Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1)[NH2:5].[CH3:13][C:14](=O)[CH2:15][CH2:16][C:17](=O)[CH3:18]>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([N:5]2[C:17]([CH3:18])=[CH:16][CH:15]=[C:14]2[CH3:13])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: CC(=O)CCC(C)=O
Reactant: Nc1cc(Br)cc(C(F)(F)F)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(C)n1-c1cc(Br)cc(C(F)(F)F)c1
Reaction time: 1 h
Yield: 98.4 %

Procedure:
A solution of 3-bromo-5-(trifluoromethyl)aniline (14.00 g, 58 mmol), hexane-2,5-dione (7.05 mL, 60 mmol) and p-toluenesulfonic acid monohydrate (220 mg, 1.2 mmol) in toluene (250 mL) was heated under Dean-Stark conditions. After 1 h, the reaction mixture was concentrated. The residue was purified by column chromatography to give 1-[3-bromo-5-(trifluoromethyl)phenyl]-2,5-dimethyl-1H-pyrrole (18.15 g, 98%) as orange oil. LCMS: (FA) ES+ 318.1.
Reaction SMILES: [C:1]([CH2:6][O:7][C:8]1[C:16]2[N:12]([C:13]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27](Cl)[CH:26]=3)=[C:14]([CH2:22]C)[C:15]=2[C:17](=[O:21])[C:18]([NH2:20])=[O:19])[CH:11]=[CH:10][CH:9]=1)([O:3][CH2:4][CH3:5])=[O:2]>CCOC(C)=O.CCCCCC>[CH2:24]([C:13]1[N:12]2[C:16]([C:8]([O:7][CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])=[CH:9][CH:10]=[CH:11]2)=[C:15]([C:17](=[O:21])[C:18]([NH2:20])=[O:19])[C:14]=1[CH3:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)COc1cccn2c(Cc3cccc(Cl)c3)c(CC)c(C(=O)C(N)=O)c12
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)COc1cccn2c(Cc3ccccc3)c(C)c(C(=O)C(N)=O)c12
Yield: 73 %

Procedure:
(8-(Carbethoxymethyloxy)-3-(m-chlorobenzyl)-2-ethylindolizin-1-yl)glyoxylamide 37h. Mp, 172-175° C. (AcOEt-hexane). 73% Yield.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=[O:4].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].CN(C=O)C.[OH-].[K+]>O>[F:15][C:16]1[CH:17]=[C:18]([NH:19][CH2:2][C:3]([NH:5][C:6]2[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=2[C:8]([OH:10])=[O:9])=[O:4])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(F)c1
Reactant: O=C(CBr)Nc1ccccc1C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CNc1cccc(F)c1)Nc1ccccc1C(=O)O
Yield: 78.3 %

