Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24](O)=[O:25])=[CH:9][N:8]=1)[CH2:2]2.[N:27]1([CH2:33][CH2:34][NH2:35])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[CH:1]12[CH2:6][CH:5]1[CH2:4][N:3]([C:7]1[N:12]=[C:11]([NH:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([Cl:23])[CH:16]=3)[C:10]([C:24]([NH:35][CH2:34][CH2:33][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:25])=[CH:9][N:8]=1)[CH2:2]2
Reactant: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)O)cc1Cl
Reactant: NCCN1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CNc2nc(N3CC4CC4C3)ncc2C(=O)NCCN2CCOCC2)cc1Cl
Reaction time: 18 h
Yield: 36.4 %

Procedure:
In THF (10 mL) were dissolved 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-pyrimidine-5-carboxylic acid (150 mg, 0.40 mmol), 2-morpholinylethylamine (59 mg, 0.45 mmol) and triethylamine (101 mg, 1 mmol). The reaction mixture was cooled in an ice bath and HATU (266 mg, 0.70 mmol) was added. The reaction was conducted at ambient temperature for 18 h. The reaction mixture was concentrated, followed by addition of water and extraction with ethyl acetate. The organic phase was dried, concentrated, and purified by silica gel column chromatography (DCM methanol=20/1) to give 2-(3-azabicyclo[3.1.0]hexan-3-yl)-4-((3-chloro-4-methoxybenzyl)amino)-N-(2-morpholinylethyl)pyrimidine-5-formamide (71 mg, 36.5% yield).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH2:4].C(=O)([O-])[O-].[Ca+2].Cl[CH2:19][CH:20]([OH:23])[CH2:21][OH:22]>O>[CH3:1][C:2]1[CH:8]=[C:7]([NH2:9])[C:6]([N+:10]([O-:12])=[O:11])=[CH:5][C:3]=1[NH:4][CH2:19][CH:20]([OH:23])[CH2:21][OH:22]
Reactant: Cc1cc(N)c([N+](=O)[O-])cc1N
Reactant: OCC(O)CCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: Cc1cc(N)c([N+](=O)[O-])cc1NCC(O)CO
Temperature: 0 °C

Procedure:
0.2 mol (33.4 g) of 2-methyl-4-amino-5-nitroaniline and 0.1 mol (10 g) of calcium carbonate suspended in 100 ml of water are first heated on a boiling waterbath, while stirring. 0.216 mol (24 g) of 1-chloropropane-2,3-diol is added. The reaction mixture is heated on a boiling waterbath for 24 hours, 0.035 mol (3.5 g) of calcium carbonate and 0.066 mol (7.3 g) of 1-chloropropane-2,3-diol being simultaneously added seven times at intervals of three hours. The reaction mixture is filtered hot and the filtrate is diluted with 60 ml of water. After the filtrate has been cooled at 0° C. for 24 hours, the expected product, which has crystallised, is filtered off with suction. The product is washed with water and recrystallised three times from ethanol. It has a melting point of 150° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([CH2:7][NH:8][C:9]2[CH:18]=[CH:17][C:16]3[C:15]([NH:19][CH2:20][CH2:21][S:22][CH3:23])=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>ClCCl>[CH3:23][S:22]([CH2:21][CH2:20][NH:19][C:15]1[C:16]2[CH:17]=[CH:18][C:9]([NH:8][CH2:7][C:5]3[O:6][C:2]([CH3:1])=[CH:3][CH:4]=3)=[N:10][C:11]=2[CH:12]=[CH:13][CH:14]=1)=[O:32]
Reactant: CSCCNc1cccc2nc(NCc3ccc(C)o3)ccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(CNc2ccc3c(NCCS(C)=O)cccc3n2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N2-(5-Methyl-furan-2-ylmethyl)-N5-(2-methylsulfanyl-ethyl)-quinoline-2,5-diamine (200 mg, 0.61 mmol) were dissolved in 6.5 mL dichloromethane and meta-chloro-perbenzoic acid was added (220 mg, 1.3 mmol). The reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched by addition of 10 mL water and 10 mL 2N sodium carbonate solution. The mixture was extracted three times with ethyl acetate (50 mL each). The organic phases ware pooled, dried with sodium sulfate, filtered and evaporated. The reaction mixture was purified by flash chromatography on silica gel (dichloromethane/methanol 100:0→90:10 gradient). The title compound was obtained as a white solid (60 mg, 29%), MS: m/e=344.3 (M+H+) together with N5-(2-methanesulfonyl-ethyl)-N2-(5-methyl-furan-2-ylmethyl)-quinoline-2,5-diamine.
Reaction SMILES: [NH2:1][C@@:2]([C:12]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]([Br:19])[N:13]=1)([CH2:10][F:11])[CH2:3][C@H:4]([OH:9])[C:5]([F:8])([F:7])[F:6].[C:20]([N:28]=[C:29]=S)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.C([O-])(O)=O.[Na+]>CC#N>[Br:19][C:14]1[N:13]=[C:12]([C@:2]2([CH2:10][F:11])[CH2:3][C@@H:4]([C:5]([F:6])([F:8])[F:7])[O:9][C:29]([NH:28][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:1]2)[C:17]([F:18])=[CH:16][CH:15]=1
Reactant: N[C@@](CF)(C[C@H](O)C(F)(F)F)c1nc(Br)ccc1F
Reactant: O=C(N=C=S)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NC1=N[C@](CF)(c2nc(Br)ccc2F)C[C@@H](C(F)(F)F)O1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.5 %

