Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][N:22]3[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]3)[CH2:17][CH2:16]1)=[CH:11][C:10]([C:35]1[CH:40]=[C:39]([F:41])[C:38]([OH:42])=[C:37]([Cl:43])[CH:36]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].O.[ClH:45]>C1COCC1>[ClH:43].[ClH:45].[Cl:43][C:37]1[CH:36]=[C:35]([C:10]2[CH:11]=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[CH:5][C:4]([C:1](=[O:3])[CH3:2])=[C:13]3[NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[CH2:17][CH2:16]2)[CH:40]=[C:39]([F:41])[C:38]=1[OH:42]
Reactant: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN2CCN(C(=O)OC(C)(C)C)CC2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)cc2c1N[C@H]1CC[C@H](CN2CCNCC2)CC1
Temperature: 65 °C

Procedure:
To a solution of tert-butyl 4-((trans-4-((3-acetyl-6-(3-chloro-5-fluoro-4-hydroxyphenyl)quinolin-4-yl)amino)cyclohexyl)methyl)piperazine-1-carboxylate (66 mg, 0.10 mmol) in THF (5 mL) was added water (5 mL) and aqueous 6 N HCl (1.0 mL). The reaction mixture was heated at 65° C. for 2 h, cooled to room temperature and concentrated. The resultant residue was purified by preparative HPLC (C18 silica, 10-90% acetonitrile/water with 0.05% TFA). The residue was dissolved in methanol (5 mL) and HCl (6 M in water, 0.5 mL, 3 mmol) was added. The resultant solution was concentrated to give the desired product (24.2 mg, 41%) as an off-white solid. 1H NMR (500 MHz, MeOD) δ 9.10 (s, 1H), 8.48 (s, 1H), 8.27 (dd, J=8.7, 1.7 Hz, 1H), 7.98 (d, J=8.7 Hz, 1H), 7.59 (s, 1H), 7.52 (d, J=11.3 Hz, 1H), 4.57-4.53 (br s, 1H), 3.67 (br s, 4H), 3.50 (br s, 2H), 3.17 (br s, 2H), 2.74 (s, 3H), 2.46 (d, J=11.9 Hz, 2H), 2.18 (d, J=12.5 Hz, 2H), 2.10 (br s, 1H), 1.83-1.77 (m, 2H), 1.41-1.34 (m, 2H). ESI MS m/z 511 [C28H32ClFN4O2+H]+; HPLC 98.3% (AUC), tR=9.38 min.
Reaction SMILES: [CH2:1]([C:4]1[C:5](=[O:19])[NH:6][C:7](=[O:18])[N:8]([CH:17]=1)[C@@H:9]1[O:16][C@H:13]([CH2:14]O)[C@@H:11]([OH:12])[CH2:10]1)[CH2:2][CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:39]=[N+:40]=[N-:41].[Na+].C(Br)(Br)(Br)Br>CN(C)C=O.CO>[N:39]([CH2:14][C@H:13]1[O:16][C@@H:9]([N:8]2[CH:17]=[C:4]([CH2:1][CH2:2][CH3:3])[C:5](=[O:19])[NH:6][C:7]2=[O:18])[CH2:10][C@@H:11]1[OH:12])=[N+:40]=[N-:41]
Reactant: [N-]=[N+]=[N-]
Reactant: CCCc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Agent: BrC(Br)(Br)Br
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: CCCc1cn([C@H]2C[C@H](O)[C@@H](CN=[N+]=[N-])O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.8 %

