Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([C:10]([CH3:13])([CH3:12])[CH3:11])[C:7]([OH:9])=O)=[O:4].C1C=CC2N(O)N=NC=2C=1.Cl.Cl.Cl.[CH3:27][O:28][C:29](=[O:77])[NH:30][CH:31]([C:35]([N:37]1[CH:43]([C:44]2[NH:45][C:46]([C:49]3[CH:54]=[CH:53][C:52]([C:55]4[CH:64]=[CH:63][C:62]5[C:57](=[CH:58][CH:59]=[C:60]([C:65]6[NH:66][C:67]([CH:70]7[CH2:74][CH:73]([C:75]#[N:76])[CH2:72][NH:71]7)=[N:68][CH:69]=6)[CH:61]=5)[CH:56]=4)=[CH:51][CH:50]=3)=[CH:47][N:48]=2)[CH2:42][C:39]2([CH2:41][CH2:40]2)[CH2:38]1)=[O:36])[CH:32]([CH3:34])[CH3:33].CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:4])[NH:5][CH:6]([C:7]([N:71]1[CH2:72][CH:73]([C:75]#[N:76])[CH2:74][CH:70]1[C:67]1[NH:66][C:65]([C:60]2[CH:59]=[CH:58][C:57]3[C:62](=[CH:63][CH:64]=[C:55]([C:52]4[CH:51]=[CH:50][C:49]([C:46]5[NH:45][C:44]([CH:43]6[CH2:42][C:39]7([CH2:41][CH2:40]7)[CH2:38][N:37]6[C:35](=[O:36])[CH:31]([NH:30][C:29]([O:28][CH3:27])=[O:77])[CH:32]([CH3:34])[CH3:33])=[N:48][CH:47]=5)=[CH:54][CH:53]=4)[CH:56]=3)[CH:61]=2)=[CH:69][N:68]=1)=[O:9])[C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: COC(=O)NC(C(=O)O)C(C)(C)C
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CC(C#N)CN6)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CC(C#N)CN6C(=O)C(NC(=O)OC)C(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47.6 %

Procedure:
2-Methoxycarbonylamino-3,3-dimethyl-butyric acid (37 mg, 0.227 mmol) EDC-HCl (44 mg, 0.227 mmol) and HOBt (32 mg, 0.237 mmol) were combined in DMF (2 mL) and stirred for 20 min at RT. (1-{6-[5-(4-{6-[2-(4-Cyano-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester-tris-hydrochloride (150 mg, 0.189 mg) was added, the reaction mixture was cooled to 0° C. and NMM (0.104 mL, 0.947 mmol) was added dropwise. After 1.5 h, the reaction mixture was warmed to RT. 30 min later, the mixture was diluted with EtOAc and washed with NaHCO3, then 1:1 brine/5M NaOH. The organic phase was dried over MgSO4, then filtered and concentrated. The resulting residue was purified by HPLC to afford the title compound (77 mg, 48%). MS (ESI) m/z 855 [M+H]+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=[O:11])=[N:2]1.C([O-])([O-])=O.[K+].[K+].[CH2:19](Br)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>CN(C=O)C>[CH2:19]([O:11][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:2]=1)=[O:12])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: BrCc1ccccc1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1nn(Cc2ccccc2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring solution of 750 mg (4.62 mmol) of 1H-Indazole-3-carboxylic acid (Snyder, H. R.; Thompson, C. B.; Hinman, R. L. J. Am. Chem. Soc. 1952, 74, 2009) in 20 mL of DMF is added 1.92 g (13.86 mmol, 3.0 equiv) of K2CO3, followed by 1.43 mL of benzyl bromide. The reaction mixture is stirred 15 min at RT then heated at 60° C. for 16 h. The reaction is cooled to RT, poured into 100 mL 1N HCl, and extracted with EtOAc (2×100 mL). The organic layers are washed with H2O (2×100 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the crude material by silica gel flash column chromatography using a gradient elution of hexane/EtOAc 20/1 to 2/1 afforded 735 mg of the title compound as a yellow oil which later solidified: 1H NMR (CDCl3, 300 MHz) δ8.20 (d, 1H), 7.55 (d, 2H), 7.40-7.18 (m, 11H), 5.70 (s, 2H), 5.57 (s, 2H); Rf =0.15 in hexane/EtOAc 10/1.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:8][N:7]([CH:9]([C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH:22]4[CH2:27][CH2:26][CH:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:24][CH2:23]4)[CH:17]=3)[N:12]=2)[CH3:10])[CH2:6]1)=[O:4].[OH-].[Li+].O1CCCC1.O>>[C:28]([C@H:25]1[CH2:24][CH2:23][C@H:22]([O:21][C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[C:11]([CH:9]([N:7]2[CH2:6][CH:5]([C:3]([OH:4])=[O:2])[CH2:8]2)[CH3:10])[CH:20]=[CH:19]3)[CH2:27][CH2:26]1)([CH3:29])([CH3:30])[CH3:31]
Reactant: COC(=O)C1CN(C(C)c2ccc3cc(OC4CCC(C(C)(C)C)CC4)ccc3n2)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1)N1CC(C(=O)O)C1

