Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[N:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=2)[C:28](O)=[O:29])[N:21]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][CH:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(CN)c1csc(-c2ccc(F)cc2)n1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Product: CC(C)(CNC(=O)c1cccc(-c2noc(C(F)(F)F)n2)c1)c1csc(-c2ccc(F)cc2)n1
Yield: 30 %

Procedure:
This compound was synthesized from 2-(2-(4-fluorophenyl)thiazol-4-yl)-2-methylpropan-1-amine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (55 mg, yield 30%). 1H NMR (400 MHz, CDCl3) δ 8.53 (m, 1H), 8.26-8.24 (d, J=7.8 Hz, 1H), 8.13-8.11 (m, 1H), 8.07-8.05 (d, J=7.5 Hz, 1H), 7.92-7.89 (m, 2H), 7.62-7.58 (t, J=7.8 Hz, 1H), 7.06-7.02 (m, 3H), 3.71-3.69 (d, J=5.3 Hz, 2H), 1.49 (s, 6H). MS (ESI) m/z: Calculated for C23H18F4N4O2S: 490.11. found: 491.0 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH:3]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=1)[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[NH2:52][CH2:53][C:54]1[C:55]([OH:62])=[N:56][C:57]([CH3:61])=[CH:58][C:59]=1[CH3:60]>ClCCl>[OH:62][C:55]1[C:54]([CH2:53][NH:52][C:15](=[O:17])[C:14]2[CH:13]=[CH:12][C:11]([CH:3]([O:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:2]([CH3:1])[CH3:20])=[CH:19][CH:18]=2)=[C:59]([CH3:60])[CH:58]=[C:57]([CH3:61])[N:56]=1
Reactant: Cc1cc(C)c(CN)c(O)n1
Reactant: CC(C)C(Oc1ccccc1)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(Oc3ccccc3)C(C)C)cc2)c(O)n1
Temperature: 25 °C
Yield: 32.1 %

Procedure:
A mixture of 4-(2-methyl-1-phenoxypropyl)benzoic acid (208 mg, 0.77 mmol), o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-te-tramethyluroniumhexafluorophosphate (439 mg, 1.2 mmol), triethylamine (0.32 mL) and dichloromethane (15 mL) were stirred at 25° C. for half an hour. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1.0 mmol) was added. The mixture was stirred at 25° C. for 12 hours. The resultant mixture was washed with water (30 mL). The organic phase was separated, dried over sodium, filtered, concentrated to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane/methanol=10:1) to give N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-(2-methyl-1-phenoxypropyl)benzamide (Compound I-43) as a white solid (100 mg, 32%). LRMS (M+H+) m/z: calcd 404.21. found 404. HPLC purity (214 nm): 100%. 1H NMR (300 MHz, d6-DMSO): δ 11.46 (s, 1H), 8.33 (t, J=5.1 Hz, 1H), 7.47 (s, 1H), 7.34 (m, 3H), 7.20 (m, 3H), 6.88 (m, 2H), 5.84 (s, 1H), 5.54 (d, J=6.6 Hz, 1H), 4.25 (d, J=4.5 Hz, 2H), 2.35-2.30 (m, 1H), 2.17 (s, 3H), 2.13 (s, 3H), 1.01 (d, J=6.6 Hz, 6H).
Reaction SMILES: O=[C:2]([CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:3][N:4]1[C:10](=O)[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6]2[N:16]=[CH:17][CH:18]=[CH:19][C:5]1=2.C([O-])(=O)C.[NH4+:32]>C(O)(=O)C>[CH2:20]([C:2]1[N:32]=[C:10]2[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[NH:7][C:6]3[N:16]=[CH:17][CH:18]=[CH:19][C:5]=3[N:4]2[CH:3]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: [NH4+]
Reactant: O=C(CCc1ccccc1)CN1C(=O)c2ccccc2Nc2ncccc21
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: c1ccc(CCc2cn3c(n2)-c2ccccc2Nc2ncccc2-3)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 25.3 %