Procedure:
0.57 g of 2'-deoxy-5-n-propyluridine, 0.6 g of triphenylphosphine and 0.69 g of sodium azide were stirred in 20 ml of dry dimethylformamide. 0.77 g of carbon tetrabromide was added over a period of 5 minutes. The mixture was stirred at room temperature for 72 hours, 20 ml of methanol were added and the mixture was stirred for a further 0.5 hour. The mixture was evaporated and the residue was stirred with a mixture of 25 ml of dichloromethane/ methanol (8:2). An insoluble solid was removed by filtration and the filtrate was chromatographed on 200 g of silica gel in the same solvent mixture to give 0.41 g of 5'-azido-2',5'-dideoxy-5-n-propyluridine of melting point 177°-179° C. (decomposition).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[Cl:13])(=O)C.[CH3:14][O-:15].[Na+].C1(S([O-])(=O)=O)C=CC=CC=1.[Na+]>CO>[CH3:1][O:4][CH:5]([O:15][CH3:14])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[Cl:13]
Reactant: C[O-]
Reactant: CC(=O)OCc1ccc(F)cc1Cl
Agent: O=S(=O)([O-])c1ccccc1
Agent: [Na+]
Solvent: CO
Product: COC(OC)c1ccc(F)cc1Cl

Procedure:
Electrolyte: 900 g (4.445 mol) of 2-chloro-4-fluorobenzyl acetate, 30 g of sodium methylate, 90 g of sodium benzenesulfonate and 5040 g of methanol
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:11]([O:13][CH3:14])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[H][H]>CO.[Rh]>[ClH:1].[NH2:2][C@@H:3]([CH2:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)[C@@H](N)Cc1ccccc1
Reactant: [H][H]
Agent: [Rh]
Agent: Cl
Solvent: CO
Product: COC(=O)[C@@H](N)CC1CCCCC1

Procedure:
L-Phenylalanine, methyl ester, hydrochloride, 292 g (1.35 mol) in about 4 L of methanol is exposed to hydrogen gas in the presence of 10% Rhodium on carbon catalyst. After hydrogen uptake is complete, the catalyst is filtered and the filtrate concentrated under reduced pressure to a volume of about 500 ml. Diethyl ether, about 1 liter, is added to the thick slurry of crystals and the mixture filtered and washed with diethyl ether to afford 288.9 g of (S)-α-aminocyclohexanepropanoic acid, methyl ester, hydrochloride; mp 157°-159° C.; [α]D23 =+21.6° (c=1.09% methanol).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[N:54]([C:57]1[CH:61]=[CH:60][O:59][C:58]=1[CH3:62])=[C:55]=[O:56]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:53]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][CH2:46][CH:47]1[CH2:48][CH2:49][N:50]([C:55]([NH:54][C:57]2[CH:61]=[CH:60][O:59][C:58]=2[CH3:62])=[O:56])[CH2:51][CH2:52]1
Reactant: Clc1cnc2nc1Nc1ccc(OCCC3CCNCC3)c(c1)CCc1cncc(c1)N2
Reactant: Cc1occc1N=C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1occc1NC(=O)N1CCC(CCOc2ccc3cc2CCc2cncc(c2)Nc2ncc(Cl)c(n2)N3)CC1
Yield: 8 %

