Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([C:15]34[CH2:22][CH2:21][C:18]([CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH2:19][CH2:20]3)[O:17][CH2:16]4)=[CH:11][CH:10]=2)O1.Br[C:30]1[N:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1>[CH3:27][O:26][C:24](=[O:25])[CH2:23][C:18]12[CH2:21][CH2:22][C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:30]4[CH:31]=[CH:32][C:33]([NH2:36])=[CH:34][N:35]=4)=[CH:14][CH:13]=3)([CH2:20][CH2:19]1)[CH2:16][O:17]2
Reactant: Nc1ccc(Br)nc1
Reactant: COC(=O)CC12CCC(c3ccc(B4OC(C)(C)C(C)(C)O4)cc3)(CC1)CO2
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)CC12CCC(c3ccc(-c4ccc(N)cn4)cc3)(CC1)CO2
Yield: 131 %

Procedure:
To a microwave vial containing methyl 2-(4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-oxabicyclo[2.2.2]octan-1-yl)acetate (100 mg, 0.26 mmol), 6-bromopyridin-3-amine (49 mg, 0.28 mmol) and Pd2(PPh3)4 (60 mg, 0.05 mmol) was added 1,4-dioxane (1.3 ml) at room temperature. 2N sodium carbonate (0.39 ml, 0.78 mmol) was added and the mixture was subjected to microwave radiation at 120° C. for 50 minutes. The resulting mixture was concentrated to dryness and taken up in EtOAc, the slurry was dried over sodium sulfate and filtered through a pad of celite. The filtrate was concentrated and purified by column chromatography to afford the title compound (120 mg, 65% yield). LC/MS, ESI-MS(+): 353.4, RT: 1.12 (Condition E).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:15])([CH3:14])[C:9]2=[O:16])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:24](Cl)(Cl)=[O:25]>O1CCCC1>[N:1]([C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][C:10]([CH3:14])([CH3:15])[C:9]2=[O:16])[CH:5]=[CH:6][CH:7]=1)=[C:24]=[O:25]
Reactant: CC1(C)CC(=O)N(c2cccc(N)c2)C1=O
Reactant: O=C(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)N(c2cccc(N=C=O)c2)C1=O
Temperature: 25 °C

Procedure:
Seventy-three g. of N-m-aminophenyl-2,2-dimethylsuccinimide, as prepared in Example II, was dissolved in 800 ml. of tetrahydrofuran containing 75 g. of triethylamine, cooled in an ice bath, and added to 60 g. of phosgene in 400 ml. of tetrahydrofuran maintained at about 0° C. in a drying and isopropanol bath. The mixture was allowed to warm to room temperature and the triethylamine hydrochloride was filtered off and the tetrahydrofuran removed under vacuum on the rotary evaporator. Yield was 84 g. of material product having a nD30 of 1.5470. The product was identified as the title compound by analysis of infrared spectra and was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:32]([O-])=O)=[CH:4][C:5]([O:30][CH3:31])=[C:6]([CH:29]=1)[C:7]([NH:9][CH2:10][CH2:11][N:12]1[CH2:28][CH2:27][C:15]2([N:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][NH:17][C:16]2=[O:26])[CH2:14][CH2:13]1)=[O:8].[H][H]>[Ni].C(O)(=O)C>[NH2:32][C:3]1[C:2]([Cl:1])=[CH:29][C:6]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[CH2:13][CH2:14][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:27][CH2:28]2)=[O:8])=[C:5]([O:30][CH3:31])[CH:4]=1
Reactant: [H][H]
Reactant: COc1cc([N+](=O)[O-])c(Cl)cc1C(=O)NCCN1CCC2(CC1)C(=O)NCN2c1ccccc1
Agent: [Ni]
Solvent: CC(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCCN1CCC2(CC1)C(=O)NCN2c1ccccc1

