Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]([F:26])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([C:23](O)=[O:24])=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1.[NH2:27][C@@H:28]1[CH2:33][CH2:32][C@H:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[F:1][CH:2]([F:26])[O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[N:8]=[C:7]2[C:14]1[N:15]=[C:16]2[C:22]([C:23]([NH:27][C@@H:28]3[CH2:33][CH2:32][C@H:31]([NH:34][C:35](=[O:41])[O:36][C:37]([CH3:39])([CH3:38])[CH3:40])[CH2:30][CH2:29]3)=[O:24])=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2cc(OC(F)F)ccc21
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)N[C@H]4CC[C@@H](NC(=O)OC(C)(C)C)CC4)c3n2)c2cc(OC(F)F)ccc21

Procedure:
2-(5-(Difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (150 mg, 0.43 mmol), tert-butyl cis-4-aminocyclohexylcarbamate (102 mg, 0.48 mmol) and HATU (196 mg, 0.51 mmol) in 15 mL of dry THF was stirred for 4 hours. The reaction mixture was evaporated to dryness, the residue was suspended in 50 mL of 0.5N HCl, extracted with ethyl acetate (3×50 mL), dried over sodium sulfate and concentrated to give tert-butyl cis-4-(2-(5-(difluoromethoxy)-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamido)cyclohexylcarbamate (54 mg, crude). LCMS: (M+H)+=556; (M+Na)+=578. Used in the next step without further purification.
Reaction SMILES: [N:1]([CH:4]1[C:10](=[O:11])[N:9]([CH2:12][CH3:13])[C:8]2[CH:14]=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[C:17]([O:18][CH3:19])[C:7]=2[CH2:6][CH2:5]1)=[N+]=[N-].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>O>[NH2:1][CH:4]1[C:10](=[O:11])[N:9]([CH2:12][CH3:13])[C:8]2[CH:14]=[CH:15][C:16]([N+:20]([O-:22])=[O:21])=[C:17]([O:18][CH3:19])[C:7]=2[CH2:6][CH2:5]1
Reactant: CCN1C(=O)C(N=[N+]=[N-])CCc2c1ccc([N+](=O)[O-])c2OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCN1C(=O)C(N)CCc2c1ccc([N+](=O)[O-])c2OC

Procedure:
Combined (+/−)-3-Azido-1-ethyl-6-methoxy-7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (280 mg), Triphenylphosphine Resin (1.0 mmol/g loading; 1.83 g), Tetrahydrofuran (25 mL) and Water (0.25 mL) and stir at rt overnight. Filter and concentrate. Strip down from benzene to remove water. (+/−)-3-Amino-1-ethyl-6-methoxy 7-nitro-1,3,4,5-tetrahydro-benzo[b]azepin-2-one as an orangish oil isolated (251 mgs). 1H-NMR (CDCl3, 400 MHz): 7.84 (d, J=8.8 Hz, 1H), 7.10 (d, J=8.9 Hz, 1H), 4.36-4.28 (m, 1H), 3.97 (s, 3H), 3.71-3.62 (m, 1H), 3.36-3.31 (m, 1H), 3.23-3.18 (m, 1H), 2.52-2.39 (m, 2H), 2.03-1.99 (m, 1H), 1.66 (broad s, 2H), 1.21 (t, J=7.3 Hz, 3H). LC/MS: (M+H)+ found 280.18.
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[CH:6][C:7]([C:15]([OH:17])=O)=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH2:18][C@@H:19]([CH2:24][CH:25]1[CH2:27][CH2:26]1)[C:20]([CH3:23])([OH:22])[CH3:21]>>[CH:25]1([CH2:24][C@H:19]([NH:18][C:15]([C:7]2[CH:6]=[N:5][C:4]([CH:1]3[CH2:2][CH2:3]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:17])[C:20]([OH:22])([CH3:23])[CH3:21])[CH2:27][CH2:26]1
Reactant: CC(C)(O)[C@@H](N)CC1CC1
Reactant: O=C(O)c1cnc(C2CC2)c(OCC2CC2)n1
Product: CC(C)(O)[C@H](CC1CC1)NC(=O)c1cnc(C2CC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 15, using 5-cyclopropyl-6-cyclopropylmethoxy-pyrazine-2-carboxylic acid (Example 10 g, 100 mg, 0.43 mmol) and (S)-3-amino-4-cyclopropyl-2-methyl-butan-2-ol (87.83 mg, 0.64 mmol) as starting materials, and isolated (20 mg, 13.03%) as off white solid, LC-MS (UV peak area, ESI) 98.68%, 360.8 (M+H).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1([F:18])[CH2:12][CH2:11][CH:10]([C:13](OCC)=[O:14])[CH2:9]1>C1COCC1.C(OCC)C>[F:7][C:8]1([F:18])[CH2:12][CH2:11][CH:10]([CH2:13][OH:14])[CH2:9]1
Reactant: CCOC(=O)C1CCC(F)(F)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: OCC1CCC(F)(F)C1
Reaction time: 1 h

