Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:23]([N:25]([CH3:49])[C@@H:26]([C@@H:45]([CH3:48])[CH2:46][CH3:47])[C@H:27]([O:43][CH3:44])[CH2:28][C:29](OC3C(F)=C(F)C(F)=C(F)C=3F)=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH:51]1([CH2:58][CH2:59][NH:60][C:61](=[O:72])[C@H:62]([CH3:71])[C@@H:63]([O:69][CH3:70])[C@@H:64]2[CH2:68][CH2:67][CH2:66][NH:65]2)[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=[CH:52]1.C(N(CC)C(C)C)(C)C>ClCCl>[CH:51]1([CH2:58][CH2:59][NH:60][C:61](=[O:72])[C@H:62]([CH3:71])[C@H:63]([C@@H:64]2[CH2:68][CH2:67][CH2:66][N:65]2[C:29](=[O:30])[CH2:28][C@@H:27]([O:43][CH3:44])[C@@H:26]([N:25]([CH3:49])[C:23](=[O:24])[C@H:19]([CH:20]([CH3:22])[CH3:21])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:17])[C@@H:45]([CH3:48])[CH2:46][CH3:47])[O:69][CH3:70])[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=[CH:57]1
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)Oc1c(F)c(F)c(F)c(F)c1F)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Reactant: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)NCCC1C=CC=CC=C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)NCCC1C=CC=CC=C1)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.7 %

Procedure:
To a solution of #174 (706 mg, 1.02 mmol, 1 eq.) and #64 (311 mg, 1.02 mmol, 1 eq.) in dichloromethane (3 mL) was added N,N-diisopropylethylamine (400 mg, 3.07 mmol, 3 eq.). After 18 hours of stirring at room temperature, the reaction was concentrated in vacuo and purified by silica gel chromatography (Gradient: 0 to 100% ethyl acetate in heptane) to afford #175 (560 mg, 68%) as a white solid. LC-MS (Protocol Q1): m/z 611.8 [M+H+], retention time=1.15 minutes.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=[O:7].[Br:8][C:9]1[CH:14]=[CH:13][C:12](I)=[CH:11][CH:10]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CNCCNC>CN(C=O)C.[Cu]I.O>[Br:8][C:9]1[CH:14]=[CH:13][C:12]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][C:2]2=[O:7])=[CH:11][CH:10]=1
Reactant: O=C1COCCN1
Reactant: Brc1ccc(I)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1COCCN1c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
To a mixture of morpholin-3-one (100 mg), 1-bromo-4-iodobenzene (282 mg), cesium carbonate (326 mg) and N1,N2-dimethylethane-1,2-diamine (9 mg) in DMF (2 mL) was added copper(I) iodide (10 mg) at room temperature under nitrogen atmosphere. The reaction mixture was stirred under microwave irradiation at 100° C. for 30 min. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/petroleum ether) to give the title compound (210 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:15]([N:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[N:42](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.N>CN(C=O)C.O1CCOCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:33]=[C:32]([Cl:34])[CH:31]=[C:14]([C:15](=[O:16])[N:17]([CH2:18][CH2:19][CH2:20][C:21](=[O:23])[NH2:42])[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH:13]=1)[C:35]1[CH:36]=[CH:37][N:38]=[CH:39][CH:40]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCC(=O)O)c2ccccc2F)c1)c1ccncc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: N
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCC(N)=O)c2ccccc2F)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 70 h
Yield: 100.2 %

