Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][O:8][C:9](=[O:10])[C:2]=12.[Li+].CC([N-]C(C)C)C.CS([C:23]1[N:28]=[C:27]([O:29][CH3:30])[CH:26]=[C:25]([O:31][CH3:32])[N:24]=1)(=O)=O.Cl>C1COCC1>[CH3:32][O:31][C:25]1[CH:26]=[C:27]([O:29][CH3:30])[N:28]=[C:23]([CH:7]2[C:3]3[C:2](=[N:1][CH:6]=[CH:5][CH:4]=3)[C:9](=[O:10])[O:8]2)[N:24]=1
Reactant: O=C1OCc2cccnc21
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(OC)nc(C2OC(=O)c3ncccc32)n1
Temperature: 25 °C

Procedure:
A solution of 1.3 g (0.0096 mols) of furo[3,4-b]pyridine-7(5H)-one in 50 ml of dry THF is cooled to -75° C. and 8 ml (0.0192 mols) of 2.5M LDA added dropwise over 5 minutes. The mixture is allowed to react for 1 hr at -75° C. and 2.1 g (0.0096 mol) of 2-methylsulfonyl-4,6-dimethoxypyrimidine in 30 ml of dry THF added dropwise over 10 minutes. The mixture is allowed to warm to RT, 1.6 ml of HCl added and the THF evaporated off. The residue is dissolved in 75 ml of CH2Cl2, washed with water (2×50 ml) and the organic phase concentrated to give a yellowish white gummy solid. This is chromatographed on a silica gel column using 50/50 hexane/ethyl acetate (500 ml), ethyl acetate (500 ml) and 80/20 acetone/methanol (1000 ml) (30 fractions). The crystalline residue (fractions 18-21) of the title product has m.p. of 167-168° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[Cu](C#N)[C:15]#[N:16]>CN(C=O)C>[C:15]([C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([CH2:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])#[N:16]
Reactant: N#C[Cu]C#N
Reactant: CCc1cc(Br)cc(C(=O)OC)c1
Solvent: CN(C)C=O
Product: CCc1cc(C#N)cc(C(=O)OC)c1
Yield: 38.6 %

Procedure:
The product methyl 3-bromo-5-ethylbenzoate (0.9 g, 3.7 mmol) was dissolved in dry DMF (50 mL) and copper cyanide (0.84 g, 9.43 mmol) was added. The reaction mixture was heated to 150° C. under argon atmosphere for 12 h (monitored by TLC; petroleum ether/EtOAc 9:1). The reaction mixture was allowed to come to room temperature and then quenched with saturated ammonium chloride solution. The reaction mixture was diluted with EtOAc and filtered through a Celite bed. The filtrate was diluted with EtOAc and the organic layer was washed with water and brine. The solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 5% EtOAc in petroleum ether) to get methyl 3-cyano-5-ethylbenzoate (0.27 g, yield 39%) as colorless liquid, which was carried through without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([CH2:18][Si](C)(C)C)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2].O.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[N:8][N:9]([CH3:18])[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nnn(C[Si](C)(C)C)c1-c1ccc(Br)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1nnn(C)c1-c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 89.1 %

Procedure:
To a stirred solution of 5-(4-bromo-phenyl)-1-trimethylsilanylmethyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (6.5 g, 17.01 mmol) in THF (100 mL), was added water (0.61 ml, 34.03 mmol) and cooled to 0° C. Then TBAF (1M) solution in THF (20.41 mL, 20.41 mmol) was added to it and the mixture was stirred at 0° C. for 10 min. Volatiles were distilled off and crude mass was purified by normal silica gel column chromatography using EtOAc-hexane as eluting solvent to get 5-(4-bromo-phenyl)-1-methyl-1H-[1,2,3]triazole-4-carboxylic acid ethyl ester (4.7 g, 89.02%) as a white solid. LC-MS: 310 (M+H); 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.14 (t, J=7.0 Hz, 3H), 3.91 (s, 3H), 4.18 (q, J=7.0 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H), 7.75 (d, J=8.4 Hz, 2H). The regio-chemistry was confirmed by NOE study.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14].[Li+].[OH-]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: COC(=O)CCCCc1cc(Cl)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCCCc1cc(Cl)ccc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 69.9 %