Procedure:
6.4 ml of a 1M solution of lithium aluminum hydride in THF are initially charged in 40 ml of diethyl ether. With ice cooling, 1.12 g of ethyl 3,3-difluoro-cyclopentanecarboxylate dissolved in 10 ml of diethyl ether are added dropwise under argon. After one hour, the cooling bath is removed, and the reaction mixture is stirred for another three hours. The reaction mixture is then poured onto ice-cold saturated ammonium chloride solution and filtered off over a filtration aid. The filtrate is washed with saturated NaHCO3 solution, dried over MgSO4 and concentrated under reduced pressure. This gives 625 mg of (3,3-difluorocyclopentyl)methanol.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH2:19])[CH:13]=2)[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[NH:8][C:7]=1[CH3:26])=[O:5])[CH3:2].[CH2:27]([N:29]([CH2:33][CH3:34])[CH2:30][CH2:31]Cl)[CH3:28]>O>[CH2:23]([O:22][C:20]([C:10]1[CH:11]([C:12]2[C:17]([Cl:18])=[CH:16][CH:15]=[C:14]([NH:19][CH2:28][CH2:27][N:29]([CH2:33][CH3:34])[CH2:30][CH3:31])[CH:13]=2)[C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[C:7]([CH3:26])[NH:8][C:9]=1[CH3:25])=[O:21])[CH3:24]
Reactant: CCN(CC)CCCl
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cc(N)ccc1Cl
Solvent: O
Product: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cc(NCCN(CC)CC)ccc1Cl

Procedure:
Thirty grams of 2,6-dimethyl-4-(3-amino-6-chlorophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester (melting point 210°) and 15 ml of 2-diethylaminoethyl chloride are heated for 15 minutes to about 200° and the mixture is taken up in hot water, rendered alkaline after addition of ice and extracted with ether.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[O:15])=[CH:4][CH:3]=1.[C:16]1([CH2:22][CH2:23][CH2:24][Mg]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:15])[CH2:24][CH2:23][CH2:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=O
Reactant: Br[Mg]CCCc1ccccc1
Solvent: CCO
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)CCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 114, Step 3, using 5-(4-bromo-phenyl)-3-methyl-isoxazole-4-carbaldehyde and 3-(phenyl)propylmagnesium bromide. After the reaction the material was submitted to chiral preparatory HPLC (Chiralcel AS Column, 2% EtOH in hexanes, 60 minute run). The first enantiomer off of the column is Enantiomer A.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13]C)=[CH:9][C:8]=1F)=[O:5].[Cl-:16].[Al+3].[Cl-].[Cl-]>CCCCCCC.C(Cl)(Cl)Cl>[Cl:16][C:12]1[CH:11]=[C:10]([OH:13])[CH:9]=[C:8]2[C:7]=1[NH:6][C:4](=[O:5])[CH2:3][CH2:2]2
Reactant: COc1ccc(NC(=O)CCCl)c(F)c1
Reactant: [Cl-]
Agent: [Al+3]
Solvent: ClC(Cl)Cl
Solvent: CCCCCCC
Product: O=C1CCc2cc(O)cc(Cl)c2N1
Temperature: 110 °C
Reaction time: 72 h
Yield: 6.9 %