Procedure:
A solution of 2-(N-bromoacetylamino) benzoic acid from Example 79 (8.00 g, 31.0 mmol), meta-fluoroaniline (7.45 mL, 77.5 mmol) and DMF (80 mL) was heated to 80° C. for 8 h. The mixture was cooled, poured over H2O (1 L) and 5% KOH (300 mL) and washed with CH2Cl2 (3×300 mL). The aqueous layer was acidified to pH 2 with 2N HCl, cooled below room temperature, and filtered. The filter cake was rinsed with cold water (100 mL) and dried under high vacuum at 45° C. to yield 7.00 g (78%) of the title compound as a grey solid; 1H NMR (DMSO-d6) δ 13.5 (broad s, 1H), 11.94 (s, 1H), 8.70 (d, J=8.4, 1H), 7.94 (dd, J=7.8, J=1.4, 1H), 7.60 (td, J=8.0, J=1.4, 1H), 7.15-7.07 (m, 2H), 6.83 (broad s, 1H), 6.43-6.35 (m, 3H), 3.88 (s, 2H); 13C NMR (DMSO-d6) δ 170.29, 169.12, 163.25 (J=240.3), 150.17 (J=10.6), 140.52, 134.18, 131.13, 130.43 (J=10.6), 122.73, 119.40, 115.98, 108.42, 103.09 (J=21.2), 98.97 (J=25), 48.48; MS (EI, m/z) 388 (M+).
Reaction SMILES: [CH3:1]Br.[Mg].[CH2:4]([CH2:11][NH:12][CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](=[O:22])[CH2:14]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>O1CCCC1>[CH2:4]([CH2:11][NH:12][CH:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:1])([OH:22])[CH2:14]1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: CBr
Reactant: O=C1CC(NCCc2ccccc2)c2ccccc21
Agent: [Mg]
Solvent: C1CCOC1
Product: CC1(O)CC(NCCc2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
In 35 milliliters of tetrahydrofuran, 4 grams methyl bromide is dissolved. One quarter of this solution is then added to 1 gram of magnesium, previously washed with chloroform, and refluxed with tetrahydrofuran for 20 minutes; and this mixture is refluxed 4 hours to initiate reaction. Additional methyl bromide solution is thereafter added to maintain the refluxing without further heating. After the addition has been completed 10 grams of 3-benzylmethylaminoindan-1-one is added and the mixture is refluxed for 2 hours. The reactants are allowed to stand overnight and then poured onto ice-cold ammonium chloride solution. Tetrahydrofuran is added and the two layers formed are allowed to separate. The solvent layer is decanted off and the aqueous layer is extracted twice with 10 milliliters of tetrahydrofuran which are decanted off and combined with the remaining solvent layer. The organic phase is dried over anhydrous magnesium sulphate, filtered and evaporated to dryness to yield 3-benzylmethylamino-1-methylindan-1-ol as a yellow oil.
Reaction SMILES: Cl[C:2]1C=C(Cl)C=C[C:3]=1C1N=C(CC)C(N[C@@H]2C3C(=CC=CC=3)C[C@@H]2OCC)=NC=1CC.[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:66][CH3:67])[C:44]([NH:49][C@H:50]2[C@@H:54]([OH:55])[CH2:53][N:52]([C:56]([O:58][CH2:59][C:60]3[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=3)=[O:57])[CH2:51]2)=[N:45][C:46]=1[CH2:47][CH3:48]>>[Cl:32][C:33]1[CH:38]=[C:37]([O:39][CH3:40])[CH:36]=[CH:35][C:34]=1[C:41]1[N:42]=[C:43]([CH2:66][CH3:67])[C:44]([NH:49][C@H:50]2[C@@H:54]([O:55][CH2:2][CH3:3])[CH2:53][N:52]([C:56]([O:58][CH2:59][C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)=[O:57])[CH2:51]2)=[N:45][C:46]=1[CH2:47][CH3:48]
Reactant: CCO[C@H]1Cc2ccccc2[C@H]1Nc1nc(CC)c(-c2ccc(Cl)cc2Cl)nc1CC
Reactant: CCc1nc(-c2ccc(OC)cc2Cl)c(CC)nc1N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1O
Product: CCO[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)cc2Cl)nc1CC

Procedure:
Following the procedure for the preparation of 5-(2,4-dichlorophenyl)-N-[(1R,2S)-2-ethoxy-2,3-dihydro-1H-inden-1-yl]-3,6-diethylpyrazin-2-amine but benzyl(3R,4S)-3-{[5-(2-chloro-4-methoxyphenyl)-3,6-diethylpyrazin-2-yl]amino}-4-hydroxypyrrolidine-1-carboxylate and making non-critical variations provided the title compound as a oil: 1H NMR (DMSO-d6) δ) 1.04, 1.16, 2.38, 2.68, 3.34, 3.40, 3.54, 3.70, 3.82, 4.18, 4.62, 5.10, 5.95, 6.98, 7.10, 7.26, 7.38; IR (diffuse reflectance) 2971, 2934, 2350 (w), 2338 (w), 2063 (w), 1949 (w), 1710 (s), 1568, 1482 (s), 1419 (s), 1397 (s), 1348, 1287, 1228, 1096, cm−1 HRMS (FAB) calcd for C29H35ClN4O4+H 539.2425, found 539.2436.
Reaction SMILES: [C:1]([N:3]=[C:4](SC)[NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1)#[N:2].C(O)C.[CH2:40]([NH:42][CH2:43]C)C>CN(C=O)C>[C:1]([N:3]=[C:4]([N:42]([CH3:43])[CH3:40])[NH:5][CH2:6][CH2:7][CH2:8][N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18]2[C:19](=[O:34])[NH:20][C:21](=[O:33])[C:22]=2[C:23]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:25]([CH3:32])[CH:24]=2)=[CH:10]1)#[N:2]
Reactant: CCNCC
Reactant: CSC(=NC#N)NCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21
Solvent: CCO
Solvent: CN(C)C=O
Product: CN(C)C(=NC#N)NCCCn1cc(C2=C(c3cn(C)c4ccccc34)C(=O)NC2=O)c2ccccc21

