Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7].CCN(C(C)C)C(C)C.Cl[C:26]([O:28][C@@H:29]1[CH2:34][C@H:33]([CH3:35])[CH2:32][CH2:31][C@H:30]1[CH:36]([CH3:38])[CH3:37])=[O:27].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:11]([O:10][C:9]([NH:8][C:3]1([CH3:7])[CH2:4][CH2:5][CH2:6][CH:2]1[NH:1][C:26](=[O:27])[O:28][C@@H:29]1[CH2:34][C@H:33]([CH3:35])[CH2:32][CH2:31][C@H:30]1[CH:36]([CH3:38])[CH3:37])=[O:15])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)NC1(C)CCCC1N
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1OC(=O)NC1CCCC1(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl N-(2-amino-1-methylcyclopentyl)carbamate (Intermediate 24; 5.49 ml, 26.1 mmol) in DCM (87 ml) at 0° C. was added DIPEA (4.56 ml, 26.1 mmol) followed by (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexyl chloroformate (CAS number 14602-86-9; 17.15 g, 78 mmol) drop wise. The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction was diluted with DCM (150 ml) and a saturated solution of sodium bicarbonate solution (200 ml). The aqueous layer was re-extracted with DCM (100 ml) and the combined organics were washed further with a saturated solution of sodium bicarbonate (100 ml), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (silica, 0-50% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=2)[CH:10]([O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+](=[CH2:38])=[N-]>C(Cl)Cl>[CH3:38][O:22][C:21]([CH2:20][C:17]1[CH:16]=[CH:15][C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH:10]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:19][CH:18]=1)=[O:23]
Reactant: C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CC(=O)O)cc2)C(OCc2ccc3ccccc3c2)C1
Solvent: ClCCl
Product: COC(=O)Cc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1
Reaction time: 2 h

Procedure:
A solution of 100 mg (0.21 mmol) of (3RS,4RS)-[4-(1-tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-phenyl]-acetic acid in 5 ml of methylene chloride was treated with 1 ml of ethereal diazomethane solution at room temperature and stirred for a further 2 hours. The reaction solution was evaporated under reduced pressure and the tert-butyl (3RS,4RS)-4-(4-methoxycarbonylmethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate, Rf : 0.5 (hexane:ethyl acetate=2:1), obtained in quantitative yield, was used in the following step without further purification and characterization.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:20]([CH2:27][C:28]([OH:30])=O)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([N:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:27][C:28]([NH:37][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: NC1CCCCC1
Reactant: O=C(O)CN(c1ccccc1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN(c1ccccc1)C1(Cc2cccc(Cl)c2)C(=O)Nc2cc(Cl)ccc21)NC1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.2 %

Procedure:
The mixture of rac-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-acetic acid (70 mg, 0.159 mmol), cyclohexylamine (19 mg, 0.191 mmol) EDC.HCl (36 mg, 0.191 mmol), HOBt (26 mmg, 0.191 mmol) and DIPEA (25 mg, 0.191 mmol) in acetonitrile (3 mL) was stirred at room temperature for overnight. The reaction mixture was concentrated and the residue was purified with chromatography to give 45 mg of rac-2-{[6-chloro-3-(3-chloro-benzyl)-2-oxo-2,3-dihydro-1H-indol-3-yl]-phenyl-amino}-N-cyclohexy-acetamide as a yellow solid. MS m/z 522 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[Cl:21]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[C:19]([CH:18]=[CH:17][C:16]=1[Cl:21])[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: O=C(Cl)c1ccccc1
Reactant: Clc1ccccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 12 h
Yield: 346.5 %

Procedure:
70.3 g of benzoyl chloride was added into the mixture of aluminium chloride (93.3 g) and 1,2-dichloro benzene (14.7 g) using 500 mL three necked flask, then reaction was carried out for 12 hrs. at 120° C. The reaction mixture was poured into 1000 g of ice water in a beaker (5000 mL), and further, 1000 g of toluene was added. The toluene layer was washed by 1000 g of water three times. After condensing the toluene layer under reduced pressure, 87 g of 3,4-dichlorobenzophenone was obtained (yield 69%)
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][N:17]([C:23]4[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccnc1Cl
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1ccc(Nc2ncnc3c2CCN(c2ncccc2C(F)(F)F)C3)cc1
Temperature: 180 °C

