Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1[C:15]([C:28]([CH3:30])=O)=[CH:16][C:17]2[C:18]([CH3:27])([CH3:26])[CH2:19][CH2:20][C:21]([CH3:25])([CH3:24])[C:22]=2[CH:23]=1.P(Cl)(OCC)(OCC)=O.C([N-]C(C)C)(C)C.[Li+]>C1COCC1>[CH3:13][C:14]1[C:15]([C:28]#[CH:30])=[CH:16][C:17]2[C:18]([CH3:27])([CH3:26])[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[C:22]=2[CH:23]=1
Reactant: CC(=O)c1cc2c(cc1C)C(C)(C)CCC2(C)C
Agent: CC(C)[N-]C(C)C
Agent: CCOP(=O)(Cl)OCC
Agent: [Li+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C#Cc1cc2c(cc1C)C(C)(C)CCC2(C)C
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 93 %

Procedure:
n-Butyllithium was added to a solution of freshly distilled diisopropylamine (3.01 mL, 21.5 mmol) and THF (41 mL) at 0° C. under argon. After 10 min, the solution was cooled to -78° C. and a solution of methyl (5,6,7,8-tetrahydro-3,5,5,8,8-pentamethylnaphthalen-2-yl) ketone (Compound 16) and THF was added dropwise. The solution was stirred for 1 h at -78° C. and then diethyl chlorophosphate (3.27 mL, 22.6 mmol) was added. The dry-ice bath was removed, and the solution was allowed to warm to room temperature over 1 hour and added dropwise to a -78° C. solution of lithium diisopropylamide (43.1 mmol) and THF (82 mL) prepared as described above. The resultant mixture was warmed to room temperature over 3 hours and quenched with water. The products were extracted with hexanes, washed with 1N HCl, water, brine, dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, hexanes) to give the title compound as a colorless solid (4.3 g, 93%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([OH:16])=[O:15])=[C:12]([S:17][C:18]3[N:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[N:19]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[C:39]([O:45][CH2:46]Cl)(=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41]>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([O:16][CH2:46][O:45][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])=[O:15])=[C:12]([S:17][C:18]3[N:19]=[C:20]([O:26][CH3:27])[CH:21]=[C:22]([O:24][CH3:25])[N:23]=3)[N:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: COc1cc(OC)nc(Sc2nccc(-c3ccc(F)cc3)c2C(=O)O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(OC)nc(Sc2nccc(-c3ccc(F)cc3)c2C(=O)OCOC(=O)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85 %

Procedure:
0.70 g (0.0019 mol) of 4-(4-fluorophenyl)-2-(4,6-dimethoxypyrimidin-2-ylthio)nicotinic acid and 0.50 g (0.0036 mol) of potassium carbonate were weighed, and 10 ml of dimethylformamide was added thereto. The mixture was then stirred at room temperature for 1 hour. Thereafter, 0.34 g (0.0022 mol) of chloromethyl pivalate was further added to the resultant mixture, and the mixture was stirred at room temperature for 2 hours. The mixture was then poured into water, and was extracted with 50 ml of ethyl acetate. After washing with water and a saturated sodium chloride aqueous solution, it was dried with anhydrous sodium sulfate. After filtration, the solvent was distilled off, and the residue was purified by silica gel chromatography (developing solvent: ethyl acetate/hexane=1/4) to obtain 0.81 g of a yellowish thick syrup-like aimed product.
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[N:10]=[C:9]([CH2:12][CH3:13])[NH:8][C:7]=2[C:6](=S)[N:5]=[CH:4]1)[CH3:2].[NH:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1>>[CH2:1]([N:3]1[C:11]2[C:7]([N:8]=[C:9]([CH2:12][CH3:13])[N:10]=2)=[C:6]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:5]=[CH:4]1)[CH3:2]
Reactant: CCc1nc2c([nH]1)c(=S)ncn2CC
Reactant: C1COCCN1
Product: CCc1nc2c(N3CCOCC3)ncn(CC)c-2n1