Procedure:
A suspension of 3-chloro-N-(2-fluoro-4-methoxyphenyl)propaneamide (1.0 g, synthesized from 3-chlorobutyryl chloride and 2-fluoro-4-methoxyaniline) and aluminum chloride (5.0 g) in n-heptane (2.0 mL) was stirred at 110° C. for 3 days. The reaction mixture was diluted with chloroform, followed by addition of ice-cold water under ice cooling. After stirring at room temperature for 2 hours, the organic layer and the aqueous layer were separated. The aqueous layer was extracted with chloroform, and the organic layers were combined, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluting solvent: hexane/ethyl acetate=3/2) and NH-type silica gel column chromatography (eluting solvent: chloroform/methanol=99/1 to 9/1) to give the titled compound (0.059 g, 7%) as a light-yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24]Br)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:31][C@H:32]1[CH2:37][CH2:36][CH2:35][C@@H:34]([CH3:38])[NH:33]1>CN(C)C=O.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:27][CH3:28])=[C:17]([NH:20][C:21](=[O:26])[CH:22]=[CH:23][CH2:24][N:33]4[CH:34]([CH3:38])[CH2:35][CH2:36][CH2:37][CH:32]4[CH3:31])[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:29]#[N:30])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCBr
Reactant: C[C@@H]1CCC[C@H](C)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1NC(=O)C=CCN1C(C)CCCC1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
A mixture of 250 mg (0.51 mmol) of 4-bromo-but-2-enoic acid[4-(3-chloro-4-fluoro-phenylamino)-3-cyano-7-methoxy-quinolin-6-yl]-amide, and 137 μL (1.02 mmol) of cis-2,6-dimethylpiperidine in 2.25 ml dimethylformamide was stirred at room temperature for 3 hr. The reaction mixture was diluted with saturated sodium bicarbonate solution and extracted with ethyl acetate. The extracts were evaporated to an oil, washed with hexane and dried under reduced pressure to yield 170.4 mg (64%) tan solid: mp 120-122° C.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13]1([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:1]([N:22]1[CH2:23][CH2:24][N:19]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:20][CH2:21]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: c1ccc(N2CCNCC2)cc1
Product: CCCCCCC/C=C/C(=O)N1CCN(c2ccccc2)CC1

Procedure:
The same procedures as in Example 1 were carried out using (E)-2-decenoic acid and 1-phenylpiperazine as starting raw materials, to produce an intended compound.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][C@H:6](O)[CH2:5][C@@H:4]1[C:9]([OH:11])=[O:10])[CH3:2].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCOCC>C(Cl)Cl>[CH2:1]([C@@H:3]1[CH2:7][C@H:6]2[CH2:5][C@@H:4]1[C:9](=[O:10])[O:11]2)[CH3:2]
Reactant: CC[C@@H]1C[C@H](O)C[C@@H]1C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: ClCCl
Solvent: CCOCC
Product: CC[C@@H]1C[C@H]2C[C@@H]1C(=O)O2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To (1S,2R,4S)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (0.943 g, 5.96 mmol) in DCM (60 mL) was added TEA (2.5 mL, 18 mmol) and BOP-Cl (1.821 g, 7.15 mmol). The reaction mixture was stirred at ambient temperature for about 2 h then poured into Et2O (350 mL). The solid was removed by filtration while washing with Et2O (50 mL). The filtrate was coned under reduced pressure to give a yellow oil which was dissolved in DCM (5 mL) and Et2O was added to give a solid. The supernatant was decanted and the solid was washed with additional Et2O. The combined organic extracts were coned under reduced pressure to give crude (1S,4S,5R)-5-ethyl-2-oxabicyclo[2.2.1]heptan-3-one containing about 15 mol % TEA (0.912 g, 99%): 1H NMR (CDCl3) δ 4.85 (s, 1H), 2.88 (s, 1H), 2.19 (m, 2H), 2.08 (m, 1H), 1.69 (m, 1H), 1.41 (m, 3H), 0.97 (t, J=5.4, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([OH:10])=O)[CH:4]=1.S(Cl)([Cl:13])=O>N1C=CC=CC=1>[Cl:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]([Cl:13])=[O:10])[CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(CCl)on1
Solvent: c1ccncc1
Product: O=C(Cl)c1cc(CCl)on1

