Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]#[C:11][C:12]2[S:13][C:14]3[CH:20]=[C:19]([O:21]C)[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:6][C:3]=1[NH:4][CH3:5].B(Br)(Br)Br.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:9]=[C:8]([C:10]#[C:11][C:12]2[S:13][C:14]3[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:15]=3[N:16]=2)[CH:7]=[CH:6][C:3]=1[NH:4][CH3:5]
Reactant: CNc1ccc(C#Cc2nc3ccc(OC)cc3s2)cc1F
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CNc1ccc(C#Cc2nc3ccc(O)cc3s2)cc1F
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a 25 mL round bottomed flask equipped with a magnetic stir bar containing DCM (5.2 mL) was placed 8 (0.08 g, 0.26 mmol). The reaction mixture was cooled to 0° C. and BBr3 (0.75 mL of 1M in DCM) was added drop wise. The reaction was stirred at RT for 8 hr. The reaction was then neutralized with sat. NaHCO3 and extracted into DCM (2×10 mL). The combined organic extracts were washed with water (10 mL), brine (10 mL), dried over MgSO4 and concentrated in vacuo. The residue was purified over silica gel using EtOAc:Hexanes (1:3) as the eluent to afford W366 (0.02 g, 26%) as a brown solid. 1H NMR (400 MHz, DMSO-d6), δ: 2.5 (d, J=10.4 Hz, 3H), 6.06-6.08 (m, 1H), 6.42 (t, J=8.8 Hz, 1H), 6.74 (dd, J=8.8, 2.4 Hz, 1H), 7.05-7.14 (m, 2H), 7.54 (d, J=8.8, 1H), 9.76 (br s, 1H); MS (ESI): 299.0 (M+H+).
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[CH:5][C:4]2[NH:8][C:9]([O:11][C:3]=2[CH:2]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]#[CH:20]>CC(C)=O>[CH2:20]([N:8]1[C:4]2[CH:5]=[C:6]([Cl:7])[CH:1]=[CH:2][C:3]=2[O:11][C:9]1=[O:10])[C:19]#[CH:18]
Reactant: O=c1[nH]c2cc(Cl)ccc2o1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C#CCn1c(=O)oc2ccc(Cl)cc21
Temperature: 25 °C

Procedure:
In a 500-mL round bottom flask equipped with a magnetic stirrer, reflux condenser and a heating mantle were placed chlorzoxazone, or 5-chlorobenzoxazol-2-one, (10 g, 0.059 mole), potassium carbonate (9.8 g, 0.071 mole), propargyl bromide (10.5 g of 80% in toluene, 0.071 mole) and acetone (200 mL). The mixture was refluxed for 20 hours. The mixture was cooled down to room temperature and the solid was filtered off by suction-filtration. The filtrate was concentrated on a rotary evaporator to a solid residue. A pure, off-white product was obtained by crystallization from ethyl acetate hexane yielding 10.5 g (86%). m.p.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[OH:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][CH:33]=[C:32]2[CH3:38]>CC(N(C)C)=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:28][C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[NH:34][CH:33]=[C:32]4[CH3:38])=[N:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c[nH]c2ccc(O)cc12
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OCc1ccccc1
Temperature: 75 °C
Reaction time: 2 h
Yield: 72.5 %