Procedure:
The product of stage (ii) (52 mg) in 5 ml of morpholine was refluxed for 21 hrs. Evaporation in vacuo gave 65 mg of crude 3,8-diethyl-6-morpholino-3H-purine.
Reaction SMILES: [N:1]([O-])=O.[Na+].[CH3:5][N:6]([CH2:8][CH2:9][CH:10]([C:16]1[CH:25]=[CH:24][C:19](C(NN)=O)=[CH:18][CH:17]=1)[C:11]1[NH:12][CH:13]=[CH:14][N:15]=1)[CH3:7].C(=O)([O-])[O-].[Na+].[Na+]>O.Cl>[NH2:1][C:19]1[CH:24]=[CH:25][C:16]([CH:10]([C:11]2[NH:12][CH:13]=[CH:14][N:15]=2)[CH2:9][CH2:8][N:6]([CH3:7])[CH3:5])=[CH:17][CH:18]=1
Reactant: CN(C)CCC(c1ccc(C(=O)NN)cc1)c1ncc[nH]1
Reactant: O=N[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CN(C)CCC(c1ccc(N)cc1)c1ncc[nH]1
Reaction time: 0.5 h

Procedure:
A solution of sodium nitrite (0.5 g) in water (5 ml) was added dropwise to a stirred solution of 4-[3-(N,N-dimethylamino)-1-(imidazol-2-yl)propyl]benzoic acid hydrazide (2.0 g) in 2 N hydrochloric acid (10.5 ml) and water (50 ml) at 0° to 5° C. After 30 min. the solution was basified by adding 2 N sodium carbonate (15 ml) and then extracted with ether (3×50 ml). The extracts were dried (Na2SO4) and concentrated to an off white solid (1.7 g). This solid was dissolved in toluene (40 ml) and benzyl alcohol (1.5 ml) and heated on a steam bath for 2 h. Solvent was removed and the residue taken up in ethanol (20 ml) and hydrogenated at atmospheric pressure over 10% palladium oxide on charcoal (0.5 g) for 3 h. The catalyst was filtered off and the filtrate treated with a solution of maleic acid (1.8 g) in ethanol (10 ml). Removal of the solvent and trituration of the residue with dry ether afforded a white solid. Recrystallisation from ethanolether gave the trimaleate salt of the title compound, m.p. 132°-133° (2.6 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:29])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:29][CH:16]([C:7]1[CH:8]=[C:9]([C:12]([CH3:13])([CH3:14])[CH3:15])[C:10]([OH:11])=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH:6]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: CCOC(=O)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 60 °C
Reaction time: 18 h
Yield: 107.7 %

Procedure:
In carbon tetrachloride (15 mL) was dissolved Intermediate 10 (1.46 g, 5.0 mmol) and NBS (1.33 g, 7.5 mmol). The solution was treated with benzoyl peroxide (~2 mg) and warmed to 60° C. and stirred for 18 hours. The mixture was cooled to room temperature and filtered free of insolubles. The filtrate was evaporated in vacuo to give 2.0 g (>100%) of the crude product as an oil.
Reaction SMILES: [O:1]=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].[BH4-].[Na+]>CCO>[CH2:6]([O:5][C:3](=[O:4])[CH:2]([OH:1])[C:8]1[CH:9]=[CH:10][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:13]=1)[CH3:7]
Reactant: CCOC(=O)C(=O)c1ccc(C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(O)c1ccc(C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 87.3 %

Procedure:
Ethyl 2-oxo-2-(4-(trifluoromethyl)phenyl)acetate (500 mg, 2.03 mmol) is dissolved in absolute EtOH (10 mL) and cooled at 0° C. under N2. NaBH4 (38.4 mg, 1.02 mmol) is added in two portions and the resulting suspension is allowed to warm to RT and stirred for 45 minutes. The solvent is evaporated, the resulting residue is diluted with Et2O and cool water is added. The organic layer is separated, washed with water and brine, dried over Na2SO4, filtered and evaporated obtaining intermediate I149 as a colorless oil (440 mg, 87% yield).
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=2)[NH2:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:18](Cl)(Cl)=[O:19]>C1(C)C=CC=CC=1>[CH:1]1([O:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([N:14]=[C:18]=[O:19])[CH:15]=[CH:16][CH:17]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)Cl
Reactant: Nc1cccc(OCCOC2CCCCC2)c1
Solvent: Cc1ccccc1
Product: O=C=Nc1cccc(OCCOC2CCCCC2)c1