Procedure:
To a solution of 5-(2-oxo-4-phenylbutyl)-5H-benzo[e]pyrido[3,2-b][1,4]diazepin-6(11H)-one (1.56 g, 1 eq.) in acetic acid (10 mL) was added ammonium acetate (3.37 g, 10 eq.). The reaction was stirred at 120° C. for 8 hours. The reaction mixture was poured onto water (100 mL) and extracted with dichloromethane (3×100 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by column chromatography (0-10% methanol in dichloromethane) gave the 2-phenethyl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepine (0.374 g, 27%). 1H NMR (CDCL3) 400 MHz δ 8.08 (dd, JA=4.8 Hz, JB=1.6 Hz, 1H), 7.97 (dd, JA=8.0 Hz, JB=1.2 Hz, 1H), 7.46 (dd, JA=8.0 Hz, JB=1.6 Hz, 1H), 7.34-7.15 (m, 6H), 7.08 (td, JA=7.6 Hz, JB=1.2 Hz, 1H), 6.98 (dd, JA=7.6 Hz, JB=4.8 Hz, 1H), 6.86 (dd, JA=7.6 Hz, JB=0.8 Hz, 1H), 6.81 (s, 1H), 6.27 (s, 1H), 3.07-2.90 (m, 4H); LCMS: 339 [M+H].
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH3:11])[CH:3]=1.[OH-].[K+].[NH:14]1[CH:18]=[CH:17][N:16]=[CH:15]1>CS(C)=O>[CH3:11][C:4]1[CH:3]=[C:2]([N:14]2[CH:18]=[CH:17][N:16]=[CH:15]2)[CH:7]=[CH:6][C:5]=1[N+:8]([O-:10])=[O:9]
Reactant: c1c[nH]cn1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc(-n2ccnc2)ccc1[N+](=O)[O-]
Temperature: 100 °C
Yield: 82.9 %

Procedure:
To a solution of 4-fluoro-2-methyl-1-nitro-benzene (300 mg, 1.84 mmol) in DMSO (2 mL) were added KOH (20 mg, 3.87 mmol) and imidazole (263 mg, 3.88 mmol). The reaction mixture was heated to 100° C. for 3.5 h, cooled to room temperature, and diluted with ice-cold water. The resulting precipitate was filtered, washed with ice-cold water, and dried under vacuum to give the title compound (310 mg, 80%) as a yellow powder. 1H NMR (300 MHz, DMSO-d6) δ 8.46 (1H, s), 8.16 (1H, d, J=8.9 Hz), 7.90-7.92 (2H, m), 7.78 (1H, dd, J=2.5, 8.9 Hz), 7.17 (1H, s), 2.61 (3H, s). LRMS (M+H)+mz 204.
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[N:11]=[CH:10][C:9]([CH2:12][N:13]2[CH2:18][C@@H:17]([CH3:19])[O:16][C@@H:15]([CH3:20])[CH2:14]2)=[CH:8][C:5]=1[C:6]#[N:7].Cl[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(=O)(O)[O-].[Na+]>C1COCC1>[C:6]([C:5]1[C:4]([NH:3][C:22](=[O:23])[O:24][CH2:25][CH3:26])=[N:11][CH:10]=[C:9]([CH2:12][N:13]2[CH2:14][C@@H:15]([CH3:20])[O:16][C@@H:17]([CH3:19])[CH2:18]2)[CH:8]=1)#[N:7]
Reactant: CCOC(=O)Cl
Reactant: C[C@@H]1CN(Cc2cnc(N)c(C#N)c2)C[C@H](C)O1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)Nc1ncc(CN2C[C@@H](C)O[C@@H](C)C2)cc1C#N
Reaction time: 0.08 h
Yield: 79.7 %