Procedure:
A mixture of 6 parts of 5-chloro-2-methoxy-4-nitro-N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5] dec-8-yl)ethyl]benzamide in 150 parts of acetic acid is hydrogenated at normal pressure and at room temperature with 1 part of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is taken up in water and the whole is alkalized. The precipitated product is filtered off and crystallized twice from ethanol, yielding 1.7 parts of 4-amino-5-chloro-2-methoxy-N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4,5]-dec-8-yl)ethyl]benzamide; mp. 247.4° C.
Reaction SMILES: [CH:1]12[NH:27][CH2:26][CH:5]([N:6]([C:8]3[C:17]([F:18])=[C:16]4[C:11]([C:12](=[O:24])[C:13]([C:21]([OH:23])=[O:22])=[CH:14][N:15]4[CH2:19][CH3:20])=[CH:10][C:9]=3[F:25])[CH2:7]1)[CH2:4][CH2:3][CH2:2]2.[CH2:28]=O>C(O)=O>[CH2:19]([N:15]1[C:16]2[C:11](=[CH:10][C:9]([F:25])=[C:8]([N:6]3[CH2:7][CH:1]4[N:27]([CH3:28])[CH2:26][CH:5]3[CH2:4][CH2:3][CH2:2]4)[C:17]=2[F:18])[C:12](=[O:24])[C:13]([C:21]([OH:23])=[O:22])=[CH:14]1)[CH3:20]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCCC3CN4)c(F)c21
Reactant: C=O
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCCC3CN4C)c(F)c21

Procedure:
A mixture of 0.20 g (0.52 mmol) of 7-(6,8-diazabicyclo[3.2.2]non-6-yl)-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, 5 ml of 37% formaldehyde solution, and 5 ml of formic acid was heated under reflux for 3.6 hr. The reaction mixture was evaporated to dryness and the residue was suspended in ethanol/HCl. The solid was collected by filtration to give 0.16 g of the title compound as the hydrochloride salt, mp >300°.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]3[C:14](=[CH2:24])[CH2:15][NH:16][CH2:17][CH2:18][N:19]([S:20]([CH3:23])(=[O:22])=[O:21])[C:10]3=[N:9][C:8]=2[O:7][C:6]=1[C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)=[O:4].[CH3:32][S:33](Cl)(=[O:35])=[O:34].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][NH:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11]3[C:14](=[CH2:24])[CH2:15][N:16]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:17][CH2:18][N:19]([S:20]([CH3:23])(=[O:22])=[O:21])[C:10]3=[N:9][C:8]=2[O:7][C:6]=1[C:25]1[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=1)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: C=C1CNCCN(S(C)(=O)=O)c2nc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C1CN(S(C)(=O)=O)CCN(S(C)(=O)=O)c2nc3oc(-c4ccc(F)cc4)c(C(=O)NC)c3cc21
Temperature: 0 °C
Yield: 44.2 %

Procedure:
2-(4-Fluoro-phenyl)-10-methanesulfonyl-5-methylene-5,6,7,8,9,10-hexahydro-1-oxa-7,10,11-triaza-cycloocta[f]indene-3-carboxylic acid methylamide (6.0 mg, 0.013 mmol) is dissolved in DCM (2 mL) and the solution is cooled to 0° C. Methanesulfonyl chloride (7.7 mg, 0.07 mmol) is added followed by triethylamine (6.83 mg, 0.07 mmol) and the reaction is allowed to warm up to RT over 3 h then evaporated to dryness and placed on the high vacuum overnight. The sample is then redissolved in EtOAc (25 mL) and then washed with 1N HCl (10 mL), then Brine (20 mL) and dried over Na2SO4. The organic is concentrated to afford 2-(4-Fluoro-phenyl)-7,10-bis-methanesulfonyl-5-methylene-5,6,7,8,9,10-hexahydro-1-oxa-7,10,11-triaza-cycloocta[f]indene-3-carboxylic acid methylamide (3 mg, 42%). MS-ES [M+H]+=523.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([O:11][CH2:12][CH:13]=[CH2:14])[CH:5]=1.CI.[C:18]([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([O:10][CH3:18])[CH:7]=[C:6]([O:11][CH2:12][CH:13]=[CH2:14])[CH:5]=1
Reactant: O=C([O-])[O-]
Reactant: C=CCOc1cc(O)cc(C(=O)OC)c1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: C=CCOc1cc(OC)cc(C(=O)OC)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
To a solution of 3-allyloxy-5-hydroxy-benzoic acid methyl ester (1a) (10.25 g, 49.2 mmol) in DMF (20 mL) was added methyl iodide (3.67 mL, 59.1 mmol) and K2CO3 (13.6 g, 98.5 mmol). The reaction mixture was stirred at 70° C. for 2 hr, cooled to room temperature. The mixture was quenched with H2O (150 mL) and extracted with EtOAc (2×150 mL). The organic layers were washed with H2O (2×150 mL), dried over MgSO4 and concentrated to give a pale yellow oil which was purified by flash column chromatography eluting with 10% EtOAc in hexane to give a colorless oil (9.63 g, 88% yield). 1H NMR (400 MHz, CDCl3) δ 7.11-7.24 (m, 2 H) 6.68 (t, J=2.40 Hz, 1 H) 5.91-6.17 (m, 1 H) 5.38-5.51 (m, 1 H) 5.31 (dd, J=10.48, 1.39 Hz, 1 H) 4.52-4.61 (m, 2 H) 3.91 (s, 3 H) 3.83 (s, 3 H); LCMS for C12H14O4 m/z 223.0 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[C:22]([C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1)([CH3:25])([CH3:24])[CH3:23]>>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH2:11][N:7]2[C:8]3[C:4](=[CH:3][C:2]([C:29]4[CH:30]=[CH:31][C:26]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:27][CH:28]=4)=[CH:10][CH:9]=3)[CH:5]=[CH:6]2)=[CH:13][CH:14]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Reactant: CC(C)(C)c1ccc(Cn2ccc3cc(Br)ccc32)cc1
Product: CC(C)(C)c1ccc(Cn2ccc3cc(-c4ccc(C(C)(C)C)cc4)ccc32)cc1