Procedure:
A solution of 14.5 g of 3-[2-(cyclohexyloxy)-ethoxy]aniline in 100 ml of toluene was added dropwise to 100 ml of toluene containing 12 g of phosgene. The resultant mixture was refluxed for 1 hour and concentrated under reduced pressure. The concentrate was purified by high vacuum distillation to give 14 g of 3-[2-(cyclohexyloxy)-ethoxy]phenyl isocyanate. B.P., 112°-115° C./0.06 mmHg. nD23 1.5283.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([CH:7]([NH:27][C:28](=[O:34])OC(C)(C)C)[CH2:8][C:9]2[CH:17]=[C:16]([CH3:18])[C:15]3[C:11](=[CH:12][N:13](COCC[Si](C)(C)C)[N:14]=3)[CH:10]=2)[NH:5][CH:6]=1.Cl.C(C1NC=CN=1)(C1NC=CN=1)=O.C(N(C(C)C)CC)(C)C.[NH:57]1[CH2:62][CH2:61][CH:60]([N:63]2[CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=3)[NH:65][C:64]2=[O:73])[CH2:59][CH2:58]1>C(OCC)(=O)C>[CH3:1][C:2]1[N:3]=[C:4]([CH:7]([NH:27][C:28]([N:57]2[CH2:58][CH2:59][CH:60]([N:63]3[CH2:72][C:71]4[C:66](=[CH:67][CH:68]=[CH:69][CH:70]=4)[NH:65][C:64]3=[O:73])[CH2:61][CH2:62]2)=[O:34])[CH2:8][C:9]2[CH:10]=[C:11]3[C:15](=[C:16]([CH3:18])[CH:17]=2)[NH:14][N:13]=[CH:12]3)[NH:5][CH:6]=1
Reactant: Cc1c[nH]c(C(Cc2cc(C)c3nn(COCC[Si](C)(C)C)cc3c2)NC(=O)OC(C)(C)C)n1
Reactant: O=C1Nc2ccccc2CN1C1CCNCC1
Agent: Cl
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c[nH]c(C(Cc2cc(C)c3[nH]ncc3c2)NC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)n1
Temperature: 0 °C
Reaction time: 72 h