Procedure:
100 mg of the product of Example 50 were treated with 10 ml of ethanol, 10 ml of DMF and 20 ml of 40% aqueous diethylamine for 16 hours. The solvents were removed under reduced pressure and the residue was chromatographed on silica gel with 10% methanol in dichloromethane to give 53 mg of 3-[1-[3-(2-cyano-3,3-dimethylguanidino)propyl]-3-indolyl]-4-(1-methyl-3-indolyl)-1H-pyrrole-2,5-dione, m.p 150°-153° C.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:13]([O:27][C:28]1[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C(Cl)Cl>[CH2:13]([O:27][C:28]1[CH:34]=[CH:33][C:31]([N:32]=[C:2]=[O:4])=[CH:30][CH:29]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCCCCCCCOc1ccc(N)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCCCCCOc1ccc(N=C=O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 8.74 g of triphosgene in 125 ml of methylene chloride cooled to 0° C. is added dropwise a solution of p-(tetradecyloxy)aniline, 7.95 g of 125 ml of methylene chloride over 30 minutes. Stirring at ambient temperature is continued for 4 hours. The solvent is evaporated and the residue stirred with ether and filtered. The cake is washed with additional ether and the combined filtrates evaporated to give the desired product as an oil.
Reaction SMILES: [CH2:1]([N:3]1[CH:6](SC2C=CC(C)=CC=2)[CH2:5][C:4]1=[O:15])[CH3:2].[C:16]([OH:19])(=[O:18])[CH3:17]>CCOCC.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:1]([N:3]1[CH:6]([O:18][C:16](=[O:19])[CH3:17])[CH2:5][C:4]1=[O:15])[CH3:2]
Reactant: CCN1C(=O)CC1Sc1ccc(C)cc1
Reactant: CC(=O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Solvent: O
Product: CCN1C(=O)CC1OC(C)=O
Temperature: 110 °C
Yield: 77.6 %

Procedure:
A mixture of 351 mg (1 mmol) of (1'R, 3S, 4R)-3-(1'-tert-butyldimethylsililoxy)ethyl-4-p-methylphenylthio-2-azetidinone and 100 mg (0.5 mmol) of copper (II) acetate monohydrate in 2 ml of acetic acid was heated at 110° C. for 5 minutes with stirring. The reaction mixture was diluted with ether and the insoluble materials were filtered off. The filtrate was washed with saturated sodium bicarbonate solution and then water, dried, and concentrated to produce 223 mg (yield: 77.6%) of the title compound as white crystals.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([Br:25])[CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1.C(N(CC)CC)C.[C:33](Cl)(=[O:35])[CH3:34]>C(Cl)Cl>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:33](=[O:35])[CH3:34])=[C:20]([Br:25])[CH:19]=3)[CH2:12][CH2:11]2)=[N:2]1
Reactant: CC(=O)Cl
Reactant: Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1Br
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A 2 dram vial was charged with 0.09 g (0.2 mmol) of 4-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-2-bromo-phenylamine and 0.87 mL CH2Cl2. This mixture was treated with 36 μL triethylamine (0.26 mmol) and 17 μL acetyl chloride and stirred at rt for 15 h. The reaction was quenched with aqueous 1M NaHCO3, the organic layer separated, dried, and concentrated in vacuo. This gave a quantitative yield of the desired product as a white solid. MS (APCI): 461 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8 Hz, 1H), 7.77 (d, J=8 Hz, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.32 (t, J=7.5 Hz, 1H), 7.26 (s, 1H), 6.95–6.93 (m, 1H), 6.7 (d, J=8 Hz, 1H), 3.98 (br s, 2H), 3.57–3.55 (m, 4H), 2.72–2.58 (m, 8H).
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[OH:19][N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:1]([O:19][N:20]1[C:24](=[O:25])[CH2:23][CH2:22][C:21]1=[O:26])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 0.5 h