Procedure:
The title compound was prepared from 5-bromo-1-[4-(tert-butyl)benzyl]-1H-indole (Step 1 of Example 34) and 4-(tert-butyl)phenylboronic acid in substantially the same manner, as described in Step 2 of Example 25. The product was obtained as an off-white solid, mp: 167-168° C. Mass spectrum (ESI, [M+H]+) m/z 396. 1 HNMR (400 MHz, DMSO-d6): δ 7.77 (d, 1H, J=1.38 Hz), 7.55 (d, 2H, J=8.56 Hz), 7.52-7.51 (m, 2H), 7.43 (d, 1H, J=8.40 Hz), 7.36 (d, 1H, J=8.55 Hz), 7.31 (d, 2H, J=8.40 Hz), 7.14 (d, 2H, J=8.40 Hz), 6.51 (d, 1H, J=3.05 Hz), 5.38 (s, 2H), 1.30 (s, 9H), and 1.21 ppm (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:10]([CH2:13][CH2:14][OH:15])(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.CC(=O)OCC>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([S:10]([CH2:13][CH2:14][O:15][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][O:16]2)(=[O:11])=[O:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: C1=COCCC1
Reactant: COc1ccc(S(=O)(=O)CCO)cc1Br
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)CCOC2CCCCO2)cc1Br
Temperature: 25 °C
Yield: 85.3 %

Procedure:
To the title compound of step 3 (1.0 g, 3.4 mmol) in CH2Cl2 (10 mL) was added 3,4-dihydro-2H-pyran (1.4 g, 17.0 mmol) followed by pyridinium p-toluensulfonate (64.6 mg, 0.34 mmol). After stirring at r.t. 12 h, the mixture was subjected to CH2Cl2 extractive work up & silica gel chromatography (PE:EA=1:0˜5:1) to give the title compound (1.1 g, 85.6%) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ 8.11 (d, J=2.4 Hz, 1H), 7.86 (dd, J1=8.8 Hz, J2=2.4 Hz, 1H), 7.00 (d, J=8.8 Hz, 1H), 4.51 (dd, J1=4.0 Hz, J2=2.4 Hz, 1H), 4.09-4.03 (m, 1H), 3.98 (s, 3H), 3.84-3.79 (m, 1H), 3.79-3.74 (m, 1H), 3.50-3.46 (m, 1H), 3.45-3.42 (m, 2H), 1.58-1.37 (m, 6H). LCMS: 401.0, 403.0 (M+Na)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[NH:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[C:36]1[NH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([O:32][CH3:33])[C:29]=1[O:30][CH3:31])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:48]2[CH2:47][CH2:46][CH:45]([NH:44][C:36]3[NH:35][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=3)[CH2:50][CH2:49]2)([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccc(F)cc3)C2)cc(OC)c1OC
Reactant: c1ccc2[nH]c(NC3CCNCC3)nc2c1
Agent: I
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5[nH]4)CC3)(c3ccc(F)cc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 4.1 using 1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-methanesulfonyloxyethyl)pyrrolidine (2.65 g, 5.5 mmol) (prepared from (+)-1-(3,4,5-trimethoxybenzoyl)-3-(4-fluorophenyl)-3-(2-hydroxyethyl)pyrrolidine) and (1H-benzimidazol-2-yl)(piperidin-4-yl)amine hydriodic acid salt (3.9 g, 8.25 mmol) to give, after chromatography on silica gel eluting with methanol/ethyl acetate 1/1, the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[CH3:12])=[CH:4][CH:3]=1.[C:13]1([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:18]=[CH:17][C:16]([C:19](O)=[O:20])=[CH:15][CH:14]=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH3:12][N:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:19]([C:16]3[CH:17]=[CH:18][C:13]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:14][CH:15]=3)=[O:20])[CH:11]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: CN1CCCc2ccc(N)cc21
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN1CCCc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc21
Temperature: 25 °C