Procedure:
tert-Butyl 1-(4-methyl-1H-imidazol-2-yl)-2-(7-methyl-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-5-yl)ethylcarbamate (25.2 mg, 0.052 mmol) was dissolved in a minimum amount of ethyl acetate, and treated with hydrochloric acid (4 N in dioxane, 1.5 mL). The mixture was stirred under nitrogen for 3 days. After removal of the solvents, the crude mixture was treated with diethyl ether to give a precipitate which was filtered. The resulting solid was dissolved in dimethylformamide (1.0 mL), cooled to 0° C., and treated with carbonyl diimidazole (10.0 mg, 0.055 mmol, 1.1 equiv) and diisopropylethylamine (36.2 μL, 4.0 equiv). The reaction was stirred for 5 min at 0° C., warmed to room temperature, stirred for 10 min, and treated with 3-(piperidin-4-yl)-3,4-dihydroquinazolin-2(1H)-one (13.0 mg, 0.055, 1.1 equiv). The mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by column chromatography to afford 10.1 mg (38%, 2 steps). 1H-NMR (CD3OD, 500 MHz) δ 1.39-1.66 (m, 4H), 2.20 (s, 3H), 2.55 (s, 3H), 2.73-2.95 (m, 2H), 3.14-3.22 (m, 1H), 4.01-4.20 (m, 4H), 4.32-4.43 (m, 1H), 5.13-5.19 (m, 1H), 6.65 (s, 1H), 6.79 (d, J=7.6, 1H), 6.97 (dd, J=7.6, 7.3, 1H), 7.02 (s, 1H), 7.12 (d, J=7.3, 1H), 7.17 (dd, J=7.9, 7.3, 1H), 7.40 (s, 1H), 7.99 (s, 1H). Mass spec.: 513.3 (MH)+.
Reaction SMILES: N1N=C(C2C=CC=CC=2C(N2CC3CN(C(OC(C)(C)C)=O)CC3C2)=O)NC=1.[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([N:37]2[CH2:44][CH:43]3[CH:39]([CH2:40][NH:41][CH2:42]3)[CH2:38]2)[N:31]=1.C(OC(N1CC2C(CNC2)C1)=O)(C)(C)C.[CH3:60][C:61]1[N:65]=[C:64]([C:66]2[CH:74]=[CH:73][CH:72]=[CH:71][C:67]=2[C:68](O)=[O:69])[O:63][N:62]=1.N1N=C(C2C=CC=CC=2C(O)=O)NC=1>>[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]=[C:32]([N:37]2[CH2:44][CH:43]3[CH:39]([CH2:40][N:41]([C:68]([C:67]4[CH:71]=[CH:72][CH:73]=[CH:74][C:66]=4[C:64]4[O:63][N:62]=[C:61]([CH3:60])[N:65]=4)=[O:69])[CH2:42]3)[CH2:38]2)[N:31]=1
Reactant: Cc1cc(C)nc(N2CC3CNCC3C2)n1
Reactant: Cc1noc(-c2ccccc2C(=O)O)n1
Agent: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccccc3-c3nnc[nH]3)CC2C1
Agent: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: O=C(O)c1ccccc1-c1nnc[nH]1
Product: Cc1cc(C)nc(N2CC3CN(C(=O)c4ccccc4-c4nc(C)no4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 59 substituting Intermediate 23 for Intermediate 15 and 2-(3-methyl-1,2,4-oxadiazol-5-yl)benzoic acid for 2-(4H-[1,2,4]triazol-3-yl)benzoic acid. MS (ESI) mass calculated for C22H24N6O2, 404.48; m/z found, 405.2. 1H NMR (500 MHz, CDCl3): 8.10 (dd, J=7.9 Hz, 0.9 Hz, 1H), 7.62 (td, J=7.6 Hz, 1.2 Hz, 1H), 7.53 (td, J=7.7 Hz, 1.3 Hz, 1H), 7.42 (dd, J=7.6 Hz, 1.0 Hz, 1H), 6.28 (s, 1H), 3.99-3.88 (m, 2H), 3.80-3.75 (m, 1H), 3.74-3.65 (m, 2H), 3.53-3.48 (m, 1H), 3.46-3.40 (m, 1H), 3.12-3.04 (m, 2H), 3.01-2.93 (m, 1H), 2.42 (s, 3H), 2.28 (s, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH2:15][C:16]([O:18]C)=O)[CH2:11]3)[CH2:9][N:8]([C:20](=[O:28])[NH:21][C:22]3[S:23][C:24]([Cl:27])=[CH:25][N:26]=3)[C:5]2=[CH:6][CH:7]=1.[CH3:29][NH2:30].O1CCCC1.N.CO>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH2:15][C:16]([NH:30][CH3:29])=[O:18])[CH2:11]3)[CH2:9][N:8]([C:20]([NH:21][C:22]3[S:23][C:24]([Cl:27])=[CH:25][N:26]=3)=[O:28])[C:5]2=[CH:6][CH:7]=1
