Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([N:17]([CH2:37][CH2:38][O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:18](=[O:36])[CH2:19][CH2:20][C@H:21]([NH:28]C(OC(C)(C)C)=O)[CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O>[CH2:1]([O:8][C:9]([C@H:11]1[CH2:16][CH2:15][C@@H:14]([N:17]([C:18](=[O:36])[CH2:19][CH2:20][C@H:21]([NH2:28])[CH:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)[CH2:37][CH2:38][O:39][CH2:40][C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)N(CCOCc1ccccc1)[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1)C1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](CCC(=O)N(CCOCc1ccccc1)[C@H]1CC[C@@H](C(=O)OCc2ccccc2)CC1)C1CCOCC1

Procedure:
A solution of 4-{(2-benzyloxy-ethyl)-[4-tert-butoxycarbonylamino-4-(S)-(tetrahydro-pyran-4-yl)-butyryl]-amino}-cis-cyclohexanecarboxylic acid benzyl ester (4.8 g, 7.5 mmol) in TFA (5% in CH2Cl2, 100 mL) was stirred at room temperature overnight. The solvent and most of the TFA was evaporated, and EtOAc (300 mL) was added to the residue. The solution was washed with aq. NaHCO3 and aq. NaCl. The organic layer was dried with MgSO4 and evaporated to yield 4-[[4-amino-4-(S)-(tetrahydro-pyran-4-yl)-butyryl]-(2-benzyloxy-ethyl)-amino]-cis-cyclohexanecarboxylic acid benzyl ester as a light brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:17][NH2:18])[CH3:16])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:19]([C:22]1[CH:31]=[CH:30][C:25]2[O:26][CH2:27][CH2:28][O:29][C:24]=2[CH:23]=1)=[C:20]=[S:21].CO.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15](=[N:17][NH:18][C:20](=[S:21])[NH:19][C:22]3[CH:31]=[CH:30][C:25]4[O:26][CH2:27][CH2:28][O:29][C:24]=4[CH:23]=3)[CH3:16])[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: S=C=Nc1ccc2c(c1)OCCO2
Reactant: CC(=NN)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CC(=NNC(=S)Nc1ccc2c(c1)OCCO2)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Reaction time: 4 h
Yield: 65 %

Procedure:
2-(3,4-Dichlorophenyl)-4-(1-hydrazonoethyl)-thiophen-3-ol (25 mg, 0.08 mmol) prepared in Reference Synthetic Example 13 in dimethylformamide (0.25 mL) was stirred with 6-isothiocyanato-2,3-dihydrobenzo[1,4]dioxine (24 mg, 0.13 mmol, at 30° C. for 4 hours. Methanol and water were added to the reaction solution, and the resulting crystals were collected by filtration, washed and dried to give 28 mg of the desired product (yield 65%).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH:15]=[CH2:16])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:17]([CH:14]([CH:15]=[CH2:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[CH2:18][CH2:19][CH3:20]
Reactant: C=CC(CCCC)CCCCCO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C=CC(CCCC)CCCCCO
Temperature: 25 °C
Reaction time: 24 h

