Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:16][CH:17]1[NH:21][C:20](=O)[CH2:19][CH2:18]1>>[CH2:16]([CH:17]1[N:21]([C:20]2[CH2:19][CH2:18][CH:17]([CH2:16][CH2:4][CH2:5][CH3:6])[N:21]=2)[C:20]([N:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[O:14][C:15]3[C:6]2=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:19][CH2:18]1)[CH2:3][CH2:2][CH3:15]
Reactant: Clc1cccc2c1Oc1ccccc1N2
Reactant: CC1CCC(=O)N1
Product: CCCCC1CCC(N2C(N3c4ccccc4Oc4ccccc43)=CCC2CCCC)=N1

Procedure:
reaction of 4-chlorophenoxazine with 5-methyl-2-pyrrolidinone according to the procedure of Example 4 provides
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([I:19])=[C:13]2[C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]1)[C:5]#[N:6].[OH:24]O.[OH-].[Na+].O>CS(C)=O>[NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N:10]1[C:14]2=[N:15][CH:16]=[CH:17][C:18]([I:19])=[C:13]2[C:12]([C:20]([F:23])([F:22])[F:21])=[N:11]1)[C:5]([NH2:6])=[O:24]
Reactant: N#Cc1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)c(N)c1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1ccc(-n2nc(C(F)(F)F)c3c(I)ccnc32)c(N)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Compound (158a) (0.100 g) was dissolved in DMSO (1.2 mL). A hydrogen peroxide solution (30 wt %) (0.053 mL) and a 4 mol % aqueous sodium hydroxide solution (0.233 mL) were added to the resulting solution, followed by stirring at room temperature for 20 min. Water was added to the reaction solution, and the precipitate was collected by filtration and was dried under reduced pressure to obtain compound (158b) (0.090 g).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[CH3:16][N+:17]([CH3:19])=[CH2:18].[I-]>CN(C=O)C>[CH3:16][N:17]([CH2:19][C:14]1[N:10]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:9][C:6]=2[C:7]#[N:8])[CH:11]=[N:12][C:13]=1[CH3:15])[CH3:18]
Reactant: Cc1ccc(-n2cnc(C)c2)c(C#N)c1
Reactant: C=[N+](C)C
Agent: [I-]
Solvent: CN(C)C=O
Product: Cc1ccc(-n2cnc(C)c2CN(C)C)c(C#N)c1
Yield: 64 %

Procedure:
As described for example 84b, 5-methyl-2-(4-methyl-imidazol-1-yl)-benzonitrile was reacted with Eschenmoser's salt in DMF for 4 h at 90° C. Evaporation of the solvent, aqueous workup and chromatography afforded the title compound as an oil that solidified upon standing (yield: 64%). MS: m/e=255.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]([O:16]CC)=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Li+].CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1(c2cccc(Br)c2)CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1(c2cccc(Br)c2)CCOCC1
Yield: 79.1 %