Procedure:
Sodium hydride in mineral oil (60%, 25 mg, 0.61 mmol) was added to 2-amino-5-(((2S,6R)-2,6-dimethylmorpholino)methyl)nicotinonitrile (100 mg, 0.41 mmol) in THF (2 mL) and the mixture was stirred for 5 minutes. Ethyl chloroformate (0.05 ml, 0.48 mmol) was added followed by additional sodium hydride (16 mg, 0.41 mmol) and the reaction stirred at room temperature for 3 hours. The reaction was poured into a saturated solution of sodium bicarbonate (10 mL), extracted with ethyl acetate (3×5 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was taken up in methanol (10 mL) and stirred with potassium carbonate (170 mg) for 10 minutes. It was then poured into saturated sodium bicarbonate (10 mL) and extracted with ethyl acetate (3×5 mL). The extracts were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography, eluting with ethyl acetate in hexanes gave the title compound as a white powder (104 mg, 80%). 1H NMR (400 MHz, DMSO-d6) δ 1.04 (d, J=6.27 Hz, 6H), 1.26 (t, J=7.03 Hz, 3H), 1.69 (t, J=10.60 Hz, 2H), 2.67 (d, J=10.67 Hz, 2H), 3.51 (s, 2H), 3.54-3.62 (m, 2H), 4.17 (q, J=7.11 Hz, 2H), 8.12-8.24 (m, 1H), 8.56 (d, J=2.01 Hz, 1H), 10.37 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]([C:17]([O:19][CH3:20])=[O:18])[N:4](C)[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14]Cl)[CH:9]=2)=[CH:6][N:7]=1.C(#N)C.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(C(C)C)CC)(C)C>C1COCC1>[NH2:1][C:2]1[C:3]([C:17]([O:19][CH3:20])=[O:18])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][NH:31][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:9]=2)=[CH:6][N:7]=1
Reactant: NCc1ccccc1
Reactant: COC(=O)C1C(N)=NC=C(c2cccc(CCl)c2)N1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1nc(-c2cccc(CNCc3ccccc3)c2)cnc1N
Temperature: 25 °C
Reaction time: 144 h
Yield: 12.8 %

Procedure:
Methyl 3-amino-6-(3-chloromethylphenyl)-N-methylpyrazine-2-carboxylate (30.6 mg, 0.11 mmol.) was taken into acetonitrile (2 mL) and THF (1 mL) followed by addition of benzylamine (12 uL, 0.11 mmol) then diisopropylethylamine (20 uL, 0.11 mmol) and the mixture was allowed to stir at room temperature over six days. The mixture was then concentrated in vacuo and the residue purified by silica gel flash chromatography initially using ethyl acetate as eluent followed by elution with 10% methanol in dichloromethane. The pure fractions were combined and concentrated then dried in vacuo to give methyl 3-amino-6-(3-{[(phenylmethyl)amino]methyl}phenyl)pyrazine-2-carboxylate (4.9 mg, 13% yield) as a yellow amorphous solid: MS (EI) for C20H21N4O2: 349 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[CH:6][CH:7]=1.[C:9]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:21]=[CH:22][CH:23]=[C:18]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH:19]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(-c2ccccc2)c1
Reactant: Brc1cccc(I)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Brc1cccc(-c2cccc(-c3ccccc3)c2)c1
Yield: 96 %

Procedure:
Commercial 3-bromoiodobenzene in an amount of 11 g, 8.7 g of commercial 3-biphenylboronic acid and 130 ml of toluene were mixed together. To the resultant mixture, 0.9 g of tetrakis(triphenyl-phosphine)palladium and 75 ml of a 2 M aqueous solution of sodium carbonate were added, and the reaction system was purged with argon. After the reaction mixture was heated under the refluxing condition for 8 hours, the reaction mixture was cooled by leaving standing. The formed crystals were separated by filtration and subjected to extraction with toluene. The organic layer was washed with water and a saturated aqueous solution of sodium chloride and dried with anhydrous sodium sulfate. The solvent was removed using an evaporator. The residue was purified in accordance with the silica gel column chromatography (the developing solvent: hexane), and 11.8 g of 3-bromo-m-terphenyl was obtained as a white solid substance (the yield: 96%).
Reaction SMILES: C(OCC=C)C=C.[K].[CH2:9]([OH:12])[CH:10]=[CH2:11].[CH3:13][C:14]1[CH2:15][S:16][C@@H:17]2[CH:37]([NH:38][C:39](=[O:46])[CH2:40][C:41]3[S:42][CH:43]=[CH:44][CH:45]=3)[C:36](=[O:47])[N:18]2[C:19]=1[C:20]([O:22]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:21]>>[CH2:9]([O:12][C:37]1([NH:38][C:39](=[O:46])[CH2:40][C:41]2[S:42][CH:43]=[CH:44][CH:45]=2)[C:36](=[O:47])[N:18]2[C:19]([C:20]([OH:22])=[O:21])=[C:14]([CH3:13])[CH2:15][S:16][C@H:17]12)[CH:10]=[CH2:11]
Reactant: C=CCO
Reactant: CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)Cc3cccs3)[C@H]2SC1
Agent: C=CCOCC=C
Agent: [K]
Product: C=CCOC1(NC(=O)Cc2cccs2)C(=O)N2C(C(=O)O)=C(C)CS[C@@H]21

