Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([N:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:16][C:17]=2[O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:12]1[C:37]#[N:38])(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:39][O:40][C:41]1[CH:42]=[C:43]([CH:46]=[C:47]([O:51][CH3:52])[C:48]=1[O:49][CH3:50])[CH2:44]Cl>CN(C)C=O>[C:3]([N:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][C:15]([O:29][CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:16][C:17]=2[O:21][CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:12]1([C:37]#[N:38])[CH2:44][C:43]1[CH:46]=[C:47]([O:51][CH3:52])[C:48]([O:49][CH3:50])=[C:41]([O:40][CH3:39])[CH:42]=1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1cc(CCl)cc(OC)c1OC
Reactant: N#CC1c2cc(OCc3ccccc3)cc(OCc3ccccc3)c2C=CN1C(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(CC2(C#N)c3cc(OCc4ccccc4)cc(OCc4ccccc4)c3C=CN2C(=O)c2ccccc2)cc(OC)c1OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (prepared by washing 553 mg of 65% sodium hydride with absolute n-hexane) is suspended in 15 ml of dimethylformamide. A solution of 3.4 g of 2-benzoyl-1-cyano-5,7-dibenzyloxy-1,2-dihydroisoquinoline in 40 ml of dimethylformamide is added dropwise to the suspension at -10° C in a nitrogen atmosphere. Then, a solution of 1.71 g of 3,4,5-trimethoxybenzyl chloride in 40 ml of dimethylformamide is added dropwise to the mixture for 30 minutes, and the mixture is allowed to stand at the same temperature for 30 minutes. The reaction mixture is poured into ice-water, and extracted with ethyl acetate. The extract is evaporated to remove solvent, whereby 2-benzoyl-1-cyano-5,7-dibenzyloxy-1-(3,4,5-trimethoxybenzyl)-1,2-dihydroisoquinoline is obtained as a crude oil. The crude oil is dissolved in 200 ml of dioxane. 50 ml of an aqueous 10% sodium hydroxide solution are added to the dioxane solution, and this mixture is stirred at 50° C for 12 hours. After the reaction, the mixture is evaporated under reduced pressure to remove solvent. The residue thus obtained is extracted with methylene chloride. The methylene chloride extract is washed with water, dried and then evaporated to remove solvent. 3.1 g of 5,7-dibenzyloxy-1-(3,4,5-trimethoxybenzyl)-isoquinoline are obtained as a crude product. Yield: 84% M.p. 158° - 160° C (recrystallized from ethanol).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH3:12][NH2:13]>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH:13][CH3:12])=[O:8])=[CH:5][CH:4]=1)#[N:2]
Reactant: CN
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Product: CNC(=O)c1ccc(C#N)cc1

Procedure:
By the reaction in the same manner as in Example 26-i) using 4-cyanobenzoyl chloride (5.17 g) and 40% aqueous methylamine solution (20 ml), the title compound (4.13 g) was obtained as colorless powder crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20](=[O:22])[CH3:21])=[C:13]3[NH:23][C:24]2[CH:25]=[N:26][C:27]([NH:30][CH2:31][CH2:32][N:33]([CH3:35])[CH3:34])=[CH:28][CH:29]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8].[Cl:36]C1C=C(B2OC(C)(C)C(C)(C)O2)C=C(Cl)C=1O>>[ClH:1].[ClH:36].[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[N:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][C:14]([C:20](=[O:22])[CH3:21])=[C:13]3[NH:23][C:24]2[CH:25]=[N:26][C:27]([NH:30][CH2:31][CH2:32][N:33]([CH3:34])[CH3:35])=[CH:28][CH:29]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[OH:8]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Agent: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)nc2c1Nc1ccc(NCCN(C)C)nc1
Product: Cl

