Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH2:10].[NH:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[C@H:12]([C:14](O)=[O:15])[CH3:13].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:14](=[O:15])[C@@H:12]([NH:11][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH3:13]
Reactant: Nc1cc(F)c(F)cc1N
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1cc(F)c(F)cc1N
Reaction time: 3 h

Procedure:
To the mixture of 1,2-diamino-4,5-difluorobenzene (2.00 g, 13.9 mmol) and Boc-L-Ala-OH (2.63 g, 13.9 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.85 g, 30.5 mmol) in DCM (139 mL) was added triethylamine (6.00 mL, 43.0 mmol) at rt and stirred for 3 h. The mixture was then concentrated in vacuo and absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep™ pre-packed silica gel column (80 g), eluting with a gradient of 0% to 100% EtOAc in hexane, to provide (S)-tert-butyl 1-(2-amino-4,5-difluorophenylamino)-1-oxopropan-2-ylcarbamate as orange solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 9.16 (1H, s), 7.21 (1H, dd, J=11.9, 8.8 Hz), 7.11 (1H, d, J=6.7 Hz), 6.65 (1H, dd, J=12.9, 8.0 Hz), 5.04 (2H, br. s.), 4.04-4.14 (1H, m), 1.39 (9H, s), 1.25 (3H, d, J=7.0 Hz); LC-MS (ESI) m/z 338.0 [M+Na]+ and m/z 314.0 [M−H]−.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([B:19]3[O:23][C:22]([CH3:25])([CH3:24])[C:21]([CH3:27])([CH3:26])[O:20]3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>O1CCOCC1>[ClH:28].[CH3:26][C:21]1([CH3:27])[C:22]([CH3:24])([CH3:25])[O:23][B:19]([C:17]2[CH:16]=[N:15][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:18]=2)[O:20]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(C)OB(c2cnn(C3CCNCC3)c2)OC1(C)C
Temperature: 35 °C
Reaction time: 3 h

Procedure:
To a solution of 4-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (3.02 g, 8.00 mmol) in 1,4-dioxane (30 mL, 400 mmol), 4.0 M of HCl in 1,4-Dioxane (30 mL) was added and the reaction was stirred at 35° C. for 3 h. The reaction mixture was concentrated in vacuo to a white solid. The material was slightly hygroscopic. All free-flowing material was transferred to a vial and dried under vacuum for several hours. The material thus obtained was used in further reactions without purification. 1H NMR (400 MHz, CDCl3): δ=1.33 (s, 12H), 2.49 (br s, 4H), 3.18 (br s, 2H), 3.59-3.70 (m, 2H), 4.71 (br s, 1H), 7.87 (s, 2H), 9.84 (br s, 2H). MS (ES+): m/z 278.11 (100) [MH+]. HPLC: tR=1.99 min (ZQ3, polar—5 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[C:19]([F:21])[CH:20]=1)[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[C:9]([C:15]([OH:17])=O)[NH:10]2.Cl.Cl.Cl.[N:25]1([CH2:32][CH2:33][N:34]2[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[N:25]1([CH2:32][CH2:33][N:34]2[CH2:35][CH2:36][CH:37]([NH:40][C:15]([C:9]3[NH:10][C:11]4[C:7]([CH:8]=3)=[C:6]([O:5][C:4]3[CH:18]=[C:19]([F:21])[CH:20]=[C:2]([F:1])[CH:3]=3)[CH:14]=[CH:13][CH:12]=4)=[O:17])[CH2:38][CH2:39]2)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Reactant: O=C(O)c1cc2c(Oc3cc(F)cc(F)c3)cccc2[nH]1
Agent: Cl
Product: O=C(NC1CCN(CCN2CCCCCC2)CC1)c1cc2c(Oc3cc(F)cc(F)c3)cccc2[nH]1

Procedure:
This compound is synthesized analogously to Example 1 from 4-(3,5-difluoro-phenoxy)-1H-indole-2-carboxylic acid 153 (preparation see below) and amine 5.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2Cl)(=[O:3])[CH3:2].[Br:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[C:21]([F:26])[CH:20]=1>C(O)(C)C>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[CH:10][N:9]=[C:8]2[NH:23][C:22]1[CH:24]=[CH:25][C:19]([Br:18])=[CH:20][C:21]=1[F:26])(=[O:3])[CH3:2]
Reactant: Nc1ccc(Br)cc1F
Reactant: COc1cc2ncnc(Cl)c2cc1OC(C)=O
Solvent: CC(C)O
Product: COc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OC(C)=O
Temperature: 83 °C
Reaction time: 8 h
Yield: 84.3 %

