Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH3:13].[NH2:14]OS(O)(=O)=O>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([NH2:14])[CH:8]=[C:7]2[CH3:13]
Reactant: NOS(=O)(=O)O
Reactant: Cc1c[nH]c2ccc(F)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cn(N)c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A suspension of NaH (2.01 g, 50.3 mmol, 60% in mineral oil) in DMF (45 mL) at 0° C. is treated with 5-fluoro-3-methyl-1H-indole (500 mg, 3.55 mmol), and the mixture is stirred at 0° C. for 1 h. NH2OSO3H (1.9 g, 16.75 mmol) is added portion wise, and the mixture is then warmed to rt and stirred for 2 h. The mixture is quenched with MeOH, diluted with water, extracted with EtOAc, dried (Na2SO4), filtered and concentrated to afford 5-fluoro-3-methyl-indol-1-ylamine. MS: 165 (M+H); 1H NMR (300 MHz, CD3OD): δ 2.22 (s, 3H), 6.86 (m, 1H), 6.99 (s, 1H), 7.08 (m, 1H), 7.36 (m, 1H).
Reaction SMILES: CS(O[CH2:6][CH2:7][S:8]([CH3:11])(=[O:10])=[O:9])(=O)=O.[NH2:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:32])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[CH:18][C:17]=1[C:33]1[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=1>CN(C=O)C>[CH3:11][S:8]([CH2:7][CH2:6][NH:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:32])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[CH:18][C:17]=1[C:33]1[N:37]([CH3:38])[N:36]=[CH:35][CH:34]=1)(=[O:10])=[O:9]
Reactant: COc1cccc(C(=O)Nc2ccc(OCCN)c(-c3ccnn3C)c2)c1
Reactant: CS(=O)(=O)CCOS(C)(=O)=O
Solvent: CN(C)C=O
Product: COc1cccc(C(=O)Nc2ccc(OCCNCCS(C)(=O)=O)c(-c3ccnn3C)c2)c1
Temperature: 150 °C
Yield: 18.5 %

Procedure:
A mixture of 2-(methylsulfonyl)ethyl methanesulfonate (16.6 mg, 81.9 μmol) and N-(4-(2-aminoethoxy)-3-(1-methyl-1H-pyrazol-5-yl)phenyl)-3-methoxybenzamide (30 mg, 81.9 μmol) in DMF was heated to 150° C. for 1 hour under microwave irradiation in a heavy-walled sealed tube. The crude product was purified by HPLC. The proper fractions were collected and lyophilized to afford the title compound as a yellow solid in 18.5% yield. LCMS m/z (%)=473 (M+H, 100).
Reaction SMILES: C1([O:7][C:8](=O)[NH:9][C:10]2[CH:15]=[C:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][C:24]([C:26]4([C:29](=[O:38])[NH:30][C:31]5[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=5)[CH2:28][CH2:27]4)=[O:25])=[CH:19][C:18]=3[F:39])[N:13]=[CH:12][N:11]=2)C=CC=CC=1.[CH3:41][N:42]1[CH2:47][CH2:46][CH:45]([NH:48][CH3:49])[CH2:44][CH2:43]1>CN(C)C=O>[F:39][C:18]1[CH:19]=[C:20]([NH:23][C:24]([C:26]2([C:29]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)=[O:38])[CH2:28][CH2:27]2)=[O:25])[CH:21]=[CH:22][C:17]=1[O:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:48]([CH3:49])[CH:45]2[CH2:46][CH2:47][N:42]([CH3:41])[CH2:43][CH2:44]2)=[O:7])[N:11]=[CH:12][N:13]=1
Reactant: CNC1CCN(C)CC1
Reactant: O=C(Nc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ncn1)Oc1ccccc1
Solvent: CN(C)C=O
Product: CN1CCC(N(C)C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncn2)CC1
Reaction time: 3 h
Yield: 79.3 %