Procedure:
A stirred mixture of ethyl 4-(3-bromophenyl)-3,4,5,6-tetrahydro-2H-pyran-4-carboxylate (36.5 g, 117 mmol), an aqueous solution of lithium hydroxide (6.14 g, 146 mmol, 50 ml), methanol (150 ml) and THF (150 ml) was refluxed for 1 day. The reaction mixture was partitioned between ether (100 ml) and 10% aqueous potassium hydroxide solution (300 ml). The ethereal layer was separated, extracted with 10% aqueous potassium hydroxide solution (2×100 ml) and discarded. The combined aqueous extracts were acidified with concentrated hydrogen chloride and the resulting white precipitates were collected by filtration, washed with water and dried to constant weight under vacuum at 80° C. to give the titled compound as white solids (26.4 g, 79%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C@H:3]1[C@H:7]([OH:8])[CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.[H-].[Na+].I[CH3:20]>C1COCC1>[C:12]([O:11][C:9]([N:5]1[CH2:6][C@@H:7]([O:8][CH3:20])[C@H:3]([N:2]([CH3:16])[CH3:1])[CH2:4]1)=[O:10])([CH3:13])([CH3:15])[CH3:14]
Reactant: CI
Reactant: CN(C)[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]1N(C)C
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of racemic (trans)-tert-butyl 3-(dimethylamino)-4-hydroxypyrrolidine-1-carboxylate (0.96 g, 4.17 mmol) in THF (40 mL) at 0° C. was added NaH (0.25 g, 6.25 mmol, 60% dispersion in mineral oil), and the reaction mixture was stirred at 0° C. for 10 min. Then, iodomethane (0.29 mL, 4.6 mmol) was added dropwise and the resulting mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with sat aq NH4Cl and extracted three times with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated to provide racemic-(trans)-tert-butyl-3-(dimethylamino)-4-methoxypyrrolidine-1-carboxylate. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.84 (br. s., 1 H), 3.46-3.54 (m, 1 H), 3.25 (s, 3 H), 3.12-3.22 (obs m, 3 H), 2.72 (br. s., 1 H), 2.16 (s, 6 H), 1.39 (s, 9 H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:14]=[C:13]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]4[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=4)[N:16]=3)[C:12]([Cl:31])=[CH:11][N:10]=2)[CH2:4][CH2:3]1.C([O-])([O-])=O.[K+].[K+].CS(C)=O.Br[CH2:43][CH2:44][CH2:45][CH2:46]Br>C(Cl)Cl>[Cl:31][C:12]1[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([NH:21][CH2:22][C:23]3[CH:24]=[C:25]([F:30])[CH:26]=[C:27]([F:29])[CH:28]=3)[N:16]=2)=[CH:14][C:9]([NH:8][C@H:5]2[CH2:6][CH2:7][C@H:2]([N:1]3[CH2:46][CH2:45][CH2:44][CH2:43]3)[CH2:3][CH2:4]2)=[N:10][CH:11]=1
Reactant: N[C@H]1CC[C@H](Nc2cc(-c3cccc(NCc4cc(F)cc(F)c4)n3)c(Cl)cn2)CC1
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: Fc1cc(F)cc(CNc2cccc(-c3cc(N[C@H]4CC[C@H](N5CCCC5)CC4)ncc3Cl)n2)c1
Temperature: 60 °C

Procedure:
To a scintillation vial containing N2′-(trans-4-aminocyclohexyl)-5′-chloro-N6-(3,5-difluorobenzyl)-2,4′-bipyridine-2′,6-diamine (12.3 mg, 0.028 mmol) (obtained following example 2) and K2CO3 (15.32 mg, 0.111 mmol) was added DMSO (0.5 ml) and 1,4-dibromobutane (5.98 mg, 0.028 mmol). The reaction mixture was capped and heated at 60° C. for 7 hr. The reaction mixture was diluted with DCM and washed with H2O, sat NaCl. The organic layer was dried over Na2SO4, filtered and concentrated. The crude solid was purified by reverse phase preparative HPLC to yield 5′-chloro-N6-(3,5-difluorobenzyl)-N2′-(trans-4-(pyrrolidin-1-yl)cyclohexyl)-2,4′-bipyridine-2′,6-diamine (7.8 mg, 46.0%), LCMS (m/z): 498.3 (MH+), retention time=0.65 min as a TFA salt after lypholyzing. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.26-1.40 (m, 2H) 1.48-1.62 (m, 2H) 1.85-1.98 (m, 2H)1.99-2.24 (m, 7H) 2.99-3.14 (m, 4H) 3.51-3.68 (m, 3H) 4.54 (s, 2H) 6.69-6.80 (m, 3H) 6.81-6.90 (m, 3H) 7.60-7.69 (m, 1H) 7.94 (s, 1H).
Reaction SMILES: [CH3:1][C:2](C)=[O:3].[F:5][C:6]1([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:11]([OH:12])[NH:10][C:9](=[O:13])[NH:8][C:7]1=[O:14].C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:2]([O:12][CH:11]1[NH:10][C:9](=[O:13])[NH:8][C:7](=[O:14])[C:6]1([F:5])[C:15]([O:17][CH2:18][CH3:19])=[O:16])(=[O:3])[CH3:1]
Reactant: CCOC(=O)C1(F)C(=O)NC(=O)NC1O
Reactant: CC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)C1(F)C(=O)NC(=O)NC1OC(C)=O

