Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[C:11]1[CH:38]=[C:37]([CH3:39])[C:14]2[N:15]=[C:16]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([S:26]([NH:29][CH2:30][CH2:31][N:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)(=[O:28])=[O:27])=[CH:22][CH:21]=3)[N:17]=[N:18][C:13]=2[CH:12]=1>CO>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:11]2[CH:38]=[C:37]([CH3:39])[C:14]3[N:15]=[C:16]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([S:26]([NH:29][CH2:30][CH2:31][N:32]5[CH2:36][CH2:35][CH2:34][CH2:33]5)(=[O:27])=[O:28])=[CH:24][CH:25]=4)[N:17]=[N:18][C:13]=3[CH:12]=2)[CH:4]=1
Reactant: Cc1cc(-c2cc([N+](=O)[O-])ccc2Cl)cc2nnc(Nc3ccc(S(=O)(=O)NCCN4CCCC4)cc3)nc12
Solvent: CO
Product: Cc1cc(-c2cc(N)ccc2Cl)cc2nnc(Nc3ccc(S(=O)(=O)NCCN4CCCC4)cc3)nc12
Reaction time: 4 h

Procedure:
4-[7-(2-chloro-5-nitro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (0.41 mmol, 1.0 equiv) was dissolved in 20 mL of MeOH, and the reaction was evacuated of air by vacuum and placed under a blanket of argon. Pd/C (10% by wt) was added to the reaction, followed by another evacuation of argon, and by blanketing with hydrogen. The reaction was stirred under hydrogen blanket for 4 h, filtered through Celite, and concentrated by reduced pressure to give a crude residue, which was precipitated using EtOAc/hexanes (1:5 v/v) to give 4-[7-(5-amino-2-chloro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide, as a dark green solid (89.4 mg, 41% yield). 1H NMR (DMSO-d6): δ 1.61 (m, 4H), 2.34 (m, 4H), 2.42 (t, J=6.9 Hz, 2H), 2.71 (s, 3H), 2.85 (t, J=7.1 Hz, 2H), 5.43 (s, 1H), 6.65 (dd, J=8.7 Hz, J=2.8 Hz, 1H), 6.73 (d, J=2.7 Hz, 1H), 7.21 (d, J=8.7 Hz, 1H), 7.83 (d, J=8.9 Hz, 2H), 7.89 (s, 1H), 8.15 (s, 1H), 8.21 (d, J=8.8 Hz, 2H). MS (ES+) m/z=538, LC retention time 2.13 min.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[C:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)#[N:18]>>[C:17]([C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:7]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=[C:4]([CH:3]=2)[C:14]([OH:16])=[O:15])=[CH:21][CH:20]=1)#[N:18]
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: N#Cc1ccc(B(O)O)cc1
Product: N#Cc1ccc(-c2cc(C(=O)O)cnc2OCC(F)(F)F)cc1

Procedure:
The title compound was synthesized in analogy to Example BQ using 5-bromo-6-(2,2,2-trifluoroethoxy)-3-pyridinecarboxylic acid (CAN 1211586-75-2) and B-(4-cyanophenyl)-boronic acid, (CAN 126747-14-6) as starting materials; MS (ESI): 321.2 (M−H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[CH2:12][N:13]([CH3:30])[C:14](=[O:29])[N:15]([CH:16]4[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]4)[C:5]=3[C:4]=2[N:3]=1.[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:31][O:32][C:33]1[N:38]=[CH:37][C:36]([C:2]2[CH:11]=[CH:10][C:9]3[N:8]=[CH:7][C:6]4[CH2:12][N:13]([CH3:30])[C:14](=[O:29])[N:15]([CH:16]5[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]5)[C:5]=4[C:4]=3[N:3]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(B(O)O)cn1
Reactant: CN1Cc2cnc3ccc(Cl)nc3c2N(C2CCN(C(=O)OC(C)(C)C)CC2)C1=O
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: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2ccc3ncc4c(c3n2)N(C2CCN(C(=O)OC(C)(C)C)CC2)C(=O)N(C)C4)cn1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
tert-butyl 4-(9-chloro-3-methyl-2-oxo-3,4-dihydropyrimido[5,4-c][1,5]naphthyridin-1(2H)-yl)piperidine-1-carboxylate (0.104 g, 0.241 mmol) and 6-methoxy-3-pyridine boronic acid (40.7 mg, 0.266 mmol) were dissolved in toluene (6 mL) and ethanol (2 mL), and to the system added tetrakis(triphenylphosphine)palladium (5 mg) and 2N sodium carbonate solution (0.36 mL), reacted under reflux under nitrogen for 16 h, cooled to room temperature, filtered and the organic layer was concentrated under reduced pressure and dissolved in 30 mL of dichloromethane, followed by washing sequentially with water and saturated brine, dried over anhydrous sodium sulfate, concentrated and subjected to silica gel column chromatography (ethyl acetate:petroleum ether=2:1) to give 75 mg of the product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=[O:15])[N:12]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:25][C:26]1[N:27]=[CH:28][S:29][CH:30]=1>>[CH3:21][C@@H:17]1[CH2:18][CH2:19][CH2:20][N:16]1[C:14](=[O:15])[CH2:13][C:11]1[N:12]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:25][C:26]3[N:27]=[CH:28][S:29][CH:30]=3)=[CH:3][CH:4]=2)[O:9][C:10]=1[CH3:22]
Reactant: Cc1oc(-c2ccc(O)cc2)nc1CC(=O)N1CCC[C@H]1C
Reactant: ClCc1cscn1
Agent: Cl
Product: Cc1oc(-c2ccc(OCc3cscn3)cc2)nc1CC(=O)N1CCC[C@H]1C