Procedure:
[6-(2-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyrimidin-4-yl]carbamic acid phenyl ester (40 mg) was dissolved in N,N-dimethylformamide (1.0 ml), and 1-methyl-4-(methylamino)piperidine (0.045 ml) was added thereto, followed by stirring for 3 hr. The reaction mixture was partitioned between ethyl acetate (50 ml) and a saturated aqueous solution of ammonium chloride (20 ml). The organic layer was washed with a saturated aqueous solution of ammonium chloride (20 ml), water (20 ml) and brine (20 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containing the target compound were concentrated under reduced pressure, and the resultant residue was suspended in diethyl ether (2 ml) and hexane (4 ml). The solid was collected by filtration and dried under aeration to provide the titled compound as white powder (33.7 mg, 79.3%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CCO.[Pt]=O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)C=C1CCN(Cc2ccccc2)CC1
Agent: O=[Pt]
Solvent: CCO
Product: CC(C)(C)OC(=O)CC1CCN(Cc2ccccc2)CC1
Yield: 92.9 %

Procedure:
To a solution of 1 g of ((1-benzyl)piperidin-4-ylidene)acetic acid, t-butyl ester (from EXAMPLE 163, Step A) in 10 mL of EtOH was added 100 mg of platinum oxide at rt. The solution was hydrogenated for 3 h under one atmosphere of hydrogen gas. After filtering through celite, the filtrate was concentrated under reduced pressure to give 936 mg of the title compound as a viscous oil.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][N:9]([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([CH3:31])[CH3:30])=[CH:25][CH:24]=2)[C:10]([CH:12]2[C:21]3[C:16](=[C:17]([OH:22])[CH:18]=[CH:19][CH:20]=3)[CH2:15][CH2:14][CH2:13]2)=[O:11])[CH:5]=[N:4]1)[CH3:2].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>>[CH2:1]([N:3]1[CH:7]=[C:6]([CH2:8][N:9]([C:23]2[CH:24]=[CH:25][C:26]([CH:29]([CH3:30])[CH3:31])=[CH:27][CH:28]=2)[C:10]([CH:12]2[CH2:13][CH2:14][CH2:15][C:16]3[C:17]([O:22][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:18][CH:19]=[CH:20][C:21]2=3)=[O:11])[CH:5]=[N:4]1)[CH3:2]
Reactant: CCn1cc(CN(C(=O)C2CCCc3c(O)cccc32)c2ccc(C(C)C)cc2)cn1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1cccc2c1CCCC2C(=O)N(Cc1cnn(CC)c1)c1ccc(C(C)C)cc1

Procedure:
By the reaction and treatment in the same manner as in Example 106 using N-[(1-ethylpyrazol-4-yl)methyl]-5-hydroxy-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.00 g) and ethyl bromoacetate (0.40 mL) as starting materials, ethyl 2-(5-{N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)carbamoyl}-5,6,7,8-tetrahydronaphthalene-1-yloxy)acetate (1.09 g) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[N+:6]([O-:13])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[C:20](=O)([O-])[O-].[K+].[K+].[K].CI>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:20])[C:7](=[O:12])[N+:6]([O-:13])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)[n+]1[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [K]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c(=O)[n+]([O-])c(-c2ccccc2)c2cc(Cl)ccc21
Reaction time: 1 h
Yield: 80 %

Procedure:
A mixture of 125 g (0.458 mole) of 6-chloro-4-phenyl-2(1H)quinazolinone 3-oxide, 3,250 ml of N,N-dimethylformamide and 75 g of powdered anhydrous potassium carbonate was heated to 50°. After heating for approximately 30 minutes at this temperature, an increased solubility of the suspended solid due to formation of the potassium salt of I was observed. At this point, 150 g (65.8 ml) of methyl iodide was added dropwise at a fast rate. The reaction with the methyl iodide was somewhat exothermic and caused the pot temperature to rise to 58°. Stirring at 50°-55° was continued for 1 hour. The contents of the flask were cooled and filtered and the solid obtained was thoroughly washed with water. The product, 6-chloro-1-methyl-4-phenyl-2(1H)quinazolinone 3-oxide was obtained in 80% yield (103.2 g), mp 253.5°-254°.
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10][C@@H:9]1[CH3:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([NH2:26])C1C=CC=CC=1>>[C:1]([N:8]1[CH2:12][C@@H:11]([NH2:26])[CH2:10][C@@H:9]1[CH3:18])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C[C@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: NCc1ccccc1
Product: C[C@H]1C[C@H](N)CN1C(=O)OC(C)(C)C
Temperature: 100 °C
Yield: 81.5 %

