Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH2:6]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10]1)[CH:7]=[CH2:8].C(O)(C(F)(F)F)=O.C([C@@H]1N[C@H](C(C)(C)C)N(C)C1=O)C1C=CC=CC=1>C(Cl)Cl.C(O)(C)C>[CH2:6]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C@H:3]([CH3:4])[CH2:2][CH:1]=[O:5])=[CH:10]1)[CH:7]=[CH2:8]
Reactant: C/C=C/C=O
Reactant: C=CCn1ccc2ccccc21
Agent: CN1C(=O)[C@H](Cc2ccccc2)N[C@@H]1C(C)(C)C
Solvent: CC(C)O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCn1cc([C@H](C)CC=O)c2ccccc21
Yield: 70.4 %

Procedure:
Prepared according to general procedure from crotonaldehyde (125 μL, 1.50 mmol), 1-allyl-1H-indole (78.5 mg, 0.500 mmol), TFA (7.7 μL, 0.10 mmol) and (2S,5S)-5-benzyl-2-tert-butyl-3-methyl-imidazolidin-4-one (24.6 mg, 0.100 mmol) in CH2Cl2 (0.90 mL) and isopropanol (0.10 mL) at −72° C. for 21 h to provide, after silica gel chromatography (7:93 EtOAc/hexanes), the title compound as a colorless oil (80 mg, 70% yield, 92% ee). IR (film) 3041, 2966, 2919, 2822, 2834, 2712, 1722, 1469, 1375, 1328, 1309, 1262, 192, 1018, 995, 929, 736 cm−1; 1H NMR (300 MHz, CDCl3) δ 9.76 (dd, J=2.1, 2.1 Hz, 1H, CHO), 7.64 (dt, J=0.9, 7.8 Hz, 1H, ArH), 7.33-7.20 (m, 2H, ArH), 7.13 (ddd, J=0.9, 6.9, 7.8 Hz, 1H, ArH), 6.89 (s, 1H, NCH), 5.98 (ddd, J=5.4, 9.9, 22.5 Hz, 1H, CH2CHCH2), 5.20 (dd, J=1.5, 10.2 Hz, 1H, CH2CHCH2), 5.10 (dt, J=1.5, 17.1 Hz, 1H CH2CHCH2), 4.68 (d, J=5.4 Hz, 2H NCH2), 3.69 (dt, J=6.9, 21.3 Hz, 1H, ArCH), 2.88 (ddd, J=2.4, 6.6, 16.2 Hz, 1H, CH2CO); 2.71 (ddd, J=2.1, 7.2, 16.2 Hz, 1H, CH2CO); 1.44 (d, J=6.9 Hz, 3H, CHCH3); 13C NMR (75 MHz, CDCl3) δ 202.8, 136.7, 133.5, 126.8, 124.1, 121.8, 119.3, 119.2, 119.0, 117.4, 109.8, 51.1, 48.9, 26.1, 21.8; HRMS (CI) exact mass calcd for (C15H17NO) requires m/z 227.1310, found m/z 227.1309. [α]D=−4.4 (c=1.0, CHCl3). The enantiomeric ratio was determined by HPLC analysis of the alcohol, obtained by NaBH4 reduction of the aldehyde, using a Chiracel AD and AD guard column (2:98 ethanol/hexanes, 1 mL/min); S isomer tr=38.7 min and R isomer tr=42.2 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].[CH3:10][S:11](Cl)(=[O:13])=[O:12]>N1C=CC=CC=1>[CH3:10][S:11]([O:9][C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[Cl:1])(=[O:13])=[O:12]
Reactant: Oc1ccc(F)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Oc1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.3 %

Procedure:
To a mixture of 2-chloro-4-fluorophenol (14.7 g) and methylsulfonyl chloride (11.5 g), under ice-cooling, pyridine (30 g) was added dropwise. The resulting mixture was stirred at room temperature for 30 minutes to complete the methylsulfonylation, after which the pyridine was distilled off under reduced pressure. Toluene and water were added to the residue and the mixture was washed with a dilute aqueous hydrochloric acid, then with water. The toluene layer as separated was dried over anhydrous sodium sulfate and then the toluene was distilled off to afford the titled compound (20.8 g) as a pale yellow oil. After purification by silica gel chromatography, the oil was made colorless with a refractive index nD23 =1.5117.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:8])[CH3:7].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCN(CC)CC>CCO.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([CH2:9][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)([CH3:8])[CH3:7]
Reactant: CCCCNC(C)(C)Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCNC(C)(C)CC1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 93.1 %

