Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[S:11][CH2:12][CH2:13][C:14]([F:23])([F:22])[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[O:4].[OH-].[Na+].O>CCO>[F:23][C:14]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)[CH2:13][CH2:12][S:11][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1ccncc1SCCC(F)(F)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccncc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
To a solution of 3-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-pyridine-4-carboxylic acid methyl ester (0.33 g, 0.96 mmol) in EtOH (10 ml) are added sodium hydroxide (0.15 g, 3.87 mmol) and water (10 ml). The reaction mixture is stirred at 80° C. for 1 h. After completion of the reaction, the solvent is evaporated and the residue is diluted with water (10 ml). The aqueous layer is acidified with 2M hydrochloric acid to pH 3 and extracted with EtOAc (3×20 ml). The combined organic layers are washed with water (20 ml), brine (20 ml), dried over anhydrous sodium sulfate and evaporated to get the crude 3-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-pyridine-4-carboxylic acid (0.26 g, 0.8 mmol, 82%), which is used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:14](Cl)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CS(C)=O.O>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][CH2:5][C:4]2[CH:9]=[CH:10][CH:11]=[CH:2][CH:3]=2)[C:11]=1[O:12][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:5]([O:7][CH3:8])=[O:6])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1

Procedure:
Methyl 3,4,5-trihydroxybenzoate (16) (55.24 g, 0.3 mol), benzyl chloride (113.93 g, 0.9 mol), potassium carbonate (124.39 g, 0.9 mol) and potassium iodide (catalytic amount) were mechanically stirred in dry DMSO (200 mL) at room temperature overnight. Water (200 mL) was added and the crude product isolated by filtration. Evaporation of residual solvents in a vacuum desiccator left a pale yellow solid which was essentially pure product. Yield: 128.2 g (94%).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:27]=[CH:26][C:8]2[N:9]=[C:10]([NH:12][C:13]3[N:17]([CH3:18])[C:16]4[CH:19]=[CH:20][C:21]([C:23](O)=[O:24])=[CH:22][C:15]=4[N:14]=3)[S:11][C:7]=2[CH:6]=1)(=[O:4])=[O:3].[CH3:28][O:29][CH2:30][CH2:31][NH2:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:28][O:29][CH2:30][CH2:31][NH:32][C:23]([C:21]1[CH:20]=[CH:19][C:16]2[N:17]([CH3:18])[C:13]([NH:12][C:10]3[S:11][C:7]4[CH:6]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:27]=[CH:26][C:8]=4[N:9]=3)=[N:14][C:15]=2[CH:22]=1)=[O:24]
Reactant: COCCN
Reactant: Cn1c(Nc2nc3ccc(S(C)(=O)=O)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(S(C)(=O)=O)cc3s1)n2C

Procedure:
2-(6-Methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (33 mg) was prepared by following General Procedure F using 2-(6-methanesulfonyl-benzothiazol-2-ylamino)-1-methyl-1H-benz-imidazole-5-carboxylic acid (40 mg), 2-methoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 461; and 1H NMR (DMSO-d6, 400 MHz): δ 8.36 (t, 1H), 8.14 (br, 1H), 7.94 (d, 2H), 7.66 (d, 1H), 7.59 (d, 1H), 7.44 (d, 1H), 7.25 (d, 1H), 3.61 (s, 3H), 3.45 (m, 4H), 3.27 (s, 3H), and 2.87 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[CH:6][N:5]=[C:4]([CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])[N:3]=1.[CH3:18][N:19]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:38]3[CH:39]=[N:40][N:41]([CH3:43])[CH:42]=3)[CH:25]=2)[C:20]1=[O:44]>>[CH:10]1([CH2:9][O:8][C:7]2[C:2]([C:27]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:38]5[CH:39]=[N:40][N:41]([CH3:43])[CH:42]=5)[CH:25]=4)[C:20](=[O:44])[N:19]([CH3:18])[CH:28]=3)=[N:3][C:4]([CH2:13][S:14]([CH3:17])(=[O:16])=[O:15])=[N:5][CH:6]=2)[CH2:12][CH2:11]1
Reactant: Cn1cc(-c2ccc3c(=O)n(C)cc(B4OC(C)(C)C(C)(C)O4)c3c2)cn1
Reactant: CS(=O)(=O)Cc1ncc(OCC2CC2)c(Cl)n1
Product: Cn1cc(-c2ccc3c(=O)n(C)cc(-c4nc(CS(C)(=O)=O)ncc4OCC4CC4)c3c2)cn1