Procedure:
A mixture of 7-benzyloxy-4-chloro-6-methoxyquinazoline (7.859 g, 26.1 mmol), (prepared as described for the starting material in Example 1), potassium carbonate (18.03 g, 130 mmol) and 5-hydroxy-3-methylindole (5.00 g, 34.0 mmol), (Journal of Organic Chemistry 1993, 58, 3757), in DMA (600 ml) was stirred at 75° C. for 2 hours and allowed to cool to ambient temperature. The reaction mixture was filtered and the filtrate evaporated in vacuo. The crude solid was purified by silica column chromatography, eluting with 2.5% methanol/97.5% dichloromethane to give 7-benzyloxy-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (7.791 g, 73%).
Reaction SMILES: O/[N:2]=[C:3]1/[C:4](=O)[C:5]2[C:10]([CH2:11]/1)=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2.P(Cl)(Cl)(Cl)(Cl)[Cl:16].[ClH:21]>O=P(Cl)(Cl)Cl>[Cl:21][C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([O:12][CH3:13])[CH:6]=2)[CH:11]=[C:3]([Cl:16])[N:2]=1
Reactant: COc1ccc2c(c1)C(=O)/C(=N/O)C2
Reactant: Cl
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: COc1ccc2cc(Cl)nc(Cl)c2c1
Temperature: 30 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a suspension of (E)-2-(hydroxyimino)-6-methoxy-2,3-dihydro-1H-inden-1-one (3.60 g, 20.0 mmol) in POCl3 (120 mL), PCl5 (6.50 g, 31.3 mmol) was added at 0° C., then HCl gas was induced until the solution was saturated. The reaction mixture was stirred at 30° C. for 2 hours. The solvent was removed in vacuo and ice water was added to the residue. The precipitate was collected by filtration, washed with water (30 mL), and dried under high vacuum to give the product (4.50 g, yield 85%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[CH:41]1([NH:44][C@H:45]2[CH2:50][CH2:49][C@H:48]([CH2:51][C:52]([O:54][CH3:55])=[O:53])[CH2:47][CH2:46]2)[CH2:43][CH2:42]1>C(Cl)Cl>[CH:41]1([N:44]([C@H:45]2[CH2:50][CH2:49][C@H:48]([CH2:51][C:52]([O:54][CH3:55])=[O:53])[CH2:47][CH2:46]2)[C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=2[F:1])[CH2:42][CH2:43]1
Reactant: COC(=O)C[C@H]1CC[C@H](NC2CC2)CC1
Reactant: Cc1ccc(C(=O)O)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C[C@H]1CC[C@H](N(C(=O)c2ccc(C)cc2F)C2CC2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 2-fluoro-4-methylbenzoic acid (0.153 g, 0.994 mmol), 1-hydroxybenzotriazole (0.0639 g, 0.473 mmol), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.181 g, 0.947 mmol) in CH2Cl2 (5 mL) was added triethylamine (0.396 ml, 2.84 mmol) and methyl 2-(trans-4-(cyclopropylamino)cyclohexyl)acetate (0.200 g, 0.947 mmol). The mixture was stirred at room temperature overnight, diluted with CH2Cl2 (50 mL), and then washed with 10% Na2CO3 and brine. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified through silica gel chromatography eluting with 18%-25% EtOAc-hexane. The desired amide product was obtained as a colorless oil (0.224 g). MS: 348 (M+1), C20H26FNO3.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=O)[C:16]([N:18]([CH2:40][CH:41]([CH3:43])[CH3:42])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:26])[CH2:22][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:20]1)=[O:17]>C(O)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N:14]=[C:15]1[C:16]([N:18]([CH2:40][CH:41]([CH3:42])[CH3:43])[C@H:19]1[CH2:24][C@@H:23]([C:25]([N:27]2[CH2:28][CH2:29][O:30][CH2:31][CH2:32]2)=[O:26])[CH2:22][N:21]([C:33]([O:35][C:36]([CH3:39])([CH3:37])[CH3:38])=[O:34])[CH2:20]1)=[O:17]
Reactant: COCCCCNc1ccccc1NC(=O)C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Solvent: CC(=O)O
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N3CCOCC3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 80 °C
Reaction time: 15 h
Yield: 66.1 %