Procedure:
Methyl 5-(2,5-Dichlorophenyl)pentanoate (1.10 g, 4.2 mmol) was dissolved in 20 ml THF and 7 mL methanol. 1N LiOH (12mL) was added dropwise and the reaction was stirred at room temperature for 2 days. The reaction was worked-up by acidification with 2N HCl and removal of most of the THF and methanol on a rotary evaporator followed by extraction of the aqueous residue with ethyl acetate. The organic phase was washed with water and saturated brine, dried over sodium sulfate and concentrated to a residue. Flash chromatography (silica gel; hexane/toluene (19/1) with 1% acetic acid) of the residue gave 725 mg (70%) of a white solid.
Reaction SMILES: I[CH2:2][CH3:3].[Br:4][C:5]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[C:9]([F:19])[C:8]([OH:20])=[C:7]([CH:21]=[O:22])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[Br:4][C:5]1[C:10]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])=[C:9]([F:19])[C:8]([O:20][CH2:2][CH3:3])=[C:7]([CH:21]=[O:22])[CH:6]=1
Reactant: CCI
Reactant: O=Cc1cc(Br)c(-c2ccc(F)cc2F)c(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1c(C=O)cc(Br)c(-c2ccc(F)cc2F)c1F
Reaction time: 2 h
Yield: 90.5 %

Procedure:
Iodoethane (0.77 g) was added at room temperature to a mixture of 6-bromo-2,2′,4′-trifluoro-3-hydroxybiphenyl-4-carbaldehyde (1.09 g), potassium carbonate (0.91 g), and DMF (20 mL), and the mixture was stirred at 60 C for 2 hours in a nitrogen atmosphere. Water was added to the reaction mixture at room temperature, followed by extraction with ethyl acetate. The organic layer was separated, washed with water and saturated saline in this order, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.07 g).
Reaction SMILES: [CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([O:21]C(C)C)=[C:17]([I:25])[CH:16]=3)[N:11]=2)[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4].ClC1C=C(C2ON=C(C3C=CC(OC(C)C)=C(I)C=3)N=2)C=CC=1OCCC>>[CH2:1]([N:5]1[CH:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([I:25])[CH:16]=3)[N:11]=2)[CH:7]=[N:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1cc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cn1
Agent: CCCOc1ccc(-c2nc(-c3ccc(OC(C)C)c(I)c3)no2)cc1Cl
Product: CCCCn1cc(-c2nc(-c3ccc(O)c(I)c3)no2)cn1
Yield: 72 %

Procedure:
When the product of Step B was substituted for 5-(3-chloro-4-propoxy phenyl)-3-(3-iodo-4-isopropoxy phenyl)-1,2,4-oxadiazole in Example 36, Step C, the similar procedure afforded the title compound in 72% yield, as creamy solid. 1H NMR (CDCl3) 8.45 (d, 1H, J=1.98 Hz); 8.12 (s, 1H); 8.09 (s, 1H); 7.99 (dd, 1H, J=8.49, 2.01 Hz); 7.06 (d, 1H, J=8.49 Hz); 4.2 (t, 2H, J=7.08 Hz); 2.02-1.85 (m, 2H); 1.42-1.26 (m, 2H); 0.95 (t, 3H, J=7.29 Hz).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[N:20]=[C:19]3[S:21][C:22]([NH:24][C:25](=[O:27])[CH3:26])=[N:23][C:18]3=[CH:17][CH:16]=2)[C:11]([F:28])=[CH:10][C:9]=1[F:29])(C)(C)C>FC(F)(F)C(O)=O>[NH2:7][C:8]1[C:9]([F:29])=[CH:10][C:11]([F:28])=[C:12]([CH:13]=1)[O:14][C:15]1[N:20]=[C:19]2[S:21][C:22]([NH:24][C:25](=[O:27])[CH3:26])=[N:23][C:18]2=[CH:17][CH:16]=1
Reactant: CC(=O)Nc1nc2ccc(Oc3cc(NC(=O)OC(C)(C)C)c(F)cc3F)nc2s1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2ccc(Oc3cc(N)c(F)cc3F)nc2s1