Procedure:
The title compound of Example 143, step 2 was reacted with the title compound of Example 46, step 2 in a manner similar to Example 143, step 3 to give the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 8.26 (d, J=8.4 Hz, 1H), 8.23 (s, 1H), 7.91 (s, 1H), 7.5 (d, J=8.4 Hz, 1H), 7.70 (s, 1H), 7.66 (s, 1H), 7.52 (s, 1H), 3.87 (s, 3H), 3.85-3.80 (m, 4H), 3.57 (s, 3H), 3.28 (s, 3H), 0.88-0.87 (m, 1H), 0.30-0.25 (m, 2H), 0.07-0.04 (m, 2H). LCMS: 480.2 (M+1)+
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[C:11](=[O:13])[CH3:12].[C:14](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:14][O:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[C:11](=[O:13])[CH3:12]
Reactant: O=C([O-])[O-]
Reactant: CC(=O)c1c(C)cc(C)c(C)c1O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(C)c(C)cc(C)c1C(C)=O
Temperature: 25 °C
Yield: 88.4 %

Procedure:
In acetone (30 mL) was dissolved 2.00 g (11.2 mmol) of 1-(2-hydroxy-3,4,6-trimethylphenyl)ethanone which can be produced by the method disclosed in Chemical Research in Toxicology, 1997, vol. 10, No. 3, pp. 335-343, 3.10 g (22.4 mmol) of potassium carbonate, then 1.40 mL (22.5 mmol) of methyl iodide were added to the solution, and the resulting mixture was refluxed for 5 hours. After cooling to room temperature, the reaction mixture was concentrated, and the residue was poured into water, and extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the residue was purified by silica gel column chromatography (Wako gel C-100, hexane:ethyl acetate gradient) to obtain 1.90 g (9.90 mmol, Yield: 88.4%) of 1-(2-methoxy-3,4,6-trimethylphenyl)ethanone.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:8][CH:9]1[C:14](=[O:15])[N:13]2[CH:16]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:17](=[O:23])[N:18]([CH:20]([CH3:22])[CH3:21])[CH2:19][CH:12]2[N:11]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[Cl:42])(=[O:34])=[O:33])[CH2:10]1>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH:16]2[N:13]3[C:14](=[O:15])[CH:9]([NH:8][C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:6])[CH2:10][N:11]([S:32]([C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=4[Cl:42])(=[O:34])=[O:33])[CH:12]3[CH2:19][N:18]([CH:20]([CH3:22])[CH3:21])[C:17]2=[O:23])=[CH:26][CH:27]=1
Reactant: O=C(Cl)C1CCC1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Product: CC(C)N1CC2N(C(=O)C(NC(=O)C3CCC3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O

Procedure:
Synthesis took place in analogy to Example 22 using cyclobutanecarbonyl chloride and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW=640.11 (calculated, monoisotopic); measured value (M+H)+: 641.09
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([OH:18])=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH:42]1[CH2:48][CH2:47][CH2:46][C@H:43]1[CH2:44][OH:45]>C1COCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([N:42]1[CH2:48][CH2:47][CH2:46][C@H:43]1[CH:44]=[O:45])=[O:18])[CH:13]([CH3:14])[CH3:15])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: OC[C@@H]1CCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: C1CCOC1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C=O
Temperature: 4 °C
Reaction time: 21 h

