Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:47])=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][C@H:25]3[C@H:30]([CH:31]4[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]4)[CH2:29][CH2:28][N:27](C(OCC4C=CC=CC=4)=O)[CH2:26]3)=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1>[Pd](Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:47])=[C:4]([C@:8]([C@@H:16]2[CH2:21][CH2:20][CH2:19][N:18]([C:22]([NH:24][CH:25]3[CH:30]([CH:31]4[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]4)[CH2:29][CH2:28][NH:27][CH2:26]3)=[O:23])[CH2:17]2)([OH:15])[CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)N[C@@H]2CN(C(=O)OCc3ccccc3)CC[C@H]2C2CCCCC2)C1
Agent: Cl[Pd]Cl
Solvent: CCOC(C)=O
Product: COCCCC[C@@](O)(c1cccc(Cl)c1F)[C@@H]1CCCN(C(=O)NC2CNCCC2C2CCCCC2)C1
Yield: 114.2 %

Procedure:
(3S,4S)-benzyl 3-((R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxamido)-4-cyclohexylpiperidine-1-carboxylate (18.4 mg, 0.027 mmol) and palladium(II) chloride (catalytic amount, c.a. 4 mg) were mixed with EtOAc (3 mL). The flask was evacuated and filled by H2 gas (3×). A balloon filled with H2 gas was attached to the flask to maintain the H2 gas atmosphere for 2 h. LC-MS showed most of the starting material had been converted to product. The mixture was concentrated, redissolved in acetonitrile (3 mL), filtered and purified by preparative HPLC to afford (3R)-3-((S)-1-(3-chloro-2-fluorophenyl)-1-hydroxy-5-methoxypentyl)-N-((3RS,4RS)-4-cyclohexylpiperidin-3-yl)piperidine-1-carboxamide (16.6 mg, quant). LC-MS (3 min) tR=1.58 min., m/z 538 (M+1).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=2[O:15][CH3:16])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:17][Li]>O1CCCC1>[CH3:17][CH:10]([OH:11])[C:9]1[CH:12]=[CH:13][C:14]([O:15][CH3:16])=[C:7]([O:6][CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)[CH:8]=1
Reactant: [Li]C
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Solvent: C1CCOC1
Product: COc1ccc(C(C)O)cc1OC1CCCC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
To a magnetically-stirred solution of 3-cyclopentyloxy-4-methoxybenzaldehyde (59.0 mmol, 13.0 g) in dry tetrahydrofuran (500 mL) at -78° C. is added methyllithium (100 mmol, 90.0 mL; 1.4M solution in ethyl ether) dropwise over 30 minutes. The resulting solution is stirred at -78° C. for 30 minutes and quenched at -78° C. by the rapid addition of aqueous saturated NH4Cl (140 mL). After warming to room temperature, water is added to dissolve the solids and the tetrahydrofuran was removed in vacuo. The residue is partitioned between water (500 mL) and ethyl acetate (500 mL), the aqueous phase extracted with ethyl acetate (500 mL) and the combined organic layers are washed with water (500 mL). The organics are dried (Na2SO4) and concentrated in vacuo to afford the title compound as a light yellow oil (58.3 mmol, 13.7 g; 99%). This material is of sufficient purity by TLC and NMR to be used as such in the subsequent transformation.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[H-].[Na+].[C:18]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)([CH3:21])([CH3:20])[CH3:19]>CN(C=O)C>[C:18]([C:22]1[CH:23]=[CH:24][C:25]([CH2:26][N:7]2[C:8]3[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)[CH:5]=[C:6]2[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:28][CH:29]=1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)c1ccc(CBr)cc1