Procedure:
A solution of tert-butyl{5-[(2-acetylamino[1,3]thiazolo[5,4-b]pyridin-5-yl)oxy]-2,4-difluorophenyl}carbamate (4.36 g, 10.0 mmol) in trifluoroacetic acid (20 mL) was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate (200 mL), washed with 0.1N aqueous sodium hydroxide solution (200 mL), and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was triturated with diethyl ether to give the title compound (3.37 g, quantitatively) as a white amorphous.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([CH2:29][S:30]C(=O)C)[CH2:6][C:7]1[CH:8]=[N:9][C:10]([N:14](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[CH:11][C:12]=1[CH3:13])C>Cl>[NH2:14][C:10]1[N:9]=[CH:8][C:7]([CH2:6][CH:5]([CH2:29][SH:30])[C:4]([OH:34])=[O:3])=[C:12]([CH3:13])[CH:11]=1
Reactant: CCOC(=O)C(CSC(C)=O)Cc1cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1C
Agent: Cl
Product: Cc1cc(N)ncc1CC(CS)C(=O)O
Yield: 114.8 %

Procedure:
2-Acetylsulfanylmethyl-3-(6-[N,N-bis(tert-butoxycarbonyl)amino]-4-methyl-pyridin-3-yl)-propionic acid ethyl ester (36 mg, 0.072 mmol) was dissolved in conc. HCl (3.0 mL). The solution was heated to reflux for 1 h. Concentration under reduced pressure gave the title compound (18.7 mg, 98%) as the hydrochloride salt.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([N:11]3[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12]3)=[N:9][N:10]=2)[CH:7]=1.[H-].[Na+].[CH2:20](Br)[CH:21]=[CH2:22].O>C1COCC1.CCOC(C)=O.CO>[CH2:22]([O:17][CH:14]1[CH2:15][CH2:16][N:11]([C:8]2[N:6]3[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]3=[N:10][N:9]=2)[CH2:12][CH2:13]1)[CH:21]=[CH2:20]
Reactant: OC1CCN(c2nnc3ccc(F)cn23)CC1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCOC1CCN(c2nnc3ccc(F)cn23)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 28.7 %

Procedure:
To an opaque pale yellow solution of Intermediate 24c (510 mg, 2.16 mmol) in dry THF at 0° C. under Ar was added NaH (60% dispersion in oil, 216 mg, 5.40 mmol) (CARE: gas evolution) and the resulting suspension was stirred at 0° C. for 30 min. Allyl bromide (0.467 mL, 5.40 mmol) was added and the suspension stirred at RT under Ar for 1 h and at 70° C. for 18 h. Water (25 mL) was added to the cooled solution, then the mixture extracted with EtOAc (3×25 mL). The combined organics were washed with brine (25 mL), dried (Na2SO4), filtered and concentrated in vacuo to leave a dark brown oil. FCC, using 0-8% MeOH in EtOAc, gave the title compound as a brown oil (171 mg, 29%). LCMS (Method 3): Rt 2.81 min, m/z 277 [MH+].
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16](OS(C(F)(F)F)(=O)=O)[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1B(O)O.C(=O)([O-])[O-].[K+].[K+].[Cl-].[Li+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][C@H:13]2[CH2:22][CH2:21][C:20]3[C:15](=[C:16]([C:33]4[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:32]=4[Cl:31])[CH:17]=[CH:18][CH:19]=3)[O:14]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: OB(O)c1cc(Cl)ccc1Cl
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cccc(OS(=O)(=O)C(F)(F)F)c3O2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2CCc3cccc(-c4cc(Cl)ccc4Cl)c3O2)cc1
Temperature: 100 °C
Yield: 90.2 %