Procedure:
The title compound was prepared according to the procedure given for Example 9 using N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.150 g, 0.51 mmol), 2-chloro-3-(trifluoromethyl)pyridine (0.185 g, 0.10 mmol), N,N-diisopropylethylamine (0.133 mL, 0.76 mmol) and heating the reaction mixture 6 h at 180° C. to obtain 0.130 g of a light yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])[N:14]=[CH:13][C:12]=3[N:25]=2)[CH:5]=[CH:6][C:7]=1[OH:8].CS(O[CH2:31][CH2:32][CH:33]1[CH2:35][C:34]1([F:37])[F:36])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:36][C:34]1([F:37])[CH2:35][CH:33]1[CH2:32][CH2:31][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]3[CH:16]=[C:15]([O:17][CH2:18][C@@H:19]([NH:21][C:22](=[O:24])[CH3:23])[CH3:20])[N:14]=[CH:13][C:12]=3[N:25]=2)=[CH:3][C:2]=1[F:1]
Reactant: CS(=O)(=O)OCCC1CC1(F)F
Reactant: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(O)c(F)c3)nc2cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)COc1cc2oc(-c3ccc(OCCC4CC4(F)F)c(F)c3)nc2cn1
Temperature: 70 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
A mixture of N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)[1,3]oxazolo[4,5-c]pyridin-6-yl)oxy)propan-2-yl)acetamide (100 mg), 2-(2,2-difluorocyclopropyl)ethyl methanesulfonate (232 mg), potassium carbonate (160 mg) and DMF (1 mL) was stirred overnight at 70° C. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The combined organic layer were washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized (ethyl acetate) to give the title compound (107 mg).
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH:12]=[CH:13][N:14]=[CH:15][C:10]3=[N:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[H][H].[Pt](=O)=O>[C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][NH:14][CH2:15][C:10]3=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: c1ccc(-c2cnc3cnccn23)cc1
Agent: O=[Pt]=O
Solvent: CCO
Product: c1ccc(-c2cnc3n2CCNC3)cc1
Yield: 99.3 %

Procedure:
3-Phenylimidazo[1,2-a]pyrazine (1.391 g, 7.13 mmol) was dissolved in ethanol (100 ml) and hydrogenated at room temperature under 1 Atm hydrogen over platinum(IV) oxide (0.202 g, 0.713 mmol) for 24 hours. The catalyst was filtered, washed with ethanol and the filtrate concentrated to afford 3-phenyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (1.41 g, 7.08 mmol, 99% yield)
Reaction SMILES: [H-].[Na+].[O:3]1[C@@H:15]2[C@@:16]34[CH2:18][CH2:19][N:20]([CH3:21])[C@@H:10]([C@@H:11]3[CH:12]=[CH:13][C@@H:14]2[OH:22])[CH2:9][C:8]2=[C:17]4[C:4]1=[C:5]([O:23][CH2:24][O:25][CH3:26])[CH:6]=[CH:7]2.Br[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1>CN(C=O)C>[O:3]1[C@@H:15]2[C@@:16]34[CH2:18][CH2:19][N:20]([CH3:21])[C@@H:10]([C@@H:11]3[CH:12]=[CH:13][C@@H:14]2[O:22][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH2:9][C:8]2=[C:17]4[C:4]1=[C:5]([O:23][CH2:24][O:25][CH3:26])[CH:6]=[CH:7]2
Reactant: Brc1ccccn1
Reactant: COCOc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc2c3c1O[C@H]1[C@@H](Oc4ccccn4)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341

Procedure:
NaH (0.432 g, 18 mmol) is stirred with absolute DMF (12 ml) at ambient temperature and then 4,5α-epoxy-3-methoxymethoxy-17-methyl-morphinan-7-en-6α-ol (1.9764 g, 6 mmol) in DMF (12 ml) is added. After the development of gas has ceased, a solution of 2-bromopyridine in absolute DMF (8 ml) is added at RT. After 3 hours at RT this reaction mixture is poured onto H2O (100 ml) and extracted 3 times with CH2Cl2 (60 ml). The combined organic phases are dried with Ha2SO4, concentrated by rotary evaporation and the residue is purified by flash chromatography (90 g silica gel, CH2Cl2 /MeOH=9/1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[O:11])[O:9][C:7](=[O:8])[C:6]2=[CH:12][C:13]=1[O:14][CH3:15].[C:16]1([Mg]Cl)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+].Cl>C1COCC1>[C:7]([C:6]1[CH:12]=[C:13]([O:14][CH3:15])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:10]([OH:9])=[O:11])(=[O:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cl[Mg]c1ccccc1
Reactant: COc1cc2c(cc1OC)C(=O)OC2=O
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1cc(C(=O)O)c(C(=O)c2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.9 %