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1Cc1ccc(C(C)(C)C)cc1
Reaction time: 0.33 h

Procedure:
To a solution of ethyl 5-chloroindole-2-carboxylate (4.50 g, 20.1 mmol) in DMF (50 mL) was added NaH (885 mg, 60% suspension in mineral oil, 22.1 mmol). After 20 min, 4-tert-butylbenzyl bromide (4.07 mL, 22.1 mmol) was added. After 3 h, the reaction mixture was quenched by addition of sat. aq. NH4Cl. The aqueous phase was extracted with EtOAc, and the organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 20%, then 20 to 100% EtOAc in hexanes) provided the title compound: LCMS B, tr=3.18 min, m/z 370.2 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 7.71 (d, J=2.0 Hz, 1H), 7.35 (s, 1H), 7.33-7.27 (m, 4H), 7.01 (d, J=8.0 Hz, 2H), 5.84 (s, 2H), 4.38 (q, J=7.0 Hz, 2H), 1.41 (t, J=7.0 Hz, 3H), 1.30 (s, 9H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:12][CH2:11][CH2:10][N:9]1[CH2:13][CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OS(O)(=O)=O.[N+:21]([O-])([OH:23])=[O:22].O>[N+](C)([O-])=O>[N+:21]([C:5]1[CH:6]=[CH:7][C:2]([CH2:1][CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[CH2:13][CH2:14][CH3:15])=[CH:3][CH:4]=1)([O-:23])=[O:22]
Reactant: O=[N+]([O-])O
Reactant: CCCN1CCCC1Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: C[N+](=O)[O-]
Product: CCCN1CCCC1Cc1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
2-Benzyl-1-propylpyrrolidine (0.90 g, 3.75 mmol) was dissolved in nitromethane (10 mL) and added to a mixture of concentrated H2SO4 (3.7 mL), concentrated nitric acid (0.3 mL) and water (0.6 mL) cooled to 5° C. After stirring for 2 h, the reaction solution was poured into water, extracted with ethyl acetate and the organic phase separated and dried over MgSO4. The filtered solution was concentrated to give a brown oil (0.95 g, 100%).
Reaction SMILES: [CH2:1]1[C@H:5]2[CH2:6][CH2:7][C@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C@H:4]2[CH2:3][NH:2]1.Br[C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1.C(N(CC)CC)C.O.C(O)C>C(O)C>[F:25][C:24]([F:27])([F:26])[C:21]1[CH:22]=[CH:23][C:18]([N:2]2[CH2:3][C@@H:4]3[C@@H:8]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH2:7][CH2:6][C@@H:5]3[CH2:1]2)=[N:19][CH:20]=1
Reactant: FC(F)(F)c1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CNC[C@@H]21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H]2CN(c3ccc(C(F)(F)F)cn3)C[C@@H]21
Temperature: 81 °C

Procedure:
tert-butyl(3aR,4S,6aS)-octahydrocyclopenta[c]pyrrol-4-ylcarbamate from Step B of Example 252 (250 mg, 1.105 mmol), 2-bromo-5-(trifluoromethyl)pyridine (250 mg, 1.105 mmol), and triethylamine (0.462 mL, 3.31 mmol) were combined in ethanol (0.6 mL). The reaction was heated at 81° C. for 16 hours. To the reaction mixture was added 50% water/ethanol (5 mL), and the precipitate was collected by filtration. This crude material was purified using a 12 g silica gel cartridge with a gradient of 0-1.5% methanol (2 N ammonia)/dichloromethane over 20 minutes to give tert-butyl(3aR,4S,6aS)-2-(5-(trifluoromethyl)pyridin-2-yl)octahydrocyclopenta[c]pyrrol-4-ylcarbamate: 1H NMR (500 MHz, pyridine-d5) δ ppm 8.62 (s, 1H), 7.76 (d, J=6.4, 1H), 7.68 (d, J=8.6, 1H), 6.38 (d, J=8.8, 