Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1)(=[O:6])[OH:5])[CH3:2].C(Cl)(=O)C(Cl)=O.[C:24]1([CH2:30][CH2:31][CH2:32]O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.FC(F)(F)C1C=C(C=CC=1)CP(=O)(OCC)OCl.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[F:16][C:14]([F:17])([F:15])[C:10]1[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=1)[CH2:7][P:4](=[O:5])([O:6][CH2:32][CH2:31][CH2:30][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[O:3][CH2:1][CH3:2]
Reactant: OCCCc1ccccc1
Reactant: CCOP(=O)(O)Cc1cccc(C(F)(F)F)c1
Agent: CCOP(=O)(Cc1cccc(C(F)(F)F)c1)OCl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOP(=O)(Cc1cccc(C(F)(F)F)c1)OCCCc1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
3-trifluoromethylbenzylphosphonic acid mono ethyl ester (1.5 g, 5.6 mmol) was dissolved in 20 mL of CH2Cl2 and cooled to 0° C. under nitrogen. After the oxalyl chloride (8.46 mmol) had been added, 0.04 mL of DMF was slowly added in 3 portions, and the resultant mixture was stirred at room temperature for 3 hours. Evaporation in vacuo gave the crude acid chloride which was used without further purification. 3-Phenyl-1-propanol (0.76 g, 5.6 mmol), in 15 mL of CH2Cl2, was added to a cold mixture of crude chloro ethyl 3-trifluoromethylbenzylphosphonate (5.6 mmol), triethylamine (0.85 g, 8.4 mmol), and CH2Cl2 (20 mL) cooled at 0° C. The resultant reaction mixture was allowed to stir at room temperature for 4 hours. Evaporation of the volatile components gave a quantitative yield of the expected product. Purification by column chromatography (silica gel, 25% ethyl acetate/hexane) gave 1.66 g (52.3%) of analytically pure product as a pale yellow oil. D.C.I.M.S.[MH+, 387].
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]4([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]4)=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])=[CH:9][C:8]=1[F:40].[Cl-].[NH4+]>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:41])=[O:4])=[C:8]([F:40])[CH:9]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]2([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31]2)=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCC(CC)(c1ccc(CCC2(O)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(F)c2)c(C)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CCC(CC)(c1ccc(CCC2(O)CCCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)O)c(F)c2)c(C)c1
Reaction time: 5 h
Yield: 115.5 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.07 mL) was added to a solution of [4′-(1-ethyl-1-{4-[2-(1-hydroxy-cyclopentyl)-ethyl]-3-methyl-phenyl}-propyl)-3-fluoro-2′-methyl-biphenyl-4-yl]-acetic acid methyl ester (Example 112-(1); 25.8 mg, 0.0486 mmol) in methanol (1.6 mL), and the mixture was stirred for five hours. A saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound (29.0 mg, 99%).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([O:9][CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)[S:8][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[NH:13]1[CH2:14][CH2:15][CH:10]([O:9][C:7]2[S:8][C:4]3[CH:3]=[C:2]([C:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH:27]=4)[CH:17]=[CH:16][C:5]=3[N:6]=2)[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: Brc1ccc2nc(OC3CCNCC3)sc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3nc(OC4CCNCC4)sc3c2)CC1
Temperature: 95 °C
Yield: 86.8 %

Procedure:
To a degassed mixture of 6-bromo-2-(piperidin-4-yloxy)benzo[d]thiazole (Compound 1B, 400 mg, 1.277 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (987 mg, 3.19 mmol) and K2CO3 (706 mg, 5.11 mmol) in dioxane (20 mL) and water (6.67 mL) was added Pd(PPh3)4 (148 mg, 0.128 mmol) and the resulting mixture was heated at 95° C. for 3.5 h. The mixture was cooled to room temperature, diluted with water (15 mL), and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine, dried (Na2SO4), and evaporated. The crude product was purified by column chromatography (silica gel, CH2Cl2-MeOH gradient 0 to 15% MeOH) to afford Compound 50A (460.7 mg, 1.109 mmol, 87% yield) as a light yellow solid. LCMS (m/z)=416 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:21]=1)[C:18]1[CH:17]=[C:16](Br)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([OH:20])=[CH:9][CH:10]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.[CH3:50][C:51]1([CH3:57])[O:56][CH2:55][CH2:54][NH:53][CH2:52]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>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]>[NH2:1][C:2]1[O:3][CH2:4][C@@:5]2([N:21]=1)[C:18]1[CH:17]=[C:16]([N:53]3[CH2:54][CH2:55][O:56][C:51]([CH3:57])([CH3:50])[CH2:52]3)[CH:15]=[CH:14][C:13]=1[O:12][C:11]1[C:6]2=[CH:7][C:8]([OH:20])=[CH:9][CH:10]=1
Reactant: NC1=N[C@@]2(CO1)c1cc(O)ccc1Oc1ccc(Br)cc12
Reactant: CC1(C)CNCCO1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Product: CC1(C)CN(c2ccc3c(c2)[C@]2(COC(N)=N2)c2cc(O)ccc2O3)CCO1
Temperature: 110 °C

Procedure:
A 2-5 ml microwave vial was charged with (S)-2-amino-2′-bromo-5H-spiro[oxazole-4,9′-xanthen]-7′-ol (300 mg, 0.864 mmol) (104780-26-0), Pd2dba3 (39.6 mg, 0.043 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethylbiphenyl-2-amine (40.8 mg, 0.104 mmol) and 2,2-dimethylmorpholine (299 mg, 2.59 mmol). The mixture was capped with argon and LiHMDS (1M in THF) (4321 μL, 4.32 mmol) was added and the vial was sealed and heated at 110° C. in microwave reactor for 1 hr. The reaction mixture was quenched by addition of 2 ml water and EtOAc, then saturated NH4Cl was added. The organic layer was filterd through Celite, concentrated in vacuo and purified on a 40 g RediSep column using 15-80% DCM/MeOH/NH4OH in DCM to afford (R)-2-amino-2′-(2,2-dimethylmorpholino)-5H-spiro[oxazole-4,9′-xanthen]-7′-ol.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([NH2:16])=[N:6][C:7]=1[C:8]#[C:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[CH3:17][C:18]1[C:22](B(O)O)=[C:21]([CH3:26])[O:20][N:19]=1.[F-].[Cs+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>C1COCC1>[CH3:17][C:18]1[C:22]([C:2]2[CH:3]=[CH:4][C:5]([NH2:16])=[N:6][C:7]=2[C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:21]([CH3:26])[O:20][N:19]=1
Reactant: Nc1ccc(Br)c(C#Cc2ccccc2)n1
Reactant: Cc1noc(C)c1B(O)O
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Agent: [Cs+]
Solvent: C1CCOC1
Product: Cc1noc(C)c1-c1ccc(N)nc1C#Cc1ccccc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A mixture of 5-bromo-6-(2-phenylethynyl)pyridin-2-amine B2a (20 g, 73 mmol), (3,5-dimethyl-1,2-oxazol-4-yl)boronic acid (24 g, 170 mmol), CsF (44 g, 289 mmol) tris-(dibenzylideneacetone)dipalladium(0) (10.28 g, 11.2 mmol), tri-tert-butylphosphonium tetrafluoroborate (8.6 g, 296 mmol) and THF (200 ml) is stirred under argon atmosphere at 50° C. for 1 h. The mixture is filtrated and the precipitate washed with THF. The combined organic layers are concentrated in vacuo, diluted with DCM and extracted with a saturated aqueous solution of NaHCO3. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by NP chromatography. Yield: 12.2 g (58%). HPLC-MS: M+H=290; tR=1.54 min (*Method—6).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[C:26]3[O:25][C:24]([CH3:28])([CH3:27])[CH2:23][C:22]=3[CH:21]=[CH:20][CH:19]=2)=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.CO.O.[Li+].[OH-]>CC(O)C.C(Cl)Cl>[CH3:27][C:24]1([CH3:28])[CH2:23][C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([C:16]([NH:15][C:6]3([C:4]([OH:5])=[O:3])[CH2:14][C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[CH2:7]3)=[O:17])[C:26]=2[O:25]1
Reactant: CCOC(=O)C1(NC(=O)c2cccc3c2OC(C)(C)C3)Cc2ccccc2C1
Agent: [Li+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)O
Product: CC1(C)Cc2cccc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)c2O1
Reaction time: 56 h
Yield: 111 %

Procedure:
A 50 mL round bottom flask containing the 2-[(2,2-dimethyl-2,3-dihydro-benzofuran-7-carbonyl)-amino]-indan-2-carboxylic acid ethyl ester (0.45 g, 1.179 mmol) is charged with MeOH (25 mL) and a stirring bar is added. Stirring is initiated. After dissolution, water (8 mL) and the LiOH (108 mg, 2.58 mmol) are added. After 56 h, tlc analysis (silica, 5% i-PrOH/DCM) indicates that the starting material is completely consumed. The pH of the reaction mixture is carefully adjusted to pH 3 by slowly adding dilute aqueous HCl (3%, ˜20 mL). The contents of the flask are poured into a reparatory funnel containing EtOAc (30 mL). The layers are separated. The aqueous layer is extracted with EtOAc (20 mL). The combined organic extracts are washed with water (30 mL) and brine (20 mL), dried over MgSO4, filtered and concentrated. Pumping to constant weight gives 460 mg of material. The sample is purified by column chromatography (silica, 2% to 15% CH3OH in DCM) using an ISCO Companion and a 12 g cartridge. Fraction 3 is collected and evaporated. After pumping to constant weight, 375 mg (90%) of a dry white powder is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH:27]1([C:30]([NH:32][CH2:33][C:34]2[CH:41]=[CH:40][C:37]([CH2:38][NH2:39])=[CH:36][CH:35]=2)=[O:31])[CH2:29][CH2:28]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:39][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([CH2:33][NH:32][C:30]([CH:27]2[CH2:28][CH2:29]2)=[O:31])=[CH:35][CH:36]=1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(CNC(=O)C2CC2)cc1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)cc1)C1CC1
Yield: 64.9 %

Procedure:
Use a method similar to the General Procedure 1-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (458 mg, 1.076 mmol) with 4-[(cyclopropanecarbonyl-amino)-methyl]-benzylamine (275 mg, 1.346 mmol) using tris(dibenzylideneacetone)dipalladium(0) (99 mg, 0.108 mmol), BINAP (134 mg, 0.215 mmol) and cesium carbonate (710 mg, 2.17 mmol) in toluene (17 mL). Purify by chromatography on silica gel (80 g, pre-packed cartridge) eluting with hexane/EtOAc (1:0 over 5 min, 49:1 over 5 min, 19:1 over 5 min, 9:1 over 5 min, 85:15 over 5 min, 3:1 over 30 min, 1:1; 50 mL/min) to obtain 7-chloro-6-{4-[(cyclopropanecarbonyl-amino)-methyl]-benzylamino}-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (335 mg, 65%) as a white solid. MS (ES+) m/z: 480 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[F:8].C([Li])CCC.[CH2:14]([C@H:17]1[CH2:22][CH2:21][C@H:20]([CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)[CH2:19][CH2:18]1)[CH2:15][CH3:16].Cl>C1(C)C=CC=CC=1.O1CCCC1.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:26]2[CH2:27][CH2:28][CH:23]([C@H:20]3[CH2:21][CH2:22][C@H:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19]3)[CH2:24][CH:25]=2)[C:3]=1[F:8]