Procedure:
Thirty grams (0.14 mole) of 4,5-dimethoxyphthalic anhydride was suspended in 300 mL of THF and 87 mL (0.17 mole) of phenylmagnesium chloride in THF was added over two hours. The reaction was stirred at room temperature for 14 hours, refluxed for two hours, cooled and poured into saturated ammonium chloride. The mixture was made acidic with 6N HCl, extracted into chloroform, dried over magnesium sulfate, concentrated to provide 30 g of 2-benzoyl-4,5-dimethoxybenzoic acid.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[C:28](=[O:29])[CH2:27][C:26]4[C:21](=[CH:22][C:23]([O:32][CH:33]([CH3:35])[CH3:34])=[C:24]([O:30][CH3:31])[CH:25]=4)[C@@H:20]3[C:36]3[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=3)=[CH:15][CH:14]=2)([OH:12])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C@H:20]2[C:21]3[C:26](=[CH:25][C:24]([O:30][CH3:31])=[C:23]([O:32][CH:33]([CH3:34])[CH3:35])[CH:22]=3)[CH2:27][C:28](=[O:29])[N:19]2[C:16]2[CH:17]=[CH:18][C:13]([C:10]3([OH:12])[CH2:11][NH:8][CH2:9]3)=[CH:14][CH:15]=2)=[CH:37][CH:38]=1
Reactant: COc1cc2c(cc1OC(C)C)[C@H](c1ccc(Cl)cc1)N(c1ccc(C3(O)CN(C(=O)OC(C)(C)C)C3)cc1)C(=O)C2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(cc1OC(C)C)[C@H](c1ccc(Cl)cc1)N(c1ccc(C3(O)CNC3)cc1)C(=O)C2
Reaction time: 0.5 h

Procedure:
Example 56 was obtained from example 55. A solution of 3-{4-[(S)-1-(4-Chloro-phenyl)-7-isopropoxy-6-methoxy-3-oxo-3,4-dihydro-1H-isoquinolin-2-yl]-phenyl}-3-hydroxy-azetidine-1-carboxylic acid tert-butyl ester (70 mg, 0.118 mmol) in DCM (1 ml) was immersed in an ice-bath followed by addition of TFA (0.045 ml, 0.590 mmol). The yellow reaction solution turned brown and was stirred for 30 minutes. The reaction mixture was treated with ice/saturated aq. sodium hydrogencarbonate solution and extracted with DCM. The organic phase was separated, dried over sodium sulfate, filtered and concentrated in vacuo to obtain the title compound as yellowish solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8](Cl)=[N:9]2)=[CH:4][CH:3]=1.[CH3:13][N:14]1[CH:18]=[C:17](B2OC(C)(C)C(C)(C)O2)[CH:16]=[N:15]1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([C:17]3[CH:16]=[N:15][N:14]([CH3:13])[CH:18]=3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Clc1cnc2ccc(Br)cc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2cnc3ccc(Br)cc3n2)cn1
Yield: 82.1 %

Procedure:
Under N2, 7-bromo-2-chloro-quinoxaline (20 g; 82.1 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (17.1 g; 82.1 mmol), 2M sodium carbonate aqueous solution (41.1 mL; 82.1 mmol) in ethylene glycol dimethyl ether (200 mL) were degassed by bubbling nitrogen through for 15 minutes. Tetrakis(triphenylphosphine)palladium (0) (0.95 g; 0.82 mmol) was added and heated at reflux for 15 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layer was dried over MgSO4, filtered and evaporated to dryness to give 29.9 g. The crude compound was purified by chromatography over silica gel (Irregular SiOH, 20-45 μm, 1000 g MATREX; mobile phase 0.1% NH4OH, 98% DCM, 2% CH3OH). The pure fractions were collected and concentrated till dryness to give 19.5 g (82%) of 7-Bromo-2-(1-methyl-1H-pyrazol-4-yl)-quinoxaline. MP=172° C.
Reaction SMILES: O.Cl.Cl.[NH2:4][C:5]1[CH:28]=[CH:27][C:8]([O:9][CH2:10][CH2:11][N:12]([CH3:26])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)=[CH:7][CH:6]=1.NC1C=CC(OCCN(CCC2C=CC(N[S:48]([CH3:51])(=[O:50])=[O:49])=CC=2)C)=CC=1.Cl.Cl.S(Cl)(C)(=O)=O>N1C=CC=CC=1>[CH3:51][S:48]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][N:12]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][S:22]([CH3:25])(=[O:24])=[O:23])=[CH:17][CH:16]=2)[CH3:26])=[CH:27][CH:28]=1)(=[O:50])=[O:49]
Reactant: CN(CCOc1ccc(N)cc1)CCc1ccc(NS(C)(=O)=O)cc1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CN(CCOc1ccc(NS(C)(=O)=O)cc1)CCc1ccc(NS(C)(=O)=O)cc1