1H), 4.10 (s, 1H), 3.73 (d, J=10.4, 1H), 3.65 (s, 1H), 3.61-3.53 (m, 1H), 3.32 (d, J=10.1, 1H), 2.82-2.71 (m, 2H), 2.15 (td, J=12.6, 6.8, 1H), 1.97 (dt, J=13.1, 6.4, 1H), 1.74 (dq, J=15.6, 7.9, 1H), 1.54 (s, 9H), 1.45-1.34 (m, 1H); MS(DCI+) m/z 372 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([O:25]C)=[O:24])[CH:14]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+]>CO.C(Cl)(Cl)Cl.O>[F:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]([N:18]([CH:20]([CH3:22])[CH3:21])[CH3:19])=[N:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:23]([OH:25])=[O:24])[CH:14]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc2nc(-c3ccnc(F)c3)c(N(C)C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CO
Product: CC(C)N(C)c1nc2cc(C(=O)O)ccc2nc1-c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
To a solution of methyl 2-(2-fluoropyridin-4-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylate (125.0 mg, 0.35 mmol) in methanol (25 mL) and chloroform (10 mL) was added sodium hydroxide (56.0 mg, 1.40 mmol) in water (1 mL). The resulting solution was stirred overnight at room temperature and concentrated under vacuum. The residue was dissolved in water (20 mL) and adjusted to pH 6 with hydrochloric acid (1N). The product was precipitated and collected by filtration to afford 2-(2-fluoropyridin-4-yl)-3-(isopropyl(methyl)amino)quinoxaline-6-carboxylic acid as a yellow solid (50 mg, 42%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14]([OH:16])=O)=[CH:9][CH:8]=1)[CH3:2].S(Cl)(Cl)=O.[CH2:24]([NH2:31])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30].C(N(CC)C(C)C)(C)C.Cl>C(Cl)(Cl)Cl.ClCCl>[CH2:1]([O:3][C:4](=[O:19])[C:5]([CH3:18])([CH3:17])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:13][C:14](=[O:16])[NH:31][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCCCCCCN
Reactant: CCOC(=O)C(C)(C)Cc1ccc(CC(=O)O)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCCCCNC(=O)Cc1ccc(CC(C)(C)C(=O)OCC)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 3-(4-carboxymethyl-phenyl)-2,2-dimethyl-propionic acid ethyl ester (0.97 g, 3.67 mmol) in chloroform (15 mL) under an nitrogen atmosphere was added thionyl chloride (11 mmol, 0.804 mL). The mixture was heated under reflux for 2.75 hours, cooled to room temperature and concentrated under reduced pressure to a clear oil. The oil was dissolved in methylene chloride (0.50 mL) then added dropwise to a solution of 1-heptylamine (4.40 mmol, 0.653 mL) and N,N-diisopropylethylamine (4.40 mmol, 0.765 mL) in anhydrous dichloromethane (5 mL) cooled to 0° C. The solution was warmed to room temperature and allowed to stir for 30 minutes, then was poured over a solution of 1 M HCl (10 mL). The aqueous layer was isolated and extracted with diethyl ether (2×). The organic layers were combined, washed with 2N HCl (2×), brine (1×), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give crude 3-(4-heptylcarbamoylmethyl-phenyl)-2,2-dimethyl-propionic acid ethyl ester as an orange oil. The oil was used in the preparation of 3-[4-(2-heptylamino-ethyl)-phenyl]-2,2-dimethyl-propionic acid ethyl ester without further purification. (1.27 g, 95%).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[CH2:10][N:11]1[CH:20]([CH3:21])[CH2:19][C:18]2[C:17]([O:22][C:23]3[CH:24]=[C:25]4[C:29](=[CH:30][CH:31]=3)[N:28]([C:32](=[O:44])[NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[CH:35]=3)[CH:27]=[CH:26]4)=[N:16][CH:15]=[N:14][C:13]=2[CH2:12]1>C1COCC1>[F:43][C:40]([F:41])([F:42])[C:36]1[CH:35]=[C:34]([NH:33][C:32]([N:28]2[C:29]3[C:25](=[CH:24][C:23]([O:22][C:17]4[C:18]5[CH2:19][CH:20]([CH3:21])[N:11]([CH2:10][CH2:9][OH:8])[CH2:12][C:13]=5[N:14]=[CH:15][N:16]=4)=[CH:31][CH:30]=3)[CH:26]=[CH:27]2)=[O:44])[CH:39]=[CH:38][CH:37]=1