Procedure:
A suspension of 4-chloro-7-methoxyquinazolin-6-yl acetate (2.05 g), 4-bromo-2-fluoroaniline (2.11 g, 1.30 eq) and isopropanol (40 mL) was stirred at 83° C. overnight. The reaction mixture was cooled to room temperature and filtered, the residue was washed with 100 mL of isopropanol and dried to afford the desired compound as a solid (2.78 g, 84.50%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([CH3:18])=O)=[CH:11][CH:10]=2)[O:4][C:3]=1[C:19]([NH2:21])=[O:20].[OH:22][CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[CH2:24][NH2:25]>>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH:16]([NH:25][CH2:24][CH:23]([OH:22])[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[CH3:18])=[CH:11][CH:10]=2)[O:4][C:3]=1[C:19]([NH2:21])=[O:20]
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CC(=O)Cc1ccc(OCc2cc(C)c(C(N)=O)o2)cc1
Product: Cc1cc(COc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2)oc1C(N)=O

Procedure:
Methyl 5-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl]phenoxymethyl]furan-2-carboxamide was prepared from methyl 5-[4-acetonylphenoxymethyl]furan-2-carboxamide (1.87 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (1.12 g) in an analogous manner to the compound described in Example 50.
Reaction SMILES: [CH:1](=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].Br[CH2:11][C:12]([CH3:16])([CH3:15])[CH2:13][OH:14].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:11][C:12]([CH3:16])([CH2:13][OH:14])[CH2:15][O:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[O:9]
Reactant: O=Cc1ccccc1O
Reactant: CC(C)(CO)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(CO)COc1ccccc1C=O

Procedure:
A solution of 20 g of salicylaldehyde, 30 g of 3-bromo-2,2-dimethylpropanol and 22 g of potassium carbonate in DMF was refluxed for 24 hours. After evaporation, the residue was dissolved in ethyl acetate and the solution was washed with water. The organic phase was dried over magnesium sulfate and evaporated. The residue was purified by chromatography (silica; dichloromethane).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([C:7](O)=[O:8])[CH2:3][C:4](O)=[O:5].[NH2:11]C(N)=O>O>[CH3:1][C:2]1([CH3:10])[CH2:3][C:4](=[O:5])[NH:11][C:7]1=[O:8]
Reactant: CC(C)(CC(=O)O)C(=O)O
Reactant: NC(N)=O
Solvent: O
Product: CC1(C)CC(=O)NC1=O
Temperature: 160 °C
Reaction time: 10 h
Yield: 89.7 %

Procedure:
The mixture of 10 g of 3,3-dimethylsuccinic acid and 102.7 g of urea was stirred for 10 hours at 160° C. Into the reaction mixture was added water at 100° C., and the mixture was cooled to near room temperature. The mixture was extracted with ethyl acetate three times. The organic layers were washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 7.8 g of 3,3-dimethylpyrrolidin-2,5-dione.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH3:25])=[CH:16][N:15]=2)[CH2:10][C@H:9]1[C:26](O)=[O:27])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:63][C@:64]1([C:69]([NH:71][S:72]([CH:75]2[CH2:77][CH2:76]2)(=[O:74])=[O:73])=[O:70])[CH2:66][C@H:65]1[CH:67]=[CH2:68]>ClCCl>[CH:75]1([S:72]([NH:71][C:69]([C@@:64]2([NH:63][C:26]([C@@H:9]3[CH2:10][C@@H:11]([O:13][C:14]4[C:23]5[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=5)[C:17]([O:24][CH3:25])=[CH:16][N:15]=4)[CH2:12][N:8]3[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:27])[CH2:66][C@H:65]2[CH:67]=[CH2:68])=[O:70])(=[O:74])=[O:73])[CH2:77][CH2:76]1
Reactant: COc1cnc(O[C@@H]2C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C2)c2ccccc12
Reactant: C=C[C@@H]1C[C@]1(N)C(=O)NS(=O)(=O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](Oc2ncc(OC)c3ccccc23)CN1C(=O)OC(C)(C)C)C(=O)NS(=O)(=O)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.4 %

