cooled and the reaction is quenched in ice water. The solid is extracted into ether, and the ether extract is washed with water, then dilute aqueous sodium bicarbonate until the acid is completely removed, and filtered. Removing the ether by evaporation gives 2,3-dibromobenzaldehyde as the residue.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[N:7]([CH2:9][CH2:10][CH2:11][C:12](=O)[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:15]=1[NH2:23])[CH3:8])([CH3:4])([CH3:3])[CH3:2]>C(O)(=O)C>[C:1]([O:5][C:6](=[O:25])[N:7]([CH3:8])[CH2:9][CH2:10][CH2:11][C:12]1[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[C:15]=2[N:23]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCCC(=O)Nc1cccc([N+](=O)[O-])c1N)C(=O)OC(C)(C)C
Solvent: CC(=O)O
Product: CN(CCCc1nc2c([N+](=O)[O-])cccc2[nH]1)C(=O)OC(C)(C)C
Yield: 91 %

Procedure:
A solution of 4.4 g of [3-(2-amino-3-nitro-phenylcarbamoyl)-propyl]methyl-carbamic acid tert-butyl ester in 36 mL of acetic acid was heated at 90° C. for 5 h and concentrated in vacuo. The residue was taken up in DCM, washed with sat. NaHCO3 solution, dried over anh. Na2SO4 and concentrated in vacuo to yield 3.8 g of methyl-[3-(4-nitro-1H-benzoimidazol-2-yl)-propyl]-carbamic acid tert-butyl ester as dark yellow oil.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[NH:18][C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:31])(=[O:30])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)#[N:33].N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:5]2[CH2:6][CH2:7][N:8]([C:11]([C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[N:18]([C:38]3[CH:39]=[C:34]([CH:35]=[CH:36][CH:37]=3)[C:32]#[N:33])[C:17]([C:22]([N:24]3[CH2:29][CH2:28][S:27](=[O:30])(=[O:31])[CH2:26][CH2:25]3)=[O:23])=[CH:16]4)=[O:12])[CH2:9][CH2:10]2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCS(=O)(=O)CC3)cc2c1)N1CCN(C2CCC2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cccc(-n2c(C(=O)N3CCS(=O)(=O)CC3)cc3cc(C(=O)N4CCN(C5CCC5)CC4)ccc32)c1
Yield: 49 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclobutyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(1,1-dioxothiomorpholin-4-yl)-methanone (example 202), 3-cyanophenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a colorless foam (49%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:11]=2[CH:29]=1.[Cl:30][C:31]1[CH:32]=[C:33]([SH:38])[CH:34]=[CH:35][C:36]=1[Cl:37]>>[Cl:30][C:31]1[CH:32]=[C:33]([S:38][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]4)([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:11]=3[CH:29]=2)[CH:34]=[CH:35][C:36]=1[Cl:37]
Reactant: Sc1ccc(Cl)c(Cl)c1
Reactant: O=C1Nc2ccc(OCCCCCl)cc2C(C2CCCCC2)(C2CCCCC2)O1
Product: O=C1Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc2C(C2CCCCC2)(C2CCCCC2)O1

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dicyclohexyl-4H-3,1-benzoxazin-2-one and 3,4-dichloro-thiophenol.