Procedure:
tert-Butyl (3S,5R)-3-{[({2-[(4-methoxybutyl)amino]phenyl}amino) (oxo) acetyl](2-methylpropyl)amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (9.11 g) was dissolved in acetic acid (50 ml), and the mixture was stirred at 80° C. for 15 hr. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, the residue was diluted with aqueous sodium bicarbonate, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to basic silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (5.85 g), and a fraction eluted with ethyl acetate-methanol (85:15) was concentrated under reduced pressure to give 1-(4-methoxybutyl)-N-(2-methylpropyl)-N-[(3S,5R)-5-(morpholin-4-ylcarbonyl)piperidin-3-yl]-1H-benzimidazole-2-carboxamide (580 mg).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][N:5]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:6]=1[C:7]([NH2:9])=[O:8].Cl.N1C=CC=C(CC(O)=O)C=1.[C:28]([O:32][C:33]([N:35]([C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1)[CH3:36])=[O:34])([CH3:31])([CH3:30])[CH3:29]>>[CH2:10]([N:5]1[C:6]([C:7]([NH2:9])=[O:8])=[C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:39]=[CH:38][C:37]([N:35]([C:33]([O:32][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:34])[CH3:36])=[CH:45][CH:44]=2)[N:3]=[CH:4]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NC(=O)c1c(N)ncn1Cc1ccccc1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)O)cc1
Agent: Cl
Agent: O=C(O)Cc1cccnc1
Product: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)Nc2ncn(Cc3ccccc3)c2C(N)=O)cc1
Yield: 69 %

Procedure:
An amidation reaction and post-treatment were carried out following the conditions of Example 17, using 2.16 g (9.99 mmol) of 4-amino-1-benzyl-5-imidazolecarboxamide prepared in the same manner as in Reference Example 2 and, instead of 3-pyridylacetic acid hydrochloride, 4-(N-t-butyloxycarbonyl-N-methylamino)benzoic acid which was prepared separately by a conventional method, to obtain 3.10 g of 1-benzyl-4-(4-(N-t-butyloxycarbonyl-N-methylamino) benzoylamino)-5-imidazolecarboxamide (yield 69%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1Cl.[F:14][C:15]([F:28])([F:27])C1C=CC=CC=1CCC(O)=O>>[ClH:2].[F:14][C:15]([F:28])([F:27])[C:6]1[CH:7]=[CH:8][CH:3]=[CH:4][C:5]=1[CH2:10][CH2:11][CH2:12][NH2:13]
Reactant: O=C(O)CCc1ccccc1C(F)(F)F
Reactant: NCCCc1ccc(Cl)c(Cl)c1
Agent: Cl
Product: NCCCc1ccccc1C(F)(F)F

Procedure:
Intermediate 4 was prepared according to the procedures described in Intermediate 1 using 3-(2-(trifluoromethyl)phenyl)propanoic acid as the starting material. LC-MS (ESI) m/z 204.0 (M+H)+, RT=1.40 min (Method B).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](=O)[CH2:7]Br)=[CH:4][CH:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.C(=O)([O-])O.[Na+]>C(O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]2[N:12]=[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]3[CH:7]=2)=[CH:4][CH:3]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: Nc1ccccn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Brc1ccc(-c2cn3ccccc3n2)cc1
Yield: 84.8 %

Procedure:
15 g (54 mmol) of 4-bromophenacyl bromide and 5.2 g (55 mmol) of 2-aminopyridine were dissolved in 100 mL of ethanol. Then, 7.0 g of sodium hydrogen carbonate was added, and the resultant was heated under reflux for 6 hours. After completion of the reaction, generated crystals were filtered out, washed with water and ethanol, whereby 12.5 g (yield 85%) of 2-(4-bromophenyl)-imidazo[1,2-a]pyridine was obtained.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].Cl[Si](C)(C)C.Br[C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:16](=[O:22])[NH:17]2>CN(C=O)C.C(N(CC)CC)C>[OH:6][CH2:1][CH2:2][CH2:3][C:4]#[C:5][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]2[C:14]=1/[C:15](=[CH:23]/[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30])/[C:16](=[O:22])[NH:17]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(Br)c21
Reactant: C#CCCCO
Agent: C[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CCCCO)c21
Temperature: 70 °C