Procedure:
8-(tert-butyldimethylsilyloxy)-3-butyloct-1-ene (4.0 g, 13.4 mmol) was added to a solution of tetrabutylammonium fluoride (1 M, 14 ml) in THF, and the mixture was stirred at ambient temperature for 24 h. Standard work-up followed by PMPLC yielded 2.05 g (83%) of 6-butyl-7-en-1-ol.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:8][C:9]=1[N:10]([CH:20]1[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]1)[C:11]([CH:13]1[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].[H-].[Na+].I[CH3:36]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:36][O:26][CH:23]1[CH2:24][CH2:25][CH:20]([N:10]([C:11]([CH:13]2[CH2:18][CH2:17][CH:16]([CH3:19])[CH2:15][CH2:14]2)=[O:12])[C:9]2[CH:8]=[C:7]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[S:6][C:5]=2[C:3]([OH:2])=[O:4])[CH2:21][CH2:22]1
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CCC(C)CC1)C1CCC(O)CC1
Reactant: CI
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: C1CCOC1
Product: COC1CCC(N(C(=O)C2CCC(C)CC2)c2cc(-c3ccccc3)sc2C(=O)O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
3-[(4-Hydroxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (27 mg, 0.059 mmol) was dissolved in THF (0.6 ml), cooled to 0° C. in an ice bath and 60% sodium hydride (5 mg, 0.118 mmol) was added, followed by a catalytic amount of tetrabutylammonium iodide. After stirring for 1 hour, iodomethane (37 ul, 0.590 mmol) was added and the reaction further stirred for 3 hours. It was then quenched with water (5 ml) and extracted with ethyl acetate (3×5 ml). The combined ethyl acetate layer was dried (Na2SO4) and concentrated. The residue was purified by preparative chromatography (10% MeOH/CH2Cl2) to obtain 5 mg (18%) of 3-[(4-Methoxy-cyclohexyl)-(4-methyl-cyclohexanecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (compound 46).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([Br:12])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH:13](OB([O-])[O-])=[CH2:14].C(N(CC)CC)C.N#N>C1COCC1.CC(O)C.CCOC(C)=O.O.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].ClCCl>[Br:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH:13]=[CH2:14])[CH:11]=[CH:10]2
Reactant: Brc1ccc2cccc(Br)c2n1
Reactant: C=COB([O-])[O-]
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C=Cc1ccc2cccc(Br)c2n1
Temperature: 55 °C
Reaction time: 12 h

Procedure:
To 2,8-dibromoquinoline (1.836 g, 6.398 mmol) in THF/IPA (20 mL/10 mL) was added vinylborate (0.9428 g, 7.038 mmol) and triethylamine (0.7769 g, 7.678 mmol). The reaction mixture was purged with N2, and PdCl2(dppf) dichloromethane adduct (0.3685 g, 0.4479 mmol) was added. The reaction was stirred at 55° C. for 12 hours, then cooled to ambient temperature. The reaction mixture was diluted with EtOAc/H2O, and the organic layer was separated and concentrated to provide the crude product.
Reaction SMILES: Cl.[CH3:2][O:3][CH2:4][NH:5][CH2:6][CH2:7][C:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=[O:9].[OH-].[Na+].[BH4-].[Na+]>CO.O>[CH3:2][O:3][CH2:4][NH:5][CH2:6][CH2:7][CH:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[OH:9]
Reactant: COCNCCC(=O)c1cccs1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COCNCCC(O)c1cccs1
Reaction time: 1 h
Yield: 102.5 %

Procedure:
38.6 g of 3-methoxymethylamino-1-(2-thienyl)-1-propanone hydrochloride salt obtained in Step 1 was dissolved in 115 g of methanol and 40 g of water. The pH value of the resulting solution was adjusted to 11 by addition of 45% NaOH. 2.5 g of sodium borohydride was added, and the mixture was stirred for 1 hour. Afterward the reaction mixture was filtered, concentrated and extracted with 80 g of toluene. The organic layer was concentrated to obtain 33.8 g of 3-methoxymethylamino-1-(2-thienyl)propan-1-ol as an oily product. 1H NMR (400 MHz, CDCl3) δ (ppm)=3.0 (s, 3H), 3.0-3.1 (m, 1H), 4.1 (s, 3H), 4.0-4.1 (m, 3H), 6.1 (dt, J=7.4, 15.4 Hz, 1H), 6.9 (d, J=15.7 Hz, 1H), 7.0 (dd, J=3.7, 5.0 Hz, 1H), 7.1 (d, J=3.4 Hz, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[CH:16]=[C:15]([CH3:17])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2].C1(C=CC(O)=CC=1)O.C1C(=O)N([Br:33])C(=O)C1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CC(O)=O>[CH2:1]([O:3][C:4]([N:6]1[CH2:13][CH:12]2[CH:8]([CH2:9][C:10]3[C:16]([Br:33])=[C:15]([CH3:17])[S:14][C:11]=32)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CC2Cc3cc(C)sc3C2C1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: Oc1ccc(O)cc1
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)N1CC2Cc3c(sc(C)c3Br)C2C1
Temperature: 40 °C

