Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH2:9][C:10]([OH:12])=O)=[CH:4]C=1.C1([NH:18]CC(O)=O)CCCC1>>[CH:5]1([NH:8][CH2:9][C:10]([NH2:18])=[O:12])[CH2:4][CH2:2][CH2:7][CH2:6]1
Reactant: Cc1ccc(NCC(=O)O)cc1
Reactant: O=C(O)CNC1CCCC1
Product: NC(=O)CNC1CCCC1

Procedure:
By replacing the p-methylphenylglycine employed in Procedure 14, Step A by an equivalent quantity of cyclopentylglycine, there is obtained cyclopentylglycinamide. Substituting this cyclopentylglycinamide for that employed in Procedure 13 and following the methods described in Steps A and B of Procedure 13, there is obtained in Step A 2-hydroxy-3-cyclopentylpyrazine and in Step B 2-chloro-3-cyclopentylpyrazine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=O)[CH2:8][CH2:7]2.[CH2:13]([NH:16][CH2:17][CH2:18][CH3:19])[CH2:14][CH3:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]=[C:9]([N:16]([CH2:17][CH2:18][CH3:19])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2
Reactant: CCCNCCC
Reactant: O=C1CCc2cccc(Br)c2C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCCN(CCC)C1=Cc2c(Br)cccc2CC1

Procedure:
To a solution of 8-bromo-2-tetralone (3.0 gm, 13.3 mMol) in toluene (25 mL) were added di-n-propylamine (3.5 mL, 26 mMol) and p-toluenesulfonic acid (100 mg, 0.52 mMol). The reaction was heated to reflux, water being collected in a Dean-Stark trap. After four hours the reaction was concentrated in vacuo to give 8-bromo-2-dipropylamino-3,4-dihydronaphthalene as a dark liquid which was immediately dissolved in methanol (50 mL) and acetic acid (5 mL). To this solution was then added sodium borohydride (2.0 gm, 52.9 mMol), and the mixture was stirred 18 hours at room temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[C:29]([F:32])([F:31])[F:30])[CH2:19][CH2:18]3)=[O:16])=[CH:7][N:8]2[CH2:11][C:12]([OH:14])=O)=[CH:4][CH:3]=1.C(OC(=O)[NH:39][CH2:40][CH2:41][NH2:42])(C)(C)C.Cl>>[ClH:1].[NH2:39][CH2:40][CH2:41][NH:42][C:12](=[O:14])[CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[C:6]([C:15]([N:17]2[CH2:18][CH2:19][CH:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:31])([F:30])[F:32])[CH2:21][CH2:22]2)=[O:16])=[CH:7]1
Reactant: O=C(O)Cn1cc(C(=O)N2CCC(c3ccccc3C(F)(F)F)CC2)c2ccc(Cl)cc21
Reactant: CC(C)(C)OC(=O)NCCN
Agent: Cl
Product: NCCNC(=O)Cn1cc(C(=O)N2CCC(c3ccccc3C(F)(F)F)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure I, the coupling of {6-chloro-3-[4-(2-trifluoromethyl-phenyl)-piperidine-1-carbonyl]-indol-1-yl}-acetic acid (prepared herein) with (commercially available) (2-amino-ethyl)-carbamic acid tert-butyl ester gave, after treatment with HCl, the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].Cl[C:13]1[C:14]2[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:15]=2[N:16]=[C:17]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[N:18]=1>>[N:21]1[CH:22]=[CH:23][CH:24]=[C:19]([C:17]2[N:18]=[C:13]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[C:14]3[C:27]([Cl:28])=[C:26]([CH3:29])[S:25][C:15]=3[N:16]=2)[CH:20]=1
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3cccnc3)nc(NCc3cccc([N+](=O)[O-])c3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of 3-nitrobenzylamine with 4-chloro-2-(pyridin-3-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3-nitrobenzylamino)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][N:9]([S:12]([C:15]3[CH:16]=[C:17]([CH3:21])[CH:18]=[CH:19][CH:20]=3)(=[O:14])=[O:13])[C:10]=2[N:11]=1.C(=[NH:35])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:17]1([CH3:21])[CH:18]=[CH:19][CH:20]=[C:15]([S:12]([N:9]2[CH2:8][CH2:7][O:6][C:5]3[CH:4]=[CH:3][C:2]([NH2:35])=[N:11][C:10]2=3)(=[O:14])=[O:13])[CH:16]=1
Reactant: Cc1cccc(S(=O)(=O)N2CCOc3ccc(Br)nc32)c1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: Cc1cccc(S(=O)(=O)N2CCOc3ccc(N)nc32)c1
Temperature: 100 °C
Yield: 32.3 %