Procedure:
To a 90 g (0.322 mol) sample of (2S,4R)-1BOC-4-methanesulfonyloxy-2-methylpyrrolidine, prepared as described in U.S. Pat. No. 4,962,112, was added 345 g (3.22 mol) of benzylamine, and the solution was heated at 100° C. under N2 for 8 hours. The solution was cooled to room temperature and the excess benzylamine removed under vacuum. The residue was dissolved in ethyl acetate and washed with water. The product was then extracted into 1.0M citric acid, which was then adjusted to pH 11.5 with conc. ammonium hydroxide solution. The product was extracted into ethyl acetate, which was dried over Na2SO4, filtered, and concentrated. After drying, 76.2 g (81.5% yield) of the title product was obtained as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:11]=[CH:12][CH:13]=1)[CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8].[OH:14][C:15]1[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[C:24]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[OH:14][C:15]1[C:27]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:25]=[C:24]([CH2:32][O:33][C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:13]=[CH:12][CH:11]=[C:4]([CH2:5][NH:6][S:7]([CH3:10])(=[O:9])=[O:8])[CH:3]=3)=[CH:36][CH:35]=2)[C:16]=1[C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18]
Reactant: CC(C)(C)OC(=O)c1c(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)ccc(C(F)(F)F)c1O
Reactant: CS(=O)(=O)NCc1cccc(Br)c1
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3cccc(CNS(C)(=O)=O)c3)cc2)ccc(C(F)(F)F)c1O

Procedure:
According to a method similar to Example (31), from N-(3-bromobenzyl)methanesulfonamide (119 mg, 0.45 mmol) and tert-butyl 2-hydroxy-6-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}-3-(trifluoromethyl)benzoate (250 mg, 0.51 mmol) obtained in Example (22-4), the title compound was obtained as a pale brown powder (49 mg, yield: 20%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH2:23].C(N(CC)CC)C>CC(O)C>[CH3:19][N:20]([CH3:24])[CH2:21][CH2:22][NH:23][C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Reactant: CN(C)CCN
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CSc1nccc(-c2n[nH]c3nc(NCCN(C)C)ncc23)n1
Yield: 75.3 %

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (400 mg, 1.43 mmol) in 2-propanol (40 mL) was added N, N-dimethylethane-1,2-diamine (139 mg, 1.58 mmol) followed by triethylamine (159 mg, 1.57 mmol). The reaction mixture was stirred at reflux for 15 hours and the solvent was then removed under reduced pressure. The residue was extracted with dichloromethane (3×30 mL), washed with water (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford N,N-dimethyl-N′-[3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-ethane-1,2-diamine (Yield 356 mg, 75%).
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][CH3:6].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH2:15][C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1.O>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]([CH2:4][CH2:5][CH3:6])[C:16]#[N:17])[CH:12]=[CH:13][CH:14]=1
Reactant: COc1cccc(CC#N)c1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(C#N)c1cccc(OC)c1
Yield: 74 %