Procedure:
A mixture of ((2R)-8-{[(trifluoromethyl)sulfonyl]oxy}-3,4-dihydro-2H-chromen-2-yl)methyl 4-methylbenzenesulfonate (0.50 g, 1.1 mmol), 2,5-dichlorophenylboronic acid (0.42 g, 2.2 mmol), potassium carbonate (0.46 g, 3.3 mmol) and lithium chloride (0.14 g, 3.3 mmol) in dioxane (3.75 ml) and water (1.25 mL) was purged with nitrogen for 30 minutes. Tetrakis(triphenylphosphine)palladium (0) (60 mg, 0.052 mmol) was added and the reaction mixture heated at 100° C. for 4 hours. The cooled reaction mixture was then partitioned between ethyl acetate (15 mL) and 1 M aqueous sodium hydroxide (15 mL). The organic layer was separated, washed with saturated brine (15 mL) dried over magnesium sulfate, filtered and concentrated under reduced pressure to afford an orange oil. Purification by flash chromatography using a solvent gradient of 5 to 20% ethyl acetate in hexane gave 0.46 g (90%) of [(2R)-8-(2,5-dichlorophenyl)-3,4-dihydro-2H-chromen-2-yl]methyl 4-methylbenzenesulfonate as an off-white solid. HRMS: calcd for C23H20Cl2O4S+H+, 463.05321. found (ESI, [M+H]+), 463.0553.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[Cl:47][C:48]1[CH:60]=[CH:59][C:51]2[NH:52][C:53]([C@@H:55]([NH2:58])[CH2:56][OH:57])=[N:54][C:50]=2[CH:49]=1.ClCl>CN(C)C=O.ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH:16]=[CH:15][CH2:14]1)=[O:12])[C:5]([NH:58][C@H:55]([C:53]1[NH:52][C:51]2[CH:59]=[CH:60][C:48]([Cl:47])=[CH:49][C:50]=2[N:54]=1)[CH2:56][OH:57])=[O:7]
Reactant: O=C(O)c1ccc(C(=O)N2CC=CC2)c(Cl)c1
Reactant: N[C@@H](CO)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CO
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(N[C@@H](CO)c1nc2cc(Cl)ccc2[nH]1)c1ccc(C(=O)N2CC=CC2)c(Cl)c1
Yield: 20 %

Procedure:
Prepared analogously to Example 1g from 3-chloro-4-(2,5-dihydropyrrol-1-ylcarbonyl)benzoic acid, TBTU, N-methylmorpholine, and (1R)-1-(5-chloro-1H-benzimidazol-2-yl)-2-hydroxyethylamine in N,N-dimethylformamide. Yield: 20%; Rf value: 0.6 (silica gel; dichloromethane/methanol=95:5); C21H18Cl2N4O3 (445.31); mass spectrum: (M+H)+=445/447/449 (chlorine isotope) and (M+H)−=443/445/447 (chlorine isotope).
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH:15]=[C:14]([N+:16]([O-])=O)[N:13]=[CH:12]1)([CH3:10])[CH2:3][NH:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7].[F:19][C:20]1[CH:29]=[C:28]([F:30])[CH:27]=[C:26]2[C:21]=1[CH2:22][CH:23]([NH:31][C@@H:32]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:33](O)=[O:34])[CH2:24][CH2:25]2>>[F:30][C:28]1[CH:27]=[C:26]2[C:21](=[C:20]([F:19])[CH:29]=1)[CH2:22][CH:23]([NH:31][C@@H:32]([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:33]([NH:16][C:14]1[N:13]=[CH:12][N:11]([C:2]([CH3:10])([CH3:1])[CH2:3][NH:4][CH2:5][C:6]([CH3:9])([CH3:8])[CH3:7])[CH:15]=1)=[O:34])[CH2:24][CH2:25]2
Reactant: CC(C)(C)CNCC(C)(C)n1cnc([N+](=O)[O-])c1
Reactant: O=C(O)[C@@H](NC1CCc2cc(F)cc(F)c2C1)c1ccccc1
Product: CC(C)(C)CNCC(C)(C)n1cnc(NC(=O)[C@@H](NC2CCc3cc(F)cc(F)c3C2)c2ccccc2)c1