Reactant: CN
Reactant: COC(=O)CN1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12
Agent: N
Solvent: C1CCOC1
Solvent: CO
Product: CNC(=O)CN1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 45, with the exceptions that the methyl 2-(5-chloro-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-1′-yl)acetate obtained in Example 58 was used instead of ethyl 2-(5-chloro-1-((5-chlorothiazol-2-yl)carbamoyl)spiro[indoline-3,3′-pyrrolidin]-1′-yl)-2-oxoacetate, and that a solution of methylamine-tetrahydrofuran was used instead of a saturated solution of ammonia-methanol.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([NH2:12])=[C:5]2[NH:13][C:14]1[C:15]([CH3:20])=[N:16][N:17]([CH3:19])[CH:18]=1.Cl[C:22](OC(Cl)(Cl)Cl)=[O:23]>C(Cl)Cl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:22](=[O:23])[N:13]([C:14]4[C:15]([CH3:20])=[N:16][N:17]([CH3:19])[CH:18]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1nn(C)cc1Nc1c(N)cnc2ccc(Br)cc12
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1nn(C)cc1-n1c(=O)[nH]c2cnc3ccc(Br)cc3c21
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
To a solution of 6-bromo-N*4*-(1,3-dimethyl-1H-pyrazol-4-yl)-quinoline-3,4-diamine (Stage A.2, 3.15 g, 8.15 mmol) and TEA (1.36 ml, 9.79 mmol) in DCM (65 ml) was added under argon, after cooling with an ice-bath, a solution of trichloromethyl chloroformate (1.08 ml, 8.97 mmol in DCM (65 ml). The mixture was stirred for 25 min at 0° C. Then the RM was quenched with sat. aqueous NaHCO3 (300 ml) and 10 M aqueous NaOH (4 ml) and well stirred. The phases were separated and extracted with EtOAc (3×). The combined organic layers were washed with brine (2×), dried over Na2SO4, filtered and evaporated to dryness to give the title compound as a brownish solid (HPLC tR 2.29 min (Method A); M+H=360; M−H=358 MS-ES)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[S:31](Cl)(=[O:33])=[O:32]>>[Cl:20][C:21]1[CH:26]=[C:25]([C:27]([F:29])([F:28])[F:30])[CH:24]=[CH:23][C:22]=1[S:31]([NH:19][C:4]1[CH:5]=[N:6][C:7]([O:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:33])=[O:32]
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 2-chloro-4-(trifluoromethyl)benzene-1-sulfonyl chloride. 1H NMR (DMSO-d6) δ: 7.60 (s, 1H), 7.72-7.77 (m, 3H), 7.90 (s, 2H), 8.00 (s, 1H), 8.13-8.20 (m, 3H), 8.75 (s, 1H), 11.21 (s, 1H); MS (ES): 513.99 (M+1).
Reaction SMILES: C(OC([NH:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12])=O)(C)(C)C.[ClH:21]>CO.C(O)(C)C>[ClH:21].[NH2:8][CH2:9][C@H:10]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)N1CCOCC1
Agent: Cl
Solvent: CO
Solvent: CC(C)O
Product: COC(=O)[C@H](CN)N1CCOCC1
Temperature: 40 °C
Reaction time: 20 h
Yield: 96 %