Procedure:
Following general procedure II, 1-[6-(3,5-dichloro-4-hydroxyphenyl)-4-{6-[2-(dimethylamino)ethylamino ]pyridin-3-ylamino}-1,5-naphthyridin-3-yl]ethanone (69 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (78 mg, 0.27 mmol) followed by formation of the trihydrochloride salt to afford the desired product (87 mg, 78%) as a yellow-orange solid: 1H NMR (500 MHz, D2O) δ 9.22 (s, 1H), 8.22 (d, J=8.9 Hz, 1H), 8.02 (d, J=9.1 Hz, 1H), 7.92 (d, J=2.5 Hz, 1H), 7.59-7.53 (m, 1H), 6.98 (s, 2H), 6.79 (d, J=9.4 Hz, 1H), 3.67 (t, J=6.4 Hz, 2H), 3.23 (t, J=6.4 Hz, 2H), 2.82 (s, 6H), 2.80 (s, 3H); ESI MS m/z 511 [M+H]+; HPLC>99% (AUC), tR=9.13 min.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:18])[C:13]=2[NH2:17])[C:8]1=[O:19])(=[O:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][C:22]=1[C:31]([F:34])([F:33])[F:32].F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.C(Cl)Cl>>[C:1]([O:4][CH2:5][CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([Cl:18])[C:13]=2[NH:17][C:28](=[O:29])[CH2:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[C:22]([C:31]([F:32])([F:34])[F:33])[CH:23]=2)[C:8]1=[O:19])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCn1ccc2c(N)c(Cl)ccc2c1=O
Reactant: O=C(O)Cc1ccc(F)c(C(F)(F)F)c1
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: ClCCl
Product: CC(=O)OCCn1ccc2c(NC(=O)Cc3ccc(F)c(C(F)(F)F)c3)c(Cl)ccc2c1=O
Temperature: 45 °C
Reaction time: 96 h

Procedure:
A reaction vial was charged with 2-(5-amino-6-chloro-1-oxoisoquinolin-2(1H)-yl)ethyl acetate (60.0 mg, 0.000214 mol), 2-(4-fluoro-3-(trifluoromethyl)phenyl)acetic acid (57.0 mg, 0.000256 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (203 mg, 0.000534 mol), N,N-diisopropylethylamine (0.093 mL, 0.00053 mol) and methylene chloride (3 mL, 0.05 mol) and the reaction stirred at 45° C. for 4 days. The reaction did not go to completion and a polar by product started increasing and so the reaction was stopped and solvent removed and the residue purified by flash chromatography to obtain the product as a light yellow solid. MS m/z=485.2 (M+H)
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][C@@H:10]([C:12]([OH:14])=[O:13])N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:15].[Na+].N([O-])=O.[Na+]>S(=O)(=O)(O)O>[Br:15][C@@H:10]([CH2:9][O:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:12]([OH:14])=[O:13]
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Reactant: [Br-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)[C@@H](Br)COCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.9 %

Procedure:
A solution of O-(phenylmethyl)-L-serine (21.6 g, 0.108 mol) in aqueous sulfuric acid (786 ml, 2.5N) containing sodium bromide (69.3 g, 6.0 eq) was cooled to 0° C. in an ice bath. Sodium nitrite (21 g, 2.7 eq) was added over 10 minutes, and the solution stirred at 0° C. for one hour. The cooling bath was removed, ether (250 ml) was added, and stirring was continued overnight at room temperature. The aqueous layer was extracted repetitively with ether (3×100 ml), and the combined extracts were dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give 25 g of a crude product. The product was purified by column chromatography (83:17; petroleum ether:ethyl acetate) to yield the title compound (10.6 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:12][CH:11]=[C:10]([CH:13]=[O:14])[CH:9]=1.[Cl:15]N1C(=O)CCC1=O.O>CN(C)C=O>[Cl:15][C:9]1[C:10]([CH:13]=[O:14])=[CH:11][NH:12][C:8]=1[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=Cc1c[nH]c(-c2ccccc2F)c1
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1c[nH]c(-c2ccccc2F)c1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 46.5 %

Procedure:
To a solution (15 mL) of 5-(2-fluorophenyl)-1H-pyrrole-3-carbaldehyde (1.0 g) in N,N-dimethylformamide was added N-chlorosuccinimide (0.71 g) at 0° C., and the mixture was stirred at 60° C. for 2 hr. The mixture was cooled to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=8:1→3:1) to give the title compound as a yellow powder (yield 0.55 g, 46%).
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([CH:13]=[CH:14][C:15]([OH:17])=O)=[CH:4]2.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][NH2:32])[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].P(C#N)(OCC)(OCC)=O.C(=O)([O-])O.[Na+]>CN(C)C=O.C(N(CC)CC)C>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][NH:32][C:15](=[O:17])[CH:14]=[CH:13][C:5]2[S:6][C:7]3[N:12]4[C:3](=[CH:2][N:1]=[C:11]4[CH:10]=[CH:9][CH:8]=3)[CH:4]=2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: O=C(O)C=CC1=Cc2cnc3cccc(n23)S1
Agent: CCOP(=O)(C#N)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CNC(=O)C=CC2=Cc3cnc4cccc(n34)S2)CC1
Reaction time: 8 h