Procedure:
6-Bromo-4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine (300 mg, 0.81 mmol) was dissolved in p-dioxane (10 mL), followed by benzophenone imine (409 μL, 2.44 mmol), sodium tert-butoxide (207 mg, 2.15 mmol), XantPhos (70 mg, 0.12 mmol), and finally Pd2(dba)3 (74 mg, 0.08 mmol). The resulting mixture was heated to 100° C. for 2.5 hours. Then, the reaction mixture was concentrated under vacuum and partitioned in a mixture of ethyl acetate and water. The aqueous phase was discarded, and the organic phase was concentrated and purified by flash chromatography (12 g silica column, 0-60% EtOAc/Hexane) to give 4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamine Yield 80 mg (32%). LCMS (ESI): calc. C14H15N3O3S=305; obs. M+H=306.
Reaction SMILES: [C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([NH:11][S:12]([C:15]2[CH:28]=[CH:27][C:26]3[C:25](=[O:29])[C:24]4[C:19](=[CH:20][C:21]([S:30]([NH:33][CH:34]5[CH2:39][CH2:38][CH:37]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:36][CH2:35]5)(=[O:32])=[O:31])=[CH:22][CH:23]=4)[C:18](=[O:44])[C:17]=3[CH:16]=2)(=[O:14])=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl.Cl[CH2:49][CH2:50][CH2:51][N:52]([CH3:54])[CH3:53].[OH-].[Na+]>CN(C=O)C>[C:1]([CH:5]1[CH2:10][CH2:9][CH:8]([N:11]([CH2:49][CH2:50][CH2:51][N:52]([CH3:54])[CH3:53])[S:12]([C:15]2[CH:28]=[CH:27][C:26]3[C:25](=[O:29])[C:24]4[C:19](=[CH:20][C:21]([S:30]([N:33]([CH:34]5[CH2:35][CH2:36][CH:37]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:38][CH2:39]5)[CH2:49][CH2:50][CH2:51][N:52]([CH3:54])[CH3:53])(=[O:31])=[O:32])=[CH:22][CH:23]=4)[C:18](=[O:44])[C:17]=3[CH:16]=2)(=[O:13])=[O:14])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)CCCCl
Reactant: CC(C)(C)C1CCC(NS(=O)(=O)c2ccc3c(c2)C(=O)c2cc(S(=O)(=O)NC4CCC(C(C)(C)C)CC4)ccc2C3=O)CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCCN(C1CCC(C(C)(C)C)CC1)S(=O)(=O)c1ccc2c(c1)C(=O)c1cc(S(=O)(=O)N(CCCN(C)C)C3CCC(C(C)(C)C)CC3)ccc1C2=O
Temperature: 40 °C
Reaction time: 0.08 h
Yield: 19.6 %