Procedure:
120 g (743 mmol) of 5-chloromethylisoxazole-3-carboxylic acid together with 500 ml of thionyl chloride and 2 drops of pyridine were refluxed for 10 hours, subsequently concentrated in vacuo and then distilled at 20 torr. The product distilled at 125-1330C. 78 g resulted (58% of theory)
Reaction SMILES: [C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([O:16]CC)=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[N:29]=[C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[S:31][CH:32]=4)=[CH:22][CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[C:1]1([C:7]2[C:11]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:10][N:9]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[N:29]=[C:30]([C:33]5[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=5)[S:31][CH:32]=4)=[CH:22][CH:21]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CCc1cn(Cc2ccc(OCc3csc(-c4ccccc4)n3)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
After a mixture of ethyl 3-[3-phenyl-1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionate (1110 mg), 1N sodium hydroxide solution (5 ml), tetrahydrofuran (5 ml), and ethanol (5 ml) was stirred at room temperature for 2 hours, 1 N hydrochloric acid (5 ml) was added to the mixture, and then the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The resulting colorless crystals were collected by filtration to obtain 3-[3-phenyl-1-[4-(2-phenyl-4-thiazolylmethoxy)benzyl]-1H-pyrazol-4-yl]propionic acid (630 mg, yield: 60%). This was recrystallized from acetone-hexane. Melting point: 132–133° C.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH:2]=[CH2:3].[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][SH:13]>>[S:7]1[CH:11]=[CH:10][CH:9]=[C:8]1[CH2:12][S:13][CH2:3][CH2:2][C:1]([O:5][CH3:6])=[O:4]
Reactant: SCc1cccs1
Reactant: C=CC(=O)OC
Product: COC(=O)CCSCc1cccs1

Procedure:
Methyl 3-[(2-thienylmethyl)thio]propanoate (55) was prepared in the manner described above in Example 52 using methyl acrylate and 2-thienylmethyl mercaptan.
Reaction SMILES: [C:1]([C:5]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:7]([C:8]([OH:10])=[O:9])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2].[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[C:1]([C:5]1[CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[C:11]([CH3:14])=[C:7]([C:8]([OH:10])=[O:9])[C:6]=1[OH:15])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C(C)(C)C)c(O)c1C(=O)O
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Cc1c([N+](=O)[O-])cc(C(C)(C)C)c(O)c1C(=O)O
Temperature: 15 °C

Procedure:
3-tert. Butyl-6-methyl salicylic acid (62.4 g 0.3M) was suspended in glacial acetic acid (300 ml) and cooled to 15°C. Concentrated nitric acid (22.5 ml) was added dropwise with stirring at such a rate that the temperature was maintained at approx. 10°-15°C. The mixture was stirred for 1 hour at this temp. and then poured onto crushed ice. A precipitate formed which was filtered off, washed with benzene and finally recrystallized from acetonitrile to give 3-tert. butyl-5-nitro-6-methyl salicylic acid (30.6 g) m.p. 225°-226°(dec)
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH:11]([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13].[C:20]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:11]([CH3:20])([C:16]([O:18][CH3:19])=[O:17])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C(=O)OC)c1ccc([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
To a stirred solution of dimethyl 2-(2-fluoro-4-nitrophenyl)malonate (200 mg, 0.73 mmol, 1.0 eq) and K2CO3 (204 mg 1.47 mmol 2.0 eq) in DMF (5 mL), was added methyl iodide (210 mg, 1.47 mmol 2.0 eq) at RT and the mixture was stirred at RT for 6 h. K2CO3 was filtered out and the filtrate concentrated under vacuum. The residue was diluted with water (50 mL) and extracted with EtOAc (20 mL). The organic layer was separated washed with brine solution, dried over anhydrous Na2SO4 and the solvent evaporated to get dimethyl 2-(2-fluoro-4-nitrophenyl)-2-methylmalonate (150 mg, 71%; TLC system: EtOAc/PE (1:9), Rf: 0.4).
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11](C(OC)=O)=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2C=[CH:23][CH:24]=[CH:25][C:19]=2[O:18][CH2:17][CH:16]([CH2:26][OH:27])[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[CH2:33][O:34][C:35]([CH3:37])=[O:36]>C(Cl)Cl>[CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]3[C:21]=2[C:20]2=[C:37]([C:35]([O:34][CH3:33])=[O:36])[CH:23]=[CH:24][CH:25]=[C:19]2[O:18][CH2:17][CH:16]([CH:26]=[O:27])[CH2:15]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CO)COc1ccccc1-3
Reactant: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)c1cccc2c1-c1c(C3CCCCC3)c3ccccc3n1CC(C=O)CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
A solution (0.03 M) of methyl 14-cyclohexyl-7-(hydroxymethyl)-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (prepared as described in example 13, steps 1-2) in DCM was added to a solution of DMP (0.04 M; 1.25 eq) in DCM at RT. The reaction was then left to stir at RT for 1 h. The mixture was diluted with EtOAc and washed with a 1:1 mixture of sat. aq. NaHCO3 and sodium thiosulfate (aq) (3×) before washing with brine, drying (Na2SO4), filtering and concentrating in vacuo to afford the product as a tinted glass (98%). The material was taken on without further purification. (ES+) m/z 418 (M+H)+; 436 (M+H2O+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][C:18]#[N:19].C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:17][C:18]#[N:19])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CCBr
Reactant: Oc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#CCOc1ccc(OCc2ccccc2)cc1
Temperature: 40 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
A mixture of 4-benzyloxyphenol (9.4 g, 47 mmol), bromoacetonitrile (6.8 g, 56.7 mmol) in acetone (50 mL) with K2CO3 (2 g, 14.5 mmol) was heated to reflux 1 min, then at 40° C. for 1 h with stirring. The reaction mixture was filtered, the solids washed with acetone, and the filtrate concentrated in vacuo to afford a tan oil which crystallized on standing, providing 10.70 g of (4-benzyloxyphenoxy)-acetonitrile.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20](Cl)[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1>O1CCOCC1.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH:14]2[O:23][C:17]3=[CH:18][N:19]=[C:20]([N:26]4[CH:27]=[CH:28][N:29]=[CH:30][C:25]4=[O:24])[CH:21]=[C:16]3[CH2:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(Cl)ncc3O2)CC1
Reactant: Oc1cnccn1
Agent: I[Cu]I
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(C2Cc3cc(-n4ccncc4=O)ncc3O2)CC1
Temperature: 180 °C

