Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:29])=O>CN(C=O)C>[Br:1][C:2]1[C:3]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:4][C:5]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:6]([CH:10]=1)[C:7]([Cl:29])=[O:8]
Reactant: O=C(O)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1

Procedure:
1.4 9 g of 5-bromo-2,4-dibenzyloxybenzoic acid, 40 ml of thionyl chloride and 1 drop of DMF are stirred at room temperature for 4 hours. The thionyl chloride is removed, and the residue is treated twice with dichloromethane, giving 9.4 g of 5-bromo-2,4-dibenzyloxybenzoyl chloride, which is processed further directly.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[Mg].[CH:23]1[C:36]2[C:35](=O)[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:28][C:27]=2[CH:26]=[CH:25][CH:24]=1.Cl>C(OCC)C.O1CCCC1>[CH:23]1[C:36]2[C:27](=[CH:28][C:29]3[C:34]([C:35]=2[C:15]2[C:16]4[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:12]([C:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[CH:2]=[CH:3][CH:4]=4)=[CH:13][CH:14]=2)=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:26]=[CH:25][CH:24]=1
Reactant: Brc1ccc(-c2cccc3ccccc23)c2ccccc12
Reactant: O=C1c2ccccc2Cc2ccccc21
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCOCC
Product: c1ccc2c(-c3ccc(-c4c5ccccc5cc5ccccc45)c4ccccc34)cccc2c1

Procedure:
4-bromo-1,1′-binaphthyl and magnesium were refluxed in diethylether for one hour, which was then added to a solution of anthrone in tetrahydrofuran. The resulting mixture was heated for two hours, which was then poured into diluted hydrochloric acid. After being extracted by diethylether, organic layer was separated and dried over magnesium sulfate. It was purified according to conventional method, whereby 1-(9-anthryl)-4-(1-naphthyl)-naphthalene was obtained. This was dissolved in chloroform to which was added two equivalent amounts of N-bromosuccinimide, and they were stirred at room temperature for one day. The product was purified according to conventional method and 1-(10-bromo-9-anthryl)-4-(4-bromo-1-naphthyl)-naphthalene was obtained. With this pdoruct, diphenylamine was reacted in nitrobenzene at 180° C. for 40 hours together with potasium carbonate and copper powder. After nitrobenzene was removed by vacuum distillation, the reaction mixture was purified according to conventional method, whereby the target compound (18) was obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].[C:29](Cl)(=[O:31])[CH3:30]>>[C:29]([N:20]1[CH2:21][CH2:22][C:16]2[C:15]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[N:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([NH:6][C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:12][CH:11]=3)=[N:18][C:17]=2[CH2:19]1)(=[O:31])[CH3:30]
Reactant: CC(=O)Cl
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(C(C)=O)C3)cc1

Procedure:
Method as example 18 using 1-ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (example 82) and acetyl chloride as starting materials.
Reaction SMILES: Cl[C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[CH:3]=1.[SH2:12].[K]>>[SH:12][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[N:5]=[C:4]([CH3:11])[CH:3]=1
Reactant: S
Reactant: Cc1cc(Cl)n2ccnc2n1
Agent: [K]
Product: Cc1cc(S)n2ccnc2n1

Procedure:
In a similar way to Reference Example 1, using 5-chloro-7-methylimidazo[1,2-a]pyrimidine and potassium hydrogen sulfide, the title compound is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[C:16]([CH3:34])=[CH:17][N:18]([CH:31]([CH3:33])[CH3:32])[C:19]=2[CH:20]=[C:21]([C:23]2[CH:24]=[N:25][C:26]([CH:29]=O)=[CH:27][CH:28]=2)[CH:22]=1)=[O:13].[NH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1.S([O-])([O-])(=O)=O.[Na+].[Na+].[BH4-].[Na+]>C(Cl)Cl.CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12]([C:14]1[C:15]2[C:16]([CH3:34])=[CH:17][N:18]([CH:31]([CH3:33])[CH3:32])[C:19]=2[CH:20]=[C:21]([C:23]2[CH:24]=[N:25][C:26]([CH2:29][N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)=[CH:27][CH:28]=2)[CH:22]=1)=[O:13]
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Reactant: C1CCNC1
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCCC4)nc3)cc3c2c(C)cn3C(C)C)c(=O)[nH]1
Temperature: 45 °C
Reaction time: 2 h