Procedure:
The title compound is prepared in a manner substantially similar to Intermediate 16 from 2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-1-(2-(R)-methyl-pyrrolidin-1-yl)-ethanone (See Intermediate 62) and 4-(chloromethyl)thiazole hydrochloride except KI (1.5 eq.) is also added. MS (ES+) 398.3
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][F:13])[N:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH3:23])=[CH:18][CH:17]=1.Cl.C([O-])(O)=O.[Na+]>C(O)(C)C>[F:13][CH2:12][C:4]1[N:3]=[C:2]([N:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=2)[CH3:23])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: CNc1ccc(OC)cc1
Reactant: FCc1nc(Cl)c2ccccc2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ccc(N(C)c2nc(CF)nc3ccccc23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.5 %

Procedure:
(2-Fluoromethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: A suspension of 2-fluoromethyl-quinazolin-4(3H)-one (70 mg, 0.39 mmol) in phosphoryl chloride (2 ml) and N,N-dimethylaniline (0.035 ml, 0.27 mmol) was heated under reflux for 12 hours. The reaction mixture was poured onto ice and the precipitate was collected by filtration, then washed and dried to give 4-chloro-2-fluoromethyl-quinazoline, which was used directly for the next reaction. To a solution of 4-chloro-2-fluoromethyl-quinazoline with (4-methoxy-phenyl)-methylamine (160 mg, 1.2 mmol) in isopropyl alcohol (5 ml) was added concentrated HCl (0.05 ml) and the solution was stirred at room temperature overnight. The solution was neutralized with saturated aqueous NaHCO3, and was extracted by ethyl acetate. The extracts were evaporated, and the residue was purified by column chromatography on silica gel with ethyl acetate and hexane (1:1) as eluent, yielding 11 mg (9.5%) of the title compound. 1H NMR (CDCl3): 7.87-7.84 (m, 1H), 7.60-7.54 (m, 1H), 7.14-7.10 (m, 2H), 7.04-7.01 (m, 2H), 6.95-6.91 (m, 2H), 5.60 (s, 1H), 5.44 (s, 1H), 3.85 (s, 3H), 3.60 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2([C:20]3[CH:21]=[N:22][CH:23]=[N:24][CH:25]=3)[C:17]3[C:12](=[C:13]([F:18])[CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:19])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[F:26][C:27]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[CH:29][C:28]=1[C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([C:9]2([C:20]3[CH:21]=[N:22][CH:23]=[N:24][CH:25]=3)[C:17]3[C:12](=[C:13]([F:18])[CH:14]=[CH:15][CH:16]=3)[C:11]([NH2:19])=[N:10]2)[CH:3]=1
Reactant: COc1cccc(B(O)O)c1F
Reactant: NC1=NC(c2cncnc2)(c2ccc(F)c(Br)c2)c2cccc(F)c21
Product: COc1cccc(-c2cc(C3(c4cncnc4)N=C(N)c4c(F)cccc43)ccc2F)c1F
Yield: 18 %