Procedure:
potassium allyloxide; allyl alcohol; benzhydryl 3-methyl-7-[2-(2-thienyl)acetamido]-3-cephem-4-carboxylate.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[CH:7]=[CH:6][C:5]=1[NH:14][C@@H:15]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16]1)([O-:3])=[O:2].FC(F)(F)C(O)=O>ClCCl>[N+:1]([C:4]1[CH:9]=[C:8]([S:10]([NH2:11])(=[O:12])=[O:13])[CH:7]=[CH:6][C:5]=1[NH:14][C@@H:15]1[CH2:19][CH2:18][NH:17][CH2:16]1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(S(N)(=O)=O)cc2[N+](=O)[O-])C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NS(=O)(=O)c1ccc(N[C@@H]2CCNC2)c([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
A suspension of EXAMPLE 428B (2.018 g) in anhydrous dichloromethane (25 mL) was cooled in an ice bath and 2,2,2-trifluoroacetic acid (20 mL) was added. After stirring 15 minutes, the ice bath was removed and the reaction was allowed to come to ambient temperature over 2 hours. The reaction mixture was concentrated and the residue was dissolved in water and basified with aqueous sodium carbonate solution. The mixture was extracted repeatedly with 10% methanol in methylene chloride and the organics were concentrated to provide the title compound.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]4[CH2:41][CH2:40][CH2:39][CH2:38][N:37]4[CH:42]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]4[CH2:41][CH2:40][CH2:39][CH2:38][N:37]4[CH:42]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn4c(n3)CCCC4)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3cn4c(n3)CCCC4)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [CH3:1][CH:2]1[C:11](=[N:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][CH2:9][C:4]2([O:8][CH2:7][CH2:6][O:5]2)[CH2:3]1.[BH4-].[Na+]>CO>[CH2:13]([NH:12][C@@H:11]1[CH2:10][CH2:9][C:4]2([O:5][CH2:6][CH2:7][O:8]2)[CH2:3][C@H:2]1[CH3:1])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC1CC2(CCC1=NCc1ccccc1)OCCO2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@@H]1CC2(CC[C@H]1NCc1ccccc1)OCCO2
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
The crude N-(7-methyl-1,4-dioxaspiro[4.5]dec-8-ylidene)-1-phenylmethanamine was dissolved in MeOH (1.3 L). The solution was cooled to −70° C. and solid NaBH4 was added in ˜10 portions over 30 min while the reaction temperature was held below −64° C. The reaction mixture was allowed to warm to −30° C. over 1 h, then to 5° C. over 15 min. The reaction was quenched with water (500 mL), the mixture was transferred into a separatory funnel, additional water (2 L) was added (resulting pH 10-11), and extracted with CH2Cl2 (1 L+2×500 mL). The combined organics were dried (Na2SO4) and filtered through a pad of silica gel eluting with CH2Cl2 (200 mL). The filtrate was concentrated and the residue was solvent-switched with EtOH. The enantiomers of the trans-diastereomer were separated by preparative HPLC to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=2)[CH:18]=1)[C:5]([NH:7][CH2:8][C:9]1[CH:10]=[N:11][C:12]([CH3:15])=[CH:13][CH:14]=1)=[O:6].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].[Cs+].[Cs+].O.CN(C)C=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:15][C:12]1[N:11]=[CH:10][C:9]([CH2:8][NH:7][C:5]([C:4]2[CH:3]=[C:2]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][CH3:26])[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)[CH:16]=2)=[O:6])=[CH:14][CH:13]=1
Reactant: Cc1ccc(-c2cc(Br)cc(C(=O)NCc3ccc(C)nc3)c2)nc1
Reactant: COc1ccccc1B(O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1-c1cc(C(=O)NCc2ccc(C)nc2)cc(-c2ccc(C)cn2)c1