Procedure:
The desired compound was prepared according to the procedure of Example D41 using 6-chloro-12-(2-piperidin-4-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 3-isocyanato-2-methylfuran as the starting materials in 8% yield. LCMS for C30H33ClN7O3 (M+H)+: m/z=574.1.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([CH:16]=[C:17]([O:19]CC4C=CC=CC=4)[CH:18]=3)[C:13]([OH:15])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[NH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=1.C(N(CC)CC)C>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[CH:11]=[C:12]([CH:16]=[C:17]([OH:19])[CH:18]=3)[C:13]([NH:51][C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[O:15])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cc(OCc2ccccc2)cc(-c2ccc3c(c2)OCO3)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)c1cc(O)cc(-c2ccc3c(c2)OCO3)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
3-Benzo[1,3]dioxol-5-yl-5-benzyloxy-benzoic acid (500 mg), PyBroP (1.2 eq.), aniline (1.1 eq.), and triethylamine (2 eq.) were combined in dichloromethane (5 mL) and stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with water. White solid which precipitated in dichloromethane layer was collected by filtration (493 mg). This material was dissolved in THF and hydrogenated over 10% Pd/C (50 mg) in Parr apparatus for 5 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure and purified on a silica gel column using ethyl acetate and hexanes to yield 362 mg of title compound (76% yield after 2 steps).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=1)=[C:11]2[C@H:25]([CH3:28])[CH2:26][NH2:27])([CH3:7])[CH3:6])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl-].C([N+]1(C)[CH2:44][CH2:43][C:42](=[O:45])[CH2:41][CH2:40]1)C>C(OCC)(=O)C>[CH2:1]([O:3][C:4](=[O:29])[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]1[CH:18]=[C:19]([CH3:24])[CH:20]=[C:21]([CH3:23])[CH:22]=1)=[C:11]2[C@H:25]([CH3:28])[CH2:26][N:27]1[CH2:44][CH2:43][C:42](=[O:45])[CH2:41][CH2:40]1)([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c([C@H](C)CN)c2c1
Reactant: CC[N+]1(C)CCC(=O)CC1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(C)c1ccc2[nH]c(-c3cc(C)cc(C)c3)c([C@H](C)CN3CCC(=O)CC3)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a solution of (S)-2-[3-(2-amino-1-methylethyl)-2-(3,5-dimethylphenyl)-1H-indol-5-yl]-2-methylpropionic acid ethyl ester (EXAMPLE 1, Step 1B, 0.50 g in 2 mL ethanol) was added 18 mg potassium carbonate followed by the dropwise addition of a solution of 1-ethyl-1-methyl-piperidinium-4-one chloride (513 mg in 0.80 water) and the mixture heated to reflux on an oil bath. After 1 hour, the mixture was cooled to room temperature, diluted with ethyl acetate and washed successively with 10% aqueous sodium bisulfate, water, saturated aqueous sodium bicarbonate and brine. The organic portion was dried over sodium sulfate, concentrated in vacuo and the residue purified by flash chromatography on silica gel (hexane:ethyl acetate, 7:3) to give the title compound (356 mg).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[CH3:9][O:8][C:6]([C:5]1[CH:10]=[CH:11][C:2]([N:18]2[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]2)=[C:3]([N+:12]([O-:14])=[O:13])[CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.9 %

Procedure:
To a solution of methyl 4-fluoro-3-nitrobenzoate (2.50 g, 12.6 mmol) in tetrahydrofuran (75 mL), tert-butyl piperazine-1-carboxylate (4.67 g, 25.2 mmol) and potassium carbonate (4.34 g, 25.2 mmol) were added sequentially under ice-cold conditions, and the mixture was stirred at room temperature for 1 hour. The reaction solution was added water under ice-cold conditions, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (ethyl acetate). The title compound (4.83 g (yield 100%)) was obtained as a yellow crystal.
Reaction SMILES: C1(C2C3C(=C(CO)C=CC=3)C=CN=2)C=CC=CC=1.C[C:20]1[CH:25]=[CH:24][C:23]([C:26]2[C:35]3[CH:34]=[CH:33][CH:32]=[C:31]([CH2:36][C:37]#[N:38])[C:30]=3[CH:29]=[CH:28][N:27]=2)=[CH:22][CH:21]=1>>[CH2:23]([C:26]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([CH2:36][C:37]#[N:38])[C:30]=2[CH:29]=[CH:28][N:27]=1)[CH2:22][CH2:21][CH2:20][CH2:25][CH3:24]
Reactant: Cc1ccc(-c2nccc3c(CC#N)cccc23)cc1
Agent: OCc1cccc2c(-c3ccccc3)nccc12
Product: CCCCCCc1nccc2c(CC#N)cccc12

Procedure:
1-Amino-2-(2-chlorophenyl)ethane and n-heptanoyl chloride were reacted in the same way as in step (a) of Example 13 to afford 1-n-heptanoylamino-2-(2-chlorophenyl)ethane as an oil. The product was successively reacted in the same way as in steps (b), (c), (d), (e), (f), (g) and (h) of Example 13 to afford 1-n-hexylisoquinoline-5-acetonitrile.
Reaction SMILES: [C:1]([CH2:4][S:5][C:6]1[C:7]([Cl:24])=[CH:8][C:9]([F:23])=[C:10]([N:12]2[C:20](=[O:21])[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[C:13]2=[O:22])[CH:11]=1)([OH:3])=[O:2].[CH2:25]([N:27]([CH2:29][CH3:30])O)[CH3:26]>O1CCCC1>[CH2:25]([N:27]([O:2][C:1]([CH2:4][S:5][C:6]1[C:7]([Cl:24])=[CH:8][C:9]([F:23])=[C:10]([N:12]2[C:20](=[O:21])[C:19]3[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=3[C:13]2=[O:22])[CH:11]=1)=[O:3])[CH2:29][CH3:30])[CH3:26]
Reactant: O=C(O)CSc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Reactant: CCN(O)CC
Solvent: C1CCOC1
Product: CCN(CC)OC(=O)CSc1cc(N2C(=O)C3=C(CCCC3)C2=O)c(F)cc1Cl
Yield: 72.5 %