Procedure:
To a stirred solution of 4-({3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoyl}-(2-fluoro-phenyl)-amino)-butyric acid (0.100 g), TBTU (0.112 g) and HOBt (0.047 g) in DMF (2 ml) was added DIPEA (0.060 ml) followed by a 0.5M solution of ammonia in 1,4-dioxane (0.70 ml) after 10 min. The reaction mixture was stirred at room temperature for 70 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.100 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=3I)[CH:11]=2)=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH2:30]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:31][C:32]#[CH:33]>CN(C=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>[CH:1]1([NH:4][C:5]([C:7]2[N:8]=[N:9][N:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([NH:20][CH2:21][CH3:22])=[O:19])=[CH:14][C:13]=3[C:33]#[C:32][CH2:31][CH2:30][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH:11]=2)=[O:6])[CH2:3][CH2:2]1
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(I)c1
Reactant: C#CCCc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2cc(C(=O)NC3CC3)nn2)c(C#CCCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
To a solution of N-cyclopropyl-1-{4-[(ethylamino)carbonyl]-2-iodophenyl}-1H-1,2,3-triazole-4-carboxamide (300 mg, 0.71 mmol) obtained in Example 382 in DMF (7.0 ml) were successively added potassium carbonate (200 mg), copper(I) iodide (15 mg), bis(triphenylphosphine)palladium(II) dichloride (25 mg) and but-3-yn-1-ylbenzene (110 mg), and the reaction mixture was stirred at room temperature overnight. Excess reagents and byproducts derived from the reagents were removed from the reaction mixture by adsorption onto silica gel column (ethyl acetate), and the eluate was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/4 to ethyl acetate) to give the title compound as a colorless powder (163 mg, 54%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][NH2:17])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].[Cl:20][CH2:21][CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25]>O1CCCC1>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH2:16][NH:17][S:24]([CH2:23][CH2:22][CH2:21][Cl:20])(=[O:26])=[O:25])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCCN1CCN(Cc2ccccc2)CC1
Reactant: O=S(=O)(Cl)CCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=S(=O)(CCCCl)NCCCN1CCN(Cc2ccccc2)CC1
Reaction time: 24 h

Procedure:
To a stirred solution of 3-(4-benzyl-1-piperazinyl)propylamine (2.01 g/8.61 mmol) in tetrahydrofuran (15 ml) were added 2 N NaOH (5.6 ml/ 11.2 mmol) and 3-chloropropanesulfonylchloride (2.00 g/11.3 mmol), and the mixture was stirred for 1 day. The reaction mixture was quenched with water (50 ml) and the whole was extracted with ethyl acetate (50 ml). The extract was washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (NH2 gel/dichloromethane) to give a colorless oil.
Reaction SMILES: Cl[C:2]1[O:3][C:4]([CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[N:6]=1.[CH2:26]([C:29]1[NH:30][CH:31]=[CH:32][N:33]=1)[CH2:27][CH3:28].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:5]2[N:6]=[C:2]([N:30]3[CH:31]=[CH:32][N:33]=[C:29]3[CH2:26][CH2:27][CH3:28])[O:3][C:4]=2[CH2:14][CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])=[CH:8][CH:9]=1
Reactant: COc1ccccc1OCCCc1oc(Cl)nc1-c1ccc(Cl)cc1
Reactant: CCCc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1nccn1-c1nc(-c2ccc(Cl)cc2)c(CCCOc2ccccc2OC)o1
Temperature: 125 °C
Reaction time: 4 h
Yield: 39 %