Procedure:
Compound D-3-8 (50.0 g, 127 mmol) is combined with palladium (II) acetate (5.0 g), dppp (5.0 g) and Et3N (25.7 g, 254 mmol) in EtOH (1.0 L). The mixture is then stirred at 80° C. overnight under an atmosphere of CO at a pressure of 4 MPa. The mixture is cooled to room temperature and the solids are removed by filtration. The filtrate is concentrated under reduced pressure and the residue is purified by flash silica gel chromatography (using 20:1 petroleum ether:EtOAc) to provide compound D-3-9 (25.0 g, 62% yield).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=[C:15]([CH3:31])[CH2:16][CH2:17][C:18]1[N:22]([CH2:23][CH2:24][C:25]#[N:26])[C:21]2[CH:27]=[CH:28][CH:29]=[CH:30][C:20]=2[N:19]=1.ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([CH:15]([CH3:31])[CH2:16][CH2:17][C:18]2[N:22]([CH2:23][CH2:24][C:25]#[N:26])[C:21]3[CH:27]=[CH:28][CH:29]=[CH:30][C:20]=3[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CCc1nc2ccccc2n1CCC#N
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClC(Cl)Cl
Product: CC(CCc1nc2ccccc2n1CCC#N)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 80.3 %

Procedure:
A mixture of 0.3 g of 4-benzyl-piperidine, 0.24 g of 3-[2-(3-oxo-butyl)-benzimidazol-1-yl]-propionitrile, 5 mL of 1,2-dichloroethane and 0.3 g of sodium triacetoxyborohydride was stirred at room temperature for 3 days. The reaction mixture was diluted with 50 mL chloroform and 10 mL saturated aqueous Na2CO3 and the layers separated. The aqueous layer was extracted with 2×25 mL of chloroform and the combined organic layers dried over magnesium sulfate and concentrated under reduced pressure. Low pressure chromatography eluting with a gradient of 80:20 ethyl acetate:methanol to 80:20:5 ethyl acetate:methanol:triethylamine gave 320 mg of 3-{2-[3-(4-benzyl-piperidin-1-yl)-butyl]-benzimidazol-1-yl}-propionitrile as a resin.
Reaction SMILES: [BH4-].[Na+].[CH3:3][N:4]([CH3:15])[CH2:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].O>CC(O)C.CO>[CH3:15][N:4]([CH3:3])[CH2:5][CH2:6][CH:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[OH:8]
Reactant: CN(C)CCC(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: CO
Solvent: O
Product: CN(C)CCC(O)c1ccccc1
Reaction time: 2 h
Yield: 97 %