Procedure:
To a 150 mL round-bottomed flask was added (2S,4S)-4-amino-4-(6-bromo-3-fluoropyridin-2-yl)-1,1,1,5-tetrafluoropentan-2-ol (1.54 g, 4.41 mmol), MeCN (30 mL) and benzoyl isothiocyanate (Aldrich; 0.712 mL, 5.29 mmol). The reaction mixture was stirred at rt for 45 min and then 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl (Oakwook Products, Inc.; 1.015 g, 5.29 mmol) and N,N-diisopropylethylamine (Aldrich; 1.54 mL, 8.82 mmol) were added. The solution was stirred at rt for 2 h and then treated with sat NaHCO3 and extracted with EtOAc (2×100 mL). The combined extracts were washed with water (1×100 mL) and brine and then dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (Gradient: 0.0 to 20% EtOAc/hexane) afforded N-((4S,6S)-4-(6-bromo-3-fluoropyridin-2-yl)-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-2-yl)benzamide (1.74 g, 3.64 mmol, 82% yield) as an off-white foam. MS m/z=480.0 [M+H]+. Calculated for C18H13BrF5N3O2: 479.0.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[I:11].Cl.[CH3:13]O>>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:13])=[O:7])=[CH:4][C:3]=1[I:11]
Reactant: O=C(O)c1ccc(O)c(I)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(O)c(I)c1
Temperature: 65 °C
Yield: 36.3 %

Procedure:
4-Hydroxy-3-iodobenzoic acid (59.6 g, 226 mmol) is combined with 3N HCl/MeOH (276 mL, 678 mmol) and heated to 65° C. for 24 h, then concentrated to dryness. The residue is diluted with water, neutralized to pH 7 with 3N NaOH and the resulting solid collected via filtration. The crude material is adsorbed onto silica gel and chromatographed over 1 kg of silica gel with 50% EtOAc/hexane. Fractions containing product are combined and concentrated to a solid (47.2 g). The material is recrystallized from EtOAc to afford 22.8 g (36%) of methyl 4-hydroxy-3-iodobenzoate as a white solid. HRMS (FAB) calcd for C8H7IO3+H: 278.9520, found 278.9534 (M+H)+.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([C:11](=[O:17])[CH2:12][NH:13][CH:14]([CH3:16])[CH3:15])=[CH:5][C:4]=1[Cl:18].[BH4-].[Na+]>>[NH2:2][C:3]1[C:8]([C:9]#[N:10])=[CH:7][C:6]([CH:11]([OH:17])[CH2:12][NH:13][CH:14]([CH3:15])[CH3:16])=[CH:5][C:4]=1[Cl:18]
Reactant: CC(C)NCC(=O)c1cc(Cl)c(N)c(C#N)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CC(C)NCC(O)c1cc(Cl)c(N)c(C#N)c1