Procedure:
2-methyl-N-neopentyl-2-(4-nitro-1H-imidazol-1-yl)propan-1-amine (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was reduced and coupled with (S)-2-(5,7-difluoro-1,2,3,4-tetrahydronaphthalen-3-ylamino)-2-phenylacetic acid to afford the title compound: MS 524 m/z (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:30])=[C:4]([F:29])[CH:5]=[C:6]2[C:11]=1[N:10]([C:12]1[CH:17]=[C:16]([N+:18]([O-])=O)[C:15]([F:21])=[CH:14][C:13]=1[Cl:22])[CH:9]=[C:8]([C:23]([O:25]CC)=[O:24])[C:7]2=[O:28]>[Fe].C(O)=O>[NH2:18][C:16]1[CH:17]=[C:12]([N:10]2[C:11]3[C:6](=[CH:5][C:4]([F:29])=[C:3]([F:30])[C:2]=3[Cl:1])[C:7](=[O:28])[C:8]([C:23]([OH:25])=[O:24])=[CH:9]2)[C:13]([Cl:22])=[CH:14][C:15]=1[F:21]
Reactant: CCOC(=O)c1cn(-c2cc([N+](=O)[O-])c(F)cc2Cl)c2c(Cl)c(F)c(F)cc2c1=O
Agent: [Fe]
Solvent: O=CO
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)c(Cl)c32)c(Cl)cc1F
Temperature: 60 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To 5 ml of formic acid were added 1.5 g of ethyl 8-chloro-6,7-difluoro-1-(2-chloro-4-fluoro-5-nitrophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylate and 2 g of iron. The solution was heated and stirred at 60° C. for 2 hours. The insoluble was removed by filtration through celite and washed with formic acid and chloroform. The filtrate was concentrated in vacua. Ethanol was added to the residue whereupon the solid was collected by filtration and washed with diethyl ether. To the solid were added 4 ml of conc. hydrochloric acid and 4 ml of acetic acid. The solution was heated at reflux for 1 hour and allowed to cool down. The precipitated was collected by filtration and washed with ethanol and diethyl ether to give 970 mg of the title compound.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:22]=[C:21]2[C:12]([N:13]3[C:18]([CH2:19][O:20]2)=[N:17][NH:16][C:15](=[O:23])[C@H:14]3[CH3:24])=[CH:11][C:10]=1[C@@H:25]1[CH2:30][CH2:29][NH:28][CH2:27][C@@H:26]1[CH3:31].C=O.[B-][C:35]#N.[Na+]>CO.CC(O)=O>[CH3:35][N:28]1[CH2:29][CH2:30][C@@H:25]([C:10]2[CH:11]=[C:12]3[C:21](=[CH:22][C:9]=2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[O:20][CH2:19][C:18]2[N:13]3[C@H:14]([CH3:24])[C:15](=[O:23])[NH:16][N:17]=2)[C@@H:26]([CH3:31])[CH2:27]1
Reactant: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c([C@@H]4CCNC[C@@H]4C)cc3N21
Reactant: [B-]C#N
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H]1C(=O)NN=C2COc3cc(-c4ccccc4F)c([C@@H]4CCN(C)C[C@@H]4C)cc3N21
Temperature: 80 °C
Reaction time: 16 h
Yield: 39.6 %