Procedure:
To a solution of (2S,4R)-1-(tert-butoxycarbonyl)-4-((4-methoxyisoquinolin-1-yl)oxy)pyrrolidine-2-carboxylic acid (1.1 g, 2.8 mmole) in dichloromethane (15 mL) was added HATU (1.07 g, 2.8 mmole) followed by DIPEA (2.4 mL, 14.1 mmole) at room temperature. The reaction mass was stirred at the same temperature for 10 min. (1R,2S)-1-amino-N-(cyclopropylsulfonyl)-2-vinylcyclopropanecarboxamide hydrochloride (prepared according to the procedure described in WO 03/099274) was added to the reaction mass and stirred at room temperature for 30 min. The reaction mass was diluted with dichloromethane and washed with water. The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get the crude compound. The crude compound was purified by silica gel chromatography (70% ethyl acetate in pet ether) to get 1.3 g (76.4%) of (2S,4R)-tert-butyl 2-(((1R,2S)-1-((cyclopropylsulfonyl)carbamoyl)-2-vinylcyclopropyl)carbamoyl)-4-((4-methoxyisoquinolin-1-yl)oxy)pyrrolidine-1-carboxylate as a white solid. MS: MS m/z 601.2 (M++1).
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[C:8]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:7][C:6]([Cl:18])=[N:5][C:4]=2[CH:3]=1.[CH:19]([C:21]1[O:25][C:24](B(O)O)=[CH:23][CH:22]=1)=[O:20].C(=O)([O-])[O-].[Na+].[Na+].CCO>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.O>[Cl:18][C:6]1[N:7]=[C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[N:10]=[CH:11][C:2]([C:24]3[O:25][C:21]([CH:19]=[O:20])=[CH:22][CH:23]=3)=[CH:3][C:4]=2[N:5]=1
Reactant: O=Cc1ccc(B(O)O)o1
Reactant: Clc1nc(N2CCOCC2)c2ncc(Br)cc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=Cc1ccc(-c2cnc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Temperature: 90 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
To a 50 mL round bottom flask, 4-(7-bromo-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine (1.0 g, 0.00303 mol; prepared as described in Scheme 7A) and 5-formyl-2-furanylboronic acid (0.38 g, 0.00273 mol), sodium carbonate (0.64 g, 0.00606 mol) toluene (5 mL), EtOH (5 mL) and water (5 mL) were added. The reaction vessel was degassed with nitrogen for 5-10 min. To the same reaction mixture, Pd(PPh3)2Cl2 (0.106 g, 0.0001515 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was cooled and diluted with chloroform. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under the reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, chloroform) to yield the desired product as a yellow solid [0.48 g, 46%]. 1H NMR (300 MHz, CDCl3): δ 9.77 (s, 1H), 9.12 (d, J=2.1 Hz, 1H), 8.34 (d, J=2.1 Hz, 1H), 7.40 (d, J=3.6 Hz, 1H), 7.11 (d, J=3.6 Hz, 1H), 4.50 (brs, 4H), 3.91-3.88 (m, 4H); LC-MS (ESI): Calculated mass: 344.1; Observed mass: 345.0 (RT: 1.39 min).
Reaction SMILES: [F:1][C:2]1[C:3]([NH2:20])=[C:4]2[C:9]3=[C:10]([CH2:13][CH:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1F.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>CN1CCCC1=O>[F:1][C:2]1[C:3]([NH2:20])=[C:4]2[C:9]3=[C:10]([CH2:13][CH:14]([CH3:15])[N:8]3[CH:7]=[C:6]([C:16]([OH:18])=[O:17])[C:5]2=[O:19])[C:11]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1
Reactant: C1CNCCN1
Reactant: CC1Cc2c(F)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Solvent: CN1CCCC1=O
Product: CC1Cc2c(N3CCNCC3)c(F)c(N)c3c(=O)c(C(=O)O)cn1c23
Yield: 56.6 %

Procedure:
In the same manner as described in Example 3, 8,9-difluoro-7-amino-2-methyl-6-oxo-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (3 g), anhydrous piperazine (4.6 g) and N-methylpyrrolidone (30 ml) are treated to give 8-fluoro-2-methyl-9-(1-piperazinyl)-7-amino-6-oxo-1,2-dihydro-pyrrolo[3,2,1-ij]quinoline-5-carboxylic acid (2.1 g), as pale yellow cubic crystals. m.p. 256°-259° C. (decomp.)
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([NH:27][C:28](=[O:41])[CH2:29][N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[C:21]=1[Cl:42])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43]N(C)C=O.[H-].[Na+].CI>O>[Si:1]([O:18][CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[C:22]([N:27]([CH3:43])[C:28](=[O:41])[CH2:29][N:30]2[C:34](=[O:35])[C:33]3=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]3[C:31]2=[O:40])[C:21]=1[Cl:42])([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)[Si](OCc1c(Cl)ccc(NC(=O)CN2C(=O)c3ccccc3C2=O)c1Cl)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: CN(C(=O)CN1C(=O)c2ccccc2C1=O)c1ccc(Cl)c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c1Cl
Reaction time: 0.83 h