Procedure:
The title compound was synthesized as described for Example 12 in 18% yield, starting from 1-(3-bromo-4-fluorophenyl)-4-fluoro-1-(pyrimidin-5-yl)-1H-isoindol-3-amine (59.6 mg, 0.15 mmol) and 2-fluoro-3-methoxybenzeneboronic acid (59.5 mg, 0.35 mmol); 1H NMR (500 MHz, DMSO-d6)6 ppm 9.08 (s, 1 H) 8.74 (s, 2 H) 7.81 (d, 1 H) 7.53-7.60 (m, 1 H) 7.42-7.49 (m, 1 H) 7.37 (dd, 1 H) 7.25-7.33 (m, 2 H) 7.18-7.25 (m, 2 H) 6.87-6.93 (m, 1 H) 6.77 (br. s., 2 H) 3.85 (s, 3 H). MS (ES−) m/z 445 [M−H]−
Reaction SMILES: F[C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH:12]1([OH:16])[CH2:15][CH2:14][CH2:13]1>>[CH:12]1([O:16][C:2]2[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: Cc1cc(C(=O)O)cnc1F
Reactant: OC1CCC1
Product: Cc1cc(C(=O)O)cnc1OC1CCC1
Yield: 88 %

Procedure:
The title compound is prepared in 88% yield (1.18 g, white solid) from 6-fluoro-5-methylnicotinic acid (1.00 g, 6.45 mmol) and cyclobutanol (837 mg, 11.6 mmol) in a similar manner to Step-1 of Amine-1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([CH3:11])=[CH:4][N+:3]=1[O-].COS(OC)(=O)=O.[C-:20]#[N:21].[K+]>>[CH3:11][C:5]1[C:4]([C:20]#[N:21])=[N:3][C:2]([CH3:1])=[CH:7][C:6]=1[N+:8]([O-:10])=[O:9]
Reactant: [C-]#N
Reactant: Cc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Product: Cc1cc([N+](=O)[O-])c(C)c(C#N)n1

Procedure:
The title compound, was prepared by treatment of 2,5-Dimethyl-4-nitropyridine-N-oxide (CAS: [21816-42-2], J. Heterocyclic Chem. 34(3), 727(1997)) with Dimethylsulfate and Potassium cyanide in accordance with the general method of example 1, step 1 to yield the title compound as a brown solid.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][CH:21]=[C:20]([OH:25])[CH:19]=3)=[O:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:26]([NH2:30])[CH2:27][CH2:28][CH3:29].COCCOC>[O-2].[O-2].[Mn+4]>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:19]4[N:30]=[C:26]([CH2:27][CH2:28][CH3:29])[O:25][C:20]=4[CH:21]=[CH:22][C:23]=3[CH:24]=2)=[O:15])[CH2:12][CH2:13]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1cc2ccc(O)cc2[nH]1)N1CCC(Cc2ccccc2)CC1
Reactant: CCCCN
Agent: [Mn+4]
Agent: [O-2]
Solvent: COCCOC
Product: CCCc1nc2c(ccc3cc(C(=O)N4CCC(Cc5ccccc5)CC4)[nH]c32)o1
Reaction time: 1 h
Yield: 124.5 %

Procedure:
Under argon, to a solution of 0.5 g (1.49 mmol) of 1-(4-benzylpiperidine-1-yl)-1-(6-hydroxy-1H-indole-2-yl)methanone and 0.14 g (0.2 mmol) of n-butylamine in 100 ml of ethylene glycol dimethyl ether 10 g (115 mmol) of manganese dioxide is added portion-wise at 0° C. After stirring for 1 h, the reaction mixture is filtered, the filtrate is concentrated and the residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and hexane:ethyl acetate=2:1 as eluent to yield 0.1 g (17.3%) of the title compound. Mp.: 195-196° C. (hexane-ethyl acetate).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[C:36]([CH3:37])=[CH:35][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:32]=[CH:31][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:21][CH:20]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:6][C:5]=1[CH3:38].[C:39](OC(=O)C)(=[O:41])[CH3:40].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.O1CCCC1>[ClH:1].[C:39]([NH:3][C:4]1[C:5]([CH3:38])=[CH:6][C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]3[N:16]=[C:15]([CH2:17][O:18][C:19]4[CH:20]=[CH:21][C:22]([CH2:23][CH:24]5[S:28][C:27](=[O:29])[NH:26][C:25]5=[O:30])=[CH:31][CH:32]=4)[N:14]([CH3:33])[C:13]=3[CH:34]=2)=[CH:35][C:36]=1[CH3:37])(=[O:41])[CH3:40]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc(C)c1N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1c(C)cc(Oc2ccc3nc(COc4ccc(CC5SC(=O)NC5=O)cc4)n(C)c3c2)cc1C
Temperature: 25 °C
Reaction time: 21 h
Yield: 62 %