Reactant: CCC[C@H]1CC[C@H](C2CCCCC2)CC1
Reactant: Fc1ccccc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC[C@H]1CC[C@H](C2CC=C(c3cccc(F)c3F)CC2)CC1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
First, 46 g of 1,2-difluorobenzene and 240 ml of dehydrated tetrahydrofuran were put in an argon-replaced 2 flask, and cooled to −60° C. Then 315 ml of a hexane solution containing n-butyllithium at a concentration of 1.6 mol/l was dropped into the resultant mixture while being stirred for one hour, and further stirred keeping the same temperature for two hours. Subsequently, 470 ml of dehydrated tetrahydrofuran containing 80 g of 4-(trans-4-propylcyclohexyl)cyclohexane dissolved therein was dropped and stirred keeping the same temperature for two hours. The resultant mixtures was left to gradually resume room temperature, stirred for eight hours and cooled again to 0° C. The reaction solution was poured into dilute hydrochloric acid to acidify the reaction solution. Toluene was added to the resultant solution for extraction. The resultant toluene layer was washed with a saturated brine and dried with sodium sulfate. The solvent was then distilled off. The residue, 2 g of p-toluenesulfonic acid, and 1 of toluene were put in a 2 flask provided with a water content quantitative tube, and subjected to azeotropic dehydration under reflux for five hours. After the reaction, the reaction solution was washed with a saturated brine and dried with sodium sulfate. The solvent was then distilled off. The residue was distilled (b.p. 151° C./16 Pa) and recrystallized from acetone to obtain 55.7 g (Y: 48.6%) of 1,2-difluoro-3-[4-(trans-4-propylcyclohexyl)cyclohexenyl]benzene. The purity of the resultant compound was 98.0% as measured by GC.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1.[C:9]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[CH:9]1([NH:1][CH2:2][C:3]2[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: NCc1cccnc1
Reactant: O=C1CCCCCCCCCCCCCC1
Product: c1cncc(CNC2CCCCCCCCCCCCCC2)c1

Procedure:
Following the general procedure of Example 33, but starting with 3-aminomethylpyridine and cyclopentadecanone, the title compound is produced, NMR (CDCl3, TMS) δ8.58, 7.72, 7.25, 3.76, 2.56, 1.32.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]1[CH2:23][CH2:22]1)[C:13]([C:24](O)=[O:25])=[C:12]2[O:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[BH4-].[Na+].Cl>O1CCCC1.CN(C)C=O.COCCOC>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[N:14]([CH2:20][CH:21]1[CH2:23][CH2:22]1)[C:13]([CH2:24][OH:25])=[C:12]2[O:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCOc1c(C(=O)O)n(CC2CC2)c(=O)c2ccc(OCc3ccccc3)cc12
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [BH4-]
Solvent: COCCOC
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCCCOc1c(CO)n(CC2CC2)c(=O)c2ccc(OCc3ccccc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 24.8 %

Procedure:
To a solution of 6-benzyloxy-4-butoxy-2-cyclopropylmethyl-1-oxo-1,2-dihydro-3-isoquinolinecarboxylic acid (7.16 g, 17 mmol) in tetrahydrofuran (50 mL) were added oxalyl chloride (1.8 mL, 20.4 mmol) and N,N-dimethylformamide (3 drops), and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in tetrahydrofuran (30 mL). The obtained solution was added dropwise to a suspension of sodium tetrahydroborate (2.25 g, 59.5 mmol) in 1,2-dimethoxyethane (50 mL) at 0° C. The obtained mixture was stirred at 0° C. for 1 h. The reaction mixture was poured into 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-n-hexane to give 6-benzyloxy-4-butoxy-2-cyclopropylmethyl-3-hydroxymethyl-1(2H)-isoquinolinone (1.72 g, 57.1%) as crystals.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH2:47])=[CH:45][C:44]([N:48]3[CH2:53][CH2:52][O:51][CH2:50][CH2:49]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1.Cl[C:55]1[C:64]2[C:59](=[CH:60][C:61]([F:65])=[CH:62][CH:63]=2)[N:58]=[C:57]([C:66]2[CH:71]=[C:70]([CH3:72])[CH:69]=[CH:68][N:67]=2)[C:56]=1[CH3:73].CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:35]1[CH2:40][CH2:39][N:38]([C:41]2[C:46]([NH:47][C:55]3[C:64]4[C:59](=[CH:60][C:61]([F:65])=[CH:62][CH:63]=4)[N:58]=[C:57]([C:66]4[CH:71]=[C:70]([CH3:72])[CH:69]=[CH:68][N:67]=4)[C:56]=3[CH3:73])=[CH:45][C:44]([N:48]3[CH2:49][CH2:50][O:51][CH2:52][CH2:53]3)=[CH:43][N:42]=2)[CH2:37][CH2:36]1
Reactant: Cc1ccnc(-c2nc3cc(F)ccc3c(Cl)c2C)c1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc3cc(F)ccc3c(Nc3cc(N4CCOCC4)cnc3N3CCOCC3)c2C)c1

Procedure:
The Buchwald coupled product was prepared according to Procedure H using dicyclohexyl(2′,4′,6′-triisopropylbiphenyl-2-yl)phosphine (0.020 g, 0.042 mmol), 2,5-dimorpholinopyridin-3-amine (0.083 g, 0.31 mmol), 4-chloro-7-fluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (0.075 g, 0.26 mmol), Pd2dba3 (9.58 mg, 10.46 μmol) and sodium tert-butoxide (0.063 g, 0.65 mmol) in toluene (2.6 mL) at 120° C. for 4.6 h. The crude product was purified by column chromatography on basic alumina (0 to 50% hexanes/EtOAc) to give the desired product N-(2,5-dimorpholinopyridin-3-yl)-7-fluoro-3-methyl-2-(4-methylpyridin-2-yl)-quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.58 (2H, d, J=5.1 Hz), 7.81 (2H, m), 7.69 (1H, s), 7.59 (1H, m), 7.32-7.25 (1H, m), 7.22 (1H, d, J=4.9 Hz), 6.74 (1H, s), 6.21 (1H, m), 3.92 (4H, t, J=4.7 Hz), 3.74 (4H, app t, J=5.0, 4.7 Hz), 3.23 (4H, br. s.), 2.92 (6H, app t, J=4.7 Hz), 2.49 (3H, s), 2.36 (3H, s). Mass Spectrum (ESI) m/e=515.2 (M+1).
Reaction SMILES: COC([C:5]1[N:9]([C:10]([CH3:29])([CH2:12][CH2:13][N:14](C(OC(C)(C)C)=O)[C:15]([O:17]C(C)(C)C)=O)[CH3:11])[C:8]2[CH:30]=[C:31]([C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:35])[CH:32]=[CH:33][C:7]=2[N:6]=1)=O.C(O)(C(F)(F)F)=O.C(N(CC)CC)C>C(Cl)Cl>[CH3:11][C:10]1([CH3:29])[N:9]2[C:5](=[N:6][C:7]3[CH:33]=[CH:32][C:31]([C:34]([O:36][CH2:37][C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)=[O:35])=[CH:30][C:8]=32)[C:15](=[O:17])[NH:14][CH2:13][CH2:12]1
Reactant: COC(=O)c1nc2ccc(C(=O)OCc3ccccc3)cc2n1C(C)(C)CCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1(C)CCNC(=O)c2nc3ccc(C(=O)OCc4ccccc4)cc3n21
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
To a stirred solution of crude 1-({4-[bis(tert-butoxycarbonyl)amino]-2-methylbutan-2-yl}-1H-benzimidazole-2,6-dicarboxylic acid 6-benzyl ester 2-methyl ester (289 mg, 0.47 mmol) in CH2Cl2 (5 mL) is added TFA (1 mL). After 1 h the solvent is evaporated, and CH2Cl2 is added and evaporated from the residue three times to remove excess TFA. The residue is dissolved in methanol (10 mL) and triethylamine (0.72 mL, 5.16 mmol) added. The solution is stirred at room temperature for 16 h. The solvent is evaporated and the residue partitioned between H2O and EtOAc. The organic layer is dried (MgSO4) and purified by flash chromatography, eluting with CH2Cl2/methanol to afford the title compound (80 mg, 44%).