Procedure:
A solution of 1.4 g (5 mmol) of methyl(S)-3-tert-butoxycarbonylamino-2-morpholin-4-ylpropanoate in 20 ml of methanol and 10 ml of a solution of hydrochloric acid having a 5-6N concentration in isopropanol is stirred at 40° C. for 20 h and then evaporated to dryness. 1.3 g (96%) of methyl(S)-3-amino-2-morpholin-4-ylpropanoate hydrochloride are obtained in the form of a solid.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:13][CH:12]([CH2:14][CH2:15][CH2:16]Cl)[C:11](=[O:18])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:19]([OH:27])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.CN(C=O)C>[CH2:2]([N:9]1[CH2:13][CH:12]([CH2:14][CH2:15][CH2:16][O:27][C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:11](=[O:18])[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccccc1
Reactant: O=C1CN(Cc2ccccc2)CC1CCCCl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(OCCCC1CN(Cc2ccccc2)CC1=O)c1ccccc1
Temperature: 100 °C
Yield: 41.1 %

Procedure:
1-benzyl-4-(3-chloropropyl)-3-pyrrolidone hydrochloride (6-2, 5.0 g, 17.3 mmol), benzoic acid (2.5 g, 20.8 mmol), potassium carbonate (7.1 g, 51.9 mmol) and potassium iodide (1.4 g, 8.65 mmol) are added to 40 ml DMF, then heated up to 100° C. and finally reacted overnight. At the end of reaction, the temperature is lowered to room temperature, 100 ml water is added, extraction is carried out by ethyl acetate (100 ml×2), organic phase is combined, washed twice by saturated saline water and dried by anhydrous sodium sulfate, and the solvent is dried by concentration under reduced pressure to obtain oily product, which is then purified by column chromatography to obtain oily product (3-1, 2.4 g, 7.1 mmol, yield: 41.1%). 1H NMR (400 MHz, CDCl3) δ 8.03 (d, J=8.1 Hz, 2H), 7.56 (t, J=7.4 Hz, 1H), 7.44 (t, J=7.7 Hz, 2H), 7.38-7.27 (m, 5H), 4.32 (t, J=6.3 Hz, 2H), 3.70 (s, 2H), 3.37-3.21 (m, 2H), 2.76 (d, J=17.2 Hz, 1H), 2.50 (dd, J=13.4, 8.0 Hz, 1H), 2.41 (t, J=8.9 Hz, 1H), 1.98-1.71 (m, 3H), 1.54 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:6][C:5](=[O:7])[N:4]([CH:8]2[CH2:13][CH2:12][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:10][CH2:9]2)[C@H:3]1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Br[C:31]1[C:32](=[O:41])[NH:33][C:34]2[C:39]([CH:40]=1)=[CH:38][CH:37]=[N:36][CH:35]=2.C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[CH3:1][C:2]1([CH3:29])[O:6][C:5](=[O:7])[N:4]([CH:8]2[CH2:13][CH2:12][C:11]([C:31]3[C:32](=[O:41])[NH:33][C:34]4[C:39]([CH:40]=3)=[CH:38][CH:37]=[N:36][CH:35]=4)=[CH:10][CH2:9]2)[C@H:3]1[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC1(C)OC(=O)N(C2CC=C(B3OC(C)(C)C(C)(C)O3)CC2)[C@H]1c1ccccc1
Reactant: O=c1[nH]c2cnccc2cc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OC(=O)N(C2CC=C(c3cc4ccncc4[nH]c3=O)CC2)[C@H]1c1ccccc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 38.6 %

Procedure:
A microwave vial was charged with (4S)-5,5-dimethyl-4-phenyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclohex-3-en-1-yl)oxazolidin-2-one (0.124 g, 0.312 mmol), 3-bromo-1,7-naphthyridin-2(1H)-one (0.105 g, 0.468 mmol), sodium carbonate (0.099 g, 0.936 mmol), dioxane (3.0 mL), and water (0.600 mL). Dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium (II) dichloromethane adduct (0.026 g, 0.031 mmol) was added, the system was purged with argon, and the tube was sealed. The mixture stirred at 100° C. in the microwave for 1.5 h. The reaction mixture was filtered through Celite® brand filter aid and the filtrate was concentrated to afford a brown oil. This oil was purified via column chromatography on silica gel (RediSep 40 g column, gradient elution with 0-10% methanol-ethyl acetate) to afford (4S)-5,5-dimethyl-3-(4-(2-oxo-1,2-dihydro-1,7-naphthyridin-3-yl)cyclohex-3-en-1-yl)-4-phenyloxazolidin-2-one (0.050 g, 38.6% yield) as an off-white solid.
Reaction SMILES: [Li+].CON(C)[C:5]([CH2:7][C@H:8]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH3:15])=[O:6].[Cl:32][C:33]1[CH:38]=[C:37](I)[CH:36]=[CH:35][N:34]=1.C(N(CC)C(C)C)(C)C>>[Cl:32][C:33]1[CH:38]=[C:37]([C:5](=[O:6])[CH2:7][C@H:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([OH:30])=[O:29])=[CH:26][CH:27]=3)=[CH:18][CH:17]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH:36]=[CH:35][N:34]=1
Reactant: CON(C)C(=O)C[C@H](c1ccc(-c2ccc(C(=O)[O-])cc2)cc1)c1ccccc1C
Reactant: Clc1cc(I)ccn1
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1[C@H](CC(=O)c1ccnc(Cl)c1)c1ccc(-c2ccc(C(=O)O)cc2)cc1