Procedure:
In 10 ml. of acetone was dissolved 8.80 g. (40 m moles) of ethyl 5-fluoro-6-hydroxy-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate, and under ice-cooling, 5.10 g. (50 m moles) of acetic anhydride and 10 ml. of pyridine were added. The mixture was reacted at room temperature overnight. (A sample of the reaction mixture was taken, the solvent was distilled off under reduced pressure and the NMR spectrum of the residue was measured to ensure that there had been produced ethyl 6-acetoxy-5-fluoro-1,2,3,4,5,6-hexahydro-2,4-dioxopyrimidine-5-carboxylate
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C[O-].[Li+].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]#[C:29][C:30]1[C:31]([O:40][CH3:41])=[CH:32][C:33]([O:38][CH3:39])=[C:34]([CH:37]=1)[CH:35]=O>CN(C=O)C.CO>[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]#[C:29][C:30]1[C:31]([O:40][CH3:41])=[CH:32][C:33]([O:38][CH3:39])=[C:34](/[CH:35]=[CH:2]/[C:1]([C:4]2[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][C:15]([OH:17])=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=2)=[O:3])[CH:37]=1
Reactant: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1N
Reactant: CC(=O)c1ccc(S(=O)(=O)NCC(=O)O)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(OC)c(/C=C/C(=O)c2ccc(S(=O)(=O)NCC(=O)O)cc2)cc1C#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 23 h
Yield: 35.8 %

Procedure:
Ex-51A: A solution (4-acetylbenzenesulfonylamino)acetic acid (Ex-26A, 238 mg, 1.01 mmol) in DMF (4.4 mL) and MeOH (1.9 mL) was treated with lithium methoxide (153 mg, 4.04 mmol), followed by the addition of 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 300 mg, 1.07 mmol). The reaction mixture was stirred at room temperature for 23 h under nitrogen. It was quenched with water (10 mL) and extracted with ethyl acetate (25 mL). The aqueous phase was acidified with 6N HCl to pH3 and was extracted with (3:1) ethyl acetate/THF (5×25 mL). The organic phase was brined, dried over sodium sulfate, and concentrated to a yellow oil. The crude material was purified by column chromatography (0–7.5% MeOH in dichloromethane) to give (4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxyphenyl]acryloyl}benzenesulfonylamino)acetic acid (188 mg, 36%) as an orange solid. 1H-NMR (300 MHz, DMSO-d6) 8.23 (d, 2H, J=8.7), 8.19 (s, 1H), 7.99 (d, 1H, J=15.9 Hz), 7.92 (d, 2H, J=7.80 Hz), 7.82 (d, 1H, J=16.5 Hz), 7.16 (d, 1H, J=6.6 Hz), 7.05 (t, 1H, J=8.1 Hz), 6.76 (s, 1H), 6.71 (d, 1H, J=7.8 Hz), 6.52 (t, 1H, J=7.2 Hz), 5.72 (s, 1H), 5.45 (br s, 1H), 3.96 (s, 3H), 3.95 (s, 3H), 3.41 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O>COCCOC>[F:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11]
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1Br
Reactant: OB(O)c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CSc1ccccc1-c1ccccc1F
Yield: 69.3 %

Procedure:
A solution of benzoic acid N′-[2-(2-bromo-phenylsulfanyl)-acetyl]-N′-isopropyl-hydrazide (100 mg, 0.246 mmol) in DME (5 ml)/2M Na2CO3 (0.43 ml, 0.86 mmoles) was treated with 2-fluorophenylboronic acid (69 mg, 0.49 mmol) and Pd[PPh3]4 (28 mg, 0.025 mmol) for 12 hours at 90° C. The reaction mixture was partitioned between water and DCM. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was adsorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexane gradient to afford the product as a solid (72 mg, 68%). MS m/e 423.22 (M+H+)
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][CH2:9][C:10]2[S:11][C:12]([CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=3)=[CH:13][CH:14]=2)=[O:7])=[CH:4][N:3]=1.CC[C@@H]([C@H](NCN[C:36]([O:38][CH2:39]C)=O)C(O)=O)C.C=O.C(OCC)(=O)C>CO>[Cl:22][C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[CH2:15][C:12]1[S:11][C:10]([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:23]=[CH:24][C:2]([NH:1][CH2:36][O:38][CH3:39])=[N:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: Nc1ccc(C(=O)NCc2ccc(Cc3cccc(Cl)c3)s2)cn1
Reactant: CCOC(=O)NCN[C@H](C(=O)O)[C@@H](C)CC
Agent: C=O
Solvent: CCOC(C)=O
Solvent: CO
Product: COCNc1ccc(C(=O)NCc2ccc(Cc3cccc(Cl)c3)s2)cn1
Yield: 54 %