Procedure:
To a solution of 165 mL (0.544 mol) of palmitoyl chloride in 1 L of chloroform while cooled with ice with stirring, 69.8 g (0.598 mol) of N-hydroxysuccinimide was gradually added, and 83.1 mL (0.598 mol) of triethylamine was added dropwise thereto over 30 minutes. The resultant solution was stirred for 30 minutes while cooled with ice and for another 7 hours during which the resultant solution gradually reached room temperature. After washed with 500 mL of water three times, the resultant solution was dried over magnesium sulfate and was then concentrated under reduced pressure to obtain 260.3 g (quant) of a colorless solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:4][C:3]=1[OH:17].[H][H]>[OH-].[K+].[Pd]>[N:12]1([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:2]=[C:3]([OH:17])[CH:4]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: [H][H]
Reactant: Oc1cc(N2CCCC2)c2ccccc2c1Cl
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Product: Oc1cc(N2CCCC2)c2ccccc2c1

Procedure:
1-Chloro-4-pyrrolidino-2-naphthol (2.47 g;0.010 mol), prepared as described in Example 6(a), was dissolved in 10% aqueous potassium hydroxide (50 ml) and was treated in the presence of palladium on charcoal (1.00 g;5%) at room temperature under 3 atmospheres of hydrogen until a stoichiometric amount of hydrogen was absorbed (approximately 24h). The palladium catalyst was removed by filtration and the filtrate neutralised with glacial acetic acid. The solution was extracted with dichloromethane (2×50 ml), the extracts combined, dried and evaporated to afford crude 4-pyrrolidino-2-naphthol as an unstable dark oil (0.58 g;27%). The crude product could not be purified further using conventional methods. ##STR28##
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11]1.C(N(CC)CC)C>CS(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([N:10]2[CH2:13][CH:12]([C:14]([OH:16])=[O:15])[CH2:11]2)=[CH:3][CH:4]=1)=[O:7]
Reactant: O=C(O)C1CNC1
Reactant: O=Cc1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1ccc(N2CC(C(=O)O)C2)cc1
Temperature: 100 °C
Yield: 48.4 %

Procedure:
To a stirred solution of 4-fluoro benzaldehyde (5 g, 40.28 mmol) in DMSO (70 mL) was added azetidine-3-carboxylic acid (8.14 g, 80.56 mmol) followed by addition of triethyl amine (20.38 g, 201.41 mmol) at room temperature. Resulting reaction mixture was heated at 100° C. for 24 hours under nitrogen atmosphere. After complete consumption of starting material, reaction mixture was cooled to room temperature and quenched with ice cold water (150 mL). Aqueous layer was extracted with EtOAc (3×150 mL). Combined organic layer was washed with water (2×300 mL), dried over sodium sulphate; filtered and evaporated in vacuo to afford brown colored solid (4 g, 48%). 1H NMR (400 MHz, DMSO-d6) δ: 3.54-3.59 (m, 1H), 4.03 (t, 2H, J=6.8 Hz), 4.16 (t, 2H, J=8.36 Hz), 6.52 (d, 2H, J=8.36 Hz), 7.69 (d, 2H, J=8.6 Hz), 9.68 (s, 1H); LC-MS (M−H): =203.70
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17]C)=[CH:13][CH:12]=3)[C:3]=12>ClCCl.B(Br)(Br)Br>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:38])[C:30]=3[C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=3)=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH3:20])[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=3)[C:3]=12
Reactant: COc1ccc(-c2nn(C(C)c3oc4ccccc4c(=O)c3-c3cccc(F)c3)c3ncnc(N)c23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(c1oc2ccccc2c(=O)c1-c1cccc(F)c1)n1nc(-c2ccc(O)cc2)c2c(N)ncnc21
Temperature: 25 °C
Reaction time: 12 h
Yield: 33 %