Procedure:
A mixture of 2-chloro-4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]oxazole (500 mg), 2-propylimidazole (1.10 g), potassium carbonate (1.38 g) and N,N-dimethylformamide (10 ml) was stirred at 120-130° C. for 4 hours. The reaction mixture was poured into water (100 ml), the resulting solid precipitate was filtered, air-dried and recrystallized from acetone-hexane to give 4-(4-chlorophenyl)-5-[3-(2-methoxyphenoxy)propyl]-2-(2-propyl-1-imidazolyl)oxazole as pale yellow prisms (233 mg, 39%). Melting point 89-90° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[C:15]([N:22]5[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24][CH2:23]5)[CH:16]=[CH:17][CH:18]=4)[N:13]=3)=[N:10][N:11]=[C:5]2[CH:4]=1)=O.[CH2:37]([NH2:39])[CH3:38].CC(O)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CO>[CH2:37]([NH:39][CH2:1][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:21]=[CH:20][C:19]4[C:14](=[C:15]([N:22]5[CH2:27][CH2:26][CH:25]([CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])[CH2:24][CH2:23]5)[CH:16]=[CH:17][CH:18]=4)[N:13]=3)=[N:10][N:11]=[C:5]2[CH:4]=1)[CH3:38]
Reactant: CCN
Reactant: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(-c4nnc5cc(C=O)ccn45)nc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCNCc1ccn2c(-c3ccc4cccc(N5CCC(CNC(=O)OC(C)(C)C)CC5)c4n3)nnc2c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To tert-butyl (1-(2-(7-formyl-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl)piperidin-4-yl)methylcarbamate (Example 11, steps A-K; 10 mg, 0.021 mmol) in DCM/MeOH (1 mL/1 mL) was added EtNH2 (0.1 mL, 2M in THF) and HOAc (0.2 mL), followed by NaB(OAc)3H (13 mg, 0.062 mmol). The reaction mixture was stirred for 5 hours at ambient temperature and then concentrated. The crude material was purified by silica gel chromatography (DCM/MeOH/NH4OH 20:1:0.1) to provide the desired product (4 mg). MS APCI (+) m/z 343 (M+1) detected.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[O:15][CH2:14][CH2:13][O:12][C:10]3=2)[N:5]=[CH:4][C:3]=1[Cl:16].O.C([O-])([O-])=O.[K+].[K+].B1(C=C)OB([CH:30]=[CH2:31])OB(C=C)O1.C1C=CN=CC=1>COCCOC.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>[Cl:16][C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[CH:30]=[CH2:31])=[C:10]1[O:12][CH2:13][CH2:14][O:15][C:9]1=[CH:8][CH:7]=2
Reactant: Clc1cnc2ccc3c(c2c1Br)OCCO3
Reactant: C=CB1OB(C=C)OB(C=C)O1
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: COCCOC
Solvent: c1ccncc1
Solvent: O
Product: C=Cc1c(Cl)cnc2ccc3c(c12)OCCO3
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
To a solution of 10-Bromo-9-chloro-2,3-dihydro-[1,4]dioxino[2,3-f]quinoline (11.5 g, 38.4 mmol, 1 eq) in DME (425 mL, degassed with Argon), was added Pd(PPh3)4, the reaction was stirred under Argon for 20 mins. Water (122 mL), K2CO3 (5.32 g, 38.4 mmol, 1 eq) and the 2,4,6-trivinylcyclotriboroxane-pyridine complex (2.49 g, 15.4 mmol, 0.4 eq) were added, the mixture was then heated to reflux at 100° C. overnight. The reaction was then cooled, the product was extracted with water and DCM, dried over Na2SO4, filtered and evaporated to dryness. The solid obtained was the passed through silica with as a pale yellow solid (5.5 g, 58%). LC/MS (ES) m/z 247 (MH+ 100%); 1H-NMR (400 MHz, CDCl), 8.69 (1H, s, CHNHC), 7.59 (1H, d, J=9.2, CHCO), 7.18 (1H, dd, J=18, 12, CCH═C), 5.68 (1H, dd, J=12, 1, Hcis of CH2=C), 5.49 (1H, dd, J=18, 1, H trans of CH2=C), 4.37-4.339 (4H, m, 2×(CH2O)).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:9][S:10]([NH:13][CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].B.C1COCC1.Cl.[OH-].[Na+]>C1COCC1>[NH2:2][CH2:1][C:3]1[CH:4]=[C:5]([CH2:9][S:10]([NH:13][CH:14]([CH3:16])[CH3:15])(=[O:12])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)NS(=O)(=O)Cc1cccc(C#N)c1
Agent: B
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)NS(=O)(=O)Cc1cccc(CN)c1
Temperature: 100 °C