Procedure:
The product of Example 15, step c) (69.1 mg, 0.30 mmol) was placed in a vial and diluted with CHCl3 (740 μl) and AcOH (740 μl). Next, hydroquinone (−5 mg) was added followed by NBS (51.4 mg, 0.31 mmol) and the contents were heated to 40° C. for 6 hours. The crude reaction mixture was carefully poured into saturated NaHCO3 (10 ml) and extracted with EtOAc (3×5 ml). The organic layer was dried (MgSO4) and purified by preparative TLC using hexanes/EtOAc 50:50 providing the subtitled product. MS calculated for C13H16BrNO2S+H 330, observed 330, 332.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[N:8]=[C:7]([CH:15]([NH:17]C(=O)OC(C)(C)C)[CH3:16])[C:6]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:4].Cl.O1CCOCC1.[NH2:38][C:39]1[C:44]([C:45]#[N:46])=[C:43](Cl)[N:42]=[CH:41][N:40]=1.CCN(C(C)C)C(C)C>C(OCC)C.CN(C=O)C.CCOC(C)=O>[NH2:38][C:39]1[N:40]=[CH:41][N:42]=[C:43]([NH:17][CH:15]([C:7]2[C:6]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][N:13]=3)[N:8]=2)[CH3:16])[C:44]=1[C:45]#[N:46]
Reactant: CNC(=O)c1c(-c2ccccc2)c(C(C)NC(=O)OC(C)(C)C)nc2cccnc12
Reactant: N#Cc1c(N)ncnc1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CNC(=O)c1c(-c2ccccc2)c(C(C)Nc2ncnc(N)c2C#N)nc2cccnc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 1-(4-(methylcarbamoyl)-3-phenyl-1,5-naphthyridin-2-yl)ethylcarbamate (110 mg, 0.27 mmol) was added 4N HCl in 1,4-dioxane (1 mL, 15 eq). The resulting mixture was stirred at rt for 30 min. The reaction mixture was diluted with ethyl ether (5 mL). The white solid was filtered and washed with ethyl ether and dried under vacuum. Mass Spectrum (ESI) m/e=307 (M+1). To a solution of the amine HCl salt in DMF (3 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (41.8 mg, 1.0 eq) and DIEA (0.19 mL, 4.0 eq). The resulting mixture was heated to 105° C. for 2 h. After cool to rt, EtOAc (10 mL) was added and the mixture was washed with water (3×3 mL), brine and dried over sodium sulfate. The solvent was removed and the residue was purified by combiflash (1:20, MeOH/DCM) to afford 2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-N-methyl-3-phenyl-1,5-naphthyridine-4-carboxamide. After chiral HPLC separation (isopropanol/hexane gradient, AD column), (S)-2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-N-methyl-3-phenyl-1,5-naphthyridine-4-carboxamide and (R)-2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-N-methyl-3-phenyl-1,5-naphthyridine-4-carboxamide were obtained as white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:28][C:27]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])=[CH:26][C:25](=O)[O:24]1>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[CH:10][C:9]=1[NH:20][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:36]=[CH:35][CH:34]=[C:31]([C:32]#[N:33])[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2cccc(C#N)c2)O1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccn2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccn2)cc1NC(=O)CC(=O)c1cccc(C#N)c1

Procedure:
Prepared from (2-amino-4-pyridin-2-yl-phenyl)-carbamic acid tert.-butyl ester (Example G17) and 3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4) according to the general procedure K. Obtained as a light brown solid (90 mg).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)(=[O:3])[CH3:2]>C1(C)C=CC=CC=1.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1/[CH:11]=[CH:12]\[C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C#Cc1ccc2ccccc2n1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: Cc1ccccc1
Product: CC(=O)Oc1ccccc1/C=C\c1ccc2ccccc2n1
Reaction time: 9 h
Yield: 29.6 %