Procedure:
m.p. of the hydrochloride: 185°-188° C., was prepared from 4'-amino-3'-chloro-5'-cyano-2-isopropylamino-acetophenone and sodium borohydride analogous to Example 2.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[N:11](C)[CH2:10][CH2:9]2)([OH:3])=O.C1([C:24]([N:26]2[CH2:30][C@@H:29]([CH:31]3[CH2:33][CH2:32]3)[C@H:28]([CH2:34][N:35]3[CH2:40][CH2:39][CH:38]([C:41]4[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=4)[CH2:37][CH2:36]3)[CH2:27]2)=O)C2C(=CC=CC=2)C=CC=1>>[CH3:24][N:26]1[CH2:30][C@@H:29]([CH:31]2[CH2:32][CH2:33]2)[C@H:28]([CH2:34][N:35]2[CH2:40][CH2:39][CH:38]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[CH:43][CH:42]=3)[CH2:37][CH2:36]2)[CH:27]1[C:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][CH2:10][CH2:9]2)=[O:3]
Reactant: CN1CCc2cccc(C(=O)O)c21
Reactant: O=C(c1cccc2ccccc12)N1C[C@@H](CN2CCC(c3ccc(F)cc3)CC2)[C@H](C2CC2)C1
Product: CN1C[C@@H](C2CC2)[C@H](CN2CCC(c3ccc(F)cc3)CC2)C1C(=O)c1cccc2c1NCC2

Procedure:
The title compound was prepared from 7-carboxy-N-methylindoline and 3-(S)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(S)-(cyclopropyl)pyrrolidine (Example 9) as described in Example 11. Mass Spectrum (EI) m/e 462 (M+1).
Reaction SMILES: [Br-].[F:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][C:4]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C([Li])CCC.[F:41][C:42](=[C:45]([CH:53]1[CH2:55][CH2:54]1)[C:46]1[CH:51]=[CH:50][C:49]([Cl:52])=[CH:48][CH:47]=1)[CH:43]=O>O1CCCC1>[Cl:52][C:49]1[CH:48]=[CH:47][C:46]([C:45]([CH:53]2[CH2:55][CH2:54]2)=[C:42]([F:41])[CH:43]=[CH:7][C:6]2[CH:27]=[CH:28][C:3]([F:2])=[C:4]([O:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:5]=2)=[CH:51][CH:50]=1
Reactant: O=CC(F)=C(c1ccc(Cl)cc1)C1CC1
Reactant: Fc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1Oc1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: FC(C=Cc1ccc(F)c(Oc2ccccc2)c1)=C(c1ccc(Cl)cc1)C1CC1
Temperature: -2.5 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
A mixture of (4-fluoro-3-phenoxybenzyl)triphenyl phosphonium bromide (41.77 g, 0.077 mol) in tetrahydrofuran is cooled to 55 to −60° C., treated dropwise with a 2.5 M solution of butyllithium in hexanes (32.15 mL, 0.080 mol), warmed to and stirred at room temperature for 2 hours, cooled 55 to −60° C., treated dropwise with a solution of 2-fluoro-3-cyclopropyl-3-(p-chlorophenyl)acrylaldehyde (15.7 g, 0.070 mol) in tetrahydrofuran, warmed to and stirred at room temperature overnight, and quenched with ethyl acetate and 2 N hydrochloric acid. The resultant aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed sequentially with water, 2 N hydrochloric acid and water, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and an ethyl acetate/hexanes solution (1:9) gives the title product as an oil (26.0 g, 91%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[CH:5]=[C:4]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[N:3]=1.[C:20](Cl)(Cl)=[S:21]>O1CCOCC1>[F:11][C:10]([F:12])([F:13])[CH2:9][O:8][C:6]1[CH:5]=[C:4]([O:14][CH2:15][C:16]([F:19])([F:17])[F:18])[N:3]=[C:2]([N:1]=[C:20]=[S:21])[N:7]=1
Reactant: Nc1nc(OCC(F)(F)F)cc(OCC(F)(F)F)n1
Reactant: S=C(Cl)Cl
Solvent: C1COCCO1
Product: FC(F)(F)COc1cc(OCC(F)(F)F)nc(N=C=S)n1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
2-Amino-4,6-bis(2,2,2-trifluoroethoxy)pyrimidine (20.0 g, 68.7 mmol) was added to a solution of thiophosgene (15.7 mL, 206 mmol) in anhydrous dioxane (100 mL) under an N2 atmosphere. The resulting solution was heated to reflux. After 18 h the heat was removed and the reaction cooled to room temperature. The dioxane was evaporated to give a dark oil. The dark oil was distilled to afford the product as a light yellow oil (13.7 g, 60% yield); by 83-86° C., (ca 0.2 mmHg): 1H NMR (CDCl3) δ 6.24 (s 1H), 4.78 (q, 4H, J=8.2 Hz); GCMS (EI, 70 eV) m/z 333 (M+).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)[C:5]#[N:6]>CO>[NH2:1][C:2]1[C:3]([CH3:13])=[C:4]([CH:7]=[CH:8][C:9]=1[NH2:10])[C:5]#[N:6]
Reactant: Cc1c(C#N)ccc([N+](=O)[O-])c1N
Solvent: CO
Product: Cc1c(C#N)ccc(N)c1N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-amino-2-methyl-4-nitrobenzonitrile (250 mg, 1.41 mmol) in methanol (15 mL), palladium-activated carbon ethylene diamine complex (255 mg, 3.5%-6.5% Pd, 0.071 mmol) was added. The reaction was stirred at rt under hydrogen atmosphere for 2 hr. The catalyst was removed by filtration through Celite® pad. The Celite® pad was washed with MeOH. The collected filtrate was concentrated to give the title compound. MS (ESI+) m/z 148.0 (M+H).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].[H-].[Na+].[CH:8]1([C:14](Cl)=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.Cl>O1CCCC1>[CH:8]1([C:14]([OH:15])=[C:2]([C:1]#[N:5])[C:3]#[N:4])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: N#CCC#N
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CC(C#N)=C(O)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77 %