Procedure:
To a solution of 7-amino-1-methyl-1,2,3,4-tetrahydroquinoline (D3) (325 mg, 2 mmol) in DCM (10 ml) was added 4-biphenylcarboxylic acid (476 mg, 2.4 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (444 mg, 2.4 mmol) and the reaction stirred at ambient temperature. After 1 h the reaction mixture was filtered to give the title compound as a white solid. The filtrate was diluted with DCM, washed with sat. aq. sodium bicarbonate solution, dried over MgSO4 and concentrated in vacuo to give further crude product which was purified by silica SPE chromatography. Elution with an EtOAc/60-80° C. petroleum ether gradient gave a mixture of the title compound and the starting acid. These fractions were washed with further sat. aq. sodium bicarbonate solution, dried over MgSO4 and concentrated in vacuo to give further title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ (ppm): 7.94 (d, 2H), 7.70 (m, 3H), 7.63 (d, 2H), 7.48 (t, 2H), 7.40 (t, 1H), 7.07 (d, 1H), 6.93 (d, 1H), 6.75 (dd, 1H), 3.25 (m, 2H), 2.94 (s, 3H), 2.76 (t, 2H), 1.98 (m, 2H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](=O)[CH2:6][C:7]#[N:8])[CH3:2].C(O)(=O)C(O)=O.[CH2:16]([NH:18][NH2:19])[CH3:17].Cl>C(O)C>[CH2:16]([N:18]1[C:7]([NH2:8])=[CH:6][C:5]([CH2:4][O:3][CH2:1][CH3:2])=[N:19]1)[CH3:17]
Reactant: CCNN
Reactant: CCOCC(=O)CC#N
Agent: Cl
Agent: O=C(O)C(=O)O
Solvent: CCO
Product: CCOCc1cc(N)n(CC)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.6 %