Procedure:
A mixture of (R)-7-(2-fluoro-phenyl)-4-methyl-6-((3R,4R)-3-methyl-piperidin-4-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid (3.05 g, 6.88 mmol) and paraformaldehyde (2.066 g, 68.8 mmol) in MeOH (60 mL) and AcOH (6 mL) was stirred at 80° C. for 16 h. Then, sodium cyanotrihydroborate (0.865 g, 13.76 mmol) was added and the reaction mixture was stirred at ambient temperature for 0.5 h. The reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on basified silica gel (eluting with 10% MeOH in DCM) to give (R)-6-((3R,4R)-1,3-dimethyl-piperidin-4-yl)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (1.15 g, 40%) as a white solid. The white solid was stirred in HCl/EtOAc (4 M, 50 mL) for 30 min and the reaction mixture was concentrated in vacuo to give (R)-6-((3R,4R)-1,3-dimethyl-piperidin-4-yl)-7-(2-fluoro-phenyl)-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one hydrochloride acid (1.215 g, 39%) as a white solid. 1H NMR (400 MHz, MeOD) δ 7.44 (m, 1H), 7.32-7.16 (m, 3H), 6.90 (m, 1H), 6.84 (s, 1H), 4.68-4.57 (d, J=13.2 Hz, 2H), 3.57 (m, 1H), 3.25 (m, 1H), 3.05 (m, 2H), 2.86 (m, 1H), 2.79 (s, 3H), 2.50 (m, 1H), 1.91 (m, 2H), 1.48 (d, J=6.8 Hz, 3H), 0.91 (m, 3H). LC/MS (Table 1, Method 5) Rt=2.275 min.; MS m/z: 423 [M+H]+. SFC (Table 1, Method 47), Rt=1.145 min.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14](B3OC(C)(C)C(C)(C)O3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])=[N:3]1.Br[C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[N:31][CH:32]=1>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:15]=[C:14]([C:27]3[CH:32]=[N:31][CH:30]=[C:29]([CH3:33])[CH:28]=3)[CH:13]=[C:12]([CH3:25])[N:11]=2)=[O:9])=[N:3]1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cc(C(=O)Nc2ccn(C)n2)n1
Reactant: Cc1cncc(Br)c1
Product: Cc1cncc(-c2cc(C)nc(C(=O)Nc3ccn(C)n3)c2)c1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (1-methyl-1H-pyrazol-3-yl)-amide in accordance with the general method of example 131, step 2 using 5-Bromo-3-picolin instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a white solid, MS (ISP): m/e=308.3 (M+H)+.
Reaction SMILES: [O:1]=[S:2]1(=[O:17])[CH:7]([CH3:8])[CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([S:13]([NH2:16])(=[O:15])=[O:14])[C:4]=2[O:3]1.N12CCCN=C1CCCCC2.[CH3:29][O:30][C:31]1[CH:36]=[C:35]([CH3:37])[N:34]=[C:33]([N:38](C2C=CC=CC=2)[C:39](=O)[O-:40])[N:32]=1>O1CCOCC1>[O:17]=[S:2]1(=[O:1])[CH:7]([CH3:8])[CH2:6][C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([S:13]([NH:16][C:39]([NH:38][C:33]3[N:32]=[C:31]([O:30][CH3:29])[CH:36]=[C:35]([CH3:37])[N:34]=3)=[O:40])(=[O:14])=[O:15])[C:4]=2[O:3]1
Reactant: CC1Cc2cccc(S(N)(=O)=O)c2OS1(=O)=O
Reactant: COc1cc(C)nc(N(C(=O)[O-])c2ccccc2)n1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc(C)nc(NC(=O)NS(=O)(=O)c2cccc3c2OS(=O)(=O)C(C)C3)n1
Reaction time: 0.75 h
Yield: 93.4 %

Procedure:
A mixture of 3.33 g of 3,4-dihydro-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonamide, 1.84 ml of 1,8-diazabicyclo[5.4.0]undec-7-ene, 3.2 g of N-(4-methoxy-6-methylpyrimidin-2-yl)phenylcarbamate and 35 ml of absolute dioxan is stirred for 45 minutes at a temperature in the range from 20° to 25° C. The mixture is concentrated and the oily residue is triturated with ether and 14 ml of 1N hydrochloric acid. The crystalline precipitate obtained is isolated, washed with water and dried, affording 4.96 g of N-(3,4-dihydro-2,2-dioxo-3-methyl-1,2-benzoxathiin-8-ylsulfonyl)-N'-(4-methoxy-6-methylpyrimidin-2-yl)urea of m.p. 215°-218° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][C:28]([CH3:32])([OH:31])[CH2:29][NH2:30]>>[NH2:26][CH2:27][C:28]([CH3:32])([OH:31])[CH2:29][NH:30][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1
Reactant: CC(O)(CN)CN
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC(C)(O)CN)c2c1