Procedure:
To a solution of 6-amino-N-(5-(3-chloro-benzyl)-thiophen-2-ylmethyl)-nicotinamide described in Example A-145 (110 mg, 0.3 mmol) in methanol (10 mL) were added 5,5-dimethylimidazo phospho-2,4-dione (43 mg, 0.33 mmol) and an aqueous solution of 37% formaldehyde (0.5 mL), and the solution was stirred under reflux for 2 hours. NH silica gel was added to the reaction solution, the solvent was evaporated in vacuo for adsorption, purification was carried out by NH silica gel column chromatography (hexane:ethyl acetate=1:1, then ethyl acetate), and the title compound (65 mg, 0.16 mmol, 54%) was obtained as a slightly yellow solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][OH:9].C([Li])CCC.[O:15]=[C:16]1[CH2:19][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:17]1.O>O1CCCC1>[OH:15][C:16]1([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][OH:9])[CH2:17][N:18]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19]1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Reactant: OCc1ccccc1Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(O)(c2ccccc2CO)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.3 %

Procedure:
To a solution of (2-bromophenyl)methanol (4.4 g) in dry tetrahydrofuran (90 mL) was added n-butyllithium (1.6 M hexane solution, 31 mL) at −78° C., and the mixture was warmed to room temperature over 2 hr. A solution of tert-butyl 3-oxoazetidine-1-carboxylate (4.0 g) in dry tetrahydrofuran (30 mL) was added at −78° C., and the mixture was stirred at room temperature for 18 hr. The reaction solution was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane to 60% ethyl acetate/hexane) to give the object product (4.0 g, 61%).
Reaction SMILES: Br[C:2]1[CH:27]=[CH:26][C:5]2[N:6]([C:9]3[CH:10]=[C:11]([NH:22][C:23](=[O:25])[CH3:24])[CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)[CH:14]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH3:28][C:29]([OH:47])([CH2:31][CH2:32][N:33]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[N:34]1)[CH3:30]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:13]2[CH:14]=[C:9]([N:6]3[C:5]4[CH:26]=[CH:27][C:2]([C:36]5[CH:35]=[N:34][N:33]([CH2:32][CH2:31][C:29]([OH:47])([CH3:28])[CH3:30])[CH:37]=5)=[CH:3][C:4]=4[N:8]=[CH:7]3)[CH:10]=[C:11]([NH:22][C:23](=[O:25])[CH3:24])[CH:12]=2)=[CH:16][CH:17]=1
Reactant: CC(=O)Nc1cc(-c2ccc(F)cc2)cc(-n2cnc3cc(Br)ccc32)c1
Reactant: CC(C)(O)CCn1ccc(B2OC(C)(C)C(C)(C)O2)n1
Product: CC(=O)Nc1cc(-c2ccc(F)cc2)cc(-n2cnc3cc(-c4cnn(CCC(C)(C)O)c4)ccc32)c1
Yield: 22.2 %

Procedure:
The compound was prepared from N-(5-(5-bromo-1H-benzo[d]imidazol-1-yl)-4′-fluoro-[1,1′-biphenyl]-3-yl)acetamide (0.07 g, 0.164 mmol) using the procedure of Example 200(c) and 2-methyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)butan-2-ol (0.092 g, 0.329 mmol, 2.0 eq.) to give the title product in 22.2% yield (0.018 g). 1H NMR (300 MHz, DMSO-d6): δ 10.42 (s, 1H), 8.68 (s, 1H), 8.25 (s, 1H), 7.99 (d, 2H), 7.93 (s, 1H), 7.83 (s, 1H), 7.69 (m, 2H), 7.65 (m, 1H), 7.61 (m, 2H), 7.36 (t, 2H), 4.48 (s, 1H); 4.26 (m, 2H); 2.12 (s, 3H); 1.91 (m, 2H); 1.15 (s, 6H); LC-MS (ESI): Calculated mass: 497.56 Observed mass: 497.9 [M+H]+ (rt: 0.9 min).
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][CH2:9][C@@H:10]([C:19]2[O:23][N:22]=[C:21]([CH2:24][NH:25][CH3:26])[N:20]=2)[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:28][C:29]([NH2:31])=[O:30]>CCN(CC)CC>[NH2:31][C:29](=[O:30])[CH2:28][N:25]([CH2:24][C:21]1[N:20]=[C:19]([C@H:10]([CH2:9][CH2:8][CH2:7][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[CH2:11][C:12]([O:14][C:15]([CH3:17])([CH3:18])[CH3:16])=[O:13])[O:23][N:22]=1)[CH3:26]
Reactant: NC(=O)CBr
Reactant: CNCc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Solvent: CCN(CC)CC
Product: CN(CC(N)=O)Cc1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Yield: 104.6 %