Procedure:
To an ice cold solution of the sulfonamide (1-36, 6.82 g, 10.61 mmol) in anhydrous DMF (100 ml) under argon was added NaH (95.0%, 697 mg, 27.58 mmol). The solution was stirred for 5 min, and then 3-chloro-N,N-dimethylpropan-1-amine hydrochloride (2.18 g, 13.8 mmol) was added. After 10 min, the reaction mixture was transferred to a pre heated oil bath at 40° C. and stirred for 3 days. LCMS showed the presence of monoalkylated and bisalkylated products (ratio, 65:25) together with unreacted starting material. After cooling, 1N NaOH was added to the reaction mixture and extracted with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate and the filtrate was evaporated under reduced pressure. The crude mixture was purified by silica gel column chromatography. The unreacted starting material was recovered when the column was eluted with 40° A) EtOAc in hexane. Pure monoalkylated product (13-1, LCMS, MS 728.0 (MH+)) was obtained when eluted using EtOAc alone and the bisalkylated product (1-70, LCMS, MS 813.2 (MH+)) was isolated with 5% triethylamine in EtOAc as the eluent. The fractions collected were evaporated under reduced pressure to dryness to get 13-1 (3.02 g, 53%) and 1-70 (1.10 g, 17%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH2:10][N+:11]([O-:13])=[O:12])[CH:4]=1.[C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])(=[O:17])[CH:15]=[CH2:16].N12CCCN=C1CCCCC2>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH:10]([N+:11]([O-:13])=[O:12])[CH2:16][CH2:15][C:14]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CC[N+](=O)[O-])c1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: COc1cccc(CC(CCC(=O)OC(C)(C)C)[N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 18.5 h
Yield: 76.2 %

Procedure:
To a solution of 1-methoxy-3-(2-nitroethyl)benzene (22.59 g) and tert-butyl acrylate (15.98 g) in dichloromethane (180 ml) was added a solution of 1,8-diazabicyclo[5.4.0]undec-7-ene (1.90 g) in dichloromethane (45 ml) in an ice bath. After stirring for 18.5 hours at ambient temperature, ice water (70 ml) was added to the solution. The organic layer was separated, washed successively with 1N hydrochloric acid, and brine. The solution was treated with silica gel (70 g) and evaporated in vacuo to give tert-butyl 5-(3-methoxyphenyl)-4-nitrovalerate (29.39 g).
Reaction SMILES: [NH2:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:30]([NH:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1)([O:29][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:31]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC1(C(=O)O)CCCC1
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Solvent: ClCCl
Product: O=C(NC1(C(=O)O)CCCC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 911.5 %

Procedure:
To a stirred suspension of 12.9 g (0.010 mole) of 1-amino-1-cyclopentane carboxylic acid in 500 ml of methylene chloride is added 25 ml (0.10 mole) of N,O-bis(trimethylsilyl)acetamide. The mixture is stoppered and stirred at room temperature for 3 days, whereupon complete solution is obtained. 17 g (0.10 mole) of benzylchloroformate is added and the mixture stirred for an additional 1 hour. It is then washed with 300 ml each 2N HCl, water and saturated brine and dried over sodium sulfate. Filtration, evaporation and trituration with hexane gives 24 g of 1-carbobenzoxyamino-1-cyclopentane carboxylic acid, mp. 93°-5° C. 5.3 g (0.020 mole) of 1-carbobenzoxyamino-1-cyclopentane carboxylic acid is dissolved in 100 ml dimethylformamide and 3.1 g (0.020 mole) of 1-hydroxybenzotriazole hydrate and 2.5 g (0.020 mole) of 1,3-diisopropylcarbodiimide are added. The mixture is stirred at room temperature for three hours and 1.8 g (0.020 mole) of 4-amino-1-butanol is added. Stirring at room temperature is continued for 24 hours. The solvent is removed in vacuo and replaced with 500 ml of methylene chloride. The mixture is washed with 2N HCl, saturated sodium bicarbonate solution and water and dried over sodium sulfate. Filtration and evaporation gives 6.7 g of 1-carbobenzoxyamino-1-cyclopentane carboxylic acid, 4-hydroxybutylamide, m.p 117°-8° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([O:10][CH2:11][CH3:12])[CH:3]=1.C([Li])CCC.CON(C)[C:21]([C:23]1[CH:31]=[C:30]2[C:26]([CH:27]=[CH:28][NH:29]2)=[CH:25][CH:24]=1)=[O:22].C(O)(C)C>C1COCC1.O>[CH2:11]([O:10][C:4]1[CH:3]=[C:2]([C:21]([C:23]2[CH:31]=[C:30]3[C:26]([CH:27]=[CH:28][NH:29]3)=[CH:25][CH:24]=2)=[O:22])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9])[CH3:12]
Reactant: CCOc1cc(Br)ccc1OC
Reactant: CON(C)C(=O)c1ccc2cc[nH]c2c1
Agent: [Li]CCCC
Solvent: CC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CCOc1cc(C(=O)c2ccc3cc[nH]c3c2)ccc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 72.1 %