Procedure:
To a mixture of 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichloro-3-(phthalimidoacetylamino)benzene (453 mg) and N,N-dimethylformamide (2.2 ml) was added sodium hydride (60% in oil, 31 mg) under ice-cooling, and the mixture was stirred for 50 minutes. To the mixture was added methyl iodide (0.055 ml), and the mixture was stirred for 2.5 hours at ambient temperature. Water (88 ml) was added to the mixture under ice-cooling, and the resulting precipitates were collected by vacuum filtration and washed with water and ethyl acetate to give 1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichloro-3-[N-methyl-N-(phthalimidoacetyl)amino]benzene (236 mg) as powder.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([N+:24]([O-:26])=[O:25])=[C:6]([CH:23]=1)[C:7]([NH:9][C:10]1[CH:14]=[CH:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[C:17]([CH3:22])[CH:16]=2)[N:11]=1)=[O:8].C(=O)([O-])[O-].[K+].[K+].[NH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>CN(C)C=O>[CH3:22][C:17]1[CH:16]=[C:15]([N:12]2[CH:13]=[CH:14][C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:23]=[C:2]([N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)[CH:3]=[CH:4][C:5]=3[N+:24]([O-:26])=[O:25])=[N:11]2)[CH:20]=[CH:19][C:18]=1[CH3:21]
Reactant: C1CCNCC1
Reactant: Cc1ccc(-n2ccc(NC(=O)c3cc(Cl)ccc3[N+](=O)[O-])n2)cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(-n2ccc(NC(=O)c3cc(N4CCCCC4)ccc3[N+](=O)[O-])n2)cc1C
Temperature: 110 °C
Reaction time: 4 h
Yield: 88.3 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of 5-chloro-N-(1-(3,4-dimethylphenyl)-1H-pyrazol-3-yl)-2-nitrobenzamide 4g (300 mg, 0.81 mmol, 1.00 equiv) in N,N-dimethylformamide (10 mL), potassium carbonate (330 mg, 2.39 mmol, 3.00 equiv), and piperidine (200 mg, 2.35 mmol, 3.00 equiv). The resulting solution was stirred for 4 h at 110° C. The resulting mixture was concentrated under vacuum. The residue was dissolved in 50 mL of ethyl acetate. The resulting mixture was washed with 2×30 mL of brine, dried over sodium sulfate, and concentrated under vacuum. This resulted in 300 mg (88%) of product as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2B2OC(C)(C)C(C)(C)O2)[O:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:36]1[CH:41]=[N:40][CH:39]=[C:38]([CH3:42])[N:37]=1>>[CH2:28]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][C:16]=2[C:36]2[CH:41]=[N:40][CH:39]=[C:38]([CH3:42])[N:37]=2)[O:11][CH2:10]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CC1(C)OB(c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)OC1(C)C
Reactant: Cc1cncc(Cl)n1
Product: Cc1cncc(-c2cccc3c2C[C@H](N(Cc2ccccc2)Cc2ccccc2)CO3)n1
Yield: 83 %

Procedure:
The title compound was synthesized as described for Intermediate example I-28 in 83% yield starting from (S)-N,N-dibenzyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)chroman-3-amine and 2-chloro-6-methylpyrazine (1.1 equiv); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.59 (s, 1 H), 8.54-8.56 (m, 1 H), 7.24-7.34 (m, 8 H), 7.16-7.22 (m, 3 H), 6.99 (dd, 1 H), 6.86 (dd, 1 H), 4.31-4.37 (m, 1 H), 4.07 (t, 1 H), 3.64-3.73 (m, 4 H), 3.12-3.21 (m, 1 H), 2.92-3.02 (m, 1 H), 2.64-2.73 (m, 1 H), 2.55 (s, 3 H); MS (APPI/APCI) m/z 422[M+H+].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@:13]([CH2:22][CH2:23][CH2:24][N:25]([CH3:29])[C:26](=[O:28])[CH3:27])([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:12][C:11]2=[O:30])[CH3:9])=[CH:4][CH:3]=1.[CH3:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1>>[CH3:29][N:25]([CH2:24][CH2:23][CH2:22][C@@:13]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[O:12][C:11](=[O:30])[N:10]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([C:36]3[CH:35]=[CH:34][N:33]=[C:32]([CH3:31])[CH:37]=3)=[CH:3][CH:4]=2)[CH3:9])[CH2:15][CH2:14]1)[C:26](=[O:28])[CH3:27]
Reactant: Cc1cc(B(O)O)ccn1
Reactant: CC(=O)N(C)CCC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Product: CC(=O)N(C)CCC[C@]1(c2ccccc2)CCN([C@@H](C)c2ccc(-c3ccnc(C)c3)cc2)C(=O)O1