Procedure:
To a 25 mL round bottom was added 4-(ethyloxy)-3-oxobutanenitrile (550 mg, 4.33 mmol), ethyl hydrazine oxalate (641 mg, 4.33 mmol), and HCl (2.163 mL, 4.33 mmol) in ethanol (10 mL). The reaction mixture was stirred at the room temperature overnight. The reaction mixture was then evaporated, and partitioned between 20 mL of ethyl acetate and 20 mL of 1 M Na2CO3. The organic layer was washed with brine, filtered and evaporated. 1-Ethyl-3-[(ethyloxy)methyl]-1H-pyrazol-5-amine (420 mg, 2.234 mmol, 51.6% yield) was isolated as yellow oil. The product was used in the next step without further purification. LCMS (M+H)+=170.1 (M+H); 1H NMR (400 MHz, DMSO-d6) ppm 1.08 (t, J=6.95 Hz, 3 H) 1.19 (t, J=7.07 Hz, 3 H) 3.37-3.43 (m, 2 H) 3.81 (q, J=7.24 Hz, 2 H) 4.15 (s, 2 H) 5.09 (s, 2 H) 5.22 (s, 1 H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[CH:19]=[C:18]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[C:21]4[CH:29]([F:31])[F:30])[N:17]=[C:16]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)[N:15]=3)[CH2:9][CH2:8]2)[C:3]1=[O:38].C(N(CC)CC)C.[CH3:46][O:47][C:48](Cl)=[O:49].C(=O)(O)[O-].[Na+]>ClCCl>[CH3:46][O:47][C:48](=[O:49])[NH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C@H:7]2[CH2:12][CH2:11][C@H:10]([O:13][C:14]3[CH:19]=[C:18]([N:20]4[C:24]5[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=5[N:22]=[C:21]4[CH:29]([F:31])[F:30])[N:17]=[C:16]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[N:15]=3)[CH2:9][CH2:8]2)[C:3]1=[O:38]
Reactant: N[C@H]1CCN([C@H]2CC[C@H](Oc3cc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)n3)CC2)C1=O
Reactant: COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)N[C@H]1CCN([C@H]2CC[C@H](Oc3cc(-n4c(C(F)F)nc5ccccc54)nc(N4CCOCC4)n3)CC2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To (3S)-3-amino-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]pyrrolidin-2-one (75 mg), triethylamine (22 μL), and dichloromethane (750 μL) was added methylchlorocarbonate (12 μL), followed by stirring at room temperature for 1 hour. After the completion of the reaction, a saturated aqueous sodium bicarbonate solution was added thereto, followed by extraction with chloroform. The organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol) to obtain methyl{(3S)-1-[trans-4-({6-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-2-(morpholin-4-yl)pyrimidin-4-yl}oxy)cyclohexyl]-2-oxopyrrolidin-3-yl}carbamate (55 mg) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:21])=[N:4][C:5](F)=[C:6]([F:19])[C:7]=1[N:8]1[C:12](=[O:13])[C:11]2=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]2[C:9]1=[O:18].[C:22]([NH2:26])([CH3:25])([CH3:24])[CH3:23]>C(#N)C>[C:22]([NH:26][C:5]1[C:6]([F:19])=[C:7]([N:8]2[C:12](=[O:13])[C:11]3=[CH:14][CH:15]=[CH:16][CH:17]=[C:10]3[C:9]2=[O:18])[C:2]([Cl:1])=[C:3]([F:21])[N:4]=1)([CH3:25])([CH3:24])[CH3:23]
Reactant: O=C1c2ccccc2C(=O)N1c1c(F)c(F)nc(F)c1Cl
Reactant: CC(C)(C)N
Solvent: CC#N
Product: CC(C)(C)Nc1nc(F)c(Cl)c(N2C(=O)c3ccccc3C2=O)c1F
Reaction time: 0.5 h

Procedure:
To 150 ml of acetonitrile was added 30.0 g of N-(3-chloro-2,5,6-trifluoropyridine-4-yl)phthalimide together with 42.2 g of t-butylamine, and the mixture was heated under reflux with stirring for 30 minutes. The solution was concentrated under reduced pressure, then 200 ml of chloroform was added, and washed with 100 ml of distilled water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain about the title compound as colorless solid residue.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.C.C(O)C>[OH-].[OH-].[Pd+2].O>[N:10]1([C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[N:9][CH:8]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: O=[N+]([O-])c1ccc(N2CCOCC2)cn1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1ccc(N2CCOCC2)cn1
Temperature: 25 °C

Procedure:
Into a round bottom flask, 4-(6-Nitro-pyridin-3-yl)-morpholine (1.67 g, 0.00798 mol), 20% Pd(OH)2/C, 50% wet (10:40:50, Palladium hydroxide:carbon black:Water, 0.350 g, 0.000249 mol), and Ethanol (50 mL, 0.9 mol) were added into a parr bottle. The mixture was evacuated under house vacuum and charged with hydrogen at 35 pSi. The reaction was shaken at room temperature at 35 pSi. The solid was filtered. The solvent was removed under vacuum to afford an off white solid. The solid was triturated with Et2O, Filtered and washed with Et2O to give 5-Morpholin-4-yl-pyridin-2-ylamine as an off white solid (1.01, 70%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C@@H:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14](Cl)=[O:15])[CH2:9]1.[NH2:23][C@@H:24]([CH2:36][CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1)[CH2:25][NH:26][C:27](=[O:35])[O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C@@H:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]([NH:23][C@@H:24]([CH2:36][CH:37]2[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42]2)[CH2:25][NH:26][C:27](=[O:35])[O:28][CH2:29][CH2:30][Si:31]([CH3:33])([CH3:34])[CH3:32])=[O:15])[CH2:9]1
Reactant: C[Si](C)(C)CCOC(=O)NC[C@@H](N)CC1CCCCC1
Reactant: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)Cl)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCCCO[C@@H](c1ccccc1)[C@@H]1CCCN(C(=O)N[C@H](CNC(=O)OCC[Si](C)(C)C)CC2CCCCC2)C1
Reaction time: 8 h
Yield: 78.6 %