Procedure:
To a solution of C-(3-cyano-phenyl)-N-isopropyl-methanesulfonamide (0.5 g, 2.06 mmol) in THF (10 mL) is added a solution of BH3−THF in THF (1 M, 10.3 mL). The mixture is sealed and heated in a microwave reactor at 100° C. for 120 seconds. The mixture is poured into 1 M HCl (50 mL), basified with 3 M NaOH to pH ˜10, extracted with DCM, dried with Na2SO4, filtered, and concentrated in vacuo to afford C-(3-aminomethyl-phenyl)-N-isopropyl-methanesulfonamide, which is used directly in the next step without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)=[CH2:2].C(Cl)(Cl)Cl.[Br].BrBr.N.[NH2-].[Na+]>C(Cl)(Cl)Cl>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1)#[CH:2]
Reactant: C=Cc1ccc2ccccc2c1
Agent: BrBr
Agent: N
Agent: [Br]
Solvent: ClC(Cl)Cl
Product: C#Cc1ccc2ccccc2c1

Procedure:
To a mixture of 15.5 g. of 2-vinylnaphthalene and 300 ml. of chloroform, a 5% bromine chloroform solution is added at -10° C until the bromine color persists. The mixture is then added to 200 ml. of ammonia containing 15 g. of sodium amide. The mixture is allowed to evaporate; the residue is extracted with diethyl ether. The extracts are combined, washed to neutrality with water, dried, and evaporated to yield 2-ethynylnaphthalene.
Reaction SMILES: O[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[C:9]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:10][CH:11]=[CH:12][CH:13]=2)[O:5][N:4]=1.C(N(CC)CC)C.COCCOC.P(Br)(Br)[Br:43]>O>[Br:43][CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[C:9]([N:14]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[N:10][CH:11]=[CH:12][CH:13]=2)[O:5][N:4]=1
Reactant: BrP(Br)Br
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccc1-c1cc(CO)no1
Solvent: O
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncccc1-c1cc(CBr)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 15.4 %

Procedure:
To a mixture of di-tert-butyl {3-[3-(hydroxymethyl)isoxazol-5-yl]pyridin-2-yl}imidodicarbonate (0.78 g, 2 mmol), triethylamine (1.95 mL, 14 mmol) and 1,2-dimethoxyethane (10 mL) was added phosphorus tribromide (0.37 mL, 4 mmol) dropwise at 0° C., which was stirred at room temperature for two hours, and then stirred at 50° C. for 30 minutes. The reaction mixture was cooled to 0° C., then water was added thereto and extracted with ethyl acetate, and the organic layer was washed with saturated sodium chloride water. After drying over anhydrous magnesium sulfate and filtering, the solvent was evaporated under a reduced pressure, the residue was purified by silica gel column chromatography to obtain the title compound (0.14 g).
Reaction SMILES: [C:1]1([C:11]2[CH2:15][CH2:14][CH:13]([OH:16])[CH:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:17]([Zn]CC)C.ICI>ClCCl>[C:1]1([C:11]23[CH2:17][CH:12]2[CH:13]([OH:16])[CH2:14][CH2:15]3)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC[Zn]CC
Reactant: OC1C=C(c2cccc3ccccc23)CC1
Solvent: ClCCl
Solvent: ICI
Product: OC1CCC2(c3cccc4ccccc34)CC12
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-naphthalen-1-yl-cyclopent-2-enol (1.00 g, 4.79 mmol) in dichloromethane (60 mL) was added diethylzinc (1.0 M in hexanes; 23.6 mL, 23.62 mmol, 4.9 eq.) and the reaction mixture was stirred for 10 min. The reaction mixture was cooled to 0° C. and treated with a solution of diiodomethane (1.93 mL, 24.04 mmol, 5 eq.) in dichloromethane (10 mL) in a dropwise fashion over 10 min. The reaction mixture was subsequently allowed to warm to ambient temperature and stirred for a further 2 h. TLC indicated that the reaction had gone to completion and was quenched with saturated aqueous ammonium chloride (50 mL). The reaction mixture was extracted with dichloromethane (3×100 mL) and the combined organics were dried over magnesium sulphate and concentrated in vacuo to afford the desired compound as a yellow oil. The crude material was purified by flash chromatography (SiO2, ethyl acetate:petroleum ether. 40-60; 20%:80%) to afford the desired compound as a yellow oil (1.00 g, 93%). 1H NMR (400 MHz, CDCl3) δ ppm 0.92-0.99 (1H, m, CH), 1.43-1.44 (2H, m, CH2), 1.82-1.86 (1H, m, CH), 1.93-2.07 (2H, m, CH2), 2.15-2.23 (1H, m, CH), 5.02-5.04 (1H, m, CH), 7.24-7.35 (4H, m, ArH), 7.75 (1H, d, J 8.0 ArH), 7.87 (1H, d, J 8.0 Hz, ArH) 8.15 (1H, d, J 8.4 Hz, ArH).
Reaction SMILES: [F:1][CH:2]([F:37])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]3[CH2:25][CH2:24][CH:23]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:45][CH2:46][CH2:47][OH:48]>CN(C=O)C.O>[F:37][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([N:20]3[CH2:21][CH2:22][CH:23]([N:26]([CH2:45][CH2:46][CH2:47][OH:48])[S:27]([CH3:30])(=[O:29])=[O:28])[CH2:24][CH2:25]3)[N:9]=2)[C:6]2[CH:31]=[CH:32][CH:33]=[C:34]([O:35][CH3:36])[C:5]=2[N:4]=1
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(NS(C)(=O)=O)CC2)n1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N2CCC(N(CCCO)S(C)(=O)=O)CC2)n1
Temperature: 20 °C
Reaction time: 168 h
Yield: 49 %