Procedure:
To a 60 ml tetrahydrofuran solution of 3.96 g (0.06 mol) of malononitrile, 4.8 g (60% in oil, 0.12 mol) of sodium hydride was added at 0° C. in four divided portions, and the mixture was stirred for 30 minutes at 0° C. Then, cyclohexanecarboxylic acid chloride was added dropwise, and the mixture was stirred for 30 minutes at room temperature. Then, 150 ml of 1M hydrochloric acid was slowly added, and the mixture was extracted with ethyl acetate. Then, the extract was dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Recrystallization of the residue from diisopropyl ether gave 8.16 g (77%) of the captioned compound.
Reaction SMILES: O.Cl.[NH2:3][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:5][SH:6].[OH-].[Na+].[C:12]([O:17][CH2:18][CH3:19])(=[O:16])[C:13]([CH3:15])=O>O>[CH3:19][CH2:18][O:17][C:12]([C:13]1([CH3:15])[NH:3][CH:4]([C:7]([OH:9])=[O:8])[CH2:5][S:6]1)=[O:16]
Reactant: CCOC(=O)C(C)=O
Reactant: N[C@H](CS)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCOC(=O)C1(C)NC(C(=O)O)CS1
Temperature: 40 °C
Reaction time: 4.5 h

Procedure:
D-Cysteine hydrochloride monohydrate (10 g, 57 mmol) was dissolved in water (20 ml), and the pH of the solution was adjusted to 5.13 with 6N aqueous sodium hydroxide solution. The reaction mixture was heated to 40° C., ethyl pyruvate (7.6 ml, 68 mmol) was gradually added thereto, and the mixture was stirred at 40° C. for 4.5 hours to give 2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (the ratio of trans form:cis form of the resultant product in the reaction mixture was confirmed by NMR to find about 55:45). After completion of the reaction, the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over magnesium sulfate. To the obtained ethyl acetate solution was added triethylamine (16 ml, 115 mmol) under argon, acetyl chloride (6.1 ml, 86 mmol) was slowly added dropwise thereto, and the reaction mixture was heated under reflux for 3 hr to give N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (the ratio of trans form:cis form of the resultant product in the reaction mixture was confirmed by NMR to be about 97:3). After completion of the reaction, water (30 ml) was added thereto, and the pH of the mixture was adjusted to 0.9 with 5.7M HCl. The aqueous layer was separated, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The obtained ethyl acetate solution was concentrated to a weight of 157 g, and to the residue was heptane to be recrystallize the residue. The solid was washed with heptane/ethyl acetate=1.5/1, and dried at 50° C. under reduced pressure to give a crystal of a trans form of N-acetyl-2-methylthiazolidine-2,4-dicarboxylic acid 2-ethyl ester (the ratio of the trans form was confirmed by the area ratio of an HPLC chart to find about 99%) (10.7 g, yield 71%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:26]2[N:30]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=3)[N:29]=[CH:28][CH:27]=2)O1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:26]4[N:30]([C:31]5[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=5)[N:29]=[CH:28][CH:27]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:12][CH:13]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(C(F)(F)F)cc2)OC1(C)C
Reactant: Fc1ccc(-c2cnc3ccc(Br)cn23)cc1
Product: Fc1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(C(F)(F)F)cc4)cn23)cc1