Procedure:
A solution of 1-{1-[6-(4-tert-Butyl-cyclohexyloxy)-quinolin-2-yl]-ethyl}-azetidine-3-carboxylic acid methyl ester (57.2 mg, 0.135 mmol) and Lithium hydroxide (20.9 mg, 0.874 mmol) in Tetrahydrofuran (2 mL, 20 mmol) and Water (0.5 mL, 30 mmol) was stirred at r.t. overnight. LCMS showed a single desired product peak RT 1.60 min M+1 at m/z 413.30, 100%. The solvent was concentrated and neutralized with citric acid and concentrated and Purified on HPLC to give product (26.2 mg, 37%). 1H NMR (300 MHz, MeOD) d=8.25 (d, J=8.3 Hz, 1H), 7.94 (d, J=9.4 Hz, 1H), 7.42 (d, J=8.3 Hz, 1H), 7.37 (dd, J=2.6, 9.1 Hz, 1H), 7.28 (d, J=3.0 Hz, 1H), 4.54-4.43 (m, 2H), 4.42-4.18 (m, 3H), 3.78-3.59 (m, 1H), 2.25 (d, J=10.2 Hz, 2H), 1.89 (d, J=11.3 Hz, 2H), 1.57 (d, J=6.8 Hz, 3H), 1.51-0.99 (m, 6H), 0.89 (s, 9H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](O)=[O:8])=[CH:5][CH:4]=1.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[N+:14]([C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:10]=[CH:11][C:3]=1[C:2]([F:13])([F:12])[F:1])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(CO)ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 20 %

Procedure:
4-(Trifluoromethyl)benzoic acid (15 g, 78.9 mmol) in 90 mL of concentrated sulfuric acid was treated dropwise with a mixture of fuming nitric acid (2 mL) and sulfuric acid (24 mL). The reaction mixture was stirred at ambient temperature for 48 hours and quenched into ice-water. The resulting precipitate (12 g) was collected by filtration, washed with water and dried under reduced pressure. The resulting dry solid (12 g) was dissolved in THF (300 mL), cooled to 0° C., treated with 1M borane-tetrahydrofuran complex (80 mL) and stirred at ambient temperature overnight. Methanol (5 mL) was added dropwise followed by dropwise addition of concentrated HCl (5 mL), refluxed for 1 hour and evaporated to dryness and partitioned between water and diethyl ether. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with 30% ethyl acetate hexanes to provide the title compound (3.6 g, 20% yield).
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][C:7](=[O:16])[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CCN(CC)CC.[Si]([I:28])(C)(C)C.II>C(Cl)Cl>[I:28][N:6]1[C:7](=[O:16])[CH2:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[C:11]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]1=2
Reactant: O=C1Cc2ccccc2-c2ccccc2N1
Reactant: C[Si](C)(C)I
Agent: II
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1Cc2ccccc2-c2ccccc2N1I
Temperature: 7.5 °C