Procedure:
Using Method I above, 4-pentyn-1-ol (40 mg, 0.57 mmol) (Aldrich) was dissolved, under argon, in 3 mL DMF and 2 mL triethylamine, and to this solution was added chlorotrimethylsilane (0.13 mL, 1 mmol) (Aldrich). The reaction was stirred at room temperature for 1 h, at which time (Z)-4-bromo-1,3-dihydro-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (110 mg, 0.38 mmol) (Starting Material 1 supra) was added and the solution was degassed for 15 min by bubbling argon through the solution. (Ph3P)2PdCl2 (15 mg) (Aldrich) and CuI (7 mg) (Aldrich) were added and the reaction was heated at 70° C. for 14 h. The reaction mixture was then poured into 25 mL 1N HCl and the yellow precipitate was filtered off. The product was purified via flash column chromatography to obtain (Z)-1,3-dihydro-4-(5-hydroxy-1-pentynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a yellow powder. (Yield 55 mg, 45%).
Reaction SMILES: Cl.N(OCCC(C)C)=O.[CH3:10][O:11][C:12]1[CH:34]=[CH:33][C:15]([CH2:16][O:17][C:18]([NH:20][C@H:21]([C:28]([N:30]=[N+]=[N-])=[O:29])[CH2:22][C:23]2[N:27]=[CH:26][NH:25][CH:24]=2)=[O:19])=[CH:14][CH:13]=1.[N-]=[N+]=[N-].Cl.N[C@@H:40]([CH2:49][CH:50]([CH3:52])[CH3:51])[CH:41]([OH:48])[C:42]([O:44][CH:45]([CH3:47])[CH3:46])=[O:43]>CN(C)C=O.C(N(CC)CC)C>[CH3:10][O:11][C:12]1[CH:34]=[CH:33][C:15]([CH2:16][O:17][C:18]([NH:20][C@H:21]([C:28]([NH:30][C@@H:40]([CH2:49][CH:50]([CH3:52])[CH3:51])[CH:41]([OH:48])[C:42]([O:44][CH:45]([CH3:46])[CH3:47])=[O:43])=[O:29])[CH2:22][C:23]2[N:27]=[CH:26][NH:25][CH:24]=2)=[O:19])=[CH:14][CH:13]=1
Reactant: CC(C)C[C@H](N)C(O)C(=O)OC(C)C
Reactant: COc1ccc(COC(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N=[N+]=[N-])cc1
Agent: CC(C)CCON=O
Agent: Cl
Agent: [N-]=[N+]=[N-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](CC(C)C)C(O)C(=O)OC(C)C)cc1
Reaction time: 16 h

Procedure:
To a suspension of the hydrazide compound in 5 ml of N,N-dimethylformamide were added successively 0.90 ml of a dry 5.1N-hydrogen chloride in N,N-dimethylformamide solution and 0.23 ml of isoamyl nitrite at -20° C. with stirring. After disappearance of hydrazide compound, the reaction mixture was cooled to -30° C., and then the reaction mixture was neutralized by adding 0.67 ml of triethylamine to prepare a solution of N-(4-methoxybenzyloxycarbonyl)-L-histidine azide. The cold azide solution was added dropwise to a solution of 350 mg of isopropyl (2RS,3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride and 0.46 ml of triethylamine in 8 ml of dry N,N-dimethylformamide under ice-cooling, and the mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added a 5% aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel flash column chromatography (eluent: chloroform/methanol=20:1 by volume) to obtain 325 mg of isopropyl (2RS,3S)-3-[N-(4-methoxybenzyloxycarbonyl)-L-histidyl]amino-2-hydroxy-5-methylhexanoate as a white powder. To a solution of 320 mg of the isopropyl ester compound in 46 ml of isopropyl alcohol were added 300 mg of p-toluenesulfonic acid (anhydride) and 48 mg of a 10% palladium charcoal. The mixture was hydrogenated under a hydrogen atmosphere at room temperature. After filtration of the reaction mixture, the filtrate was concentrated under reduced pressure to obtain 513 mg of isopropyl (2RS,3S)-3-(L-histidyl)amino-2-hydroxy-5-methylhexanoate.2p-toluene sulfonic acid salt as a white powder.
Reaction SMILES: [C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([S:15](Cl)(=[O:17])=[O:16])[CH:6]=1)(=[O:3])[CH3:2].[CH:19]12[CH2:25][CH:22]([NH:23][CH2:24]1)[CH2:21][S:20]2.N1C=CC=CC=1>C(Cl)(Cl)Cl>[C:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([S:15]([N:23]2[CH2:24][CH:19]3[CH2:25][CH:22]2[CH2:21][S:20]3)(=[O:17])=[O:16])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: C1SC2CNC1C2
Reactant: CC(=O)Oc1cc(S(=O)(=O)Cl)cc2ccccc12
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(=O)Oc1cc(S(=O)(=O)N2CC3CC2CS3)cc2ccccc12
Yield: 35.3 %