Procedure:
While 0.708 g (2.898 mM) of 3-(5-thia-1,8b-diazaacenaphthylen-4-yl)acrylic acid, 0.68 g (3.19 mM) of 1-(tert-butoxycarbonyl)piperidin-4-ylmethylamine, and 0.48 ml (3.48 mM) of triethylamine were stirred together in 10 ml of N,N-dimethylformamide, 0.53 ml (3.48 mM) of diethyl cyanophosphate was added dropwise at room temperature and the mixture was stirred at the prevailing temperature overnight. This reaction mixture was poured in aqueous solution of sodium hydrogen carbonate and extracted with 3 portions of ethyl acetate. The organic layers were pooled and dried over MgSO4 and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate to ethyl acetate-methanol=9/1) to provide crude N-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-3-(5-thia-1,8b-diazaacenaphthylen-4-yl)acrylamide.
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[N:13][N:12]([OH:15])[C:11]=3[CH:16]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH:24]([CH3:26])[CH3:25]>CS(C)=O>[N:1]1([CH2:6][C:7]2[CH:8]=[CH:9][C:10]3[N:14]=[N:13][N:12]([O:15][CH:24]([CH3:26])[CH3:25])[C:11]=3[CH:16]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: On1nnc2ccc(Cn3ccnc3)cc21
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)On1nnc2ccc(Cn3ccnc3)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.5 %

Procedure:
A mixture of 3.23 parts of 6-(1H-imidazol-1-ylmethyl)-1H-benzotriazol-1-ol, 2.07 parts of potassium carbonate and 20 parts of dimethyl sulfoxide was stirred for 10 minutes at room temperature. Then there were added 2.55 parts of 2-iodopropane and stirring was continued first for 15 minutes at room temperature and then for 1 hour at 50° C. The reaction mixture was evaporated. 50 Parts of water were added. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 14 parts of 1,1'-oxybisethane. The product was filtered off and dried, yielding 3.3 parts (85.5%) of 6-(1H-imidazol-1-ylmethyl)-1-(1-methylethoxy)-1H-benzotriazole; mp. 114.3° C. (compound 195).
Reaction SMILES: [C:1]([NH:9][CH2:10][C:11]1([CH2:20][OH:21])[CH:16]([OH:17])[CH:15]([OH:18])[CH:14]([OH:19])[CH2:13][NH:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].[C:26](O)(=O)[CH3:27]>CO.O>[CH2:1]([N:12]1[CH2:13][CH:14]([OH:19])[CH:15]([OH:18])[CH:16]([OH:17])[C:11]1([CH2:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:26][CH3:27]
Reactant: O=C(NCC1(CO)NCC(O)C(O)C1O)c1ccccc1
Reactant: CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCCCCCCN1CC(O)C(O)C(O)C1(CO)CNC(=O)c1ccccc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
2.96 g of 2-benzoylaminomethyl-2-hydroxymethyl-3,4,5-trihydroxypiperidine (Example 3) are dissolved in a mixture of 40 ml of methanol, 2 ml of water and 2.7 ml of acetic acid, and 5.7 ml of nonylaldehyde are added. The solution is cooled to 5° C. in an ice-bath; 1.35 g of sodium cyanoborohydride are then added. The mixture is stirred for 30 minutes, whilst cooling, and then at room temperature for 24 hours. It is concentrated, the residue is dissolved in 30 ml of methanol/water 6:1 and the solution is discharged onto a column 30 cm long and 3 cm wide which is filled with Amberlite IR 120, H+ form. The column is washed thoroughly with methanol/water in the ratio 8:1 and then eluted with 0.2% strength ammonia in methanol/water 6:1. The pure fractions, determined by thin layer chromatography, are combined and concentrated. 2.6 g of an almost colourless oil are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:48]2[CH2:47][CH2:46][CH:45]([NH:44][C:36]3[NH:35][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=3)[CH2:50][CH2:49]2)([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(F)cc3)C2)cc(OC)c1OC
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Agent: I
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)cc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 4.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (2.65 g, 5.5 mmol) (prepared from (+)-1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine) and (1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt (3.9 g, 8.25 mmol) to give, after chromatography on silica gel eluting with methanol/ethyl acetate 1/1, the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[CH:6][C:7]=1[F:8].CCN(CC)CC.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)Cl>[CH3:18][S:19]([O:10][CH2:9][C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Br:1])[CH:3]=1)(=[O:21])=[O:20]
Reactant: OCc1ccc(F)c(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCc1ccc(F)c(Br)c1
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a solution of (3-bromo-4-fluorophenyl)methanol (53 g, 0.258 mol) in DCM (500 mL) at 0° C. was added Et3N (108 mL, 775 mmol, 3 eq) and methanesulfonyl chloride (24 mL, 310 mmol, 1.2 eq) successively. After stirring 30 min, the reaction mixture was partitioned in DCM and water. The organic layer was dried over MgSO4 and evaporated in vacuo to give 3-bromo-4-fluorobenzyl methanesulfonate (60 g), which used to the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.65-7.62 (m, 1H), 7.37-7.33 (m, 1H), 7.16 (t, J=4.4 Hz, 1H), 5.17 (s, 2H), 2.99 (s, 3H).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]2[C:20]3[N:19]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[NH:17][C:16]=3[CH:15]=[CH:14][CH:13]=2)=[O:11])[CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([CH:47]=O)[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[C:34]([O:38][C:39]([N:41]1[CH2:46][CH2:45][CH:44]([CH2:47][N:2]2[CH2:7][CH2:6][CH:5]([CH2:8][NH:9][C:10]([C:12]3[C:20]4[N:19]=[C:18]([C:21]([CH3:24])([CH3:23])[CH3:22])[NH:17][C:16]=4[CH:15]=[CH:14][CH:13]=3)=[O:11])[CH2:4][CH2:3]2)[CH2:43][CH2:42]1)=[O:40])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1nc2c(C(=O)NCC3CCNCC3)cccc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCC(C=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CN2CCC(CNC(=O)c3cccc4[nH]c(C(C)(C)C)nc34)CC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.8 %