Reactant: COC(=O)CN1Cc2ncnc(Oc3ccc4c(ccn4C(=O)Nc4cccc(C(F)(F)F)c4)c3)c2CC1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1Cc2c(ncnc2Oc2ccc3c(ccn3C(=O)Nc3cccc(C(F)(F)F)c3)c2)CN1CCO

Procedure:
LiAlH4 (0.46 mL, 1.0 M THF) is added to a solution of {6-methyl-4-[1-(3-trifluoromethyl-phenylcarbamoyl)-1H-indol-5-yloxy]-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl}-acetic acid methyl ester (0.125 g, 0.232 mmol) in THF (5 mL). After 0.5 h the excess LiAlH4 is quenched by the addition of saturated aqueous NH4Cl. Workup is done with saturated aqueous NH4Cl and DCM (25 mL each). The residue is then separated via semi-prep HPLC to give 5-[7-(2-hydroxy-ethyl)-6-methyl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidin-4-yloxy]-indole-1-carboxylic acid (3-trifluoromethyl-phenyl)-amide. MS (ESI) m/z 512.3 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.42 (s, 1 H), 8.30 (d, J=8.6 Hz, 1 H), 8.11 (d, J=3.5 Hz, 1 H), 8.09 (s, 1 H), 7.94 (d, J=8.3 Hz, 1 H), 7.57-7.65 (m, 1 H), 7.41-7.46 (m, 2 H), 7.11 (dd, J=9.0, 2.4 Hz, 1 H), 6.72-6.78 (m, 1 H), 4.47 (t, J=5.4 Hz, 1 H), 3.75 (s, 2 H), 3.57 (q, J=6.1 Hz, 2 H), 3.12-3.22 (m, 1 H), 2.88-3.00 (m, 1 H), 2.54-2.76 (m, 3 H), 1.10 (d, J=6.6 Hz, 3 H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)[NH:4][N:3]=1.[Cl:19][C:20]1[CH:21]=[C:22]([N:26]=[C:27]=[O:28])[CH:23]=[CH:24][CH:25]=1.N1C2C=NC=NC=2C=N1>O1CCOCC1.CN1C(=O)N(C)CC1.C(O)C>[Cl:18][C:14]1[CH:13]=[C:12]([NH:11][C:9]2[N:8]=[CH:7][N:6]=[C:5]3[NH:4][N:3]=[C:2]([NH:1][C:27]([NH:26][C:22]4[CH:23]=[CH:24][CH:25]=[C:20]([Cl:19])[CH:21]=4)=[O:28])[C:10]=23)[CH:17]=[CH:16][CH:15]=1
Reactant: O=C=Nc1cccc(Cl)c1
Reactant: Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Agent: c1ncc2[nH]ncc2n1
Solvent: C1COCCO1
Solvent: CCO
Solvent: CN1CCN(C)C1=O
Product: O=C(Nc1cccc(Cl)c1)Nc1n[nH]c2ncnc(Nc3cccc(Cl)c3)c12
Temperature: 60 °C
Reaction time: 16 h

Procedure:
With the exclusion of moisture, 261 mg (1.00 mmol) of 3-amino-4-(3-chlorophenylamino)-1H-pyrazolo[3,4-d]pyrimidine (see Step 1.6) are dissolved in 2.5 ml of dioxane and 1 ml of DMEU; 137 I (1.1 mmol) of 3-chloro-phenyl isocyanate are added and the reaction mixture is stirred overnight at RT and finally for 16 hours at 60° C. Since, according to HPLC, not all of the pyrazolo-pyrimidine has reacted, a further 40 all of 3chloro-phenyl isocyanate are added and the mixture is stirred for a further 20 hours at 60° C. Working-up analogously to Example 66 and stirring in hot ethanol yield 4-(3-chloro-phenylamino)-3-[(3-chloro-phenyl-amino)-carbonylamino]-1H-pyrazolo[3,4-d]pyrimidine; HPLC: tRet(grad20-100)=12.4; FARMS: (M+H)+=414.