Procedure:
4-Acetoxy-2-naphthalenesulfonyl chloride (375 mg, 2.50 mmol) and 2-thia-5-azabicyclo[2.2.1]heptane (711 mg, 2.50 mmol) were combined in CHCl3 (20 ml) and pyridine (20 ml) and the mixture was stirred at room temperature for 15 hr. At this time the solvent was evaporated under reduced pressure and the residue was partitioned between EtOAc and 1N aq HCl. The EtOAc was then washed with saturated aq NaHCO3, dried over Na2SO4, and concentrated. The residue was purified by flash chromatography using 3% acetone in CHCl3 to provide of the pure product as a white foam (321 mg, 35% yield): 1H NMR (CDCl3) δ 1.60-1.79 (2H, m, CH2), 2.48 (3H, s, CH3CO), 2.98 (1H, dd, J=7.78, 2.44 Hz, 1/2 CH2), 3.18 (1H, d, J=10.21 Hz, 1/2 CH2), 3.51 (2H, br m, CH2), 3.67 (1H, d, J=9.48 Hz, CH), 4.70 (1H, s, CH), 7.61-7.70 (3H, m, ArH), 7.94-8.05 (m, 2H, ArH, 8.28 (s, 1H, ArH).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:6]([CH3:22])[C:7](=[O:21])[C:8]3([CH2:20][CH2:19]3)[CH2:9][N:10]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH2:23][C:24]1[C:38]([O:39][CH3:40])=[CH:37][C:27]([C:28]([NH:30][C@@H:31]2[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32]2)=[O:29])=[C:26]([F:41])[CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(C)CC(O)C>[CH:13]1([N:10]2[CH2:9][C:8]3([CH2:20][CH2:19]3)[C:7](=[O:21])[N:6]([CH3:22])[C:5]3[CH:4]=[N:3][C:2]([NH:23][C:24]4[C:38]([O:39][CH3:40])=[CH:37][C:27]([C:28]([NH:30][C@@H:31]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32]5)=[O:29])=[C:26]([F:41])[CH:25]=4)=[N:12][C:11]2=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COc1cc(C(=O)N[C@@H]2CCN(C)C2)c(F)cc1N
Reactant: CN1C(=O)C2(CC2)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)CC(C)O
Product: COc1cc(C(=O)N[C@@H]2CCN(C)C2)c(F)cc1Nc1ncc2c(n1)N(C1CCCCC1)CC1(CC1)C(=O)N2C
Yield: 39.7 %

Procedure:
2′-chloro-9′-cyclohexyl-5′-methyl-8′,9′-dihydrospiro[cyclopropane-1,7′-pyrimido[5,4-b][1,4]diazepin]-6′(5′H)-one (Intermediate 270; 103 mg, 0.32 mmol), 4-amino-2-fluoro-5-methoxy-N-[(3R)-1-methylpyrrolidin-3-yl]benzamide (Intermediate 182; 87 mg, 0.32 mmol) and p-toluenesulphonic acid monohydrate (154 mg, 0.81 mmol) were heated in 4-methyl-2-pentanol (3 mL) at 140° C. for 3 hours. The mixture was cooled and absorbed on to an SCX column, which was then washed with methanol and eluted with ammonia in methanol. Product containing fractions were combined and evaporated and purified by base modified reverse phase preparative HPLC to yield the title compound as a white solid (70 mg, 40%).
Reaction SMILES: [C:1]([C:4]1[C:13]([F:14])=[C:12]2[C:7]([C:8](=[O:22])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][N:11]2[CH2:15][CH3:16])=[CH:6][C:5]=1[F:23])(=[O:3])[CH3:2].C(O[CH:29](OC(C)(C)C)[N:30]([CH3:32])[CH3:31])(C)(C)C>CN(C)C=O>[CH3:29][N:30]([CH3:32])[CH:31]=[CH:2][C:1]([C:4]1[C:13]([F:14])=[C:12]2[C:7]([C:8](=[O:22])[C:9]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][N:11]2[CH2:15][CH3:16])=[CH:6][C:5]=1[F:23])=[O:3]
Reactant: CCOC(=O)c1cn(CC)c2c(F)c(C(C)=O)c(F)cc2c1=O
Reactant: CN(C)C(OC(C)(C)C)OC(C)(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CC)c2c(F)c(C(=O)C=CN(C)C)c(F)cc2c1=O
Reaction time: 8 h