Procedure:
A stirred mixture of 4-bromo-2-ethoxy-1-methoxy-benzene (6.52 g, 23.7 mmol) and anhydrous THF (20 mL) was cooled to −78° C., evacuated and refilled with nitrogen for 10 cycles. To this clear solution was slowly added n-butyllithium (9.5 mL, 23.7 mmol) and stirred for 20 min. Then a mixture of 1H-indole-6-carboxylic acid methoxy-methyl-amide (2.20 g, 10.8 mmol) in anhydrous THF (25 mL) was added and stirred for 1 hour at −78° C. The mixture was quenched with isopropanol (4.9 mL, 65 mmol) and water (15 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organic phases were washed with water (2×50 mL), dried over MgSO4 and concentrated to give an oil, which was purified by flash column chromatography (EtOAc, Hexane) to give (3-ethoxy-4-methoxy-phenyl)-(1H-indol-6-yl)-methanone as an oil (2.30 g). The product was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[S:6][CH:5]=[N:4][C:3]=1[CH3:7].C(N(CC)CC)C.[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>COCCOC.C(OCC)(=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:7][C:3]1[N:4]=[CH:5][S:6][C:2]=1[C:22]#[C:21][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C#Cc1ccccc1
Reactant: Cc1ncsc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: COCCOC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ncsc1C#Cc1ccccc1
Reaction time: 16 h
Yield: 26 %

Procedure:
5-Bromo-4-methyl-1,3-thiazole (570 mg, 3.2 mmol) and CuI (120 mg, 0.63 mmol) were combined in DME (5 mL) and argon gas was bubbled through the suspension for several minutes to deoxygenate the mixture. Triethylamine (2.0 mL, 14 mmol) and PdCl2(PPh3)2 (220 mg, 0.32 mmol) were added, followed by the dropwise addition of phenylacetylene (1.0 mL, 9.5 mmol). After 16 h stirring at ambient temperature additional phenylacetylene (0.35 mL, 3.2 mmol), CuI, (61 mg, 0.32 mmol), and PdCl2(PPh3)2 (110 mg, 0.16 mmol) were added and the reaction mixture was stirred for a further 16 h. The reaction was then heated to reflux, and after 3 h the reaction mixture was cooled, diluted with ethyl acetate (20 mL), and filtered through Celite™. The filter pad was washed thoroughly with ethyl acetate and the combined filtrates were washed with water (20 mL), brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 95:5 hexane:ethyl acetate to afford 4-methyl-5-(phenylethynyl)-1,3-thiazole (166 mg, 26% yield) as a red oil. 1H NMR (CDCl3, 300 MHz) δ 8.62 (s, 1H), 7.54–7.50 (m, 2H), 7.37–7.26 (m, 3H), 2.6 (s, 3H). MS (ESI) 200.1 (M++H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7](=O)[C:6]=2[CH:11]=1.[C:12]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)#[N:13].[PH5]>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]=[C:7]([CH2:14][C:12]#[N:13])[C:6]=2[CH:11]=1
Reactant: O=C1COc2ccc(Br)cc21
Reactant: N#CC=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [PH5]
Solvent: Cc1ccccc1C
Product: N#CCc1coc2ccc(Br)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A suspension of 5-bromo-3-(2H)-benzofuranone (4.26 g) and cyanomethylene triphenylphosphorane (9.06 g) in dry xylene (100 ml) was heated at reflux for 24 h . A further quantity of the phosphorane (450 mg) was added and heating continued for a further period of 12 h. On cooling to ambient temperature the brown coloured suspension was evaporated to dryness in vacuo. Chromatography of the residue using dichloromethane:hexane (1:3) as eluant afforded a cream coloured product. Recrystallization (from ethanol) of the chromatographed material afforded the title compound as cream flakes, m.p. 120°.
Reaction SMILES: [F:1][C:2]1[C:11]([O:12][CH3:13])=[C:10]2[C:5]([C:6](=[O:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][N:9]2[C@@H:14]2[CH2:16][C@@H:15]2[F:17])=[C:4]([N+:24]([O-])=O)[CH:3]=1.C(Cl)(Cl)Cl>C(#N)C.[C].[Pd]>[NH2:24][C:4]1[CH:3]=[C:2]([F:1])[C:11]([O:12][CH3:13])=[C:10]2[C:5]=1[C:6](=[O:23])[C:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:8][N:9]2[C@@H:14]1[CH2:16][C@@H:15]1[F:17]
Reactant: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(OC)c(F)cc([N+](=O)[O-])c2c1=O
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)c1cn([C@@H]2C[C@@H]2F)c2c(OC)c(F)cc(N)c2c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 78.4 %