Procedure:
The title compound was prepared by mesylation of 1-(4-aminophenoxy)-2-[N-methyl-N-(4-methanesulphonamidophenethyl)amino]ethane dihydrochloride hemihydrate (95 mg) with mesyl chloride in pyridine according to the procedure of Example 19(C), yield 30 mg, m.p. 147°-149°, confirmed spectroscopically to be identical to the product of Example 7(C).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH:7][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=O)=[CH:10][CH:9]=1>>[N:1]1([CH2:12][C:11]2[CH:14]=[CH:15][C:8]([O:7][CH2:4][CH2:3][CH2:2][NH2:1])=[CH:9][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=Cc1ccc(O)cc1
Reactant: C1CCNCC1
Product: NCCCOc1ccc(CN2CCCCC2)cc1

Procedure:
Starting materials:piperidine and 4-hydroxybenzaldehyde
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([C:13]2[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH2:20])[CH:14]=2)=[N:10][C:9]=1[C:21]1[N:25](COCC[Si](C)(C)C)[CH:24]=[N:23][N:22]=1.[CH:34]1([C:37](Cl)=[O:38])[CH2:36][CH2:35]1.CO>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([C:13]2[C:18]([CH3:19])=[CH:17][N:16]=[C:15]([NH:20][C:37]([CH:34]3[CH2:36][CH2:35]3)=[O:38])[CH:14]=2)=[N:10][C:9]=1[C:21]1[NH:25][CH:24]=[N:23][N:22]=1
Reactant: O=C(Cl)C1CC1
Reactant: Cc1cnc(N)cc1-c1nc(-c2nncn2COCC[Si](C)(C)C)c(-c2ccccc2Cl)o1
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(NC(=O)C2CC2)cc1-c1nc(-c2nnc[nH]2)c(-c2ccccc2Cl)o1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 23.8 %

Procedure:
A mixture of 4-[5-(2-chlorophenyl)-4-(4-{[2-(trimethylsilyl)-ethoxy]methyl}-4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-amine (0.12 g, 0.25 mmol) and TEA (0.087 mL, 0.62 mmol) in DCM (2 mL) was allowed to stir at 0° C. for 20 min. To this mixture was added cyclopropanecarbonyl chloride (0.056 mL, 0.62 mmol). The reaction mixture was allowed to stir at 0° C. for 2 h and then MeOH (20 mL) was added. The mixture was allowed to stir at rt for 20 min and was then concentrated. MeOH (25 mL) and aqueous saturated NaHCO3 (4 mL) were added to the residue and the mixture was allowed to stir at rt overnight before NaOH (1M, 3 mL) was added. The reaction mixture was allowed to stir rt for 3 h and then concentrated. EtOAc (30 mL) was added to the residue and the mixture was allowed to stir at rt for 30 min. The mixture was filtered and the filtrate was concentrated. DCM (5 mL) and TFA (2 mL) were added to the residue and the mixture was allowed to stir at rt overnight. The reaction mixture was concentrated and purified by column chromatography to give N-{4-[5-(2-chlorophenyl)-4-(4H-1,2,4-triazol-3-yl)-1,3-oxazol-2-yl]-5-methylpyridin-2-yl}cyclopropanecarboxamide (Compound I-77) (0.025 g, 24%). LCMS (AA): m/z=421 (M+H).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[NH4+:15].[OH-]>CCO>[NH2:15][CH2:3][C@H:2]([OH:1])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1
Reactant: [NH4+]
Reactant: c1ccc2c(c1)CCN(C[C@@H]1CO1)C2
Agent: [OH-]
Solvent: CCO
Product: NC[C@H](O)CN1CCc2ccccc2C1
Temperature: 100 °C

Procedure:
To a solution of (R)-2-(oxiran-2-ylmethyl)-1,2,3,4-tetrahydroisoquinoline (200 mg, 5.2 mmol) in EtOH (20 mL) was added NH4OH (600 mg, 35.2 mmol) at −78° C. The reaction mixture was then warmed and heated at 100° C. for 3 h in a seal tube. The reaction mixture was concentrated and the crude product was used in next step without further purification. LCMS (m/z): 207.1 (M+1).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][CH:8]([CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:18]2[CH:27]=[C:26]([C:28](OC)=[O:29])[CH:25]=[CH:24][C:19]=2[C:20](OC)=[O:21])[CH:15]=[CH:16][CH:17]=1>C1COCC1>[OH:21][CH2:20][C:19]1[CH:24]=[CH:25][C:26]([CH2:28][OH:29])=[CH:27][C:18]=1[C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][CH2:10][CH2:9][CH:8]([CH3:7])[CH2:32][CH2:33][CH2:34][CH:35]([CH3:37])[CH3:36])[CH:13]=1
Reactant: COC(=O)c1ccc(C(=O)OC)c(-c2cccc(OCCC(C)CCCC(C)C)c2)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CCCC(C)CCOc1cccc(-c2cc(CO)ccc2CO)c1
Yield: 82.3 %