Procedure:
A solution of 5,7-dihydro-6H-dibenz[b,d]azepin-6-one (1.0 g, 4.77 mmol) (Example 3-A) and Et3N (2.66 mL, 19.12 mmol) were stirred for 5.0 minutes at −15° C. in CH2Cl2 and treated with TMSI (1.36 mL, 9.54 mmol). After stirring for 15 minutes I2 (1.81 g, 7.16 mmol) was added in a single portion and the reaction allowed to warm to 5-10° C. over 3 h. The reaction was quenched with sat. Na2SO3, diluted with CH2Cl2 and separated. The organics were washed with Na2SO3 and NaHSO3 and dried over MgSO4. After filtration, the organics were concentrated to approximately 20 mL and diluted with an additional 20 mL of hexanes. The title compound was isolated as a tan precipitate by filtration.
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[CH3:16][N:17]1[CH:21]=[CH:20][N:19]=[C:18]1[S:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[Cl:29][C:30]1[CH:57]=[CH:56][C:33]([C:34]([C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[N:42]([CH3:46])[C:41](=[O:47])[CH:40]=[C:39]3[C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([CH:54]=[CH2:55])[CH:49]=2)=[O:35])=[CH:32][CH:31]=1>C1COCC1.COCCOC>[Cl:29][C:30]1[CH:57]=[CH:56][C:33]([C:34]([OH:35])([C:21]2[N:17]([CH3:16])[C:18]([S:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[N:19][CH:20]=2)[C:36]2[CH:37]=[C:38]3[C:43](=[CH:44][CH:45]=2)[N:42]([CH3:46])[C:41](=[O:47])[CH:40]=[C:39]3[C:48]2[CH:53]=[CH:52][CH:51]=[C:50]([CH:54]=[CH2:55])[CH:49]=2)=[CH:32][CH:31]=1
Reactant: Cn1ccnc1Sc1ccccc1
Reactant: C=Cc1cccc(-c2cc(=O)n(C)c3ccc(C(=O)c4ccc(Cl)cc4)cc23)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: COCCOC
Solvent: C1CCOC1
Product: C=Cc1cccc(-c2cc(=O)n(C)c3ccc(C(O)(c4ccc(Cl)cc4)c4cnc(Sc5ccccc5)n4C)cc23)c1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 60.9 %

Procedure:
2,2,6,6-tetramethylpiperdine (4.5 mL, 26.5 mMol) was dissolved in a solution of anhydrous THF (100 mL) and anhydrous 1,2-dimethoxyethane (50 mL) under an atmosphere of dry N2 and the solution was then cooled to −78° C. To this solution was added 2.5 M n-butyllithium in hexanes (9.6 mL, 24.1 mMol) and the mixture was stirred for 20 minutes. To this solution was added 1-methyl-2-phenylthio-1-H-imidazole (4.58 g, 24.1 mMol) and the solution was stirred at −78° C. for 45 minutes. 6-(4-Chloro-benzoyl)-1-methyl-4-(3-vinyl-phenyl)-1H-quinolin-2-one (9.64 g, 24.1 mMol) was then added and the solution was slowly warmed to ambient temperature and stirred overnight. The reaction was quenched with saturated aqueous NH4Cl and the solution was partitioned between water and EtOAc. The aqueous layer was washed 2 more times with EtOAc. The EtOAc extracts were combined and dried over Na2SO4, filtered and concentrated under vacuum to give a yellow oil. The oil was chromatographed on flash silica gel eluting with a gradient from EtOAc/hexanes (1:1) to EtOAc/hexanes (4:1) to give 8.66 g of the titled compound as a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.CS(C)=O.[H-].[Na+].Cl[CH2:24][C:25]#[CH:26]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([O:16][CH2:26][C:25]#[CH:24])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: OC(Cn1cncn1)c1ccc(Cl)cc1Cl
Reactant: C#CCCl
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CS(C)=O
Product: C#CCOC(Cn1cncn1)c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 33.8 %

Procedure:
A mixture of 5.2 parts of α-(2,4-dichlorophenyl)-1H-1,2,4-triazole-1-ethanol, 50 parts of dimethyl sulfoxide and 45 parts of benzene is stirred till all solid enters solution. Then there is added 1 part of a sodium hydride dispersion 78% and stirring is continued till gasevolution has ceased. After stirring for one hour at 40°-50° C., there are added 2.3 parts of 3-chloro-1-propyne. The whole is stirred overnight at room temperature. The reaction mixture is poured onto ice-water and the product is extracted with 1,1'-oxybisethane. The extract is washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. Upon standing overnight at room temperature, the residue solidifies. The product is filtered off and crystallized from 2,2'-oxybispropane, yielding 2 parts (33.8%) of 1-[2-(2,4-dichlorophenyl)-2-(2 -propynyloxy)ethyl]-1H-1,2,4-triazole; mp. 84° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH3:9])[CH:6]=[CH:7][CH:8]=1.[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2=[O:21]>>[Cl:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])[C:14]2([OH:21])[C:8]1[CH:7]=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: O=C1Nc2ccc(Cl)cc2C1=O
Reactant: COc1cccc(C)c1
Product: COc1cc(C)ccc1C1(O)C(=O)Nc2ccc(Cl)cc21
Yield: 12.6 %