Procedure:
NaH (55-65%, 1.44 g, 36 mmoles) and, after 30 minutes under stirring, 1-bromo-propane (4.46 g, 36 mmoles) were added to a solution of 3-methoxy-phenyl-acetonitrile (4.4 g, 30 mmoles) in anhydrous DMF (30 ml) under N2 at room temperature. After 1.5 hours the mixture was poured into water (200 ml), extracted 3 times with ethyl ether, anhydrified and brought to dryness to give a residue which was chromatographed (eluent: petrolatum, then petrolatum/ethyl ether 95:5) to give 4.2 g of the title compound (yield: 74%).
Reaction SMILES: [CH3:1][CH:2]([CH2:8][CH2:9][CH3:10])/[CH:3]=[CH:4]/[C:5](O)=[O:6].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:44][O:45][C:46]1[CH:55]=[C:54]([N:56]2[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]2)[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:47]=1>CN(C=O)C>[CH3:44][O:45][C:46]1[CH:55]=[C:54]([N:56]2[CH2:61][CH2:60][N:59]([C:5](=[O:6])/[CH:4]=[CH:3]/[CH:2]([CH3:1])[CH2:8][CH2:9][CH3:10])[CH2:58][CH2:57]2)[C:53]2[C:48](=[CH:49][CH:50]=[CH:51][CH:52]=2)[N:47]=1
Reactant: COc1cc(N2CCNCC2)c2ccccc2n1
Reactant: CCCC(C)/C=C/C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(C)/C=C/C(=O)N1CCN(c2cc(OC)nc3ccccc23)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
(E)-4-Methyl-hept-2-enoic acid (21.3 mg, 0.15 mmol) was dissolved in DMF (350 μl), diisopropylethylamine was added (26 μl, 0.15 mmol) followed by HATU (57 mg, 0.15 mmol dissolved in 0.25 ml DMF). The mixture was stirred at room temperature for 15 minutes, then 2-methoxy-4-piperazin-1-yl-quinoline (36.4 mg, 0.15 mmol, dissolved in 1 ml DMF) was added and stirring was continued overnight. The mixture was evaporated under reduced pressure, the residue was dissolved in dichloromethane and the resulting solution was washed with 5% sodium bicarbonate solution, water, evaporated to dryness under reduced pressure. The residue was purified by preparative HPLC (gradient of water containing 0.1% NH3 and acetonitrile) to yield 21.1 mg (0.06 mmol, 39.8%) of a solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][NH2:11])([O-:3])=[O:2].[C:12]([N:17]=[C:18]([CH:22]1[CH2:24][CH2:23]1)OCC)(OCC)=[O:13]>CO.C(Cl)Cl>[CH:22]1([C:18]2[NH:17][C:12](=[O:13])[N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[N:11]=2)[CH2:24][CH2:23]1
Reactant: CCOC(=O)N=C(OCC)C1CC1
Reactant: NNc1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: CO
Product: O=c1[nH]c(C2CC2)nn1-c1ccccc1[N+](=O)[O-]
Yield: 69 %

Procedure:
By the procedure of Example 4, Step C, 2-nitrophenylhydrazine was reacted with ethyl N-(carbethoxy)cyclopropanecarboximidate. After work-up, the residue was purified by flash chromatography on silica gel (150 mL for 2.0 mmole, eluted with 1.5% MeOH/CH2Cl2) to give the desired material as a yellow foam in 69% yield, homogeneous by TLC in 5% MeOH/CH2Cl2, mass spectrum (FAB) m/e 247 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([NH:16][N:17]([CH3:19])[CH3:18])=[O:15])[S:13][C:6]=12.Cl[C:28]1C=CN=C2C=C(C(N(C)N(C)C)=O)SC=12>>[F:1][C:2]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]([N:16]([CH3:28])[N:17]([CH3:19])[CH3:18])=[O:15])[S:13][C:6]=12
Reactant: CN(C)NC(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Reactant: CN(C)N(C)C(=O)c1cc2nccc(Cl)c2s1
Product: CN(C)N(C)C(=O)c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Yield: 66 %

Procedure:
Following the procedure described above for compound 238 (step 2, example 95, scheme 63) but replacing chloride 237 with compound 242, title compound 243 was obtained in 66% yield. MS (m/z): (M+1) 391.1 (100%).
Reaction SMILES: [Cl:1][C:2](=[CH2:20])[CH2:3][N:4]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[NH:7][C:6]2[N:16]=[CH:17][CH:18]=[CH:19][C:5]1=2.[H-].[Na+].[CH2:23](I)[CH3:24]>CN(C)C=O>[Cl:1][C:2](=[CH2:20])[CH2:3][N:4]1[C:10](=[O:11])[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[N:7]([CH2:23][CH3:24])[C:6]2[N:16]=[CH:17][CH:18]=[CH:19][C:5]1=2
Reactant: C=C(Cl)CN1C(=O)c2ccccc2Nc2ncccc21
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(Cl)CN1C(=O)c2ccccc2N(CC)c2ncccc21
Temperature: 25 °C