Procedure:
The title compound, white solid (37 mg, 26%), MS (ISP) m/z=423.6 [(M+H)+], mp 147° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-fluoro-phenyl)-imidazo[1,2-a]pyridine (intermediate E) (0.1 mg, 0.34 mmol) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1-(4-trifluoromethyl-phenyl)-1H-pyrazole (intermediate P) (0.15 g, 0.45 mmol).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:7]([CH3:12])=[N:8][NH:9][C:10]=1[CH3:11])[CH3:2].[Cl:14][C:15]1[CH:22]=[C:21]([N+:23]([O-:25])=[O:24])[CH:20]=[CH:19][C:16]=1[CH2:17]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C.CO>[CH2:1]([O:3][C:4](=[O:13])[CH2:5][C:6]1[C:7]([CH3:12])=[N:8][N:9]([CH2:17][C:16]2[CH:19]=[CH:20][C:21]([N+:23]([O-:25])=[O:24])=[CH:22][C:15]=2[Cl:14])[C:10]=1[CH3:11])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Reactant: CCOC(=O)Cc1c(C)n[nH]c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: CCOC(=O)Cc1c(C)nn(Cc2ccc([N+](=O)[O-])cc2Cl)c1C
Temperature: 25 °C
Reaction time: 48 h
Yield: 88.3 %

Procedure:
To a solution of (3,5-dimethyl-1H-pyrazol-4-yl)acetic acid ethyl ester (1.40 g, 7.7 mmol) and 2-chloro-4-nitrobenzyl bromide (4.60 g, 20.7 mmol) in 20 mL acetonitrile is added K2CO3 (1.59 g, 11.5 mmol) and the mixture is stirred for 48 hours at room temperature. The solvent is removed by evaporation and the residue is dissolved in dichloromethane/water. After extraction with dichloromethane the organic layer is dried over Na2SO4 and evaporated under reduced pressure to yield 2.79 g of [3,5-dimethyl-1-(2-chloro-4-nitro-benzyl)-1H-pyrazol-4-yl]-acetic acid ethyl ester (ESI mass spectrum: [M+H]+=352; Retention time: 1.95 min (method A). b) To a solution [3,5-dimethyl-1-(2-chloro-4-nitrobenzyl)-1H-pyrazol-4-yl]acetic acid ethyl ester (2.39 g, 6.8 mmol) in methanol (40 mL) is added Raney nickel (250 mg) and the mixture is hydrogenated. The catalyst is filtered off and the filtrate is concentrated under reduced pressure to yield 1.18 g of the title compound (ESI mass spectrum: [M+H]+=322; Retention time HPLC: 1.76 min (method A)).
Reaction SMILES: FC(F)(F)S([C:6]1[CH:22]=[CH:21][C:9]([CH:10]2[CH2:19][C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:11]2)=[CH:8][CH:7]=1)(=O)=O.C(=O)(O)[O-].[Na+].[F:30]C(F)(F)S([O-])(=O)=O.[Na+].F[P-](F)(F)(F)(F)F.F[P-](F)(F)(F)(F)F.ClC[N+]12CC[N+](F)(CC1)CC2>CC(C)=O.[Ag]=O>[F:30][C:6]1[CH:22]=[CH:21][C:9]([CH:10]2[CH2:19][C:18](=[O:20])[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[O:11]2)=[CH:8][CH:7]=1
Reactant: O=C1CC(c2ccc(S(=O)(=O)C(F)(F)F)cc2)Oc2ccccc21
Reactant: O=S(=O)([O-])C(F)(F)F
Agent: O=[Ag]
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(C)=O
Product: O=C1CC(c2ccc(F)cc2)Oc2ccccc21
Temperature: 65 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
To 4′-(Trifluoromethanesulfonyl)flavanone (51.4 mg, 0.100 mmol, 1.00 equiv) in acetone (2.0 mL) at 23° C. was added silver oxide (1.16 mg, 0.00500 mmol, 0.05 equiv), sodium bicarbonate (16.8 mg, 0.200 mmol, 2.00 equiv), sodium trifluoromethanesulfonate (17.2 mg, 0.100 mmol, 1.00 equiv) and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate) (2) (70.5 mg, 0.150 mmol, 1.50 equiv). The reaction mixture was stirred for 5 h at 65° C. in a sealed vial, then cooled to 23° C. and concentrated in vacuo. The residue was purified by preparative TLC with hexane/EtOAc 5:1 (v/v) to afford 21.8 mg of the title compound as a white solid (90% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[N:19]=[CH:18][NH:17][C:16](=[O:20])[N:15]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:21]=[O:22]>C(O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]3[N:19]=[CH:18][N:17]([CH2:21][OH:22])[C:16](=[O:20])[N:15]=3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: C=O
Reactant: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)nc[nH]1
Solvent: CCO
Solvent: O
Product: O=c1nc(N2CCN(c3ccc(F)cc3)CC2)ncn1CO