Procedure:
With 22.3 g of 3-methoxy toluene and 33.1 g of 5-chloroisatin as starting materials, 6.98 g of the title compound (colorless solid) was obtained by a similar method to Step 239-1.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:24])[NH:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:20]=[C:19]([C:21](O)=[O:22])[O:18][N:17]=3)=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:26][O:27][C:28](=[O:34])[C@@H:29]([NH2:33])[CH:30]([CH3:32])[CH3:31].[K+].[Br-]>>[CH3:26][O:27][C:28](=[O:34])[C@@H:29]([NH:33][C:21]([C:19]1[O:18][N:17]=[C:16]([C:13]2[CH:12]=[CH:11][C:10]([NH:9][C:8]([NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:24])=[CH:15][CH:14]=2)[CH:20]=1)=[O:22])[CH:30]([CH3:32])[CH3:31]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: O=C(Nc1ccccc1)Nc1ccc(-c2cc(C(=O)O)on2)cc1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: COC(=O)[C@@H](NC(=O)c1cc(-c2ccc(NC(=O)Nc3ccccc3)cc2)no1)C(C)C
Yield: 65 %

Procedure:
The title compound was prepared from 3-[4-(3-phenyl-ureido)-phenyl]-isoxazole-5-carboxylic acid and (S)-2-amino-3-methyl-butyric acid methyl ester hydrochloride as set forth in Example 5 and was obtained in 65% yield. Mass (ES+): 437 (M++1); IR (KBr): 3342, 3262, 1743; 1665, 1598, 1550; 1H NMR (DMSO-d6) δ: 0.92 (2×d, 6H), 2.18 (m, 1H), 3.63 (s, 3H), 4.27 (t, 1H), 6.94 (t, 1H), 7.25 (t, 2H), 7.42 (d, 2H), 7.58 (d, 2H), 7.64 (s, 1H), 7.80 (d, 2H), 8.72 (s, 1H), 8.92 (s, 1H), 9.14 (d, 1H).
Reaction SMILES: COC1C=CC(C2CCC3C(=CC=C(OC)C=3)C2(C)C)=C(N)C=1.BrC1C=CC(OCCN2CCCCC2)=C(F)C=1.[F:41][C:42]1[CH:43]=[C:44]([NH:57][C:58]2[CH:63]=[C:62]([O:64]C)[CH:61]=[CH:60][C:59]=2[CH:66]2[CH2:75][CH2:74][C:73]3[C:68](=[CH:69][CH:70]=[C:71]([O:76]C)[CH:72]=3)[C:67]2([CH3:79])[CH3:78])[CH:45]=[CH:46][C:47]=1[O:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1>>[F:41][C:42]1[CH:43]=[C:44]([NH:57][C:58]2[CH:63]=[C:62]([OH:64])[CH:61]=[CH:60][C:59]=2[CH:66]2[CH2:75][CH2:74][C:73]3[CH:72]=[C:71]([OH:76])[CH:70]=[CH:69][C:68]=3[C:67]2([CH3:79])[CH3:78])[CH:45]=[CH:46][C:47]=1[O:48][CH2:49][CH2:50][N:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1Nc1ccc(OCCN3CCCCC3)c(F)c1)C2(C)C
Agent: COc1ccc(C2CCc3cc(OC)ccc3C2(C)C)c(N)c1
Agent: Fc1cc(Br)ccc1OCCN1CCCCC1
Product: CC1(C)c2ccc(O)cc2CCC1c1ccc(O)cc1Nc1ccc(OCCN2CCCCC2)c(F)c1
Yield: 84.6 %