Procedure:
9.7 g (0.034 mol) of 5-(2-chloro-2-propenyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one, were suspended in 100 ml of anhydrous dimethylformamide. The mixture was thoroughly purged with dry nitrogen and stirred rapidly while 1.8 g (0.0375 mol) of a 50% dispersion of sodium hydride in mineral oil was slowly added portionwise through an inlet protected by a calcium chloride drying tube. Addition of the first portion sodium hydride resulted in an immediate exothermic reaction, and the temperature of the mixture rose rapidly to about 60° C. After addition of the sodium hydride was complete (30-35 minutes), the reaction mixture was cooled to room temperature, and 7.8 g (0.05 mol) of ethyl iodide were added dropwise. Thereafter, the flask was placed in an oil bath heated to 100° C., and the reaction mixture was stirred and heated for 2 hours, during which time a slow stream of dry nitrogen was passed through the apparatus. After this time no starting material was detected by thin-layer chromatography.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:11]([C:19]([F:22])([F:21])[F:20])=[CH:10][C:9]=1[NH:23][C:24](=[O:41])[CH2:25][C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([CH3:40])[CH:35]=2)[CH:29]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:40][C:36]1[CH:35]=[C:34]([C:30]2[CH:29]=[C:28]([C:26]3[CH2:25][C:24](=[O:41])[NH:23][C:9]4[CH:10]=[C:11]([C:19]([F:21])([F:22])[F:20])[C:12]([N:14]5[CH2:15][CH2:16][CH2:17][CH2:18]5)=[CH:13][C:8]=4[N:7]=3)[CH:33]=[CH:32][CH:31]=2)[CH:39]=[CH:38][N:37]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N4CCCC4)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N5CCCC5)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-pyrrolidin-1-yl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M278) (0.34 g, 0.58 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (217 mg, 80%).
Reaction SMILES: [N+:1]([C:4]1[C:9]2[NH:10][CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH2:18](Br)[CH:19]=[CH2:20]>CN(C=O)C>[CH2:20]([N:10]1[C:9]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=2[C:14](=[O:15])[NH:13][CH2:12][CH2:11]1)[CH:19]=[CH2:18]
Reactant: O=C1NCCNc2c1cccc2[N+](=O)[O-]
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCN1CCNC(=O)c2cccc([N+](=O)[O-])c21
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.3 %

Procedure:
9-Nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one (763 mg, 3.67 mmol) was dissolved in anh DMF (10 ml). NaH (60% dispersion in mineral oil) (147 mg, 3.67 mmol) was added followed by allyl bromide (310 μL, 3.67 mmol). The resulting mixture was stirred at rt for 2 h. Reaction mixture was concentrated, diluted with CH2Cl2, and washed with H2O. The organic layer was dried over MgSO4, filtered, concentrated, and purified with silica gel chromatography (0-100% EtOAc in hexanes) to afford 1-Allyl-9-nitro-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one as an orange solid (647 mg, 71%). mp 80-82° C.; LCMS: m/z=248.27 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.67 (m, 1H), 8.30 (dd, J=8.3 Hz, 1.5 Hz, 1H), 8.17 (dd, J=7.6 Hz, 1.5 Hz, 1H), 6.78 (t, J=7.8 Hz, 1HO, 5.85 (m, 1H), 5.29 (m, 2H), 4.22 (m, 2H), 3.74 (m, 2H), 3.58 (m, 2H).
Reaction SMILES: Cl[C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[Br-].[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][Zn+])=[CH:13][CH:12]=1>O1CCCC1.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>[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15][C:2](=[O:8])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:13][CH:12]=1
Reactant: CCOC(=O)C(=O)Cl
Reactant: Fc1ccc(C[Zn+])cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)Cc1ccc(F)cc1
Temperature: 0 °C
Yield: 33.5 %