Procedure:
Crude (R)-3-((R)-(3-methoxypropoxy)(phenyl)methyl)piperidine-1-carbonyl chloride (60 mg, 0.184 mmol), 2-(trimethylsilyl)ethyl (S)-2-amino-3-cyclohexylpropylcarbamate (69 mg, 0.23 mmol, 1.25 equiv) and triethylamine (64 μL, 0.46 mmol, 2.5 equiv) were combined in CH2Cl2 (1 mL) at rt and left on the shaker overnight. After concentration, the product was isolated by prep HPLC to afford 2-(trimethylsilyl)ethyl (S)-2-((R)-3-((R)-(3-methoxypropoxy)-(phenyl)methyl)piperidine-1-carboxamido)-3-cyclohexyl-propylcarbamate (85.3 mg, 79%). LC-MS (3 min) tR=2.44 min, m/z 590 (M+1).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([CH:13]=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=3)[C:11]=2[N:12]=1.[CH3:19][C:20]1[O:24][N:23]=[C:22]([C@:25]([OH:29])([C:27]#[CH:28])[CH3:26])[CH:21]=1>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>[OH:29][C@:25]([C:22]1[CH:21]=[C:20]([CH3:19])[O:24][N:23]=1)([CH3:26])[C:27]#[C:28][C:2]1[CH:3]=[CH:4][C:5]2[O:6][CH2:7][CH2:8][C:9]3[N:10]([CH:13]=[C:14]([C:16]([NH2:18])=[O:17])[N:15]=3)[C:11]=2[N:12]=1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Reactant: NC(=O)c1cn2c(n1)CCOc1ccc(Cl)nc1-2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(n2)-n2cc(C(N)=O)nc2CCO3)no1
Yield: 21 %

Procedure:
Similar to as described in General Procedure G with the exception of replacing PdCl2(PPh3)2 with Pd (PPh3)4, 2-chloro-6,7-dihydroimidazo[1,2-d]pyrido[3,2-b][1,4]oxazepine-9-carboxamide was reacted with (R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol (US2012/214762A1) to give the titled compound as a white solid (36 mg, 21%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.O.[NH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)(Cl)Cl.O>[CH3:16][S:17]([N:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)N1CCC(=O)CC1
Temperature: 0 °C
Reaction time: 72 h
Yield: 87.1 %

Procedure:
Potassium carbonate (324 g, 2340 mmol) was added to a solution of 4-piperidone monohydrate hydrochloride (90 g, 586 mmol) in chloroform (300 mL) and water (300 mL). The slurry was cooled to 0° C. and treated with methylsulfonyl chloride (136 mL, 1760 mmol) by dropwise addition over a 1 h period (gas evolution was observed). The reaction mixture was allowed to shake for 72 h and was partitioned between CH2Cl2 (500 mL) and saturated aqueous NaHCO3 (500 mL). The aqueous layer was extracted with CH2Cl2 (3 ×200 mL). The organic layer was washed with 1% KHSO4 (250 mL), dried (Na2SO4), and concentrated to afford 90.5 g (87%) of a white solid. MS (electrospray): exact mass calculated for C6H11NO3S, 177.1; m/z found, 178.1 [M+H]+. HPLC (reverse phase conditions): tR=2.19 min. 1H NMR (400 MHz, CDCl3): 3.60 (t, J=6.5 Hz, 4H), 2.89 (s, 3H), 2.59 (t, J=6.3 Hz, 4H).
Reaction SMILES: [S:1](Cl)(Cl)=O.[Br:5][C:6]1[CH:7]=[C:8]([NH2:17])[C:9]([NH2:16])=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13].C(N(CC)CC)C>ClCCl>[Br:5][C:6]1[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]2=[N:16][S:1][N:17]=[C:8]2[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: Nc1cc(Br)c(C(F)(F)F)cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cc2nsnc2cc1Br
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.6 %

Procedure:
Thionyl chloride (373 mg, 3.1 mmol) in dichloromethane (0.8 mL) was added dropwise to a refluxing solution of diamine 18 (500 mg, 2.0 mmol) and triethylamine (794 mg, 7.8 mmol) in dichloromethane (8.0 mL). The mixture was refluxed with stirring for 4 h. The mixture was then cooled to room temperature, quenched with water (20 mL), and extracted with dichloromethane (3×75 mL). The combined extracts were dried with sodium sulfate and concentrated under reduced pressure. Flash chromatography (ISCO system, silica, 0-25% ethyl acetate in hexane) provided 19 (377 mg, 68%) as a solid: LRESIMS m/z 294.1.