Procedure:
To a suspension of the bis HCl salt of 2-tert-butyl-1H-benzoimidazole-4-carboxylic acid (piperidin-4-ylmethyl)amide (4.28 g, 11.06 mmol) in dichloromethane (55 mL) at room temperature was added N,N-diisopropylethylamine (1.71 g, 2.31 mL), 1-(tert-butoxycarbonyl)piperidine-4-carboxaldehyde (2.58 g, 12.17 mmol) and sodium triacetoxyborohydride (3.28 g, 15.48 mmol) sequentially. The resulting mixture was stirred at room temperature for 2 h then extracted with 1M aqueous hydrochloric acid. The combined aqueous layers were basified to pH 12 with sodium hydroxide pellets, then extracted with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered and evaporated. The resulting residue was dried under high vacuum to give a light brownish foam (4.9 g, 9.6 mmol, 87%) which was used without further purification. (m/z): [M+H]+ calcd for C29H45N5O3 512.35, found: 512.4.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[F:7][C:8]1[CH:13]=[CH:12][C:11](B(O)O)=[CH:10][CH:9]=1>>[F:7][C:8]1[CH:13]=[CH:12][C:11]([C:2]2[S:3][CH:4]=[CH:5][N:6]=2)=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1nccs1
Product: Fc1ccc(-c2nccs2)cc1

Procedure:
Using 2-bromothiazole (5.0 g, 30.482 mmol) and (4-fluorophenyl)boronic acid (8.528 g, 60.964 mmol) as reactants and following the procedure described in Example 7 step 1, the title compound was obtained after purification by flash chromatography (60-120μ; 4% ethyl acetate in hexane) as colorless liquid (5.0 g, 91% yield). 1H NMR (400 MHz, DMSO-d6): δ 8.00-7.89 (m, 2H), 7.90 (d, 1H), 7.76 (d, 1H), 7.32 (t, 2H); LC-MS m/z calculated for [M+H]+180.02. found 180.1.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24]OS(C3C=CC(C)=CC=3)(=O)=O)[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:36]([NH2:39])([CH3:38])[CH3:37]>>[CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:39][CH:36]([CH3:38])[CH3:37])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)OCc2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)cc1
Reactant: CC(C)N
Product: CC(C)NCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1