Procedure:
To a stirred mixture of ethyl 2-chloro-2-oxoacetate (35 g, 256.35 mmol, 1.00 equiv) and Pd(PPh3)2Cl2 (9 g, 12.82 mmol, 0.05 equiv) in tetrahydrofuran (200 mL) maintained under nitrogen at 0° C. was added dropwise a solution of (4-fluorobenzyl)zinc(II) bromide (65 g, 255.47 mmol, 1.00 equiv) in tetrahydrofuran (500 mL). The reaction mixture was refluxed for 12 h then cooled to 0° C. and quenched by dropwise addition of 500 mL of saturated NH4Cl solution. The resulting mixture was extracted with 2×500 mL of ethyl acetate. The combined organic layers was washed with 1×1 L of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-5% of ethyl acetate in petroleum ether to give 18 g (34%) of ethyl 3-(4-fluorophenyl)-2-oxopropanoate as a yellow oil. 1H-NMR (300 MHz, DMSO): δ 7.36-7.33 (m, 2H), 7.18-7.12 (m, 2H), 4.50 (s, 1H), 4.26 (q, J=7.0 Hz, 2H), 1.20 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(CCN)CC1
Product: CC(C)(C)OC(=O)N1CCN(CCNc2c([N+](=O)[O-])cnc3cc(Br)ccc23)CC1
Reaction time: 8 h
Yield: 59.8 %

Procedure:
7-Bromo-4-chloro-3-nitroquinoline (33.0 g, 115 mmol) was treated with 4-(2-aminoethyl)-1-(tert-butoxycarbonyl)piperazine (26.4 mL, 115 mmol) according to the method described in Part E of Example 1. The reaction was stirred overnight. The crude product was triturated with diethyl ether and isolated by filtration to provide 33.05 g of tert-butyl 4-[2-(7-bromo-3-nitroquinolin-4-ylamino)ethyl]piperazine-1-carboxylate as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[CH:5]=1.[C:12]([O:16][C:17](=[O:21])[C@H:18](O)[CH3:19])([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][C@H:18]([C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:21])[CH3:19])[CH:5]=1
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Reactant: COC(=O)c1cccc(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cccc(O[C@@H](C)C(=O)OC(C)(C)C)c1
Yield: 83.4 %

Procedure:
Cool a solution of 3-hydroxy-benzoic acid methyl ester (0.50 g, 3.42 mmol) in tetrahydrofuran (8 mL) to 0° C., and add (R)-2-hydroxy-propionic acid tert-butyl ester (0.52 g, 3.42 mmol) and triphenyl phosphine (0.90 g, 3.42 mmol). Add diethylazodicarboxylate (0.70 mL, 4.4 mmol) to this mixture via a syringe pump over a 1 hour period. Concentrate the reaction mixture under reduced pressure and purify the residue by flash silica gel chromatography to provide 0.80 g of 3-((S)-1-tert-butoxycarbonyl-ethoxy)-benzoic acid methyl ester as an oil.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15](=[O:32])[N:16]([CH:20]2[CH2:29][CH2:28][C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[CH:25][CH:26]=3)[CH2:21]2)[CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:31][O:30][C:24]1[CH:23]=[C:22]2[C:27]([CH2:28][CH2:29][CH:20]([N:16]([CH2:17][CH2:18][CH3:19])[C:15](=[O:32])[CH2:14][N:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH2:21]2)=[CH:26][CH:25]=1
Reactant: CCCN(C(=O)CN1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(OC)cc2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCN(C(=O)CN1CCNCC1)C1CCc2ccc(OC)cc2C1
Reaction time: 3 h
Yield: 95.6 %

Procedure:
Compound 36a (5.1 g, 11.5 mmol) was dissolved in 40 ml of dichloromethane and 40 ml of trifluoroacetic acid was added. The mixture was stirred for 3 hr, at which time the solution was concentrated to dryness, dissolved in sat. NaHCO3, and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated to yield 3.8 g (96%) of 37a, which was used as is in the next reaction. 1H NMR (400 MHz, CDCl3) 0.93-0.96 (t, 3H, J=7.6 Hz), 1.62 (m, 3H), 1.85-1.97 (m, 3H), 2.56 (m, 1H), 2.81-2.88 (m, 5H), 2.98-3.34 (m, 9H), 3.81 (s, 3H), 6.60-6.61 (dd, 1H, J=1.6 Hz), 6.65-6.78 (m, 1H), 6.95-6.98 (d, 1H, J=8.8 Hz).