Procedure:
In an autoclave, 2-(quinolin-2-ylethynyl)phenyl acetate (0.40 g, 1.4 mmol, 1.0 eq.) was dissolved in degassed toluene (15 mL). Lindlar catalyst (5% Pd on CaCO3, 80 mg) was added and the vessel was sealed. The mixture was hydrogenated under 4 bar pressure for 9 h at r.t. The mixture was filtered through a pad of Celite to remove the Pd catalyst and concentrated under reduced pressure which gave the crude product. The product was purified by column chromatography (SiO2, 98.75:1:0.25 dichloromethane-methanol-ammonia) which yielded the product (0.12 g, 30% yield) as a tan solid.
Reaction SMILES: [SH2:1].[CH3:2][O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][C:21]=3[CH2:28][CH2:29][CH3:30])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1.C(NCC)C>CN(C=O)C>[CH3:2][O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([NH2:27])=[S:1])=[CH:22][C:21]=3[CH2:28][CH2:29][CH3:30])=[CH:12][CH:13]=2)[CH:8]=[CH:7]1
Reactant: CCCc1cc(C#N)ccc1OCCCOc1ccc2c(ccn2CC(=O)OC)c1
Reactant: S
Solvent: CN(C)C=O
Solvent: CCNCC
Product: CCCc1cc(C(N)=S)ccc1OCCCOc1ccc2c(ccn2CC(=O)OC)c1
Temperature: 70 °C

Procedure:
Hydrogen sulfide was passed through a solution of methyl{5-[3-(4-cyano-2-propylphenoxy)propoxy]-1H-indol-1-yl}acetate (Example 51, 787 mg, 1.94 mmol) in DMF (15 mL) for 30 minutes at rt. Diethyl amine (0.3 mL, 2.90 mmol) was added, and the solution was heated to 70° C. for 3 h. The reaction mixture was cooled to rt, and the residual H2S was removed by passing argon through the reaction mixture for 30 minutes. The solvent was evaporated under reduced pressure and the residue was filtered through a plug of silica and washed with EtOAc. Concentration of solvent yielded a brown oil which was used in the next step without further purification. LC/MS m/z 441.2 (M+H)+; RT 3.35 min.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH:22]([CH2:27][CH2:28][CH3:29])[CH2:21][C:20]=3[NH:19][C:18]([CH3:30])=[C:17]2[C:31]#[N:32])[CH:13]=[C:12]([O:33][CH2:34][CH3:35])[C:3]=1[O:4][CH2:5][CH2:6]OS(C)(=O)=O.[NH4+:36].[OH-]>O1CCOCC1>[NH2:36][CH2:6][CH2:5][O:4][C:3]1[C:12]([O:33][CH2:34][CH3:35])=[CH:13][C:14]([CH:16]2[C:25]3[C:24](=[O:26])[CH2:23][CH:22]([CH2:27][CH2:28][CH3:29])[CH2:21][C:20]=3[NH:19][C:18]([CH3:30])=[C:17]2[C:31]#[N:32])=[CH:15][C:2]=1[Br:1]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCCOS(C)(=O)=O)c(OCC)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCCN)c(OCC)c1
Temperature: 80 °C
Reaction time: 17 h