Procedure:
Method as for preparation 5 using tert-butyl(3R)-6-cyclohexyl-3-[3-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,2,4-oxadiazol-5-yl]hexanoate (preparation 177) (490 mg, 0.97 mmol) and isopropylamine (175 mg, 3.00 mmol) as starting materials.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]2[O:16][CH2:15]2)=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[NH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=2)=[CH:25][C:24]=1[Cl:36]>>[CH2:1]([O:5][CH2:6][CH2:7][C:8]1[CH:18]=[CH:17][C:11]([O:12][CH2:13][CH:14]([OH:16])[CH2:15][NH:19][CH2:20][CH2:21][O:22][C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH2:30][CH2:31][C:32](=[O:35])[NH:33][N:34]=3)=[CH:25][C:24]=2[Cl:36])=[CH:10][CH:9]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: NCCOc1ccc(C2=NNC(=O)CC2)cc1Cl
Reactant: CC(C)COCCc1ccc(OCC2CO2)cc1
Product: CC(C)COCCc1ccc(OCC(O)CNCCOc2ccc(C3=NNC(=O)CC3)cc2Cl)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-isobutoxy-ethyl)-phenoxy]-2,3-epoxypropane and 6-[4-(2-aminoethoxy)-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[N:23]1([CH:28]2[CH2:32][CH2:31][NH:30][CH2:29]2)[CH:27]=[N:26][CH:25]=[N:24]1.C1CCN2C(=NCCC2)CC1>N1C=CC=CC=1>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([CH3:17])[C:10]([F:16])=[C:11]([N:30]4[CH2:31][CH2:32][CH:28]([N:23]5[CH:27]=[N:26][CH:25]=[N:24]5)[CH2:29]4)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: c1ncn(C2CCNC2)n1
Reactant: Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1c(F)c(N2CCC(n3cncn3)C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Yield: 28.9 %

Procedure:
1-Cyclopropyl-5-methyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (30 mg, 0.1 mmol) was reacted with 40 mg (0.2 mmol) of 3-(1,2,4-triazol-1-yl)pyrrolidine hydrochloride in 2 ml of pyridine in the presence of 70 mg (0.45 mmol) of DBU at 95° C. overnight. The orange solution was evaporated to dryness and to the residue water was added. The orange solid was collected and washed with methanol to yield 19 mg of the crude product, which upon further purification from methanol yielded 12 mg of the desired product. m.p. 207°-210° C. 1H NMR (TFA) δ: 9.81 (s, 1H), 9.27 (s, 1H), 8.78 (s, 1H), 5.75-5.55 (m, 1H), 4.83-4.12 (m, 5H), 3.0-2.7 (m, 5H), 1.7-1.2 (m, 4H). Anal. calcd. for C20H19F2N5O3H2O: C, 55.43; H, 4.88; N, 16.16. Found: C, 55.72; H, 4.73; N, 15.65.
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][C:24]1([CH3:27])[CH2:26][O:25]1>CO.O1CCCC1>[CH2:16]([N:8]([CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:23][C:24]([CH3:27])([OH:25])[CH3:26])[CH2:14][CH2:15]1)[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)CO1
Reactant: c1ccc(CN(Cc2ccccc2)CC2CCNCC2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(O)CN1CCC(CN(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 40 °C
Reaction time: 17 h
Yield: 73 %

Procedure:
A mixture of N,N-dibenzyl-N-(piperidin-4-ylmethyl)amine (EXAMPLE 4, Step 3, 3.3 g, 11.21 mmol) and 2,2-dimethyloxirane (12.1 mL, 134.5 mmol) in methanol (40 mL) and tetrahydrofuran (5 mL) was heated at 40° C. with stirring for 17 h. The volatile components were removed and the residue was purified by flash column chromatography on amine gel eluting with hexane/ethyl acetate (50:1) to afford 3.0 g (73%) of the title compound as a colorless amorphous.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2].[S:22]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[CH:24]=[C:23]1B(O)O>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:23]4[S:22][C:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=5[CH:24]=4)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: OB(O)c1cc2ccccc2s1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1
Product: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3cc4ccccc4s3)ccc2o1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and benzothiophene-2-boronic acid (306 mg, 1.71 mmol) the subtitle compound was obtained (569 mg, 123%). The product was used directly in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][C:15]([OH:17])=O)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH:27]([NH2:31])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH2:28][CH:27]([NH:31][C:15](=[O:17])[CH2:14][C:10]2[S:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)=[N:12][C:11]=2[CH3:13])[CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCCC(N)C1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1CC(=O)O
Product: Cc1nc(-c2ccc(Cl)cc2)sc1CC(=O)NC1CCCN(C(=O)OC(C)(C)C)C1
Yield: 59 %

Procedure:
Using 2-[2-(4-chlorophenyl)-4-methylthiazol-5-yl]acetic acid (1.60 g, 5.99 mmol) and 1-(tert-butoxycarbonyl)-3-aminopiperidine (1.20 g, 5.99 mmol), the same procedure was followed as in Step 1a of Example 1 to give 1.59 g (59%) of the desired compound as a colorless powder.