Procedure:
Sodium borohydride (6.7 g) was slowly added to a solution of 3-dimethylaminopropiophenone (15.5 g) in 2-propanol (125 ml) and methanol (25 ml). After two hrs, the reaction mixture was stirred with water and extracted with ethyl acetate-ether. The organic extract was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to give 15.2 g (97%) of 3-dimethylamino-1-phenyl-1-propanol, as an oil. A solution of 3-dimethylamino-1-phenyl-1-propanol (15 g) in dimethylformamide (75 ml) was slowly added to a suspension of sodium hydride (60% oil-dispersion, washed with hexane, 5.5 g) in dimethylformamide (20 ml). A solution of 4-fluorobenzotrifluoride (18 g) in dimethylformamide (20 ml) was added. After two hrs, the reaction mixture was stirred with ice-water and extracted with ether. The ether extract was dried over anhydrous magnesium sulfate, filtered, and the filtrate was evaporated to provide 27 g (100%) of N,N-dimethyl-3-[ 4-(trifluoromethyl)phenoxy]benzenepropanamine.
Reaction SMILES: C([Mg]Cl)(C)C.I[C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1.S([O-])(O)(=O)=[O:16].[K+].C1[CH2:25][O:24][CH2:23][CH2:22]1>>[CH3:25][O:24][CH2:23][C:22]([C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=1)=[O:16]
Reactant: C1CCOC1
Reactant: N#Cc1ccc(I)cc1
Reactant: O=S(=O)([O-])O
Agent: CC(C)[Mg]Cl
Agent: [K+]
Product: COCC(=O)c1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Iso-propyl magnesium chloride (2 M solution in THF; 3.0 mL; 6.0 mmol) was added to an ice-cooled solution of 4-iodobenzonitrile (1.2 g, 5.0 mmol) in anhydrous THF (10 mL). This solution was stirred at this temperature for 10 minutes and then added dropwise to a cooled (−78° C.) solution of N-2-dimethoxy-N-methylacetamide (0.998 g, 7.50 mmol) in anhydrous THF (5 mL). The reaction mixture was stirred at this temperature for 1 hour and then stirred at RT for 1 hour. The reaction mixture was then treated with 10% aqueous potassium hydrogen sulfate solution and extracted with DCM. The organic phase was passed through a hydrophobic frit and evaporated under reduced pressure. The residue was purified by flash chromatography eluting with iso-hexane/EtOAc (3:2) to afford the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.06-8.04 (m, 2H), 7.80-7.77 (m, 2H), 4.67 (s, 2H), 3.50 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:10])[CH:8]=2)[CH:3]=[N:2]1.[N:11]([O-])=O.[Na+].O.O.[Cl:17][Sn]Cl>Cl>[ClH:17].[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][NH2:11])[CH:8]=2)[CH:3]=[N:2]1
Reactant: O=N[O-]
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Cl[Sn]Cl
Agent: Cl
Agent: [Na+]
Solvent: O
Product: NNc1ccc2cn[nH]c2c1
Reaction time: 1 h

Procedure:
To a solution of 1H-indazol-6-ylamine (20 g, 153 mmol) in conc. HCl (50 mL) was added an aqueous solution (50 mL) of NaNO2 (19 g, 158 mmol) at 0° C. and the resulting mixture was stirred for 1 h. A solution of SnCl2.2H2O (90 g, 306 mmol) in conc. HCl (70 mL) pre-cooled to 0° C. was then added, and the mixture stirred for 2 h at RT. The precipitate was filtered and washed with Et2O to yield (1H-indazol-6-yl)-hydrazine hydrochloride as a yellow solid, which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[Cl:18][C:19]1[N:24]=[CH:23][C:22]([C:25](O)=[O:26])=[CH:21][CH:20]=1>>[Cl:18][C:19]1[N:24]=[CH:23][C:22]([C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:12](=[CH:13][CH:14]=2)[NH:11][C:10]2[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]3=2)=[O:26])=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(Cl)nc4)cc3c2C1
Yield: 33.2 %

Procedure:
Beginning with 9.2 mg (0.040 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 4.9 mg (0.101 mMol) 6-chloro-3-pyridinecarboxylic acid, 4.9 mg (31%) of the title compound were recovered as a brown solid.
Reaction SMILES: [OH:1][CH:2]([CH3:8])[CH2:3][NH:4][CH2:5][CH2:6][NH2:7].[C:9](=S)=[S:10]>C(O)C>[OH:1][CH:2]([CH3:8])[CH2:3][N:4]1[CH2:5][CH2:6][NH:7][C:9]1=[S:10]
Reactant: S=C=S
Reactant: CC(O)CNCCN
Solvent: CCO
Product: CC(O)CN1CCNC1=S
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A 100 g portion of (N-2-hydroxypropyl)ethylenediamine was dissolved in 500 ml of ethanol, then cooled to -10° C. and 55 ml of carbon disulfide was added. Another 500 ml of ethanol was added, the mixture was stirred 30 minutes and then the precipitate was collected, washed with ether and dried. This solid was heated at 140°-150° C. until hydrogen sulfide evolution ceased and then cooled to room temperature. The solid was dissolved in 500 ml of boiling water, treated with charcoal, clarified and cooled at 4° C. overnight. The solid was collected, washed with water and dried at 60° C. in vacuo, giving 34.1 g of 1-(2-hydroxypropyl)-2-imidazolidinethione mp 101°-102° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[N:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[N:14][CH:13]=1.NC1N=CC(C2SC(CN3CCCCC3)=CC=2)=CC=1C(NC1C=CN=CC=1)=O>>[NH2:1][C:2]1[C:7]([C:8]([NH:18][C:15]2[CH:16]=[CH:17][N:12]=[CH:13][N:14]=2)=[O:10])=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1
Reactant: Nc1ccncn1
Reactant: Nc1ncc(Br)cc1C(=O)O
Agent: Nc1ncc(-c2ccc(CN3CCCCC3)s2)cc1C(=O)Nc1ccncc1
Product: Nc1ncc(Br)cc1C(=O)Nc1ccncn1