Procedure:
In analogy to example 74, step 5, from 4′-[(R)-2-(methoxy-methyl-carbamoyl)-1-o-tolyl-ethyl]-biphenyl-4-carboxylic acid lithium salt, 2-chloro-4-iodopyridine and N,N-diisopropyl-ethylamine was prepared the title compound as a brown foam, MS (ESI−): m/z=454.1 [M−H]−.
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][C@@H:6]1[CH2:10][S:9][C:8]([C:11]2[NH:12][C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=3[NH:21][CH:22]2[CH2:31][CH2:30][C:25]3(OCC[O:26]3)[CH2:24][CH2:23]2)=[N:7]1)C.Cl>CO>[CH3:20][C:16]1[CH:17]=[C:18]2[C:13](=[C:14]([NH:21][CH:22]3[CH2:31][CH2:30][C:25](=[O:26])[CH2:24][CH2:23]3)[CH:15]=1)[NH:12][C:11]([C:8]1[S:9][CH2:10][C@@H:6]([CH2:5][C:4]([OH:32])=[O:3])[N:7]=1)=[CH:19]2
Reactant: CCOC(=O)C[C@@H]1CSC(c2cc3cc(C)cc(NC4CCC5(CC4)OCCO5)c3[nH]2)=N1
Agent: Cl
Solvent: CO
Product: Cc1cc(NC2CCC(=O)CC2)c2[nH]c(C3=N[C@H](CC(=O)O)CS3)cc2c1
Yield: 4.9 %

Procedure:
{(R)-2-[7-(1,4-dioxa-spiro[4,5]dec-8-yl)amino-5-methyl-1H-indol-2-yl]-4,5-dihydro-thiazol-4-yl}-acetic acid ethyl ester (177 mg, 4 mmol) prepared in Step A was dissolved in methanol (10 mL). HCl (conc. 2 mL) was added thereto, and the mixture was reacted for 6 h at 60°. The solvent was removed under reduced pressure, and water was added to the residue. The reaction mixture was extracted with EtOAc, dried, concentrated, and purified by HPLC to give the title compound (76 mg, Yield 50%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.[CH:14]([Sn](CCCC)(CCCC)CCCC)=[CH2:15]>CN(C=O)C.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>[CH:14]([C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1)=[CH2:15]
Reactant: CCOC(=O)Cc1cccc(Br)c1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=Cc1cccc(CC(=O)OCC)c1
Temperature: 90 °C

Procedure:
A mixture of 1.0 mmol of ethyl 3-bromophenylacetate, 1.5 mmol of vinyltributyltin, and 0.1 mmol of Pd(PPh3)4 in 4 mL DMF was stirred and heated at 90° C. for 1-16 h. Chromatography provided ethyl 3-vinylphenylacetate.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][CH2:7][C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][CH:9]=1)C(C)=O.C(O)C.[OH-].[K+].Cl>O>[NH2:1][CH2:5][CH2:6][CH2:7][C:8]1[CH:20]=[CH:19][C:11]([O:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][CH:9]=1
Reactant: CCOC(=O)COc1ccc(CCCNC(C)=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NCCCc1ccc(OCC(=O)O)cc1

Procedure:
A mixture of 16.2 g. (58 mMol) ethyl 4-(3-acetaminopropyl)-phenoxyacetate, 100 ml. ethanol, 100 ml. water and 32.5 g. (0.58 mol) potassium hydroxide is kept at reflux temperature for 16 hours. The reaction mixture is then cooled, adjusted to pH 6.5 with 6 N hydrochloric acid and the resultant sand-colored precipitate filtered off with suction. After washing with water and drying, there are obtained 12.0 g. (quantitative yield) 4-(3-aminopropyl)-phenoxyacetic acid; m.p. 248° C.