Procedure:
The title compound was prepared from N-(3-((R)-3-((S)-1-(4-bromophenyl)ethyl)-2-oxo-6-phenyl-1,3-oxazinan-6-yl)propyl)-N-methylacetamide and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.98, m/z=486.2; 1H NMR (CDCl3) 1.21-1.38 (m, 1H), 1.52 (d, 3H), 1.61-1.90 (m, 3H), 2.05 (d, 3H), 2.17 (m, 1H), 2.42 (m, 2H), 2.78 (s, 1H), 2.83 (s, 3H), 2.85 (s, 2H), 2.92 (m, 1H), 3.11-3.33 (m, 2H), 5.65 (m, 1H), 7.05 (d, 2H), 7.21 (m, 2H), 7.30 (m, 3H), 7.38 (d, 2H), 7.60 (s, 1H), 7.71 (d, 1H), 8.72 (d, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][C:13]([C@@H:16]([NH:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:18]=[CH2:19])=[N:14][N:15]=2)=[C:7]([N+:28]([O-:30])=[O:29])[CH:6]=1.C([O:36]C(N[C@@H](CC=C)C(O)=O)=O)(C)(C)C.CCOC(C)=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:31])[NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:15][NH:14][C:13](=[O:12])[C@@H:16]([NH:20][C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])[CH2:17][CH:18]=[CH2:19])=[O:36])=[C:7]([N+:28]([O-:30])=[O:29])[CH:6]=1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)c1nnc(-c2ccc(NC(=O)OC)cc2[N+](=O)[O-])o1
Reactant: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CC[C@H](NC(=O)OC(C)(C)C)C(=O)NNC(=O)c1ccc(NC(=O)OC)cc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 5 h
Yield: 86 %