Procedure:
6.1 Reaction of 2-amino-5-bromo-pyridine-3-carboxylic acid with pyrimidin-4-amine according to the synthesis described for “A1” step 1, gives 2-amino-5-bromo-N-pyrimidin-4-yl-pyridine-3-carboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH2:17](O)[CH3:18]>>[CH2:17]([O:6][C:5](=[O:7])[C:4]1[CH:8]=[C:9]([O:11][CH3:12])[N:10]=[C:2]([Cl:1])[CH:3]=1)[CH3:18]
Reactant: CCO
Reactant: COc1cc(C(=O)O)cc(Cl)n1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1cc(Cl)nc(OC)c1
Temperature: 70 °C
Yield: 98 %

Procedure:
Treat an ethanol suspension of 2-chloro-6-methoxy-isonicotinic acid (3.75 g, 20 mmol) at 0° C. with thionyl chloride for 30 min. Heat at 70° C. overnight. Cool to room temperature, concentrate, dissolve the residue in ethyl acetate (200 mL), wash the organic layer with saturated aqueous sodium bicarbonate solution, saturated aqueous sodium chloride solution, dry (magnesium sulfate) and concentrate to give the title compound (4.2 g, 98%).
Reaction SMILES: [CH3:1][C:2]1([CH3:7])[N:6]=[CH:5][CH2:4][CH2:3]1.[CH2:8]([Mg]Br)[CH:9]=[CH2:10].C(OCC)C>C1COCC1>[CH2:10]([CH:5]1[NH:6][C:2]([CH3:7])([CH3:1])[CH2:3][CH2:4]1)[CH:9]=[CH2:8]
Reactant: CC1(C)CCC=N1
Reactant: C=CC[Mg]Br
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CCC1CCC(C)(C)N1
Temperature: 0 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of 5,5-dimethyl-1-pyrroline (2.3 g, 23.7 mmol) in anhydrous THF (50 ml) 1.0 M solution of allylmagnesium bromide in diethyl ether (43.3 ml, 47.3 mmol) was added dropwise at 0° C. The reaction mixture was allowed to stir at 0° C. for 1 hour and brought to room temperature and stirred for 3 hours. Analysis of the reaction mixture by LC-MS indicated the completion of the reaction. The reaction mixture was cooled to 0° C. and quenched with 5 ml of 1N aqueous HCl and partitioned with 50 ml of EtOAc. Organic layer was separated and the aqueous layer was worked up with 2×50 ml of EtOAc. Combined organic layers were dried over MgSO4 and concentrated under vacuum gave the product as light yellow oil in 44% yield (1.5 g). The crude product was taken to the next step without further purification.
Reaction SMILES: C([Cl:4])(=O)C.[N:5]1([C:10]([CH:12]2[CH2:29][CH2:28][C:15]3([CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]3)[CH2:14][CH2:13]2)=[O:11])[CH2:9][CH2:8][CH2:7][CH2:6]1>C(O)C>[ClH:4].[N:5]1([C:10]([CH:12]2[CH2:13][CH2:14][C:15]3([CH2:16][CH2:17][NH:18][CH2:19][CH2:20]3)[CH2:28][CH2:29]2)=[O:11])[CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(C(=O)N3CCCC3)CC2)CC1
Reactant: CC(=O)Cl
Solvent: CCO
Product: Cl
Product: O=C(C1CCC2(CCNCC2)CC1)N1CCCC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Ethanol (4 ml) and acetyl chloride (0.23 ml, 0.66 mmol) were added to tert-butyl 9-(pyrrolidine-1-carbonyl)-3-azaspiro[5.5]undecane-3-carboxylate (0.25 g, 0.788 mmol) and the mixture was stirred at room temperature for 12 h. When the reaction was complete, the solvent was removed in vacuo. Yield: 0.18 g (96%)
Reaction SMILES: Br[CH2:2][CH2:3][C:4]([NH:6][C:7]1[S:8][C:9]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[N:14]=2)=[C:10]([CH3:12])[N:11]=1)=[O:5].[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>CC#N>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([NH:19][C:15]2[N:14]=[C:13]([C:9]3[S:8][C:7]([NH:6][C:4](=[O:5])[CH2:3][CH2:2][N:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)=[N:11][C:10]=3[CH3:12])[CH:18]=[CH:17][N:16]=2)=[CH:21][CH:22]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc(Nc2nccc(-c3sc(NC(=O)CCBr)nc3C)n2)cc1
Solvent: CC#N
Product: COc1ccc(Nc2nccc(-c3sc(NC(=O)CCN4CCN(C)CC4)nc3C)n2)cc1