Procedure:
To a solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-6-(6-formylpyridin-3-yl)-1-isopropyl-3-methyl-1H-indole-4-carboxamide (100 mg, 0.219 mmol), in DCM (10 mL) and methanol (2 mL) was added pyrrolidine (0.035 mL, 0.438 mmol), followed by sodium sulfate (31.1 mg, 0.219 mmol). The reaction stirred at rt for 12 h, at which time sodium borohydride (16.57 mg, 0.438 mmol) was added and the reaction stirred rt for 2 h and 45° C. for 2 h. The reaction was quenched with water and extracted with EtOAc. The organic layer was evaporated. Purification by reverse phase Gilson HPLC (10-60% acetonitrile/water+0.1% TFA, YMC ODS-A C18 Column 75×30 mm ID S-5 um, 12 nM Column 7 minutes), followed by isolation and extraction with EtOAc/0.1 N NaOH provided N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1-isopropyl-3-methyl-6-(6-(pyrrolidin-1-ylmethyl)pyridin-3-yl)-1H-indole-4-carboxamide, which was evaporated from the organic layer as a yellow foam solid (68 mg, 0.125 mmol, 57.0% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.48 (br. s., 1H) 9.06 (d, J=2.02 Hz, 1H) 8.30 (dd, J=8.08, 2.27 Hz, 1H) 8.20 (t, J=5.18 Hz, 1H) 7.94 (d, J=1.26 Hz, 1H) 7.60 (d, J=8.08 Hz, 1H) 7.40 (s, 1H) 7.32 (s, 1H) 5.88 (s, 1H) 4.92-4.89 (m, 1H) 4.59 (d, J=5.56 Hz, 2H) 4.36 (d, J=5.05 Hz, 2H) 3.34 (br. s., 4H) 2.25 (s, 3H) 2.17 (d, J=1.01 Hz, 3H) 2.11 (s, 3H) 1.99 (br.s., 4H) 1.45 (d, J=6.57 Hz, 6H). LCMS: [M+H]+=512.3.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].Cl.[CH3:14]O>>[CH3:14][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([O:11][CH3:12])[CH:4]=1
Reactant: COc1cc(C(=O)O)ccc1O
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc(O)c(OC)c1
Yield: 91.5 %

Procedure:
A solution of 4-hydroxy-3methoxy benzoic acid (7.2 g) in methanol (150 ml) was refluxed in presence of concentrated hydrochloric acid (0.5 ml) for 12 hrs. After concentrating under reduced pressure, the residue was dissolved in ethyl acetate (200 ml) and washed with water (50 ml) 10% sodium bicarbonate solution (2×50 ml), water (50 ml) and dried over anhydrous magnesium sulfate. Removal of the solvent under reduced pressure provided 7.25 g of 4-hydroxy-3-methoxy benzoic acid methyl ester. (Yield=91.5%).
Reaction SMILES: [CH2:1]1[O:20][C:4]2([CH2:9][CH2:8][C:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=4)[NH:12][CH:11]=3)=[CH:6][CH2:5]2)[O:3][CH2:2]1>[Pd].C(O)C>[CH2:2]1[O:3][C:4]2([CH2:9][CH2:8][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[C:16]([F:19])[CH:17]=4)[NH:12][CH:11]=3)[CH2:6][CH2:5]2)[O:20][CH2:1]1
Reactant: Fc1ccc2[nH]cc(C3=CCC4(CC3)OCCO4)c2c1
Agent: [Pd]
Solvent: CCO
Product: Fc1ccc2[nH]cc(C3CCC4(CC3)OCCO4)c2c1
Reaction time: 96 h
Yield: 101.7 %