Procedure:
To a mixture of N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}methanesulfonamide (Example 17) (1.95 g, 3.62 mmol) and K2CO3 (6 g, excess) in DMF (20 mL) was added 3-bromo-1-propanol (4 mL, excess). The reaction mixture was stirred at 20° C. for 7 days and diluted with water. The resulting sticky material was extracted into CH2Cl2 (4×30 mL) and dried (Na2SO4). Evaporation of the solvent and the chromatography of the residue on silica, eluting with a gradient of CH2Cl2 and EtOAc (0-20%) followed by CH2Cl2/MeOH (97:3) gave N-{1-[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-4-piperidinyl}-N-(3-hydroxypropyl)methanesulfonamide (1.04 g, 49%): mp (CH2Cl2/MeOH) 219-221° C.; 1H NMR (DMSO-d6) δ7.89 (d, J=8.2 Hz, 1H), 7.69 (t, JHF=52.9 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 4.73 (d, J=12.8 Hz, 1H), 4.82 (d, J=12.3 Hz, 1H), 4.44 (t, J=5.1 Hz, 1H), 3.97 (S, 3H), 3.92-3.83 (m, 1H), 3.80-3.79 (m, 4H), 3.69 (m, 4H), 3.40-3.32 (m, 2H), 3.14-2.96 (m, 4H), 3.96 (s, 3H), 1.87-1.80 (m, 2H), 1.74-1.64 (m, 4H); Anal Calcd. for C25H34F2N8O5S: C, 50.33; H, 5.74; N, 18.78. Found: C, 50.2; H, 5.9; N, 18.5%.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][NH:11][C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[C:15]([C:23]([F:26])([F:25])[F:24])[CH:14]=2)[CH2:6][CH2:5]1.C(Cl)Cl.[C:31](Cl)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33].C([O-])(O)=O.[Na+]>CCOC(C)=O.CN(C=O)C>[C:31]([NH:1][CH2:2][CH2:3][N:4]1[CH2:5][CH2:6][CH:7]([CH2:10][NH:11][C:12](=[O:27])[C:13]2[CH:18]=[C:17]([C:19]([F:21])([F:22])[F:20])[CH:16]=[C:15]([C:23]([F:24])([F:25])[F:26])[CH:14]=2)[CH2:8][CH2:9]1)(=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: NCCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Reactant: CC(C)(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCCN1CCC(CNC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)CC1
Temperature: -20 °C
Reaction time: 8 h