Procedure:
By treatment of 3-bromo-N-{5-[2-(4-methoxyphenylamino)-pyrimidin-4-yl]-4-methyl-thiazol-2-yl}-propionamide with 1-methyl-piperazine. Anal. RP-HPLC: tR=13.0 min (0-60% MeCN, purity >94%). 1H-NMR (DMSO-D6) δ: 1.17 (m, 2H, CH2), 2.11 (m, 2H, CH2), 2.48 (m, 4H, CH2), 2.57 (s, 3H, CH3), 3.28 (s, 3H, CH3), 3.30 (m, 4H, CH2), 3.72 (s, 3H, CH3), 6.85 (m, 2H, Ph-H), 6.97 (m, 1H, pyrimidinyl-H), 7.63 (m, 2H, Ph-H), 8.38 (d, 1H, J=5.1 Hz, pyrimidinyl-H). MS (ESI+) m/z 468.57 [M+H]+ (C23H26N7SO2 requires 467.59).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]=[CH:5]2.[H-].[Na+].Cl[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=1)[C:7](=[O:12])[CH:6]=[CH:5]2
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1ccc2cc(Br)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(=O)ccc3cc(Br)ccc32)cc1
Reaction time: 0.5 h
Yield: 78.2 %

Procedure:
To a stirred solution of 6-bromoquinolin-2(1H)-one (2 g, 8.92 mmol) in DMF (20 mL) was added NaH (0.26 g, 10.7 mmol) at 0° C. After stirring for 30 min, 1-(chloromethyl)-4-methoxybenzene (1.67 g, 10.7 mmol) was added and the resulting reaction mixture was stirred at RT overnight. The reaction mixture was diluted with water and the precipitate was filtered, washed with water and dried. The crude product was purified by flash chromatography on silica gel using hexane/ethyl acetate to give 6-bromo-1-(4-methoxybenzyl)quinolin-2(1H)-one as yellow solid (2.4 g, 80%). 1HNMR: 400 MHz, DMSO-d6: δ 3.70 (s, 3H), 5.43 (s, 2H), 6.78 (d, J=9.60 Hz, 1H), 6.87 (dd, J=2.00, 6.40 Hz, 2H), 7.14 (d, J=8.80 Hz, 2H), 7.38 (d, J=8.80 Hz, 1H), 7.66 (dd, J=2.40, 8.80 Hz, 1H), 7.94 (d, J=−8.40 Hz, 1H), 8.01 (d, J=2.40 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:11])[C:7](Br)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[CH2:12]([O:14][C:15](=[O:35])[C@@H:16]([O:33][CH3:34])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]CC(OC(C)(C)C)=O)=[CH:20][CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:35])[C@@H:16]([O:33][CH3:34])[CH2:17][C:18]1[CH:19]=[CH:20][C:21]([O:24][C:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:11])([CH3:9])[CH3:8])=[CH:22][CH:23]=1)[CH3:13]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)OC(C)(C)C)cc1)OC
Product: CCOC(=O)[C@H](Cc1ccc(OC(C)(C)C(=O)OC(C)(C)C)cc1)OC