Procedure:
Synthesized from 5-methoxy-2-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine and 1-[2-(4-bromo-2-fluorophenoxy)ethyl]piperidine according to an analogous synthetic method to Example 116, [3-fluoro-4-(2-piperidin-1-ylethoxy)phenyl][5-methoxy-2-(6-methoxy-1,1-dimethyl-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (348 mg) was used according to an analogous synthetic method to Example 111 to provide the title compound (279 mg).
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[CH:18]([NH2:21])([CH3:20])[CH3:19].CCN(C(C)C)C(C)C>C(#N)C>[F:11][C:4]1[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[C:2]([NH:21][CH:18]([CH3:20])[CH3:19])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)c(-c2ccccn2)c1F
Reactant: CC(C)N
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Nc1c([N+](=O)[O-])ccc(F)c1-c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
A mixture of 2-(2,6-difluoro-3-nitrophenyl)pyridine (0.85 g, 3.6 mmol), isopropylamine (0.31 mL, 3.6 mmol) and DIPEA (0.63 mL, 3.6 mmol) in acetonitrile (10 mL) was stirred overnight at RT. The mixture was concentrated in vacuo and the resulting residue was purified by chromatography (Si—PPC, gradient 0-50% EtOAc/cyclohexane) to afford the title compound as a yellow oil (0.49 g, 50%). 1H NMR (CDCl3, 400 MHz): δ 8.76 (1H, ddd, J=6.5, 3.7, 2.4 Hz), 8.26 (1H, dd, J=12.7, 8.1 Hz), 7.86 (1H, br s), 7.81 (1H, td, J=10.4, 2.5 Hz), 7.46 (1H, dq, J=10.5, 1.5 Hz), 7.34 (1H, ddd, J=10.2, 6.5, 1.6 Hz), 6.57 (1H, dd, J=12.7, 10.8 Hz), 2.70-2.54 (1H, m), 0.93 (6H, d, J=8.4 Hz)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:29](=O)[CH2:30][CH3:31]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([Cl:28])[N:23]=3)[CH:17]=2)[CH2:29][CH2:30][CH3:31])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(NCc2cccc(-c3ccnc(Cl)n3)c2)CC1
Reactant: CCC=O
Product: CCCN(Cc1cccc(-c2ccnc(Cl)n2)c1)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Intermediate 29 was coupled with propionaldehyde following procedure E. LC-MS showed the product had the expected M+H+ of 445.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1)#[N:2].Cl.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:29])=[C:18]([C@@:20]2([CH3:28])[NH:26][C:25](=[O:27])[CH2:24][CH2:23][O:22][CH2:21]2)[CH:19]=1>>[F:29][C:17]1[CH:16]=[CH:15][C:14]([NH:13][C:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][N:7]=2)=[O:11])=[CH:19][C:18]=1[C@@:20]1([CH3:28])[NH:26][C:25](=[O:27])[CH2:24][CH2:23][O:22][CH2:21]1
Reactant: C[C@@]1(c2cc(N)ccc2F)COCCC(=O)N1
Reactant: N#Cc1ccc(C(=O)O)nc1
Agent: Cl
Product: C[C@@]1(c2cc(NC(=O)c3ccc(C#N)cn3)ccc2F)COCCC(=O)N1

Procedure:
Starting from 5-cyano-pyridine-2-carboxylic acid and (R)-3-(5-amino-2-fluoro-phenyl)-3-methyl-[1,4]oxazepan-5-one hydrochloride, the 5-cyano-pyridine-2-carboxylic acid [4-fluoro-3-((R)-3-methyl-5-oxo-[1,4]oxazepan-3-yl)-phenyl]-amide was obtained as a white solid. MS (ISP): m/z=369.1 [M+H]+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[N:15][CH:14]=[C:13](Cl)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[O:18]1[CH2:23][CH2:22][N:21]([C:24]2[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.F[B-](F)(F)F.C(C1C=CC=C(CCC)C=1[N+]1CCN(C2C(CCC)=CC=CC=2CCC)C=1)CC.CC(C)([O-])C.[K+]>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O1CCOCC1>[O:18]1[CH2:19][CH2:20][N:21]([C:24]2[CH:25]=[CH:26][C:27]([NH:28][C:13]3[N:12]=[C:11]([C:7]4[CH:6]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:10]=[CH:9][CH:8]=4)[CH:16]=[N:15][CH:14]=3)=[CH:29][CH:30]=2)[CH2:22][CH2:23]1
Reactant: CC(=O)Nc1cccc(-c2cncc(Cl)n2)c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CCCc1cccc(CCC)c1N1C=[N+](c2c(CCC)cccc2CCC)CC1
Solvent: C1COCCO1
Product: CC(=O)Nc1cccc(-c2cncc(Nc3ccc(N4CCOCC4)cc3)n2)c1
Yield: 3.8 %