Procedure:
A mixture of the product of step b (3.38 g) and conc. aq. NH4OH (60 ml) in dioxane (90 ml) was stirred at 80° C. in an autoclave for 17 h. The mixture was concentrated in vacuo. Yield: 3.82 g (MeSO3H salt). MS-ESI: [M+H]+=488.2/490.2
Reaction SMILES: CC(C)=[O:3].[ClH:5].Cl.[CH3:7][O:8][C:9](=[O:65])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([NH:39][C:40]([C:42]4[CH:43]=[N:44][C:45]([N:48]5[CH2:53][C@H:52]([CH3:54])[N:51]([C:55](=[O:58])[NH:56][CH3:57])[CH2:50][C@H:49]5[CH3:59])=[CH:46][CH:47]=4)=[O:41])=[CH:35][C:34]=3[O:60][C:61]([F:64])([F:63])[F:62])=[CH:29][CH:28]=2)[N:26]=1)=[O:16])[CH:12]([CH3:14])[CH3:13]>C(O)C>[OH2:3].[ClH:5].[ClH:5].[CH3:7][O:8][C:9](=[O:65])[NH:10][C@H:11]([C:15]([N:17]1[CH2:21][CH2:20][CH2:19][C@H:18]1[C:22]1[NH:23][CH:24]=[C:25]([C:27]2[CH:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][C:36]([NH:39][C:40]([C:42]4[CH:43]=[N:44][C:45]([N:48]5[CH2:53][C@H:52]([CH3:54])[N:51]([C:55](=[O:58])[NH:56][CH3:57])[CH2:50][C@H:49]5[CH3:59])=[CH:46][CH:47]=4)=[O:41])=[CH:35][C:34]=3[O:60][C:61]([F:64])([F:62])[F:63])=[CH:31][CH:32]=2)[N:26]=1)=[O:16])[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)=O
Agent: CNC(=O)N1C[C@@H](C)N(c2ccc(C(=O)Nc3ccc(-c4ccc(-c5c[nH]c([C@@H]6CCCN6C(=O)[C@@H](NC(=O)OC)C(C)C)n5)cc4)c(OC(F)(F)F)c3)cn2)C[C@@H]1C
Agent: Cl
Solvent: CCO
Product: O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Ethanol (2 mL) and acetone (15 mL) were added to amorphous ((S)-1-{(S)-2-[4-(4′-{[6-((2R,5S)-2,5-dimethyl-4-methylcarbamoyl-piperazin-1-yl)-pyridine-3-carbonyl]-amino}-2′-trifluoromethoxy-biphenyl-4-yl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester diHCl (1102 mg, Example 4). The reaction mixture was warmed to 60° C. and sonicated for 1 min to give a hazy solution. Ethanol (2 mL) was added to provide a clear solution, which was heated at 60° C. After about 5 mL of solvent had evaporated, acetone (10 mL) was added until the solution turned cloudy. The contents were stirred overnight to provide a crystalline slurry which was stirred for an additional 48 h and then allowed to settle. The supernatant solvents were decanted. To the remaining solid suspension was added water (0.5 mL) and dioxane (2 mL). The resulting mixture was filtered to give a white to off-white solid which was dried under vacuum for 12 h to provide the title compound (628 mg).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)[C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:7]=1.[C:23]([C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31])#[N:24].COC1C=CC=C(OC)C=1C1C=CC=CC=1P(C1CCCCC1)C1CCCCC1.[OH-].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(O)(C)(C)C>[F:31][C:30]1[CH:29]=[CH:28][C:27]([C:2]2[C:3]3[CH2:16][CH2:15][N:14]([C:17]4[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=4)[C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=2)=[CH:26][C:25]=1[C:23]#[N:24]
Reactant: Clc1nc(N2CCOCC2)nc2c1CCN2c1ccncc1
Reactant: N#Cc1cc(B(O)O)ccc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: CC(C)(C)O
Product: N#Cc1cc(-c2nc(N3CCOCC3)nc3c2CCN3c2ccncc2)ccc1F
Temperature: 100 °C
Reaction time: 3 h
Yield: 24.5 %

Procedure:
To 4-chloro-2-morpholin-4-yl-7-pyridin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine (10 mg, 0.0315 mmol), 3-cyano-4-fluorophenylboronic acid (10.4 mg, 0.0630 mmol), palladium acetate (1.4 mg, 0.0063 mmol), S-Phos (5.2 mg, 0.0126 mmol) and sodium hydroxide (2.5 mg, 0.063 mmol), t-butanol (1 ml) was added, followed by being degassed under ultrasonic irradiation. This was stirred at 100° C. for 3 hours, followed by extraction with ethyl acetate with the addition of water, and the organic layer was washed with brine. After drying over anhydrous sodium sulfate, concentration was carried out under reduced pressure, followed by elution with 2M ammonia methanol solution through SCX resin and then concentration. Purification by preparative TLC afforded the desired compound as a colorless solid (3.1 mg, yield 12%).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2].[I-:12].[Na+].ClN1C(=O)CCC1=O>C(OCC)(=O)C.O>[CH2:1]([C:3]1[C:11]([I:12])=[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][N:5]2[N:4]=1)[CH3:2]
Reactant: CCc1cc2ccccn2n1
Reactant: [I-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1nn2ccccc2c1I
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 99.1 %