Procedure:
In 20 ml of tetrahydrofuran, 1.85 g of 2-(5-carboxymethylthio-4-chloro -2-fluorophenyl)-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione was dissolved, to which 0.97 g of N,N'-carbonyldiimidazole was added and the resultant mixture was stirred for 30 minutes at room temperature. To the resultant mixture, 0.53 g of N,N-diethylhydroxylamine was added, and the resultant mixture was stirred for 2 hours at room temperature. After completion of the reaction, the reaction mixture was poured into a saturated saline solution and extracted with ethyl acetate. The extract was washed with a saturated saline solution, dried with anhydrous magnesium sulfate, and evaporated to remove the solvent under reduced pressure. The residue was purified by silica gel chromatography (eluent; hexane:ethyl acetate=5:1 to 3:1), which afforded 1.60 g of 2-[5-(N,N-diethylaminooxycarbonylmethylthio)-4-chloro-2-fluorophenyl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:13]([OH:15])=[O:14])[CH:7]=C[C:9]=1F)(=[O:3])[NH2:2].[NH2:26]C1C=NC=C(C=1)C(N)=O.COC1C=C(B(O)O)C=CC=1OC.O.C(O)(=O)C=O>>[C:1]([C:4]1[CH:5]=[C:6]([NH:11][CH:12]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH3:25])[CH:17]=2)[C:13]([OH:15])=[O:14])[CH:7]=[N:26][CH:9]=1)(=[O:3])[NH2:2]
Reactant: COc1ccc(C(Nc2ccc(F)c(C(N)=O)c2)C(=O)O)cc1OC
Reactant: NC(=O)c1cncc(N)c1
Agent: COc1ccc(B(O)O)cc1OC
Agent: O=CC(=O)O
Solvent: O
Product: COc1ccc(C(Nc2cncc(C(N)=O)c2)C(=O)O)cc1OC
Yield: 63 %

Procedure:
97C was prepared in a procedure similar to that of 13A using 97B, 3,4-dimethoxyphenylboronic acid and glyoxylic acid monohydrate. Yield: 63%. 1H NMR (400 MHz, Methanol-d4) δ ppm 3.82 (s, 3H) 3.84 (s, 3H) 5.28 (s, 1H) 6.97 (d, J=8.35 Hz, 1H) 7.08 (s, 1H) 7.13 (d, J=2.20 Hz, 1H) 8.14 (s, 2H) 8.38 (s, 1H); LCMS: 331 (M+1).
Reaction SMILES: [H-].[Na+].Cl[C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[C:14]#[N:15])=[N:11][C:10]([O:16][CH3:17])=[CH:9][CH:8]=2.[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>O1CCCC1>[CH2:18]([O:25][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[C:14]#[N:15])=[N:11][C:10]([O:16][CH3:17])=[CH:9][CH:8]=2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1ccc2ncc(Cl)c(C#N)c2n1
Reactant: OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc2ncc(OCc3ccccc3)c(C#N)c2n1
Temperature: -30 °C
Reaction time: 2 h
Yield: 63.1 %