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:24][S:25]([C:28]1[CH:36]=[CH:35][C:31]2[N:32]=[CH:33][S:34][C:30]=2[CH:29]=1)(=[O:27])=[O:26])[C:11]1[S:12][C:13](/[CH:16]=[N:17]\[S:18]([C:20]([CH3:23])([CH3:22])[CH3:21])=[O:19])=[CH:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:37](O)[CH:38]([CH3:40])[CH3:39].C(P(=CC#N)(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Si:1]([O:8][CH2:9][C@@H:10]([N:24]([CH2:37][CH:38]([CH3:40])[CH3:39])[S:25]([C:28]1[CH:36]=[CH:35][C:31]2[N:32]=[CH:33][S:34][C:30]=2[CH:29]=1)(=[O:27])=[O:26])[C:11]1[S:12][C:13](/[CH:16]=[N:17]\[S:18]([C:20]([CH3:21])([CH3:22])[CH3:23])=[O:19])=[CH:14][CH:15]=1)([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)CO
Reactant: CC(C)(C)S(=O)/N=C\c1ccc([C@@H](CO[Si](C)(C)C(C)(C)C)NS(=O)(=O)c2ccc3ncsc3c2)s1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)CN([C@H](CO[Si](C)(C)C(C)(C)C)c1ccc(/C=N\S(=O)C(C)(C)C)s1)S(=O)(=O)c1ccc2ncsc2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of N-[(1R)-2-{[tert-butyl(dimethyl)silyl]oxy}-1-(5-{(Z)-[(tert-butylsulfinyl)imino]methyl}thiophen-2-yl)ethyl]-1,3-benzothiazole-6-sulfonamide (2.1 g, 3.58 mmol) and isobutanol (0.66 mL, 7.17 mmol) in toluene (18 mL) was added (tributyl-λ5-phosphanylidene)acetonitrile (1.74 mL, 7.17 mmol) and the reaction mixture was stirred at 100° C. for 2 hours. The mixture was cooled and then directly injected on a silica gel column eluting with hexanes and ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:27])=[C:7]([C:16]([NH:18][CH2:19][C:20]([O:22]C(C)(C)C)=[O:21])=[O:17])[C:8](=[O:15])[C:9]2([CH2:13][CH3:14])[CH3:12])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:27])=[C:7]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])[C:8](=[O:15])[C:9]2([CH2:13][CH3:14])[CH3:12])=[CH:4][CH:3]=1
Reactant: CCC1(C)C(=O)C(C(=O)NCC(=O)OC(C)(C)C)=C(O)c2ccc(Cl)cc21
Solvent: O=C(O)C(F)(F)F
Product: CCC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2ccc(Cl)cc21
Yield: 81.3 %

Procedure:
1,1-Dimethylethyl N-((7-chloro-1-ethyl-4-hydroxy-1-methyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (393 mg, 998 μmol) was stirred in TFA (3 mL, 40.4 mmol) at room temperature for 20 minutes. The TFA was removed in vacuo, and water was added. The resulting precipitate was filtered and washed with water to give the desired product as a white solid (274 mg). MS (m/e)=338 (M+H)+. Calculated for C16H16ClNO5 337.07.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([N+:20]([O-])=O)=[CH:18][CH:17]=[C:16]([CH3:23])[N:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:2]>CO.[Pd]>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C@@H:6]([NH:13][C:14]1[C:19]([NH2:20])=[CH:18][CH:17]=[C:16]([CH3:23])[N:15]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C[C@@H](Nc1nc(C)ccc1[N+](=O)[O-])c1ccccc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C[C@@H](Nc1nc(C)ccc1N)c1ccccc1
Reaction time: 2 h
Yield: 107.7 %

Procedure:
To a solution of (R)-3-(6-methyl-3-nitro-pyridin-2-ylamino)-3-phenyl-propionic acid ethyl ester (398 mg, 1.21 mmol) in MeOH (10 mL) was added slurry of Pd/C (150 mg) in MeOH (2 mL). The reaction mixture was degassed using house vacuum. The flask was saturated with H2 and stirred under H2 balloon for 2 hours. When the reaction was completed, the mixture was filtered through a pad of celite and the filtrate was concentrated to afford 390 mg (100%) of the oily residue. The resulting residue was used for the next reaction without further purification. LCMS, M++1, m/z: 300.15.