Procedure:
In a 5 mL microwave vial, 3-bromo-5-(5-methylpyridin-2-yl)-N-((6-methylpyridin-3-yl)methyl)benzamide (20 mg, 0.05 mmol), 2-methoxyphenylboronic acid (15.38 mg, 0.1012 mmol), cesium carbonate (82.42 mg, 0.2530 mmol), tetra-n-butylammonium iodide (18.69 mg, 0.05060 mmol), and POPd (2.538 mg, 0.005060 mmol) were dissolved in Water (0.04 mL, 2 mmol) and N,N-dimethylformamide (0.2 mL, 2 mmol). The reaction mixture was microwaved for 20 mins at 150 degrees. The reaction was purified directly by reversed phase HPLC (acetonitrile:water gradient) at pH10. The combined pure fractions were reduced in vacuo to afford the title compound as colorless oil.
Reaction SMILES: C(OCC)(=O)C.[F:7][C:8]([F:20])([F:19])[C:9]([NH:11][C@@H:12]1[C:17](=[O:18])[O:16][C:14](=[O:15])[CH2:13]1)=[O:10].C([O-])(=O)C.[Na+].Cl.[CH3:27][O:28][C:29](=[O:39])[C@H:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH2:31]>>[CH3:27][O:28][C:29](=[O:39])[C@H:30]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[NH:31][C:17](=[O:18])[C@H:12]([CH2:13][C:14](=[O:15])[OH:16])[NH:11][C:9](=[O:10])[C:8]([F:20])([F:19])[F:7]
Reactant: O=C1C[C@H](NC(=O)C(F)(F)F)C(=O)O1
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(=O)O)NC(=O)C(F)(F)F
Yield: 78.5 %

Procedure:
In 84.4 g of ethyl acetate 21.1 g (0.1 mole) of N-trifluoroacetyl-L-aspartic anhydride was suspended, and 9.2 g (0.11 mole) of sodium acetate was added at -5 - 0° C. with stirring, and 21.6 g (0.1 mole) of L-phenylalanine methyl ester hydrochloride was added at the same temperature. The mixture was reacted for 3 hours with stirring at the same temperature and concentrated under reduced pressure. Thereafter 63.3 g of acetic acid was added and stirred for an hour at 15°-20° C. Precipitated crystals were filtered, washed and dried. Crystals of N-trifluoroacetyl-α-L-aspartyl-L-phenylalanine methyl ester were obtained in a yield of 30.6 g (78.5% yield on L-phenylalanine methyl ester hydrochloride). The crystals obtained were analyzed by high performance liquid chromatography to give a ratio of α-isomer:β-isomer of 99.0:1.0.
Reaction SMILES: [CH3:1][NH2:2].C(O)C.Cl[C:7]1[N:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[CH:8]=1>>[CH3:1][NH:2][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:10]=[CH:11][N:12]=1
Reactant: FC(F)(F)c1cccc(Nc2cc(Cl)ncn2)c1
Reactant: CN
Solvent: CCO
Product: CNc1cc(Nc2cccc(C(F)(F)F)c2)ncn1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A solution of methylamine in ethanol (32 mL, 256 mmol) is added to (6-chloro-pyrimidin-4-yl)-(3-trifluoromethyl-phenyl)-amine (3.49 g, 12.8 mmol) and the mixture is stirred for 5 h at 100° C. in a pressure bottle. The reaction mixture is concentrated in vacuo, the residue diluted with CH3OH and basified using conc. aqueous ammonia solution. The product is filtered off, washed with H2O and CH3OH and dried in vacuo.
Reaction SMILES: Cl[C:2]1[N:6]2[N:7]=[C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:9]3[C:14]([C:5]2=[N:4][N:3]=1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C>[C:15]1([C:8]2[C:9]3[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]3=[N:4][N:3]=[C:2]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[N:6]3[N:7]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C1CCNC1
Reactant: Clc1nnc2c3ccccc3c(-c3ccccc3)nn12
Solvent: CCO
Product: c1ccc(-c2nn3c(N4CCCC4)nnc3c3ccccc23)cc1
Temperature: 100 °C