Procedure:
Sodium hydride (70 mg, 1.73 mmol, 2.0 eq) is added at −30° C. to a stirred solution of 3-chloro-6-methoxy-[1,5]naphthyridine-4-carbonitrile (190 mg, 0.87 mmol, 1.0 eq) and benzyl alcohol (187 mg, 1.73 mmol, 2.0 eq) in tetrahydrofuran (12 mL). After 2 hours stirring at −30° C., the reaction mixture is concentrated and extracted with ethyl acetate (3×20 mL) and water (20 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: petroleum ether:ethyl acetate, 5:1, v/v) to afford 3-benzyloxy-6-methoxy-[1,5]naphthyridine-4-carbonitrile as a light yellow solid (160 mg, 64% yield).
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([OH:16])=O)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[CH:19]([NH:22][N:23]=[C:24]([NH2:26])[CH3:25])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:18]=[CH:17][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]([N:26]=[C:24]([NH:23][NH:22][CH:19]([CH3:21])[CH3:20])[CH3:25])=[O:16])[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1
Reactant: O=C(O)c1cn2c(n1)-c1ccc(Br)cc1OCC2
Reactant: CC(N)=NNC(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CC(=NC(=O)c1cn2c(n1)-c1ccc(Br)cc1OCC2)NNC(C)C

Procedure:
Coupling of 28 with N′-isopropylacetohydrazonamide 6 and coupling reagent HBTU in DMF gives intermediate, 9-bromo-N-(1-(2-isopropylhydrazinyl)ethylidene)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide 34, which forms III upon heating.
Reaction SMILES: P(Cl)(Cl)(OC)=O.[CH3:7][O:8][C:9]1[N:14]=[C:13](/[CH:15]=[CH:16]/[C:17]([NH2:19])=O)[CH:12]=[CH:11][C:10]=1[N:20]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]1.C1CCN2C(=NCCC2)CC1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[CH3:7][O:8][C:9]1[N:14]=[C:13](/[CH:15]=[CH:16]/[C:17]#[N:19])[CH:12]=[CH:11][C:10]=1[N:20]1[CH:24]=[C:23]([CH3:25])[N:22]=[CH:21]1
Reactant: COc1nc(/C=C/C(N)=O)ccc1-n1cnc(C)c1
Agent: COP(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc(/C=C/C#N)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 0.58 h
Yield: 85.8 %

Procedure:
Methyl dichlorophosphate (33 ml) was added dropwise to a suspension of (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide (42.96 g) and 1,8-diazabicyclo[5,4,0]-7-undecene (112 ml) in methylene chloride (400 ml) under ice-cooling over 20 minutes. The reaction solution was stirred at the same temperature for 10 minutes and at room temperature for further 35 minutes. Then, a saturated sodium bicarbonate solution (200 ml) was added to the reaction solution, and the reaction solution was stirred at room temperature for 10 minutes. Water was added to the reaction solution. Then, the reaction solution was filtered and the organic layer in the filtrate was separated. The aqueous layer was reextracted with methylene chloride (twice). The combined organic layers were dried over anhydrous magnesium sulfate and purified by short silica gel column chromatography (carrier: Chromatorex NH; elution solvent: methylene chloride). The eluted fraction was concentrated. The resulting residue was triturated with ethyl acetate and tert-butyl methyl ether and dried under reduced pressure overnight to obtain 34.28 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31](OCC)=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)(=[O:24])=[O:23])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH3:37][O:38][CH2:39][CH2:40][NH2:41]>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:36])=[C:14]([C:31]([NH:41][CH2:40][CH2:39][O:38][CH3:37])=[O:32])[C:15](=[O:30])[N:16]3[CH2:19][CH2:20][CH2:21][S:22]([N:25]3[CH2:26][CH2:27][CH2:28][CH2:29]3)(=[O:23])=[O:24])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(=O)(=O)N2CCCC2)c1=O
Solvent: CCO
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCS(=O)(=O)N2CCCC2)c1=O
Temperature: 140 °C