Procedure:
A mixture of 4-(5-fluoro-1H-3-indolyl)-cyclohex-3-en-one ethylene ketal (2.7 g, 0.01 mol) and 10% palladium on carbon (1.2 g) in ethanol (200 ml) was hydrogenated for 4 days. The catalyst was filtered off and the filtrate was concentrated. The product was dried under vacuum to afford 2.8 g (100%) of product as a white solid: mp 183-185° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@@H:10]2[CH2:19][CH2:18][C:17]3[N+:16]([O-])=[CH:15][C:14]([CH3:21])=[CH:13][C:12]=3[CH2:11]2)=[CH:5][CH:4]=1.C(OC(=O)C)(=[O:24])C>C1(C)C=CC=CC=1>[OH:24][C@@H:18]1[C:17]2[N:16]=[CH:15][C:14]([CH3:21])=[CH:13][C:12]=2[CH2:11][C@H:10]([CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:19]1
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C[C@@H]2CCc3c(cc(C)c[n+]3[O-])C2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(C[C@H]2Cc3cc(C)cnc3[C@@H](O)C2)cc1
Reaction time: 3 h

Procedure:
(+)-(6S)-5,6,7,8-Tetrahydro-6-((4-methoxyphenyl)methyl)-3-methylquinoline-N-oxide (3,48g 0.012 mol) in toluene (40 ml) was added slowly to refluxing acetic anhydride (18 ml) and the mixture stirred for a further 3 hours. After cooling overnight, the reaction mixture was concentrated under reduced pressure and dissolved in methanol. The resulting solution was treated with 5M KOH until it was basic and again concentrated under reduced pressure. The residue was dissolved in water (40 ml) and washed with chloroform (3×40 ml). The combined organic phases were washed with brine (1×40 rml), dried (MgSO4) and concentrated under reduced pressure to give an oil (3.98 g) which solidified on standing. The product (1.9 g) was chromatographed on silica gel eluting with ethyl acetate to give the title compound (0.21 g), [α]D25 =+115% (1% CHCl3) mp 105°-7° C.
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([C:23]4[N:27]=[C:26]([C:28](OC)=[O:29])[O:25][N:24]=4)[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:40]([NH:47][CH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>C(O)C>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([C:23]4[N:27]=[C:26]([C:28]([N:51]5[CH2:50][CH2:49][CH:48]([NH:47][C:40](=[O:41])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])[CH2:53][CH2:52]5)=[O:29])[O:25][N:24]=4)[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1nc(-c2cncc(-c3nc(NCc4ccccn4)c4c(-c5ccccc5)cccc4n3)c2)no1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)c2nc(-c3cncc(-c4nc(NCc5ccccn5)c5c(-c6ccccc6)cccc5n4)c3)no2)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 38.5 %

Procedure:
To a solution of methyl 3-(5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)pyridin-3-yl)-1,2,4-oxadiazole-5-carboxylate (from example 187, 0.2 g, 0.38 mmol) in ethanol (10 mL) was added 4-(Boc-amino)piperidine (0.389 g, 1.90 mmol). Upon completion of addition, the reaction mixture was heated to 80° C. where it stirred for 16 h. At the conclusion of this period, the ethanol was evaporated and the resulting residue was purified by flash silica gel column chromatography (1.6% methanol in DCM) to yield tert-butyl 1-(3-(5-(5-phenyl-4-(pyridin-2-ylmethylamino)quinazolin-2-yl)pyridin-3-yl)-1,2,4-oxadiazole-5-carbonyl)piperidin-4-ylcarbamate (0.1 g, 38% yield) as yellow solid. LCMS Method T: retention time 2.08 min; [M+1]=684.2.
Reaction SMILES: C(O[C:4]([C:6]1[C:11](=[O:12])[N:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[N:9]2[CH:21]=[CH:22][CH:23]=[C:8]2[C:7]=1[OH:24])=[O:5])C.[NH2:25][CH2:26][C:27]([O-:29])=[O:28].[Na+]>>[F:20][C:17]1[CH:16]=[CH:15][C:14]([CH2:13][N:10]2[C:11](=[O:12])[C:6]([C:4]([NH:25][CH2:26][C:27]([OH:29])=[O:28])=[O:5])=[C:7]([OH:24])[C:8]3=[CH:23][CH:22]=[CH:21][N:9]23)=[CH:19][CH:18]=1
Reactant: NCC(=O)[O-]
Reactant: CCOC(=O)c1c(O)c2cccn2n(Cc2ccc(F)cc2)c1=O
Agent: [Na+]
Product: O=C(O)CNC(=O)c1c(O)c2cccn2n(Cc2ccc(F)cc2)c1=O