Procedure:
A mixture of 3-chloro-6-phenyl-1,2,4-triazolo[3,4-a]phthalazine (4.5 g), pyrrolidine (6 ml) and ethanol (40 ml) is poured in a steel cylinder and heated to 100° C. for 8 hours. Then the mixture is cooled, and concentrated to dryness by evaporating off the solvent. The obtained residue is washed with water and crystallized from ethanol giving 3.5 g of the compound of the title. M.p. 245°-47° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([OH:14])=O)=[N:4][C:5]([O:9][CH2:10][CH3:11])=[CH:6][C:7]=1[Cl:8].Cl.Cl.Cl.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]1[S:25][C:26]([CH2:29][N:30]2[CH2:35][CH2:34][CH:33]([CH2:36][NH2:37])[CH2:32][CH2:31]2)=[CH:27][N:28]=1>>[NH2:1][C:2]1[C:3]([C:12]([NH:37][CH2:36][CH:33]2[CH2:34][CH2:35][N:30]([CH2:29][C:26]3[S:25][C:24]([C:19]4[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=4)=[N:28][CH:27]=3)[CH2:31][CH2:32]2)=[O:14])=[N:4][C:5]([O:9][CH2:10][CH3:11])=[CH:6][C:7]=1[Cl:8]
Reactant: CCOc1cc(Cl)c(N)c(C(=O)O)n1
Reactant: NCC1CCN(Cc2cnc(-c3ccccn3)s2)CC1
Agent: Cl
Product: CCOc1cc(Cl)c(N)c(C(=O)NCC2CCN(Cc3cnc(-c4ccccn4)s3)CC2)n1

Procedure:
According to the same procedure described in Example 16, using the compound prepared in Example 428 instead of 4-chloro-3-methoxybenzoic acid and the compound prepared in Example 214 instead of the compound prepared in Example 9, the title compound having the following physical data was obtained.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[S:3].[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=O)[CH3:13])=[CH:8][CH:7]=1.S(Cl)(Cl)(=O)=O>CC(C)=O>[CH3:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:1]=[C:2]([NH2:4])[S:3][CH:13]=2)=[CH:8][CH:7]=1
Reactant: CC(=O)c1ccc(C)cc1
Reactant: NC(N)=S
Solvent: CC(C)=O
Solvent: O=S(=O)(Cl)Cl
Product: Cc1ccc(-c2csc(N)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 53.7 %

Procedure:
To a mixture of thiourea (2.18 g, 28.6 mmol) and p-methylacetophenone (1.92 ml, 14.3 mmol) was added dropwise sulfuryl chloride (1.264 ml, 15.74 mmol) and the resulting mixture was stirred at room temperature for 10 minutes (until solidification was complete). The reaction mixture was allowed to react at 105° C. for 3 hours and acetone was added thereto. Then insoluble matters were filtered with suction, treated with 300 ml of water and heated at 80° C. Insoluble solids were removed by filtration. After the filtrate was made alkaline (pH 11) with 1N-KOH under ice-cooling, the deposited solids were filtered with suction, washed with water and recrystallized from methanol-water to afford 1.46 g (yield 54%) of 4-(4-methylphenyl)-2-thiazolamine as pale yellowish crystals, m.p.130° C.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[C:11]([N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)[CH2:14]1)=O>C1COCC1>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][C@@H:2]1[CH2:11][N:13]1[CH2:18][CH2:17][CH2:16][C@H:15]([C:19]2[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=2)[CH2:14]1
Reactant: O=C([C@H]1COc2ccccc2O1)N1CCC[C@H](c2cccc(O)c2)C1
Solvent: C1CCOC1
Product: Oc1cccc([C@H]2CCCN(C[C@H]3COc4ccccc4O3)C2)c1
Yield: 47.8 %

Procedure:
(R)-2,3-Dihydrobenzo[1,4]dioxin-2-yl-[(R*)-3-(3-hydroxyphenyl)piperidin-1-yl]-methanone (17.8 g, 54.7 mmol) was treated with BH3 THF according to the above general procedure. Crystallisation from hot EtOH gave 8.5 g of the title compound as almost white crystals.
Reaction SMILES: [ClH:1].[NH:2]1[CH2:5][CH:4]([C:6]2[CH:13]=[CH:12][C:9](C#N)=[CH:8][CH:7]=2)[CH2:3]1.[Cl:14]C1C=CC(B(O)O)=CC=1>>[ClH:14].[Cl:1][C:9]1[CH:12]=[CH:13][C:6]([CH:4]2[CH2:5][NH:2][CH2:3]2)=[CH:7][CH:8]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: N#Cc1ccc(C2CNC2)cc1
Agent: Cl
Product: Clc1ccc(C2CNC2)cc1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 5.2, except (4-chlorophenyl)boronic acid was used in place of (4-cyanophenyl)boronic acid. The title compound was obtained in 20% yield over two steps.