Reaction SMILES: S(Cl)(Cl)=O.[CH:5]1([CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([OH:14])=O)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH2:21]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=1)[CH3:22].C(N(CC)CC)C>CN(C=O)C.ClCCl>[CH2:21]([O:23][C:24](=[O:32])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:12](=[O:14])[CH:11]([CH:5]2[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:27][CH:26]=1)[CH3:22]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: O=C(O)C(c1ccccc1)C1CCCCC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(NC(=O)C(c2ccccc2)C2CCCCC2)cc1
Reaction time: 1 h
Yield: 97.4 %

Procedure:
To a flask containing thionyl chloride (1.52 g, 929 μl, 12.8 mmol) and 1 drop of DMF is added cyclohexylphenylacetic acid (1.87 g, 8.54 mmol). The resulting solution is stirred for 1 h. The thionyl chloride is evaporated under reduced pressure and the resulting crude acid chloride is diluted in dichloromethane (15 ml). To this solution is added dropwise a solution of 4-amino-benzoic acid ethyl ester (1.41 g, 8.54 mmol) and triethylamine (1.49 ml, 1.08 g, 10.67 mmol) in dichloromethane (15 ml). The resulting mixture is stirred for 30 min at rt. It is diluted with dichloromethane and the resulting organic phase is washed with a 10% aqueous citric acid solution, with a saturated aqueous Na2CO3 solution and with water. It is dried over Na2SO4 and the solvent is evaporated in vacuo. The crude residue is purified on silica gel (AcOEt/heptane, 1.4), yielding the title compound (3.04 g) in 97% as a white solid: tR=8.00 min (LC-1), ESI-MS (pos.): m/z 366.18 [M+H]+, ESI-MS (neg.): m/z 364.25 [M−H]+.
Reaction SMILES: Cl.[C:2]([O:7][C@@H:8]1[C@H:25](O)[C:24]2[C:23]3[N:22]([CH3:27])[C:21]4[N:20]=[C:19]5[CH:28]=[CH:29][CH:30]=[CH:31][C:18]5=[CH:17][C:16]=4[C:15](=[O:32])[C:14]=3[C:13]([O:33][CH3:34])=[CH:12][C:11]=2[O:10][C:9]1([CH3:36])[CH3:35])(=[O:6])[CH2:3][CH2:4][CH3:5]>ClCCl>[C:2]([O:7][C:8]1[C:9]([CH3:35])([CH3:36])[O:10][C:11]2[CH:12]=[C:13]([O:33][CH3:34])[C:14]3[C:15](=[O:32])[C:16]4[CH:17]=[C:18]5[CH:31]=[CH:30][CH:29]=[CH:28][C:19]5=[N:20][C:21]=4[N:22]([CH3:27])[C:23]=3[C:24]=2[CH:25]=1)(=[O:6])[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(=O)O[C@@H]1[C@H](O)c2c(cc(OC)c3c(=O)c4cc5ccccc5nc4n(C)c23)OC1(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCC(=O)OC1=Cc2c(cc(OC)c3c(=O)c4cc5ccccc5nc4n(C)c23)OC1(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Add 4 drops of a 10% solution of HCl to a solution of 0.29 mmol of the compound of Example 13 in 6 ml of dichloromethane. The reaction mixture is stirred for 3 days at ambient temperature and then dried and concentrated under reduced pressure. Chromatography of the residue on silica gel (dichloromethane/methanol gradient) allows the expected product to be isolated.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[C:14]([O:20][CH3:21])[C:15](=[O:19])[O:16]2)=[CH:11][C:10]=1[N+:22]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].CCOC(C)=O>C1COCC1.O>[NH2:22][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[O:16][C:15](=[O:19])[C:14]([O:20][CH3:21])=[CH:13]2
Reactant: COc1cc2cc([N+](=O)[O-])c(OCc3ccccc3)cc2oc1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc2cc(N)c(OCc3ccccc3)cc2oc1=O
Temperature: 80 °C

Procedure:
To a solution of 7-benzyloxy-3-methoxy-6-nitrochromen-2-one (0.20 g, 0.61 mmol) in 20 mL of THF is added a solution of Na2S2O4 (1.0 g) in water (6 mL). The mixture is heated at 80° C. for 18 h. Additional Na2S2O4 is added until the reaction is complete. After cooling to ambient temperature, EtOAc is added and the mixture is washed with water and sat. NaCl, then dried over sodium sulfate. The solvent is removed under reduced pressure to afford 6-amino-7-benzyloxy-3-methoxychromen-2-one as a pale yellow solid: 1H NMR (CDCl3) δ 7.44-7.34 (m, 5H), 6.81 (s, 1H), 6.70 (s, 1H), 6.68 (s, 1H), 5.11 (s, 2H), 3.85 (s, 3H); (M+H)+=298.