Procedure:
Prepared according to the glycinolysis condition used in Example 1 step d) from 1-(4-fluoro-benzyl)-4-hydroxy-2-oxo-1,2-dihydro-pyrrolo[1,2-b]pyridazine-3-carboxylic acid ethyl ester and sodium glycinate. ESI (m/z): 360 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].O[CH2:22][CH2:23][NH:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42].C1(C)C(C)=CC=CC=1>CCCC[O-].CCCC[O-].CCCC[O-].CCCC[O-].[Ti+4].O>[C:1]([C:5]1[CH:6]=[C:7]([CH2:16][CH2:17][C:18]([O:20][CH2:22][CH2:23][NH:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[O:19])[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]=1[OH:11])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCCO
Agent: [Ti+4]
Agent: CCCC[O-]
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCCCCCCC(=O)NCCOC(=O)CCc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
A mixture of 30.6 g (0.11 mole) 3-(3,5-di-tert-butyl-4-hydroxyphenyl)propionic acid, 32.6 g (0.1 mole) N-(2-hydroxyethyl)stearamide, 0.8 g Tyzor TBT, and 100 ml xylene was refluxed for six hours. The water (1.8 ml) was trapped in a Stark & Dean trap. The solution was filtered through Microcel (trademark, synthetic calcium silicate) and the solvent was removed by vacuum stripping. The title compound (51 g) was recrystallized from acrylonitrile. It melted at 52°-55° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[C:16](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:16])[C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2
Reactant: CCOC(=O)c1cc2cc(Br)ccc2[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Br)ccc2n1C
Temperature: 50 °C
Yield: 30.1 %

Procedure:
In dimethylformamide (5 mL), combine ethyl 5-bromo-1H-indole-2-carboxylate (1.00 g, 13.7 mmole), potassium carbonate (1.4 g, 10 mmole), and methyl iodide (280 μL, 4.50 mmole). Heat the mixture to 50° C. for 18 hours. Cool to room temperature and partition between EtOAc and water. Extract with EtOAc (3×), wash with brine (3×), dry (MgSO4) and concentrate to provide crude material. The crude material is purified on 120 g silica gel with 0 to 50% EtOAc in heptane to give 850 mg (81%) of the title compound. ES/MS m/e (81Br) 284.0 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[S:3]([O:6]S(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[C:16]([O:27][CH2:28][CH3:29])(=[O:26])[C:17]1[CH:25]=[CH:24][C:22](O)=[C:19]([O:20][CH3:21])[CH:18]=1.N1C=CC=CC=1.Cl>C(Cl)Cl.C(OCC)(=O)C>[CH3:21][O:20][C:19]1[CH:18]=[C:17]([CH:25]=[CH:24][C:22]=1[O:6][S:3]([C:2]([F:15])([F:14])[F:1])(=[O:5])=[O:4])[C:16]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CCOC(=O)c1ccc(O)c(OC)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(OC)c1
Temperature: 0 °C

Procedure:
Trifluoromethanesulfonic anhydride (0.94 mL) was added to an ice-cooled mixture of ethyl vanillate (1.0 g) and pyridine (0.45 mL) in methylene chloride (5 mL) with stirring. The mixture was stirred for 10 min, and poured into a mixture of 1 mol/L hydrochloric acid and ethyl acetate. The organic layer was separated, washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to afford ethyl 3-methoxy-4-trifluoromethanesulfonyloxybenzoate (1.47 g).
Reaction SMILES: C([N:8]1[C:13](=[O:14])[C:12]([C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[CH:10]=[N:9]1)C1C=CC=CC=1.[Al+3].[Cl-].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([C:11]2[CH:10]=[N:9][NH:8][C:13](=[O:14])[C:12]=2[C:15]2[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=2)=[CH:28][CH:27]=1
Reactant: N#Cc1ccc(-c2c(-c3ccc(Cl)cc3)cnn(Cc3ccccc3)c2=O)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2c(-c3ccc(Cl)cc3)cn[nH]c2=O)cc1
Temperature: 80 °C
Reaction time: 4 h
Yield: 78.7 %