Procedure:
To a solution of ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[3-(1-pyrrolidinylsulfonyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.0387 mmol) in ethanol (1 mL) was added 2-methoxyethylamine (40 μL, 0.460 mmol). The reaction mixture was heated in a microwave at 140° C. for 20 minutes. The reaction mixture was concentrated in vacuo. Purification by reverse phase HPLC provided 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(methyloxy)ethyl]-2-oxo-1-[3-(1-pyrrolidinylsulfonyl)propyl]-1,2-dihydro-1,5-naphthyridine-3-carboxamide as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.26 (s, 1H), 8.57 (s, 1 H), 7.75 (s, 1 H), 7.22 (dd, J=8.5, 5.4 Hz, 2 H), 7.02 (t, J=8.7 Hz, 2 H), 4.40 (t, J=8.0 Hz, 2 H), 4.13 (s, 2 H), 3.66 (q, J=5.1 Hz, 2 H), 3.59 (m, 2 H), 3.42 (s, 3 H), 3.37-3.34 (m, 4 H), 3.05 (t, J=6.6 Hz, 2 H), 2.18 (m, 2 H), 1.97-1.93 (m, 4 H); HRMS C26H31FN4O6S (M+H)+ calcd 547.1948, found 547.2009.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2C(=O)C(F)(F)F)=[CH:4][CH:3]=1.[C:18]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([C:24](O)=[O:25])=[CH:20][CH:19]=1.Cl.CN(C)CCCN=C=NCC.[OH-].[Na+]>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOC(C)=O>[NH:9]1[C:10]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][C:24]([C:21]3[CH:22]=[CH:23][C:18]([C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[CH:19][CH:20]=3)=[O:25])[CH:11]=2)[CH2:6][CH2:7][CH2:8]1
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc2c(c1)N(C(=O)C(F)(F)F)CCC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc2c(c1)NCCC2)c1ccc(-c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 7-amino-1-trifluoroacetyl-1,2,3,4-tetrahydroquinoline (D5) (1.17 g, 4.78 mmol) in DCM (20 ml) was added 4-biphenylcarboxylic acid (1.14 g, 5.73 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.06 g, 5.73 mmol) and 4-dimethylaminopyridine (70 mg, 0.57 mmol) and the reaction stirred at room temperature. After 3.75 h the reaction mixture was treated with 2M sodium hydroxide solution overnight. An acid/base work-up followed by flash column chromatography with an EtOAc/60-80° C. petroleum ether gradient gave the title compound as a beige solid. 1H NMR (250 MHz, CDCl3) δ (ppm): 7.91 (d, 2H), 7.63 (m, 5H), 7.47 (t, 2H), 7.41 (t, 1H), 7.11 (d, 1H), 6.91 (d, 1H), 6.61 (dd, 1H), 3.94 (br, 1H), 3.31 (m, 2H), 2.74 (t, 2H), 1.93 (m, 2H), 1.57 (br, 2H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])[CH2:4][CH2:3]1.[CH2:14](OC(=N)C(Cl)(Cl)Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.FC(F)(F)S(O)(=O)=O>C1CCCCC1.C(Cl)Cl>[CH2:14]([O:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])[CH2:4][CH2:3]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N=C(OCc1ccccc1)C(Cl)(Cl)Cl
Reactant: CON(C)C(=O)[C@H]1CC[C@@H](O)CC1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: CON(C)C(=O)[C@H]1CC[C@@H](OCc2ccccc2)CC1
Reaction time: 0.5 h

Procedure:
To a mixture of cis-4-hydroxy-N-methoxy-N-methylcyclohexanecarboxamide (3.556 g, 0.0190 mol) and benzyl-2,2,2-trichloroacetimidate (4.0 mL, 0.021 mol, 1.1 eq) in cyclohexane/DCM (20 mL/10 mL) at 0° C. was added trifluoromethanesulfonic acid dropwise with stirring under nitrogen atmosphere over 30 min. There was an immediate precipitate. The mixture was stirred at room temperature for 15 h, filtered, and the filtrate washed with sodium bicarbonate solution and brine. The organic layer was concentrated and purified by silica gel column chromatography using petroleum ether/ethyl acetate (5/1) as eluent to give product as a colorless oil (5.079 g, 77%). 1H NMR (400 MHz, CDCl3) δ7.38-7.23 (m, 5H), 4.50 (s, 2H), 3.71 (s, 3H), 3.70-3.66 (m, 1H), 3.18 (s, 3H), 2.78-2.62 (m, 1H), 2.07-1.89 (m, 4H), 1.59-1.25 (m, 4H).