Procedure:
Method as for preparation 106 using tert-butyl (3R)-6-cyclohexyl-3-{3-[(methylamino)methyl]-1,2,4-oxadiazol-5-yl}hexanoate (preparation 5) (244 mg, 0.67 mmol) and 2-bromoacetamide (95 mg, 0.69 mmol) as starting materials and Et3N as the base to afford the title compound as a colourless oil (296 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]2=[C:6]3[C:11](=[C:12]([NH2:14])[N:13]=[C:4]2[CH:3]=1)[N:10]=[CH:9][C:8]([CH:15]=[CH2:16])=[CH:7]3.[H][H]>C(OCC)(=O)C.CO.[Pd]>[CH2:15]([C:8]1[CH:9]=[N:10][C:11]2[C:6]([CH:7]=1)=[C:5]1[CH:17]=[CH:18][C:2]([CH3:1])=[CH:3][C:4]1=[N:13][C:12]=2[NH2:14])[CH3:16]
Reactant: C=Cc1cnc2c(N)nc3cc(C)ccc3c2c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1cnc2c(N)nc3cc(C)ccc3c2c1
Reaction time: 3 h

Procedure:
To a solution of 8-methyl-2-vinylbenzo[f][1,7]naphthyridin-5-amine (from the previous step) in ethyl acetate/methanol (1:4, 0.05 M) was added 10% wt palladium on carbon (0.2 eq.). Hydrogen gas was introduced via a balloon, and the reaction was stirred for 3 hours. The mixture was filtered through a pad of celite and washed with dichloromethane. The filtrate was concentrated en vaccuo and purified by a COMBIFLASH® system (ISCO) using 0-80% ethyl acetate in hexane to give 2-ethyl-8-methylbenzo[f][1,7]naphthyridin-5-amine as an offwhite solid. 1H NMR (CDCl3): δ 8.61 (d, 1H), 8.42 (d, 1H), 8.10 (d, 1H), 7.44 (s, 1H), 7.12 (dd, 1H), 6.00 (bs, 2H), 2.84 (q, 2H), 2.45 (s, 3H), 1.33 (t, 3H). LRMS [M+H]=238.1.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([O:24]CC3C=CC(OCCCCCCCCCCC4C5C(=C6C=CC=CC6=C6C=CC=CC6=5)C5C4=C4C=CC=CC4=C4C=CC=CC4=5)=CC=3)=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:20])=[C:11]([N:14]4[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]4)[CH:12]=3)[C:7](=[O:21])[C:6]([C:22]([OH:24])=[O:23])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: O=C(OCc1ccc(OCCCCCCCCCCC2c3c(c4ccccc4c4ccccc34)-c3c2c2ccccc2c2ccccc32)cc1)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)c1cn(C2CC2)c2cc(N3CCNCC3)c(F)cc2c1=O

Procedure:
The compound obtained in Step (j) may be stirred in a solution of TFA/DCM to afford the title compound.
Reaction SMILES: [Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]#[N:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:34])[C:18]([C:20]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[C:21]=1[CH2:30][CH2:31][CH2:32][CH3:33])=[O:19])=[CH:7]2.[N-:35]=[N+:36]=[N-:37].[Na+].[Cl-].[OH-].[Na+]>CN(C=O)C.O>[Br:1][C:2]1[C:11]([O:12][CH2:13][C:14]2[NH:37][N:36]=[N:35][N:15]=2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:16][N:17]([CH3:34])[C:18]([C:20]1[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([CH3:29])[C:21]=1[CH2:30][CH2:31][CH2:32][CH3:33])=[O:19])=[CH:7]2
Reactant: [N-]=[N+]=[N-]
Reactant: CCCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(OCC#N)ccc3c2)c2ccccc2n1C
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCc1c(C(=O)N(C)Cc2ccc3c(Br)c(OCc4nnn[nH]4)ccc3c2)c2ccccc2n1C
Temperature: 100 °C
Reaction time: 4.25 h
Yield: 90.3 %