Procedure:
Ethyl 7-fluoro-1-[2-(S)-fluoro-1-(R)-cyclopropyl]-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (3.71 g, 10.1 mmol) was dissolved in acetonitrile (50 ml), and after adding a 5% palladium carbon catalyst (water content: 50%, 1.5 g) thereto, it was stirred at room temperature for 20 hours under a hydrogen atmosphere at atmospheric pressure. After removing the catalyst by filtering (methanol washing), the filtrate was concentrated under a reduced pressure, the residue obtained was applied to a silica gel chromatography, and 2.68 g (79%) of the title compound was obtained as a yellow amorphous substance from a chloroform:methanol=30:1 eluate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[C:14]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)=[N:15][C:16]3[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([O:25]C)=[O:24])=[CH:18][CH:17]=3)[CH2:8][CH2:7][CH2:6]2)#[N:2]>CO.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([C:13]1[C:14]([C:27]3[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=3)=[N:15][C:16]3[C:21]([N:22]=1)=[CH:20][C:19]([C:23]([OH:25])=[O:24])=[CH:18][CH:17]=3)[CH2:8][CH2:7][CH2:6]2)#[N:2]
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(N3CCCc4cc(C#N)ccc43)nc2c1
Solvent: CO
Solvent: O
Product: N#Cc1ccc2c(c1)CCCN2c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1
Reaction time: 8 h
Yield: 31.5 %

Procedure:
To a solution of methyl 3-(6-cyano-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (From Ex 14, step 5, 50 mg, 0.11 mmol) in methanol (20 mL) and water (1 mL) was added lithiumol hydroxide (10 mg, 0.40 mmol) with stifling overnight at room temperature. The resulting mixture was concentrated under vacuum, dissolved in water (10 mL) and adjusted to 7 with AcOH, collected by filtration to give 3-(6-cyano-1,2,3,4-tetrahydroquinolin-1-yl)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid as a yellow solid (14.7 mg, 30%). [M+H]+ 425.1
Reaction SMILES: [OH:1][C:2]1([C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9](O)=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)[N:38]([CH3:40])[CH3:39])C2C=CC=CC=2N=N1.CNC>C(Cl)Cl>[OH:1][C:2]1([C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:9]([N:38]([CH3:40])[CH3:39])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: COc1ccc([C@@H](C(=O)O)C2(O)CCCCC2)cc1
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: COc1ccc([C@@H](C(=O)N(C)C)C2(O)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
A solution of (2R)-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)acetic acid (156 mg, 0.59 mmol) in methylene chloride (1 mL) was treated with benzotriazol-1-yl-oxy-tris(dimethylamino)phosphonium hexafluorophosphate (313 mg, 0.71 mmol) and dimethylamine (2.0 M in tetrahydrofuran, 1.5 mL, 2.95 mmol). The reaction was stirred at 25° C. for 1.5 h after which time the solvent was evaporated and the product was purified via Biotage™ Horizon chromatography (FLASH 25 M, silica, gradient from 5% ethyl acetate/hexane to 36% ethyl acetate/hexane over 650 mL) to yield 160 mg (93%) (2R)-2-(1-hydroxycyclohexyl)-2-(4-methoxyphenyl)-N,N-dimethylacetamide as a white solid. MS (ESI) m/z 292; [α]D25=+81° (c=0.010 g/mL, EtOH).
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=2)[CH2:8][N:7](CC2C=CC=CC=2)[CH2:6]1)=[O:4]>CO.[OH-].[Pd+2].[OH-]>[CH3:1][O:2][C:3]([C@H:5]1[C@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[CH:11]=2)[CH2:8][NH:7][CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1cccc(Br)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC(=O)[C@@H]1CNC[C@H]1c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 96.8 %