Procedure:
A mixture of 155 mg of 5-{4-[6-(4-amino-3,5-dimethylphenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl}thiazolidine-2,4-dione dihydrochloride, 36 mg of acetic anhydride, 107 mg of pyridine, 7.3 mg of 4-(N,N-dimethylamino)pyridine and 5 ml of anhydrous tetrahydrofuran was heated under reflux for 2 hours. The reaction mixture was concentrated by evaporation. Water was added to the concentrate, followed by extraction with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. To the residue, 10 ml of 4N hydrochloric acid/ethyl acetate were added, followed by stirring at room temperature for 21 hours. The insoluble product was collected by filtration, followed by washing with ether, whereby 97 mg of the title compound were obtained.
Reaction SMILES: O(P(O[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1)(OC1C=CC=CC=1)=O)C1C=CC=CC=1.[O:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[CH:33]=[C:32]1B(O)O>>[O:31]1[C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[CH:33]=[C:32]1[C:18]1[N:19]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH2:21][O:22][CH:23]=1
Reactant: OB(O)c1cc2ccccc2o1
Reactant: CC(C)(C)OC(=O)N1CCOC=C1OP(=O)(Oc1ccccc1)Oc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOC=C1c1cc2ccccc2o1
Yield: 58 %

Procedure:
This compound was prepared from tert-butyl 5-((diphenoxyphosphoryl)oxy)-2H-1,4-oxazine-4(3H)-carboxylate and benzofuran-2-ylboronic acid using a procedure similar to that described in Example 2 (Steps 1-3a) above. The product was isolated as a yellow solid (58% yield); 1H-NMR (d6-DMSO) 1.08 (9H, s), 3.70 (2H, m), 4.18 (3H, m), 6.68 (1H, s), 6.77 (1H, s), 7.18-7.25 (2H, m), 7.48-7.56 (2H, m); 13C-NMR (CDCl3) 27.7, 41.3, 67.2, 100.7, 110.6, 120.4, 122.8, 123.4, 134.2; MS ES(+) 246.1 (M+-tBu); Anal. Calcd for C17H19NO4: C, 67.76; H, 6.35; N, 4.65. Found: C, 67.34; H, 6.38; N, 4.68. IR λmax=1690 cm−1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1O>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]1[O:6][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: Nc1ccccc1O
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Product: Clc1ccc(Cl)c(-c2nc3ccccc3o2)c1
Reaction time: 16 h
Yield: 47.2 %

Procedure:
2,5-Dichlorobenzoic acid (800 g, 4.2 mol), 2-aminophenol (415 g, 3.8 mol) and polyphosphoric acid (1600 g) were placed in a flask and heated at 180°-190° C. for 2 days. The viscous dark solution was poured onto ice while hot. The solid was collected by filtration and washed with water thoroughly. The solid cake was transferred into a large beaker and stirred with 2 liters of saturated aqueous sodium bicarbonate for 16 hours. The brownish suspension was filtered and washed with water and dried at 80° C. overnight to give 1 kg of crude product. The crude product was purified by recrystallization from cyclohexane twice to give 474 g of monomer as white crystals.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.Cl[CH2:10][C:11]([N:13]1[CH2:34][CH2:33][C:16]2([C:20](=[O:21])[N:19]([C:22]3[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:15][CH2:14]1)=[O:12]>C1COCC1.C(Cl)(Cl)Cl>[CH:3]1([O:8][CH2:10][C:11]([N:13]2[CH2:14][CH2:15][C:16]3([C:20](=[O:21])[N:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][C:29]([F:30])([F:31])[F:32])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)[CH2:33][CH2:34]2)=[O:12])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: OC1CCCC1
Reactant: O=C(CCl)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(COC1CCCC1)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 33 %