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=O)[CH:9]=2)[N:4]2[C:15]([CH2:18][CH2:19][CH3:20])=[N:16][N:17]=[C:3]12.[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][CH:28]=1)[NH2:25].ON1C2C=CC=CC=2N=N1.N=C=N.C(=O)([O-])[O-].[N-]=C=O>CN(C)C=O.C(N(CC)CC)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:12]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[N:4]2[C:15]([CH2:18][CH2:19][CH3:20])=[N:16][N:17]=[C:3]2[C:2](=[O:1])[NH:11]3)=[O:14])[CH:26]=[CH:27][CH:28]=1
Reactant: Nc1cccc(Cl)c1
Reactant: CCCc1nnc2c(=O)[nH]c3cc(C(=O)O)ccc3n12
Agent: N=C=N
Agent: O=C([O-])[O-]
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCc1nnc2c(=O)[nH]c3cc(C(=O)Nc4cccc(Cl)c4)ccc3n12
Temperature: 60 °C
Reaction time: 8 h
Yield: 18.2 %

Procedure:
To a mixture of 8.2 mg of 4-oxo-1-propyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxylic acid, 1.6 mg of 3-chloroaniline, 4.1 mg of 1-hydroxybenzotriazole, 8.4 μl of triethylamine, and 1 mL of N,N-dimethylformamide was added 100 mg of PS-Carbodiimide (Biotage AB), followed by stirring at 60° C. overnight. To the reaction mixture were added 50 mg of MP-Carbonate (Biotage AB) and 50 mg of PS-Isocyanate (Biotage AB) at room temperature, followed by stirring for 4 hours. The reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The obtained residue was purified by preparative HPLC (methanol/0.1% aqueous formic acid solution) to obtain 0.87 mg of N-(3-chlorophenyl)-4-oxo-1-propyl-4,5-dihydro[1,2,4]triazolo[4,3-a]quinoxaline-7-carboxamide.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@H:26]([NH:30]C(=O)OC(C)(C)C)[CH2:25]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([F:54])[C:40]=1[OH:55]>>[NH2:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:21]2[N:22]=[CH:23][C:18]([NH:17][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([C:43]5[CH:42]=[C:41]([F:54])[C:40]([OH:55])=[C:39]([Cl:38])[CH:44]=5)[CH:3]=4)[N:8]=[CH:7][C:6]=3[C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])=[CH:19][CH:20]=2)[CH2:25]1
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Product: N[C@H]1CCCN(c2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(-c5cc(F)c(O)c(Cl)c5)cc34)cn2)C1
Yield: 29.9 %

Procedure:
Following general procedure D, (S)-tert-butyl 1-(5-(6-bromo-3-(cyclopropanecarbonyl)quinoline-4-ylamino)pyridin-2-yl)piperidin-3-ylcarbamate (100 mg, 0.17 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (71 mg, 0.26 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (27 mg, 30% over 2 steps) as an orange-yellow solid: 1H NMR (500 MHz, MeOD+TFA-d) δ 9.40 (br s, 1H), 8.28-8.15 (m, 2H), 8.06 (br s, 1H), 8.00 (d, J=8.8 Hz, 1H), 7.66 (dd, J=9.1, 2.8 Hz, 1H), 7.16-7.05 (m, 3H), 4.53 (d, J=11.0 Hz, 1H), 4.01 (dd, J=13.4, 4.6 Hz, 1H), 3.41-3.23 (m, 3H), 2.86 (br s, 1H), 2.23-2.15 (m, 1H), 1.99-1.88 (m, 1H), 1.79-1.66 (m, 2H), 1.27-1.16 (m, 4H). ESI MS m/z 532 [C29H27ClFN5O2+H]+; HPLC>99.0% (AUC), tR=10.78 min.