Procedure:
Add palladium hydroxide (3.1 g, 22 mmol) to a solution of trans-1-benzyl-4-(3-bromo-phenyl)-pyrrolidine-3-carboxylic acid methyl ester (15 g, 40 mmol) in MeOH (200 mL). Place the mixture under an atmosphere of hydrogen and stir at room temperature for 12 h. Filter the reaction mixture through a pad of diatomaceous earth and concentrate under reduced pressure to provide 11 g (97%) of trans-4-(3-bromo-phenyl)-pyrrolidine-3-carboxylic acid methyl ester.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.O[C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:9]([CH2:23][CH2:24][CH3:25])[N:8]=1.[C:26](#N)[CH3:27]>>[CH2:23]([C:9]1[C:10]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:11][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:7]([CH:26]=[CH2:27])[N:8]=1)[CH2:24][CH3:25]
Reactant: CCCc1nc(O)c(C(=O)OCC)cc1C(=O)OCC
Reactant: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: C=Cc1nc(CCC)c(C(=O)OCC)cc1C(=O)OCC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
Phosphoryl trichloride (7.95 mL) was added to a solution of diethyl 2-hydroxy-6-propylpyridine-3,5-dicarboxylate (12.0 g) in acetonitrile (120 mL) at room temperature. The mixture was stirred at 90° C. under a dry atmosphere with calcium chloride tube for 3 hours. After cooling to room temperature, the mixture was quenched with aqueous saturated sodium hydrogen carbonate solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with brine and water, dried over anhydrous magnesium sulfate and concentrated in vacuo. A mixture of the residue, triethylamine (11.8 mL), potassium trifluoro(vinyl)borate (8.51 g) and dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane adduct (2.42 g) in ethanol (130 mL) was stirred at 90° C. overnight under nitrogen atmosphere. After cooling to room temperature, the mixture was concentrated in vacuo. The residue was diluted with ethyl acetate and water. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was passed through a silica gel-pad (hexane/ethyl acetate) to give the title compound (10.3 g).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[C:9]2=[O:12])=[CH:4][CH:3]=1.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[O:29][C:30]3[CH:40]=[C:39]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])[C:38](B4OC(C)(C)C(C)(C)O4)=[CH:37][C:31]=3[C:32]=2[C:33]([NH:35][CH3:36])=[O:34])=[CH:24][CH:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.O.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[F:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:2]([C:38]4[C:39]([N:41]([CH3:46])[S:42]([CH3:45])(=[O:44])=[O:43])=[CH:40][C:30]5[O:29][C:28]([C:25]6[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=6)=[C:32]([C:33]([NH:35][CH3:36])=[O:34])[C:31]=5[CH:37]=4)=[CH:3][CH:4]=3)[C:9]2=[O:12])=[CH:15][CH:16]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=C1c2cc(Br)ccc2CCN1Cc1ccc(F)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(c3)C(=O)N(Cc3ccc(F)cc3)CC4)cc12
Temperature: 90 °C
Reaction time: 3 h
Yield: 95.3 %

Procedure:
To a degassed solution of 7-bromo-2-(4-fluorobenzyl)-3,4-dihydroisoquinolin-1(2H)-one (222 mg, 0.66 mmol) and 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (200 mg, 0.40 mmol) in 1,4-dioxane (5 mL) and water (200 μl) was added Cs2CO3 (260 mg, 0.80 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (26 mg, 0.04 mmol) under N2 protection. The resulting mixture was heated to 90° C. and stirred at this temperature for 3 h. The reaction was cooled, filtered through a pad of celite and washed with ethyl acetate. The combined filtrate was evaporated in vacuo. The resulting residue was purified using column chromatography (eluted with 0-30% EtOAc/DCM) to provide 5-(2-(4-fluorobenzyl)-1-oxo-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (240 mg, yield: 96%). MS (M+H)+: 630.