Procedure:
To a suspension of NaH (5 mg, 0.13 mmol) in THF (2 mL) at 0° C. was added cyclopentanol (10 uL, 0.11 mmol) and the mixture was stirred for 30 min at 0° C. A solution of 8-(2-chloro-acetyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (example 225, 42 mg, 0.11 mmol) in THF (500 uL) was added drop-wise and the reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was diluted with chloroform and the resultant precipitate was filtered off and the filtrate was concentrated in vacuo to give the crude residue which was purified by flash column chromatography (7:3 AcOEt/heptane) which afforded the desired product as a white solid (16 mg, 34%). MS (ESI): 441.3 (MH+).
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]([C:25]([O:27]C)=O)[CH2:16][CH2:17][NH:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[CH:11][CH:10]=1>C(Cl)Cl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:16][CH2:17][N:18]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=3)[C:25]2=[O:27])=[CH:11][CH:10]=1
Reactant: COC(=O)N(CCNc1cccnc1)c1ccc(Cl)cc1
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=C1N(c2ccc(Cl)cc2)CCN1c1cccnc1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
A 10 ml toluene solution of 4.54 g (14.8 mmol) of N-(4-chlorophenyl)-N-methoxycarbonyl-N'-(3-pyridyl)ethylenediamine in a 100 ml round-bottomed flask was heated gradually and, while distilling off toluene, it was heated for 1.5 hours at 190° to 210° C. The amorphous reaction mixture was cooled to room temperature and methylene chloride was added to dissolve. This was purified by column chromatography (silica gel, ethyl acetate:n-hexane=5:1) to obtain 2.28 g (yield 56%) of 1-(4-chlorophenyl)-3-(3-pyridyl)-2-imidazolidinone as brown crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH2:9][CH2:10][CH3:11])[C:3]=1[CH2:12][O:13][CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][O:15]1.[H-].[Na+].[CH3:22][O:23][CH2:24]Cl.O>CN(C)C=O>[Br:1][C:2]1[C:3]([CH2:12][O:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][O:15]2)=[C:4]([CH2:9][CH2:10][CH3:11])[C:5]([O:8][CH2:22][O:23][CH3:24])=[CH:6][CH:7]=1
Reactant: COCCl
Reactant: CCCc1c(O)ccc(Br)c1COC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1c(OCOC)ccc(Br)c1COC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.6 %

Procedure:
To a solution of 4-bromo-2-propyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]phenol (972 mg, 2.95 mmol) in N,N-dimethylformamide (5 mL), sodium hydride (55% in oil, 257 mg, 5.90 mmol) and chloromethyl methyl ether (475 mg, 5.90 mmol) were added at 0° C. The mixture was stirred at room temperature for 2 hours. The reaction solution was added with water and extracted with ethyl acetate. Subsequently, the organic layer was washed with saturated saline, dried using anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by silica-gel column chromatography (hexane/ethyl acetate), and the title compound (910 mg, 83%) was obtained as colorless oil.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[C:9]([C:11]([NH:13][C:14]2[O:15][C:16]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[N:17][N:18]=2)=[O:12])[CH:10]=1)(=[O:3])[CH3:2].[CH2:25]([C:27]1[CH:32]=[CH:31][C:30]([C:33]2[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=2)=[CH:29][CH:28]=1)[CH3:26]>>[C:1]([NH:4][C:5]1[CH:10]=[C:9]([C:11]([NH:13][C:14]2[O:15][C:16]([C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)=[N:17][N:18]=2)=[O:12])[CH:8]=[C:7]([C:36]2[CH:37]=[CH:38][C:33]([C:30]3[CH:29]=[CH:28][C:27]([CH2:25][CH3:26])=[CH:32][CH:31]=3)=[CH:34][CH:35]=2)[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cc(Br)cc(C(=O)Nc2nnc(-c3ccco3)o2)c1
Reactant: CCc1ccc(-c2ccc(B(O)O)cc2)cc1
Product: CCc1ccc(-c2ccc(-c3cc(NC(C)=O)cc(C(=O)Nc4nnc(-c5ccco5)o4)c3)cc2)cc1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 5-acetylamino-3-bromo-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]benzenecarboxamide prepared in Reference Example 38 instead of compound Ia-50 and using commercially available 4′-ethyl-4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[C:6]([CH:17]=1)[C:7]([O:9]CC1C=CC=CC=1)=[O:8].[OH-].[Li+].O>O1CCCC1>[Br:1][C:2]1[C:3]([CH2:26][N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)=[CH:4][C:5]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[C:6]([CH:17]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(OCc1ccccc1)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(CN2CCOCC2)cc1OCc1ccccc1