Procedure:
To the suspension of 4-(2-benzyl-5-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile (3.62 gm, 9.12 mmol) in toluene (50 ml) at rt under argon was added AlCl3 (3.65 gm, 27.4 mmol). The reaction was heated to 80° C. and stirred at this temperature for 4 hrs. After this time, the solution was cooled to rt and concentrated under reduced pressure. Ice water (100 ml) was added to the reaction residue and the resulting slurry was stirred for 20 min. The solution was then diluted with EtOAc and the layers were separated. The aqueous layer was extracted with EtOAc (2×50 ml). The combined organic layers were washed with 1N NaOH (50 ml). The organic layer was then slurried with MgSO4 to remove excess water, filtered and concentrated to give the crude product. The crude product was triturated with EtOAc/Hex to give 2.21 gm (79% yield) 4-(5-(4-chlorophenyl)-3-oxo-2,3-dihydropyridazin-4-yl)benzonitrile. HPLC retention time (method B) 3.22 min; LCMS (M+H)=308.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][N:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:10][CH:11]=O)([CH3:4])([CH3:3])[CH3:2].[CH3:22][O:23][C:24](=[O:37])[C@@H:25]([NH2:36])[CH2:26][CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.Cl.C(N(CC)CC)C.B.N1C=CC=CC=1>ClCCCl.CCO.CC(O)=O>[CH3:22][O:23][C:24](=[O:37])[C@@H:25]([NH:36][CH2:11][CH2:10][N:9]([CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:21])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[CH2:26][CH2:27][O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COC(=O)[C@@H](N)CCOCc1ccccc1
Reactant: CC(C)(C)OC(=O)CCN(CC=O)c1ccc(Cl)c(Cl)c1
Agent: B
Agent: Cl
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: COC(=O)[C@H](CCOCc1ccccc1)NCCN(CCC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
6.26 g (18.83 mmol) of 3-[(3,4-dichloro-phenyl)-(2-oxo-ethyl)-amino]-propionic acid tert-butyl ester and 4.89 g (18.83 mmol) of (S)-2-amino-4-benzyloxy-butyric acid methyl ester; hydrochloride (intermediate 5) were dissolved in DCE:EtOH (1:1, 134 ml) and treated slowly with 3.15 ml (18.83 mmol) of triethylamine, 4.94 ml of AcOH and 4.94 ml (39.55 mmol, 8 M in pyridine) of pyridine-borane complex (cooling with a water bath to RT). The reaction was stirred at RT over 1 h, then partitioned between aq. NaHCO3 solution and EtOAc (3×). The organic phases were washed with aq. sat. NaHCO3 solution, aq. 10% NaCl solution, dried over Na2SO4 evaporated and purified by flash silica gel column (CH2Cl2:MeOH 99:1) to yield 9.35 g (92%) of the title compound as yellow oil. MS: 539.5 (MH+, 2Cl).
Reaction SMILES: [CH2:1](O)[C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].N1C=CC=CC=1.P(Br)(Br)[Br:17]>CCOCC>[Br:17][CH2:1][C:2]#[C:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: BrP(Br)Br
Reactant: CCCCCC#CCO
Solvent: CCOCC
Solvent: c1ccncc1
Product: CCCCCC#CCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 202.6 %

Procedure:
A solution of 2-octyne-1-ol (37.8 g) in ether (150 mL) containing pyridine (3 ml) was cooled to -35° and treated with a solution of phosphorous tribromide (28.9 g) over 45 min. The mixture was then stirred at -30° for 2 hours, 3 hours at room temperature and 1/2 hour at 40°. The reaction mixture was then cooled to room temperature, poured onto ice and extracted with ether. The combined ether extracts were washed with aqueous NaHCO3 solution, brine and dried (MgSO4). Removal of the solvents and distillation of the residue yielded 1-bromo-2-octyne (40.9 g), bp, 106°-110° (25 mmHg).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][N:14]=1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[N:18][C:13]([CH3:12])=[N:14][CH:15]=1)[CH:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: Cc1ncc(C(CN)C2CCOCC2)cn1
Product: Cc1ncc(C(CNC(=O)c2cccc(Cl)c2Cl)C2CCOCC2)cn1