Procedure:
LiAlH4 (9.4 g, 248 mmol) was initially introduced in 300 ml of THF under N2. Dimethyl 2-(3′-(3,7-dimethyloctyloxy)phenyl)terephthalate (75.5 g, 177 mmol), dissolved in 120 ml of THF, was then slowly added dropwise at RT. The mixture was subsequently stirred under reflux for 4 hours and cooled. Excess LiAlH4 was then carefully destroyed by addition of H2O. Semiconcentrated H2SO4 was subsequently carefully added dropwise (about 50 ml). The batch was of very low viscosity at this point. After a subsequent stirring time of 1 hour, a clear solution and a gray precipitate at the bottom of the flask were observed. The clear solution was decanted off, and the solvent was stripped off. The precipitate which remained was stirred with plenty of water and ethyl acetate and filtered, the organic phase was separated off, the solvent was stripped off, and combined with the first organic phase. The combined organic phases were taken up in ethyl acetate and extracted five times with water. After the extracts had been dried over MgSO4, the solvent was stripped off. The resultant oil was stirred a number of times with hexane and dried in an oil-pump vacuum, giving the product as a pure, pale-yellow, high-viscosity oil (54 g, 82%).
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][C:15]1[CH:16]=[C:17]([C:22]2[CH:27]=[CH:26][C:25](I)=[C:24]([CH3:29])[CH:23]=2)[CH:18]=[CH:19][C:20]=1[I:21].C(=O)([O-])[O-].[K+].[K+]>[Cu].[N+](C1C=CC=CC=1)([O-])=O>[CH3:29][C:24]1[CH:23]=[C:22]([C:17]2[CH:18]=[CH:19][C:20]([I:21])=[C:15]([CH3:14])[CH:16]=2)[CH:27]=[CH:26][C:25]=1[N:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1cc(-c2ccc(I)c(C)c2)ccc1I
Reactant: c1ccc(Nc2ccccc2)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1cc(-c2ccc(N(c3ccccc3)c3ccccc3)c(C)c2)ccc1I
Yield: 57.1 %

Procedure:
20.3 g (0.12 mol) of diphenylamine, 65.1 g (0.15 mol) of 3,3'-dimethyl-4,4'-diiodobiphenyl, 19.3 g (0.14 mol) of anhydrous potassium carbonate, 1.52 g (0.024 mol) of copper powder, and 20 ml of nitrobenzene were mixed. The reaction mixture was then allowed to undergo reaction at a temperature of 190° C. to 205° C. for 21 hours. The reaction product was then extracted with 200 ml of toluene. The insoluble contents were removed by filtration. The filtrate was then concentrated to dryness. The concentrate was then purified by column chromatography (carrier: silica gel; elute: 2/7 mixture of toluene and n-hexane) to obtain 32.6 g (yield: 57.2%) of N-(3,3'-dimethyl-4'-iodo-4-biphenylyl)-N,N-diphenylamine.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:16])[CH2:3][NH:4][C:5]1[S:6][C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:8]([CH3:10])[N:9]=1.N[C@H](C)CNC1SC([C:27](OCC)=[O:28])=C(C)N=1>>[CH3:10][C:8]1[N:9]=[C:5]([N:4]2[CH2:3][C@@H:2]([CH3:16])[NH:1][C:27]2=[O:28])[S:6][C:7]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)c1sc(NC[C@H](C)N)nc1C
Reactant: CCOC(=O)c1sc(NC[C@@H](C)N)nc1C
Product: CCOC(=O)c1sc(N2C[C@@H](C)NC2=O)nc1C

Procedure:
Following the procedure as described in Preparation 4, making variations as required to replace (S)-ethyl 2-(2-aminopropylamino)-4-methylthiazole-5-carboxylate with (R)-ethyl 2-(2-aminopropylamino)-4-methylthiazole-5-carboxylate, the title compound was obtained as a colorless solid (74%): MS (ES+) m/z 269.7 (M+1).