Procedure:
To a mixture of 2-ethylpyrazolo[1,5-a]pyridine (360 g, 2.46 mol), ethyl acetate (3600 mL), water (1800 mL) and sodium iodide (480 g, 3.20 mol, 1.3 equivalent) was added N-chlorosuccinimide (411 g, 3.08 mol) over a period of 30 minutes under cooling in an ice water bath, then, the reaction mixture was stirred at room temperature for 2 hours and 20 minutes. To the reaction mixture was added water and ethyl acetate, and the resulting mixture was extracted with ethyl acetate. The separated organic layer was washed twice with a 10% sodium thiosulfate aqueous solution, and concentrated under reduced pressure. To the resulting residue was added hexane, the residue was dissolved with heating. The hexane solution was filtrated to remove an insoluble substance. The hexane solution was washed with water, and concentrated under reduced pressure. Then, the resulting residue was dissolved in ethyl acetate, and the solvent was distilled off under reduced pressure, to obtain 663 g of a title compound (yield: 98.9%).
Reaction SMILES: [BH4-].[Li+].C([O:7][C:8]([C@:10]1([CH2:24][CH:25]=[CH2:26])[CH2:14][C:13](=[O:15])[N:12]([C@@H:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])[CH2:11]1)=O)(C)(C)C.C(O)C.[Cl-].[NH4+]>O1CCCC1>[CH2:24]([C@:10]1([CH2:8][OH:7])[CH2:11][N:12]([C@@H:16]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17])[C:13](=[O:15])[CH2:14]1)[CH:25]=[CH2:26]
Reactant: C=CC[C@@]1(C(=O)OC(C)(C)C)CC(=O)N([C@H](C)c2ccccc2)C1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CC[C@@]1(CO)CC(=O)N([C@H](C)c2ccccc2)C1
Temperature: 40 °C
Reaction time: 12 h
Yield: 75.8 %

Procedure:
Lithium borohydride (4.96 g, 0.228 mol) was suspended in tetrahydrofuran (500 mL). A solution of (3R)-3-allyl-5-oxo-1-[(1R)-1-phenylethyl]pyrrolidine-3-carboxylic acid tert-butyl ester (50.0 g, 0.152 mol) in tetrahydrofuran (100 mL)-ethanol (17.7 mL) was added to the suspension using a dropping funnel over 10 minutes. The mixture was heated to 40° C., stirred for 12 hours, and then heated to reflux for 20 hours. After cooling to 0° C., a saturated ammonium chloride solution (100 mL) was carefully added. After the tetrahydrofuran component was evaporated under reduced pressure, the reaction solution was poured into a mixture of ethyl acetate (100 mL) and a saturated ammonium chloride solution (100 mL), followed by extraction with ethyl acetate (1000 mL, 750 mL). The organic layers were combined and washed with brine (200 mL). After drying over anhydrous sodium sulfate and filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:4) to give 29.9 g (76%) of the title compound as a colorless viscous oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH:4]=O.[O-2].[Mg+2].CS(C)=O.[C:19]([CH2:21]P(=O)(OCC)OCC)#[N:20]>C(OCC)(=O)C>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:3]=1[CH:4]=[CH:21][C:19]#[N:20]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1c(Br)cccc1[N+](=O)[O-]
Agent: [Mg+2]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CC=Cc1c(Br)cccc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
After stirring 2-bromo-6-nitrobenzaldehyde (30.4 g), magnesium oxide (75 g) and dimethyl sulfoxide (11.3 ml) sufficiently for 1 minute, diethyl (cyanomethyl)phosphonate (25.8 ml) was added thereto and the mixture was stirred for further 2 hours. After the completion of stirring, the mixture was left stand overnight. Then, ethyl acetate was added thereto, and the mixture was stirred and then filtered. The filtrate was concentrated and the residue was purified by silica gel column chromatography (ethyl acetate), to give 32 g of 3-(2-bromo-6-nitrophenyl)-2-propenenitrile (E-isomer:Z-isomer=3:1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:23]([NH:22][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[O:24])[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Cl)cc21
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)NC1CCCc2c1[nH]c1ccc(Cl)cc21

Procedure:
N-(6-Chloro-2,3,4,9-tetrahydro-1H-carbazol-1-yl)-N′-phenylurea was prepared from 6-chloro-2,3,4,9-tetrahydro-1H-carbazol-1-amine and phenyl isocyanate in a similar manner as described above to give a white solid (74% yield). 1H-NMR (DMSO-d6): δ 10.93 (s, 1H), 8.30 (s, 1H), 7.41-7.36 (m, 3H), 7.28 (d, 1H), 7.21 (m, 2H), 7.00 (dd, 1H), 6.88 (m, 1H), 6.57 (d, 1H), 4.95 (m, 1H), 2.59 (m, 2H), 1.98 (m, 1H), 1.88-1.70 (m, 3H); MS m/z 338 (M−1).