Procedure:
Using Method O, 2-(3-acetamidophenyl)-6-chloropyrazine (150 mg, 0.61 mmol), 4-morpholinoaniline (155.4 mg, 0.87 mmol), tris(dibenzylideneacetone) dipalladium (0) (28 mg, 0.030 mmol), 1,3-bis(2,6-di-1-propylphenyl)-4,5-dihydro-imidazolium tetrafluoroborate (29 mg, 0.061 mmol), potassium tert-butoxide (102 mg, 0.91 mmol), and dioxane (3.5 mL) were reacted at 100° C. for 30 minutes with microwave heating. The reaction crude was passed through a short silica gel column (2 g silica), which was thoroughly washed with ethyl acetate. The last fractions of this column were collected to give 9 mg of pure title compound. The first fractions were collected, the solvent was evaporated under vacuo and the resulting solid was crystallised in ethyl acetate to produce 61 mg of the title compound. Yield: 29.8%. 1H NMR (250 MHz, DMSO-d6) δ 2.09 (s, 3 H), 3.03-3.07 (bt, 4 H), 3.72-3.76 (bt, 4 H), 6.97 (d, 2 H, J=9.0 Hz), 7.42 (t, 1 H, J=7.9 Hz), 7.65-7.68 (m, 2 H), 7.70 (d, 2H, J=8.9 Hz), 8.11 (s; 1 H), 8.33 (bs, 2 H), 9.36 (s, 1 H), 10.09 (s, 1 H); 13C NMR (62.9 MHZ, DMSO-d6) δ 24.11, 49.24, 66.16, 116.01, 117.08, 119.61, 119.89, 121.08, 129.16, 133.03, 133.15, 137.23, 139.87, 146.10, 147.95, 151.70, 168.45; m/z 390.2 [(M+H)+, calcd for C22H23N5O2 389.2].
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[N:5]=[C:4]2[NH:14][N:15]=[CH:16][C:3]=12.[H-].[Na+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22].C(=O)=O>CN(C=O)C.CO>[OH:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[N:5]=[C:4]2[NH:14][N:15]=[C:16]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[C:3]=12
Reactant: CC(C)C(=O)Nc1nc(O)c2cn[nH]c2n1
Reactant: COC(=O)CBr
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)Cc1n[nH]c2nc(NC(=O)C(C)C)nc(O)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 16 (4.42 g; 20 mmole) is suspended in dry DMF (40 ml), sodium hydride (0.5 g; 20.8 mmole) is added in portions, and the mixture is stirred at room temperature for 60 min. Methyl bromoacetate (1.9 ml; 20.6 mmole) is then added at room temperature, by syringe, and stirring is continued at room temperature. At completion of the reaction (monitored by TLC), the reaction mixture is treated with a small amount of carbon dioxide in methanol. The solvent is then evaporated and the residue dissolved in CH2Cl2, washed once with water and then evaporated to dryness. The product is purified by chromatography to yield the desired isomer (17).
Reaction SMILES: [C:1](Cl)(=O)C(Cl)=O.C([O:10][C:11]1[C:19]([O:20][CH3:21])=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[C:13]([N+:22]([O-:24])=[O:23])[C:12]=1[O:25][CH3:26])(=O)C>CN(C=O)C.C1COCC1>[CH3:26][O:25][C:12]1[C:13]([N+:22]([O-:24])=[O:23])=[C:14]([CH:18]=[C:19]([O:20][CH3:21])[C:11]=1[OH:10])[C:15]([O:17][CH3:1])=[O:16]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])c(OC)c1OC(C)=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)c(O)c(OC)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.2 %

Procedure:
A catalytic amount of DMF (5 drops) was added to a solution of oxalyl chloride (6.3 g, 49.8 mmol) and o-nitrobenzoic acid 83 (12.4 g, 45.2 mmol) in anhydrous THF (100 mL) and the reaction mixture allowed to stir at room temperature for 16 h. The resulting acid chloride was quenched dropwise with anhydrous methanol (100 mL) at 0° C. The reaction mixture was treated with potassium carbonate and allowed to stir at room temperature for 3 h. Excess solvent was removed by rotary evaporation at reduced pressure and the residue dissolved in water. The aqueous solution was acidified to pH 8 and the resulting white precipitate was collected by filtration, washed with water (2×100 mL) and dried to afford the product as an off-white solid (10.6 g, 83%). H1 NMR (270 MHz, CDCl3) δ10.07 (br s, 1H), 7.26 (s, 1H), 3.97 (s, 3H), 3.91 (s, 3H), 3.85 (s, 3H).