Procedure:
To a solution of Example 88 (0.150 g, 0.295 mmoles) in dichloromethane (4 ml), BBr3 (1M in dichloromethane, 1.5 ml) was added at 0° C. and the reaction mixture was warmed to RT and then stirred for 12 h. The reaction mixture was quenched with 1.5N HCl solution and extracted with dichloromethane. The organic layer was dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with methanol:dichloromethane to afford the title compound as off-white solid (0.048 g, 33% yield). MP: 244-247° C. 1H-NMR (δ ppm, DMSO-D6, 400 MHz): δ 9.79 (s, 1H), 8.04 (s, 1H), 8.04 (dd, J=8.5, 1.4 Hz, 1H), 7.85 (m, 1H), 7.68 (d, J=8.5 Hz, 1H), 7.53 (t, J=7.6 Hz, 1H), 7.42 (d, J=8.5 Hz, 2H), 7.28 (br s, 1H), 7.06 (t, J=8.5 Hz, 1H), 6.91 (d, J=8.5 Hz, 2H), 6.91 (br s, 2H), 6.00 (q, J=7.1 Hz, 1H), 1.88 (d, J=7.0 Hz, 3H). Mass: 492.69 (M+−1).
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][C:8]2[CH:13]=[C:12]([CH3:14])[N:11]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:18]([O:20]C)=[O:19])[C:10](=[O:26])[CH:9]=2)=[C:4]([CH2:29][NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:3]=1.[OH-].[Na+].O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][C:8]2[CH:13]=[C:12]([CH3:14])[N:11]([C:15]3[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:18]([OH:20])=[O:19])[C:10](=[O:26])[CH:9]=2)=[C:4]([CH2:29][NH:30][C:31]([O:33][CH3:34])=[O:32])[CH:3]=1
Reactant: COC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)OC)ccc2C)c(=O)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COC(=O)NCc1cc(F)ccc1COc1cc(C)n(-c2cc(C(=O)O)ccc2C)c(=O)c1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
To methyl 3-[4-[(4-fluoro-2-{[(methoxycarbonyl)amino]methyl}benzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-methylbenzoate (from Step 3) (0.17 g, 0.36 mmol) was added 1.5 N NaOH solution in 1:1 MeOH:water (0.39 mL, 0.59 mmol). The reaction mixture was stirred at 60° C. for 2.5 h. The solution was cooled (0° C.), neutralized by the slow addition of 5% citric acid, and organic products extracted in DCM. A white solid suspended in the organic layer was filtered, washed with DCM and water, dried in vacuo, and found to be the desired product (0.090 g, 55%). 1H NMR (CD3OD/400 MHz) δ8.03 (m, 1H), 7.75 (s, 1H), 7.52 (d, 1H, J=8.0 Hz), 7.47 (m, 1H), 7.12 (m, 1H), 7.03 (m, 1H), 6.21 (s, 1H), 6.08 (s, 1H), 5.18 (s, 2H), 4.38 (s, 2H), 3.65 (s, 3H), 2.12 (s, 3H), 1.90 (s, 3H). ESHRMS m/z 455.1632 (M+H calculated for C24H24FN2O6 requires 455.1613).
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=[O:18])[CH2:8][C:9]3[CH:14]=[N:13][C:12](S(C)=O)=[N:11][C:10]=3[C:4]=2[CH:3]=1.[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[Br:1][C:2]1[CH:20]=[CH:19][C:5]2[NH:6][C:7](=[O:18])[CH2:8][C:9]3[CH:14]=[N:13][C:12]([N:22]([CH3:21])[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)=[N:11][C:10]=3[C:4]=2[CH:3]=1
Reactant: CS(=O)c1ncc2c(n1)-c1cc(Br)ccc1NC(=O)C2
Reactant: CNc1ccccc1
Solvent: O
Product: CN(c1ccccc1)c1ncc2c(n1)-c1cc(Br)ccc1NC(=O)C2
Temperature: 150 °C

Procedure:
A mixture of 10-bromo-2-methanesulfinyl-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (100 mg) was stirred with N-methyl aniline (1 mL) and refluxed overnight at 150° C. Water was added and the product was extracted with methylene chloride, dried over MgSO4, filtered and concentrated. Purification by C-18 RP LC-MS chromatography afforded I-85 (10%): MS m/z=395 (M+H).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].[C:7]1([S:13]([NH:16][C:17]2[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:18]=2[NH2:19])(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[C:7]1([S:13]([NH:16][C:17]2[CH:23]=[C:22]([C:24]#[N:25])[CH:21]=[CH:20][C:18]=2[NH:19][C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#Cc1ccc(N)c(NS(=O)(=O)c2ccccc2)c1
Reactant: CC(C)N=C=O
Solvent: CN(C)C=O
Product: CC(C)NC(=O)Nc1ccc(C#N)cc1NS(=O)(=O)c1ccccc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 64.1 %