Procedure:
A mixture of 4-(5-chloro-2,3-dihydro-furo[2,3-c]pyridin-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (60 mg), 2-hydroxypyrazine (17 mg), and copper iodide (7 mg) in 1,4-dioxan (1 mL) is sparged with argon. N,N′-Dimethylethylendiamine (8.54) and tri-potassium orthophosphate (72 mg) are added and the resulting mixture is heated in a microwave oven to 180° C. for 1 h. The reaction mixture is filtered and chromatographed on silica gel (ethyl acetate) to give the title compound. LC (method 7): tR=1.32 min; Mass spectrum (ESI+): m/z=399 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([CH3:11])=[CH:4][CH:3]=1.[NH2:12][C:13]1[C:22]([CH3:23])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[CH3:24].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([C:8]([NH:12][C:13]2[C:14]([CH3:24])=[CH:15][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:21][C:22]=2[CH3:23])=[O:10])[C:5]([CH3:11])=[CH:4][CH:3]=1
Reactant: Cc1ccc(Cl)nc1C(=O)O
Reactant: COC(=O)c1cc(C)c(N)c(C)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc(C)c(NC(=O)c2nc(Cl)ccc2C)c(C)c1
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
To a solution of 6-chloro-3-methyl-pyridine-2-carboxylic acid (0.70 g, 4.093 mmol, see preparation 1) in CH2Cl2 (6 mL) at 0° C. are added methyl 4-amino-3,5-dimethylbenzoate (0.74 g, 4.093 mmol, see preparation 12), and triethylamine (0.83 g, 8.187 mmol). After stirring the reaction mixture for 10 minutes, 1-propanephosphonic acid cyclic anhydride (50% solution in ethyl acetate, 2.60 g, 8.187 mmol) is added via syringe and stirred at ambient temperature. After 12 hours, the solvent is removed under reduced pressure and the residue is diluted with water and extracted with ethyl acetate. The organic layers are combined and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) using a gradient of 0-40% ethyl acetate in hexanes to give the title compound as an off-white solid (1.10 g, 81%). Mass spectrum (m/z): 333.2 (M+1).
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:29])=[C:14]([C:24](OCC)=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:30][CH2:31][C@H:32]([OH:34])[CH3:33]>>[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:29])=[C:14]([C:24]([NH:30][CH2:31][C@H:32]([OH:34])[CH3:33])=[O:25])[C:15](=[O:23])[N:16]3[CH2:19][CH2:20][CH2:21][OH:22])=[N:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: C[C@@H](O)CN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Product: C[C@@H](O)CNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCCO)c1=O
Yield: 25 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate (60 mg, 0.15 mmol) and (2R)-1-amino-2-propanol (0.05 mL) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[(2R)-2-hydroxypropyl]-1-(3-hydroxypropyl)-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (16 mg, 25% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 10.02 (s, 1 H), 8.35 (s, 1 H), 7.56 (s, 1 H), 7.06-7.03 (m, 2 H), 6.89-6.84 (m, 2 H), 4.17 (m, 2 H), 4.01 (s, 2 H), 3.89 (m, 1 H), 3.45-3.39 (m, 3 H), 3.19 (m, 1 H),1.71 (m, 2 H), 1.09 (m, 3 H); MS m/z 430 (M+1).