Procedure:
To an ethanol/water solution (2/1 (v/v)) of 4-[4-(4-fluorophenyl)piperazin-1-yl]-1,3,5-triazin-2(1H)-one (94 mg, 0.34 mmol) synthesized in Reference Synthesis Example 3, a formaldehyde aqueous solution (42 mg, 0.51 mmol) was added and the resultant solution was stirred at 50° C. for 5 hours. To the reaction solution, a formaldehyde aqueous solution (83 mg, 1.02 mmol) was added and the resultant mixture was stirred at 50° C. for 3 hours. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product of 4-[4-(4-fluorophenyl)piperazin-1-yl]-1-(hydroxymethyl)-1,3,5-triazin-2(1H)-one. Subsequently, to a dichloromethane solution (2 mL) of 4-[4-(4-fluorophenyl)piperazin-1-yl]-1-(hydroxymethyl)-1,3,5-triazin-2(1H)-one, triethylamine (57 mg, 0.41 mmol) and p-toluenesulfonic acid anhydride (123 mg, 0.38 mmol) were added and the resultant mixture was stirred at room temperature. After completion of the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product of the title compound and the crude product was used in the next reaction as it was.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][C:29]1([NH2:33])[CH2:32][O:31][CH2:30]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:18]4[CH:26]=[CH:25][C:21]([C:22]([NH:33][C:29]5([CH3:28])[CH2:32][O:31][CH2:30]5)=[O:23])=[CH:20][N:19]=4)[CH:17]=3)=[C:11]([CH3:27])[N:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)O)cn2)cn1
Reactant: CC1(N)COC1
Product: Cc1nnn(-c2ccc(F)cc2)c1-c1cn(-c2ccc(C(=O)NC3(C)COC3)cn2)cn1
Yield: 86 %

Procedure:
As described for example 36b, 6-(4-(1-(4-fluorophenyl)-4-methyl-1H-1,2,3-triazol-5-yl)-1H-imidazol-1-yl)nicotinic acid (56 mg, 0.154 mmol) was converted, using 3-methyloxetan-3-amine instead of isopropylamine, to the title compound (57 mg, 86%) which was obtained as an off white solid. MS: m/e=434.3 [M+H]+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([NH2:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[C:12]([BH3-])#[N:13].[Na+]>CO>[NH2:11][C:9]1[CH:8]=[C:4]([CH:3]=[C:2]([NH:13][CH2:12][CH:2]2[CH2:3][CH2:4][CH2:8][CH2:9][CH2:10]2)[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: [BH3-]C#N
Reactant: Nc1cc(N)cc(C(=O)O)c1
Agent: [Na+]
Solvent: CO
Product: Nc1cc(NCC2CCCCC2)cc(C(=O)O)c1

Procedure:
15.2 g. (0.1 mol) of 3,5-diaminobenzoic acid was placed in a 500 ml. round bottom flask to which 200 ml. of methanol was added. To the round bottom flask 11.22 g. (0.1 mol) of cyclohexane carboxyaldehyde was added. The solution was stirred for several minutes. While the solution stirred, 3.77 g. (0.06 mol) sodium cyanoborohydride was added slowly. After 5 hours the solution was filtered and then concentrated to dryness. The reaction mixture was dissolved in 200 ml. of 2M hydrochloric acid. The acid solution was extracted twice with 200 ml. ethyl acetate. The ethyl acetate solutions were combined and back washed with 200 ml. distilled water, and then dried over sodium sulfate. The solution was concentrated to dryness and 4.18 gm. of product was collected. The product was then purified by column chromatography using a solution of tetrahydrofuran/ethanol/water/ammonium hydroxide in the following ratio--10:3:1:0.04 as the eluent. Structural verification was obtained by carbon magnetic resonance, proton magnetic resonance and infra-red analysis.