Procedure:
{4-[5-((S)-1-tert-Butoxycarbonylamino-but-3-enyl)-1,3,4-oxadiazol-2-yl]-3-nitro-phenyl}-carbamic acid methyl ester: 168B (0.3 g, 0.393 mmol) and (S)-2-(tert-butoxycarbonylamino)pent-4-enoic acid (0.085 g, 0.393 mmol) were dissolved in DMF (2 mL) in a 15 mL rbf and TEA (0.274 mL, 1.967 mmol) was added. Mixture was stirred under nitrogen at room temperature while propane phosphonic acid anhydride (T3P), 50% in EtOAc (0.293 mL, 0.983 mmol) was added dropwise. The flask was fitted with a reflux condenser, and the resulting mixture was stirred in an 80° C. oil bath for 5 h. Reaction mixture was poured into ice water and extracted 3× with EtOAc. Combined extracts were washed with sat'd aq. NaHCO3, water and brine, dried over anh. Na2SO4, filtered and evaporated to provide {4-[N′-((S)-2-tert-butoxycarbonylamino-pent-4-enoyl)-hydrazinocarbonyl]-3-nitro-phenyl}-carbamic acid methyl ester, (0.46 g, 86%) as a light yellow solid which was used without further purification. The solid (0.46 g, 1.019 mmol) was dissolved in anhydrous THF (20 mL) under argon and the solution transferred to a 75 mL pressure flask. Burgess reagent (1.33 g, 5.58 mmol) was added, the flask was sealed with a pressure relief cap and then heated in a 75° C. oil bath for 2 h behind a blast shield then left standing overnight at room temperature. Reaction mixture was evaporated on rotary evaporator. Residue was purified by normal phase chromatography to give 168C as a light yellow foam (0.315 g, 71.3%). MS (ESI) m/z: 434.3 (M+H)+ 378.3 (M+H−tBu)+.
Reaction SMILES: Cl.[CH3:2][CH:3]([CH3:7])[C:4](=[NH:6])[NH2:5].[Cl:8][C:9](Cl)(Cl)[S:10]Cl.[OH-].[Na+]>C(Cl)Cl>[Cl:8][C:9]1[S:10][N:5]=[C:4]([CH:3]([CH3:7])[CH3:2])[N:6]=1
Reactant: ClSC(Cl)(Cl)Cl
Reactant: CC(C)C(=N)N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: CC(C)c1nsc(Cl)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
To a mixture of 2-methyl propanimidamide hydrochloride (5.0 g, 40.8 mmol), trichloromethanesulfenyl chloride (7.14 g, 38.4 mmol) in methylene chloride (200 mL) at 0° C. was added dropwise an aqueous solution of sodium hydroxide (50%, 9.9 mL) over 20 minutes. The reaction mixture was stirred for 2 h at 0° C. and then was allowed to warm to room temperature, and stirred for an additional 3 h. Ice was added to the reaction mixture, the mixture was separated, and the aqueous layer was extracted with methylene chloride (3×25 mL). The combined organic extracts were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by medium pressure liquid chromatography (0 to 100% gradient of ethyl acetate in hexanes as eluant) to provide the title compound as a oil (3.8 g).
Reaction SMILES: [N+]([O-])(O)=O.[N+]([O-])(O)=O.[F:9][C:10]1[CH:11]=[C:12]([NH:22][C:23]([NH2:25])=[NH:24])[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1.CN(C)[CH:28]=[CH:29][C:30](=O)[C:31]([CH3:42])([C:33]1[CH:38]=[C:37]([F:39])[C:36]([F:40])=[C:35]([F:41])[CH:34]=1)[CH3:32]>>[F:9][C:10]1[CH:11]=[C:12]([NH:22][C:23]2[N:25]=[C:30]([C:31]([CH3:42])([C:33]3[CH:34]=[C:35]([F:41])[C:36]([F:40])=[C:37]([F:39])[CH:38]=3)[CH3:32])[CH:29]=[CH:28][N:24]=2)[CH:13]=[CH:14][C:15]=1[N:16]1[CH:20]=[C:19]([CH3:21])[N:18]=[CH:17]1
Reactant: Cc1cn(-c2ccc(NC(=N)N)cc2F)cn1
Reactant: CN(C)C=CC(=O)C(C)(C)c1cc(F)c(F)c(F)c1
Solvent: O=[N+]([O-])O
Product: Cc1cn(-c2ccc(Nc3nccc(C(C)(C)c4cc(F)c(F)c(F)c4)n3)cc2F)cn1
Yield: 56 %

Procedure:
The title compound was prepared in analogous manner as described in example 5b) from N-[3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (81 mg, 0.30 mmol) and 1-dimethylamino-4-methyl-4-(3,4,5-trifluoro-phenyl)-pent-1-en-3-one (98 mg, 0.36 mmol) as a light yellow solid (74 mg) in 56% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1.S(=O)(=O)(O)O.[CH3:22]O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([O:16][CH3:22])=[O:15])[C:5]2[O:10][CH:9]([CH3:11])[C:8](=[O:12])[NH:7][C:6]=2[CH:13]=1
Reactant: CO
Reactant: CC1Oc2c(cc(Cl)cc2C(=O)O)NC1=O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(Cl)cc2c1OC(C)C(=O)N2
Reaction time: 40 h

Procedure:
A mixture of 10 g of 6-chloro-3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylic acid, 150 ml of methanol and 5 ml of concentrated sulfuric acid is refluxed under heating with stirring for 40 hours, and then cooled. The precipitated crystals are collected by filtration, washed with methanol and dried to give 9.5 g of methyl 6-chloro-3,4-dihydro-2-methyl-3-oxo-2H-1,4-benzoxazine-8-carboxylate, melting at 186°-189° C.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14]Br)=[C:10]([F:16])[CH:9]=1>CN(C=O)C.CCOC(C)=O>[CH3:5][O:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([CH2:14][N:1]=[N+:2]=[N-:3])=[C:10]([F:16])[CH:9]=1
Reactant: COC(=O)c1ccc(CBr)c(F)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(CN=[N+]=[N-])c(F)c1
Reaction time: 18 h
Yield: 100 %

Procedure:
Sodium azide (609 mg) was added to a solution of 4-bromomethyl-3-fluorobenzoic acid methyl ester from Example E3.2 (2.1 g, 8.5 mmol) in DMF (30 ml). The mixture was stirred for 18 h, diluted with EtOAc, washed with water and brine and concentrated in vacuo to give a colourless oil identified as the title compound (1.8 g, 100%).