Procedure:
The racemic mixture which was prepared in a similar manner to example 3a from 2,3-dichlorobenzoic acid and 2-(2-methylpyrimidin-5-yl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine was separated into the two enantiomers by preparative SFC to yield the title compound LCMS (MH+): m/z=394.1, tR (minutes, Method F)=1.88. [α]D20=+57.50 (c=2.0 mg/mL,CHCl3)
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH:3]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:4]#[N:5].[CH2:13](N)[CH2:14][NH2:15]>>[CH3:1][CH:2]([CH3:12])[CH:3]([C:4]1[NH:5][CH2:13][CH2:14][N:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)C(C#N)c1ccccc1
Reactant: NCCN
Product: CC(C)C(C1=NCCN1)c1ccccc1

Procedure:
rac-2-(2-Methyl-1-phenyl-propyl)-4,5-dihydro-1H-imidazole was prepared from rac-3-methyl-2-phenyl-butyronitrile and ethylene diamine in analogy to Example 22: colourless powder; MS (ISP): 203.0 ((M+H)+.).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[CH:42]=[C:41]([CH3:43])[N:40]=[C:39]([O:44][CH2:45][CH3:46])[CH:38]=1>>[CH2:45]([O:44][C:39]1[CH:38]=[C:37]([C:16]2[CH:17]=[CH:18][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:14][CH:15]=2)[CH:42]=[C:41]([CH3:43])[N:40]=1)[CH3:46]
Reactant: CCOc1cc(Br)cc(C)n1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: CCOc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccccc4)OC3=O)cc2)cc(C)n1

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4-bromo-2-ethoxy-6-methylpyridine following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.259 min, m/z=489.2; 1H NMR (CDCl3) 1.10 (s, 3H), 1.15 (s, 3H), 1.34 (m, 3H), 1.49 (m, 3H), 2.16 (m, 3H), 2.19 (m, 1H), 2.32 (m, 1H), 2.42 (m, 3H), 2.79 (m, 1H), 4.32 (m, 2H), 5.66 (m, 1H), 6.55 (s, 1H), 6.76 (s, 1H), 6.98 (m, 2H), 7.19-7.29 (m, 7H).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].C([O-])([O-])=O.[K+].[K+].[O:21]=[C:22]1[CH2:27][N:26]([CH2:28][C:29]([OH:31])=[O:30])[CH2:25][C:24](=[O:32])[O:23]1>CN(C=O)C>[CH2:8]([O:7][C:5](=[O:6])[CH2:4][CH2:3][NH:2][C:22](=[O:21])[CH2:27][N:26]([CH2:25][C:24]([OH:32])=[O:23])[CH2:28][C:29]([OH:31])=[O:30])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(O)CN1CC(=O)OC(=O)C1
Reactant: NCCC(=O)OCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)CN(CC(=O)O)CC(=O)NCCC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
To an ice bath cooled solution of benzyl 3-aminopropanoate hydrochloride (4.49 g, 20.8 mmol) in DMF (30 mL) was added K2CO3 (3.02 g, 21.84 mmol) and the resulting mixture was stirred at o° C. for 2 hr. The mixture was then filtered and the filtrate was added to an ice bath cooled solution of 2-(2,6-dioxomorpholino)acetic acid (4.47 g, 25.8 mmol) in DMF (30 mL). The resulting mixture was stirred at 0° C. for 30 min, then at rt for 2 hr. The reaction was quenched by the addition of water (30 mL) and the resulting mixture was concentrated. The residue was stirred with water (40 mL), and the resulting precipitate was collected through filtration and dried to give the title compound. 1H NMR (DMSO-d6) δ 2.53 (t, J=6.8, 2H), 3.27 (s, 2H), 3.36 (q, J=6.2, 2H), 3.42 (m, m 2H), 3.49 (s, 2H), 5.09 (s, 2H), 7.28 (m, 4H), 8.16 (m, 1H), 12.45 (br s, 2H).