Procedure:
To a solution of isopropylisocyanate (31.2 mg, 0.37 mmol) in DMF (0.5 ml), 2-benzenesulfonylamino-4-cyanoaniline (100 mg, 0.37 mmol) was added. The reaction mixture was stirred at 80° C. for 3 hours. Chromatography of the resulting liquid on silica gel gave the desired product (85 mg, 65%). EI-MS m/z 359.4 (M+).
Reaction SMILES: [CH2:1]([C:3]1[C:12]([OH:13])=[CH:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[CH3:2].Cl[C:15]1[C:24]2[C:19](=[CH:20][C:21]([O:27][CH3:28])=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1.O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1Cl>[CH3:26][O:25][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][C:21]=1[O:27][CH3:28])[N:18]=[CH:17][CH:16]=[C:15]2[O:13][C:12]1[C:3]([CH2:1][CH3:2])=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][N:6]=2
Reactant: CCc1nc2ncccc2cc1O
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: Clc1ccccc1Cl
Solvent: O
Product: CCc1nc2ncccc2cc1Oc1ccnc2cc(OC)c(OC)cc12
Temperature: 140 °C
Reaction time: 2 h
Yield: 56.2 %

Procedure:
2-Ethyl-[1,8]naphthyridin-3-ol (30 mg), 4-chloro-6,7-dimethoxyquinoline (115 mg), and 4-dimethylaminopyridine (63 mg) were suspended in o-dichlorobenzene (2 ml), and the suspension was stirred at 140° C. for 2 hr. The reaction solution was cooled to room temperature, water was then added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (35 mg, yield 57%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][C@@H:16]([CH3:19])[CH2:17][OH:18])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:15][C@@H:16]([CH3:19])[CH2:17][O:18][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@@H](CO)Nc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: C[C@@H](CO[Si](C)(C)C(C)(C)C)Nc1c([N+](=O)[O-])cnc2cc(Br)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A solution of (2S)-2-[(7-bromo-3-nitroquinolin-4-yl)amino]propan-1-ol (30.0 g, 92.0 mmol) dissolved in 100 mL of anhydrous pyridine was treated with tert-butyldimethylsilyl chloride (15.2 g, 101.2 mmol) and a catalytic amount of DMAP (112 mg, 0.92 mmol). After stirring overnight at ambient temperature under an atmosphere of N2, the reaction mixture was concentrated under reduced pressure. The resulting solid was partitioned between CH2Cl2 (500 mL) and H2O (500 mL). The layers were separated and the organic portion was concentrated under reduced pressure to give 40.5 g of 7-bromo-N-((1S)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-methylethyl)-3-nitroquinolin-4-amine as a yellow, crystalline solid.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C@H:25]([O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:10][CH2:11][C:12](=O)[CH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1)=O)(C)(C)C>C(Cl)Cl>[Si:35]([O:34][C@@H:25]([C@H:9]1[CH2:10][CH2:11][C:12]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=2)=[N:8]1)[CH2:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:38]([CH3:41])([CH3:39])[CH3:40])([CH3:37])[CH3:36]
Reactant: COC(=O)c1ccc(CC(=O)CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](COc2ccccc2)O[Si](C)(C)C(C)(C)C)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CC2=N[C@@H]([C@@H](COc3ccccc3)O[Si](C)(C)C(C)(C)C)CC2)cc1
Yield: 124.3 %

Procedure:
Methyl 4-{(5R,6S)-5-[(tert-butoxycarbonyl)amino]-6-{[tert-butyl(dimethyl)silyl]oxy}-2-oxo-7-phenoxyheptyl}benzoate from step F (130 mg, 0.22 mM) in 5 ml of methylene chloride was treated with 0.5 ml of TEA at RT for 20 min. The volitiles were removed via concentrating under reduced pressure to afford 129 mg of the title compound. This material was directly used for next step. LC-MS: m/z (ES) 468.17 (M+1).