Procedure:
To a solution of phenylmethyl 5-bromo-4-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 6; 379 mg, 0.76 mmol) in tetrahydrofuran (6 ml) was added lithium hydroxide (110 mg, 4.58 mmol) followed by water (1.5 ml). The reaction was stirred over the weekend, the solvent removed in vacuo and purified by MDAP to yield the title compound as a solid. 249 mg.
Reaction SMILES: [CH2:1]([N:8]([CH2:22][CH2:23][NH:24][CH2:25][CH2:26][C:27]1[C:35]2[S:34][C:33](=[O:36])[NH:32][C:31]=2[C:30]([OH:37])=[CH:29][CH:28]=1)[C:9](=O)[CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.[CH3:39]O>O1CCCC1>[OH:37][C:30]1[C:31]2[NH:32][C:33](=[O:36])[S:34][C:35]=2[C:27]([CH2:26][CH2:25][NH:24][CH2:23][CH2:22][N:8]([CH2:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:1][CH2:2][C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:39]=2)=[CH:28][CH:29]=1
Reactant: CO
Reactant: O=C(CCOCCc1ccccc1)N(CCNCCc1ccc(O)c2[nH]c(=O)sc12)Cc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: O=c1[nH]c2c(O)ccc(CCNCCN(CCCOCCc3ccccc3)CCc3ccccc3)c2s1
Temperature: 0 °C

Procedure:
N-Benzyl-N-[2-[2-(4-hydroxy-2-oxo-3H-benzothiazol-7-yl)ethylamino]ethyl]-3-phenethyloxy-propanamide (Example 4, 0.1 g) was dissolved in tetrahydrofuran (6 mL) and treated with borane (1M in tetrahydrofuran, 1 mL) at room temperature. The resultant solution was heated at 50° C. for 3 hours. The reaction was then cooled to 0° C. and methanol (6 mL) was added dropwise. Following this, the mixture was concentrated and the collected residue was dissolved in methanol (6 mL) and treated with concentrated hydrochloric acid (1.6 mL). The acidic solution was heated at 60° C. for 14 hours, then cooled to room temperature and concentrated. The resulting residue was purified by preparative HPLC (95:05, ammonia (0.2%):acetonitrile) to give the titled compound (0.035 g) as a glass like solid.
Reaction SMILES: I.CS[C:4](=[N:17][CH3:18])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[CH2:19]([NH2:22])[CH:20]=[CH2:21].[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27]>C(O)C>[C:23]([OH:30])(=[O:29])/[CH:24]=[CH:25]/[C:26]([OH:28])=[O:27].[CH2:19]([NH:22][C:4]([NH:17][CH3:18])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1)[CH:20]=[CH2:21]
Reactant: CN=C(Nc1ccccc1N1CCCC1)SC
Reactant: C=CCN
Agent: I
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: C=CCNC(=Nc1ccccc1N1CCCC1)NC
Reaction time: 1200 h

Procedure:
A mixture of 2-methyl-1-[2-(1-pyrrolidinyl)phenyl]-3-methyl-2-thiopseudourea hydroiodide (14.7 g), allylamine (4.45 g) and ethanol (65 ml) was stored at ambient temperature for 50 days and was then heated under reflux for 20 hours to give an oil which was treated with fumaric acid to give 1-allyl-2-[2-(1-pyrrolidinyl)phenyl]-3-methylguanidine monofumarate (m.p. 162°-163° C.) which was recrystallised from a 1:2 mixture of methanol and ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][N:7]1[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]1.Cl.[NH2:18][OH:19]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:14]=[CH:15][CH:16]=1)[CH2:6][N:7]1[CH2:12][CH2:11][C:10](=[N:18][OH:19])[CH2:9][CH2:8]1
Reactant: NO
Reactant: COc1cccc(CN2CCC(=O)CC2)c1
Agent: Cl
Product: COc1cccc(CN2CCC(=NO)CC2)c1

Procedure:
1-(3-Methoxybenzyl)-4-piperidone oxime is prepared from 1-(3-methoxybenzyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.