Procedure:
The title compound was prepared in analogy to Example 11-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 1,3-diamino-2-methylpropan-2-ol. MS obsd. (ESI+) [(M+H)+] 441, 1H NMR (400 MHz, CD3OD) δ ppm 7.97 (d, J=7.6 Hz, 1 H), 7.88 (d, J=7.6 Hz, 1 H), 7.60 (t, J=7.6 Hz, 1 H), 7.57 (s, 1 H), 7.43 (m, 2 H), 7.29 (dd, J=1.2, 8.4 Hz, 1 H), 6.18 (s, 1 H), 5.15 (s, 2 H), 4.53 (brs, 2 H), 3.58 (t, J=4.4 Hz, 2 H), 3.34 (m, 2 H), 2.85-2.76 (m, 2 H), 2.42 (s, 3 H), 1.32 (s, 3 H).
Reaction SMILES: [CH:1]1([C:11]2[CH:12]=[C:13]([C:17](=[O:19])[CH3:18])[CH:14]=[CH:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:20](OCC)(=[O:26])[C:21]([O:23]CC)=[O:22].[O-]CC.[Na+]>>[O:26]=[C:20]([CH2:18][C:17](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([CH:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH2:4][CH2:3][CH2:2]2)[CH:12]=1)[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1cccc(C2CCCc3ccccc32)c1
Agent: CC[O-]
Agent: [Na+]
Product: O=C(O)C(=O)CC(=O)c1cccc(C2CCCc3ccccc32)c1

Procedure:
Isomer B: As described above, 0.048 g (0.19 mmol) of 1-[3-(1,2,3,4-tetrahydronaphthalen-1-yl)-phenyl]-ethanone (isomer B), 0.056 g (0.38 mmol) diethyl oxalate, and 0.026 g (0.38 mmol) sodium ethoxide were reacted to give the title compound which was used without further purification.
Reaction SMILES: C1COCC1.C(O)C.[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[C:25]3[C:20](=[N:21][C:22]([CH:26]=[O:27])=[CH:23][CH:24]=3)[N:19]([CH2:28][CH3:29])[C:18](=[O:30])[C:17]=2[CH2:31][CH2:32][C:33]([O:35]C)=[O:34])[CH:13]=[CH:14][CH:15]=1.[BH4-].[Na+]>O>[Cl:9][C:10]1[CH:11]=[C:12]([C:16]2[C:25]3[C:20](=[N:21][C:22]([CH2:26][OH:27])=[CH:23][CH:24]=3)[N:19]([CH2:28][CH3:29])[C:18](=[O:30])[C:17]=2[CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH:13]=[CH:14][CH:15]=1
Reactant: CCn1c(=O)c(CCC(=O)OC)c(-c2cccc(Cl)c2)c2ccc(C=O)nc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCn1c(=O)c(CCC(=O)O)c(-c2cccc(Cl)c2)c2ccc(CO)nc21
Reaction time: 1 h
Yield: 44.7 %

Procedure:
To a 7 ml THF-ethanol (5:2) solution containing 300 mg of methyl 3-[4-(3-chlorophenyl)-1-ethyl-7-formyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoate was added 9 mg of sodium borohydride under ice cooling. After stirring for 1 hour, water was added to the reaction mixture and the whole was extracted with ethyl acetate. The organic layer was washed with saturated brine and then the solvent was evaporated. The residue was purified by a silica gel column chromatography (hexane-ethyl acetate). Using a 200 mg portion of 210 mg of the resulting compound, the compound was treated in a similar manner to Example 2 to obtain 130 mg of 3-[4-(3-chlorophenyl)-1-ethyl-7-hydroxymethyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoic acid as pale yellow crystals.