Procedure:
The title compound was prepared from (2S)-3-(4-hydroxy-phenyl)-2-methoxy-propionic acid ester (Preparation 1) and 2-bromo-2-methyl-propionic acid tert-butyl ester via the same procedure used to prepare (2S)-3-(4-tert-butoxycarbonylmethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (example 121, step 1) to produce a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[C:10]([O:13]CC)(=[O:12])C.CCC[CH2:19][CH2:20][CH3:21]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:20]([CH3:19])([CH3:21])[C:10]([OH:13])=[O:12]
Reactant: CCOC(C)=O
Reactant: Cc1ccc(C)c(O)c1
Reactant: CCCCCC
Product: Cc1ccc(C)c(OC(C)(C)C(=O)O)c1
Yield: 57 %

Procedure:
Using 2,5-dimethylphenol, the title compound was synthesized in the same manner as in Reference Example 36. Yield 57%. Melting point: 107-109° C. (ethyl acetate-hexane).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([CH2:22][N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.[C:38](OC(=O)C)(=[O:40])[CH3:39]>ClCCl>[C:38]([N:26]1[CH2:25][CH2:24][N:23]([CH2:22][C:16]2([C:13]3[CH:14]=[CH:15][C:10]([O:9][CH2:8][CH2:7][CH2:6][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:11][CH:12]=3)[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[CH2:28][CH2:27]1)(=[O:40])[CH3:39]
Reactant: c1cc(C2(CN3CCNCC3)CCOCC2)ccc1OCCCN1CCCC1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCN(CC2(c3ccc(OCCCN4CCCC4)cc3)CCOCC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 19.3 %

Procedure:
To a stirred solution of 1-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydropyran-4-ylmethyl}piperazine (160 mg, 0.41 mmol) and N,N-diisopropylethylamine (180 μl, 1.03 mmol) in dichloromethane (2 ml) at 0° C. was added dropwise acetic anhydride (47 μl, 0.49 mmol). The reaction was allowed to warm up to room temperature and stirred for 18 hours. The reaction mixture was concentrated under reduced pressure and the residue partitioned between dichloromethane (20 ml) and aqueous sodium carbonate solution (20 ml). The layers were separated and the aqueous layer was extracted again with dichloromethane (20 ml). The organics were combined, dried over sodium sulphate, filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (96:4:0.4 to 90:10:1 by volume) to provide the title compound (34 mg, 19%) as a clear oil. 1H NMR (400 MHz, CDCl3) δ 1.78-1.81 (m, 4H), 1.83-1.89 (m, 2H), 1.99 (s, 3H), 2.01-2.03 (m, 2H), 2.06-2.11 (m, 3H), 2.15-2.18 (m, 3H), 2.40 (s, 2H), 2.51-2.53 (m, 4H), 2.63 (t, 2H), 3.22 (t, 2H), 3.42-3.44 (m, 2H), 3.52 (t, 2H), 3.73-3.76 (m, 2H), 4.02 (t, 2H), 6.86 (d, 2H), 7.21 (d, 2H). HRMS ESI+ m/z 430.3052 [MH]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([C:13](=[O:15])[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+].C(O)(=O)C>CO>[CH3:1][C:2]1[CH:3]=[C:4]([N:8]2[N:12]=[N:11][C:10]([CH:13]([OH:15])[CH3:14])=[N:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1nnn(-c2cccc(C)c2)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cccc(-n2nnc(C(C)O)n2)c1
Yield: 97.1 %

Procedure:
1-[2-(3-Methylphenyl)-2H-tetrazol-5-yl}ethanone (96.89 g, 479 mmol) in methanol (1000 mL) was cooled in an ice/water bath. Sodium borohydride (29 g, 767 mmol) was added over 1 hour 30 minutes. After stirring for 40 minutes aq. acetic acid (70%, 20 mL) was added and the mixture was concentrated. Dichloromethane (400 mL) was added to the residue and was extracted with saturated aqueous sodium hydrogen carbonate (500 mL). The aqueous layer was extracted with dichloromethane (170 mL), and the combined organic layer was washed with aqueous hydrochloric acid (0.5 M, 250 mL), followed by aqueous hydrogen carbonate (280 mL), then washed with brine (500 mL), dried over sodium sulfate, filtered and concentrated to give the title product (95 g, 97%).