Procedure:
To 5.00 g (15.5 mmol) of the ethyl 7-acetyl-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate in 65 ml of dimethylformamide was added 4.27 ml (1.3 eq) of bis t-butoxydimethylaminomethane. The mixture was taken to 55° C. overnight. The mixture was concentrated and the solids suspended in ethyl ether. Filtration gave 4.88 g of the ethyl 7-(2'-dimethylaminoethenyl)carbonyl-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, mp 175°-177° C.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)(=O)=O.[Br:19][C:20]1[CH:24]=[CH:23][NH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CN(C=O)C>[Br:19][C:20]1[CH:24]=[CH:23][N:22]([CH:6]2[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]2)[N:21]=1
Reactant: Brc1cc[nH]n1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2ccc(Br)n2)CC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 25.2 %

Procedure:
A mixture of tert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate (0.837 g, 3.00 mmol), 3-bromo-1H-pyrazole (0.441 g, 3.02 mmol), and cesium carbonate (2.94 g, 9.02 mmol) in DMF (10 mL) stirred for 5 h at 100° C. The reaction mixture was cooled to room temperature and poured ethyl acetate (50 mL). The mixture was washed with water (3×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue purified via column chromatography on silica gel (eluting with 10% dichloromethane/methanol to afford tert-butyl 4-(3-bromo-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.25 g, 25%) as a white solid. MS (ESI, pos. ion) m/z 330, 332 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[C:31]=1[F:38])=[O:27])[C:23](O)=[O:24]>>[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[C:32]([F:37])[C:31]=1[F:38])=[O:27])[C:23]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:24]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)cc(F)c1F
Product: CC(C(=O)NCc1cc(F)cc(F)c1F)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=509.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(2,3,5-trifluoro-benzyl)-malonamic acid.
Reaction SMILES: [H-].[Na+].CS(O[CH2:8][CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH3:12])(=O)=O.[CH3:20][CH:21]([CH3:24])[CH2:22][SH:23]>O1CCCC1>[CH2:22]([S:23][CH2:8][CH2:9][CH2:10][N:11]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH3:12])[CH:21]([CH3:24])[CH3:20]
Reactant: CN(CCCOS(C)(=O)=O)C(=O)OC(C)(C)C
Reactant: CC(C)CS
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CSCCCN(C)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.4 %

Procedure:
To a stirred suspension of sodium hydride (336 mg : 60% dispersion in oil) in anhydrous tetrahydrofuran (12 ml) was added a solution of 3-(N-t-butoxycarbonyl-N-methylamino)propyl methanesulfonate (2.139 g) in tetrahydrofuran (10 ml) dropwise over 5 minutes. After being stirred for 30 minutes, the mixture was cooled to 0° C., and 2-methyl-1-propanethiol (758 mg) was added dropwise at 0°-5° C. The mixture was then allowed to warm to ambient temperature and stirred for 24 hours. Additional 168 mg of sodium hydride and 379 mg of 2-methyl-1-propanethiol was added above the same condition. After being stirred for another 16 hours, the solvent was evaporated and the resulting residue was dissolved in ethyl acetate (100 ml). The solution was washed with 0.5N hydrochloric acid (100 ml water (100 ml), aqueous sodium bicarbonate (100 ml), water (100ml), and brine (100 ml) successively, dried over magnesium sulfate and concentrated. The residue was chromatographed on silica gel eluting with a mixture of n-hexane and ethyl acetate (6:4 V/V) to give 3-(N-t-butoxycarbonyl-N-methylamino)propyl isobutyl sulfide (595 mg) as an oil.