Procedure:
A solution of N-((1-(2-aminoethyl)piperidin-4-yl)methyl)-3,5-bis(trifluoromethyl)benzamide (70 mg, 0.18 mmol) and TEA (123 μL, 0.881 mmol) in a 1:1 mixture of CH2Cl2:DMF (2 mL) was treated with pivaloyl chloride (42 mg, 0.35 mmol). The reaction mixture was stirred overnight then transferred to a test tube containing saturated aqueous NaHCO3 (4 mL) and EtOAc (4 mL). The biphasic mixture was mixed vigorously and allowed to separate for 15 min. After separation, the mixture was cooled to −20° C. until the aqueous layer was frozen. The organic layer was then poured off and the solvent was removed under reduced pressure at 50° C. The resulting residue was purified by HiTOPs.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([CH2:8][N:9]=[N+:10]=[N-:11])=[CH:6][CH:5]=1)(=[NH:3])[NH2:2].C(N(CC)CC)C.Cl[C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23].Cl>C(Cl)Cl.O>[CH2:25]([O:24][C:22]([NH:3][C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][N:9]=[N+:10]=[N-:11])=[CH:12][CH:13]=1)=[NH:2])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: [N-]=[N+]=NCc1ccc(C(=N)N)cc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [N-]=[N+]=NCc1ccc(C(=N)NC(=O)OCc2ccccc2)cc1
Reaction time: 0.5 h

Procedure:
The crystals from (ii) above were dissolved in 500 ml methylene chloride and the resulting solution was dried (K2CO3), filtered and 27 ml (194 mmol) triethyl amine was added. 25 ml Benzyl chloroformate was slowly added to the stirred solution while the reaction mixture was cooled in an ice bath. After 30 minutes an additional 2 ml benzyl chloroformate was added and stirring was continued for another 30 minutes. Subsequently, water was added and the aqueous phase was adjusted to pH 7 with 2M HCl. The organic phase was dried (MgSO4) and the solvent was removed in vacuo. 4-(benzyloxycarbonylamidino)benzyl azide was finally isolated as colorless crystals from ether/methylene chloride/hexane.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21](=[O:23])[CH3:22])[C@@H:16]([CH3:24])[CH2:15][NH:14]2.Cl[C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27]>ClCCCl>[C:21]([N:17]1[C:18]2[C:13](=[CH:12][C:11]([Br:10])=[CH:20][CH:19]=2)[N:14]([C:26]([O:28][CH:29]([CH3:31])[CH3:30])=[O:27])[CH2:15][C@@H:16]1[CH3:24])(=[O:23])[CH3:22]
Reactant: CC(C)OC(=O)Cl
Reactant: CC(=O)N1c2ccc(Br)cc2NC[C@@H]1C
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(Br)cc2N(C(=O)OC(C)C)C[C@@H]1C
Temperature: 50 °C
Reaction time: 16 h
Yield: 84.5 %

Procedure:
N,N-Diisopropylethylamine (0.973 mL, 5.57 mmol) was added to a solution of (S)-1-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)ethanone (0.500 g, 1.858 mmol) and isopropyl chloroformate (1.0 M in toluene, 2.79 mL, 2.79 mmol) in 1,2-dichloroethane (10.0 mL), and the mixture stirred at 50° C. for 16 h. The reaction mixture was concentrated to afford a yellow oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford (S)-isopropyl 4-acetyl-7-bromo-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.558 g, 85%) as an off-white solid. MS (ESI, pos. ion) m/z 355, 357 [M+1]+.