Procedure:
A mixture of 2-butyl-1-methyl-1H-indole-3-carboxylic acid (5-bromo-6-cyanomethoxy-naphthalen-2-ylmethyl)-methyl-amide (1.79 g, 3.45 mmol), prepared in the previous step, sodium azide (673 mg, 10.35 mmol) and ammoniun chloride (554 mg, 10.36 mmol) in 100 mL of DMF was stirred under nitrogen at 100° C. for 4.25 h. The reaction was diluted with water, made basic by the addition of 20 mL of 1 N NaOH and extracted multiple times with ethyl acetate. The aqueous layer was acidified with 40 mL of 1 N HCl. A brown oil separated. The oil was partitioned between the aqueous layer and methylene chloride. The organic layer separated and the aqueous layer was extracted three times with methylene chloride. The combined extracts were dried (MgSO4) and the solvent removed under reduced pressure. The residue was dissolved in 20 mL of 1 N NaOH and then acidified with 30 mL 1 N HCl. The solid that formed was collected by filtration, rinsed with water and dried under reduced pressure to give the title compound (1.75 g, 89%) as an off-white solid, mp 147-149° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C@@:15]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:14]3[C:9](=[N:10][CH:11]=[C:12]([O:21][CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:13]=3)[O:8][C:5]2=[CH:6][CH:7]=1.CN(C=O)C.C(NC(C)C)(C)C.C[Si](C)(C)[C:41]#[C:42][C:43]1([CH3:47])[CH2:46][O:45][CH2:44]1>[Cu](I)I.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>[CH3:47][C:43]1([C:42]#[C:41][C:2]2[CH:3]=[C:4]3[C@@:15]4([CH2:19][O:18][C:17]([NH2:20])=[N:16]4)[C:14]4[C:9](=[N:10][CH:11]=[C:12]([O:21][CH2:22][C:23]([CH3:26])([CH3:24])[CH3:25])[CH:13]=4)[O:8][C:5]3=[CH:6][CH:7]=2)[CH2:46][O:45][CH2:44]1
Reactant: CC1(C#C[Si](C)(C)C)COC1
Reactant: CC(C)(C)COc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(Br)ccc1O2
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)COc1cnc2c(c1)[C@]1(COC(N)=N1)c1cc(C#CC3(C)COC3)ccc1O2
Temperature: 90 °C

Procedure:
A sealable tube was charged with (S)-7-bromo-3-(neopentyloxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine (75 mg, 0.179 mmol), copper iodide (3.38 mg, 0.018 mmol), tetrakis(triphenylphosphine)palladium (20.53 mg, 0.018 mmol). To this mixture was added DMF (355 μL, 0.178 mmol), diisopropylamine (498 μL, 3.55 mmol) and trimethyl((3-methyloxetan-3-yl)ethynyl)silane (90 mg, 0.533 mmol). The tube was flushed with argon, sealed and heated to 90° C. for 12 hours. The reaction was diluted with water (100 mL) and poured into a separatory funnel containing ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water and then brine, dried over sodium sulfate, filtered and concentrated in vacuo to provide a brown oil that was purified by silica gel chromatography (Redi-Sep pre-packed silica gel column (12 g), 0-10% methanol in methylenechloride with 0.1% ammonium hydroxide) to provide (S)-7-((3-methyloxetan-3-yl)ethynyl)-3-(neopentyloxy)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-oxazol]-2′-amine as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.[Cl:25][C:26]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:27]=1[C:28](Cl)=[O:29]>ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:33]([Cl:35])=[CH:34][C:26]=4[Cl:25])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: ClCCl
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccc(Cl)cc1Cl
Yield: 44.8 %

Procedure:
As described for Example 9, 0.111 g (1.1 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 8 ml of dichloromethane is reacted with 0.230 g of (1.1 mmol) of 2,4-dichlorobenzoyl chloride. The product is recrystallized from hexane-dichloromethane to give 0.24 g of crystals, m.p. 212°-215° C.