Reaction SMILES: [F:1][CH:2]([F:36])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[N:17]([N:21]=[C:22]([NH:24][C:25]3[CH:35]=[CH:34][C:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33][C:27]=4[CH:26]=3)[N:23]=2)[CH:18]=[CH:19][CH:20]=1.Cl[CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40]>>[F:36][CH:2]([F:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[C:15]1[C:16]2[N:17]([N:21]=[C:22]([NH:24][C:25]3[CH:35]=[CH:34][C:28]4[CH2:29][CH2:30][N:31]([CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=[O:40])[CH2:32][CH2:33][C:27]=4[CH:26]=3)[N:23]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: CN(C)C(=O)CCl
Reactant: CS(=O)(=O)c1ccc(OCC(F)F)c(-c2cccn3nc(Nc4ccc5c(c4)CCNCC5)nc23)c1
Product: CN(C)C(=O)CN1CCc2ccc(Nc3nc4c(-c5cc(S(C)(=O)=O)ccc5OCC(F)F)cccn4n3)cc2CC1

Procedure:
2-(7-{8-[2-(2,2-Difluoro-ethoxy)-5-methanesulfonyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino}-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-N,N-dimethyl-acetamide was prepared from {8-[2-(2,2-difluoro-ethoxy)-5-methanesulfonyl-phenyl]-[1,2,4]triazolo[1,5-a]pyridin-2-yl}-(2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)-amine (0.127 g, 0.247 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.038 mL, 0.371 mmol) in a manner analogous to Example 313 to give product (0.060 g, 40%). MP=128-130° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.50 (s, 1H), 8.81 (d, 1H), 8.20 (s, 1H), 8.00 d, 1H), 7.65 (d, 1H), 7.50 (m, 2H), 7.32 (s, 1H), 7.10 (t, 1H), 6.98 (d, 1H), 6.28 (br m, 1H), 4.54 (m, 2H), 3.25 (m, 5H), 3.10 (s, 3H), 2.80 (m, 7H), 2.60 (m, 4H). MS=599 (MH)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.[OH-].[Na+].C([O-])=O.[Na+]>[Pd].O>[F:13][C:11]1[CH:12]=[C:4]([NH2:1])[C:5](=[CH:9][C:10]=1[F:14])[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cc(F)c(F)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Product: Nc1cc(F)c(F)cc1C(=O)O
Temperature: 90 °C
Yield: 93 %

Procedure:
2-nitro-4,5-difluorobenzoic acid (1.0 g) was added to 10 mL of water. 0.2 g of NaOH was added, followed by 1.0 g of sodium formate. 0.05 g of 10% palladium on carbon was added, and the mixture was heated to 90° C. for 2.5 h. After cooling, a suitable internal standard was added. 19F NMR internal standard analysis of the entire reaction mixture indicated a 93% yield of 4,5-difluoroanthranilic acid.