Procedure:
In 200 ml of THF was dissolved 22.1 g of N-benzyloxycarbonylvaline. To this solution were added under cooling with edible salt and ice 11.5 g of HOSu and 20.6 g of DCC, and the mixture was stirred for 21 hours at 4° C. The reaction liquid was filtered and the filtrate was evaporated whereby a semi-solid substance was obtained. This substance was recrystallized from isopropyl alcohol to obtain a white solid substance which was then dissolved in 470 ml of THF. To this solution was added 8.6 g of L-prolinol, and the mixture was stirred for 72 hours at room temperature. After removal of THF by distillation, the residue was dissolved in 300 ml of ethyl acetate and the solution was washed with 100 ml of 1-M Na2CO3, dehydrated with anhydrous Na2SO4 and evaporated until dryness. To the resultant oily substance were added 43.1 g of WSCD.HCl and 150 ml of redistilled DMSO, and the mixture was stirred for 10 minutes. Subsequently, 7 ml of a DMSO solution of 2-M anhydrous H3PO4 was added and the mixture was stirred for further 2 hours. The reaction was stopped with 300 ml of a buffer solution of 1-M potassium phosphate of pH 7.5. The reaction mixture was extracted with 200 ml of ethyl acetate, and the extract was dried over anhydrous Na2SO4. The ethyl acetate was distilled off and the residue was dissolved in 200 ml of ethanol. To this solution was added 200 g of NaHSO3 in 350 ml of water, and the mixture was stirred vigorously for 10 minutes. After concentration of the ethanol up to about 350 ml, unreacted materials were eliminated twice with 100 ml of ether, and solid Na2CO3 was added until the pH value of the liquid became 9. After 5 minutes, the reaction liquid was extracted twice with 100 ml of ether, and the ether was then distilled off to leave an oily substance. Yield 5.7 g (17.2%).
Reaction SMILES: [CH2:1]([C:5]1[CH:23]=[CH:22][C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[C:18]([O:20]C)=[O:19])[O:11][C:7]=2[CH:6]=1)[CH:2]([CH3:4])[CH3:3].[OH-].[Li+]>>[CH2:1]([C:5]1[CH:23]=[CH:22][C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]3[C:18]([OH:20])=[O:19])[O:11][C:7]=2[CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)[C@@H]1CCCCN1c1nc2ccc(CC(C)C)cc2o1
Agent: [Li+]
Agent: [OH-]
Product: CC(C)Cc1ccc2nc(N3CCCC[C@H]3C(=O)O)oc2c1

Procedure:
The title compound was prepared by a similar method to Preparation 3 from methyl (2S)-1-(6-isobutyl-1,3-benzoxazol-2-yl)-2-piperidinecarboxylate [see Preparation 41] and 1N aqueous lithium hydroxide solution, to afford (2S)-1-(6-isobutyl-1,3-benzoxazol-2-yl)-2-piperidinecarboxylic acid as a foam.
Reaction SMILES: [CH2:1]([Li])CCC.CCCCCC.[C:12]([C:16]1[CH:36]=[CH:35][C:19]([CH2:20][N:21]([CH2:25][C:26]2[CH:27]=[C:28]([C:32](=O)[CH3:33])[CH:29]=[CH:30][CH:31]=2)[CH:22]2[CH2:24][CH2:23]2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:12]([C:16]1[CH:36]=[CH:35][C:19]([CH2:20][N:21]([CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([CH3:1])=[CH2:33])[CH:27]=2)[CH:22]2[CH2:24][CH2:23]2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: [Li]CCCC
Reactant: CC(=O)c1cccc(CN(Cc2ccc(C(C)(C)C)cc2)C2CC2)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Product: C=C(C)c1cccc(CN(Cc2ccc(C(C)(C)C)cc2)C2CC2)c1
Yield: 35.2 %

Procedure:
The procedure described in Example 60 was repeated, except that methyl triphenylphosphonium bromide (0.32 g; 8.94×10−1 mmol), n-butyl lithium in n-hexane (1.56 M: 0.6 ml; 8.9×10−1 mmol), and Compound 82 (0.20 g; 5.96×10−1 mmol) were used, to thereby yield 0.07 g of the target compound (yield: 35.2%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.[N:19]1([C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH:34]=[CH:33][NH:32][C:31]3=[O:35])=[CH:26][CH:25]=2)[CH:23]=[N:22][CH:21]=[N:20]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:10])([CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C@H:11]([N:32]1[CH:33]=[CH:34][N:30]([C:27]2[CH:26]=[CH:25][C:24]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)=[CH:29][CH:28]=2)[C:31]1=[O:35])[CH3:12]
Reactant: O=c1[nH]ccn1-c1ccc(-n2cncn2)cc1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@@H](n1ccn(-c2ccc(-n3cncn3)cc2)c1=O)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 80 °C
Reaction time: 9.5 h
Yield: 21.6 %

Procedure:
(2R,3S)-2-(2,4-Difluorophenyl)-3-methyl-2-(1H-1,2,4-triazol-1-yl)methyloxirane (2.5 g), 1-[4-(1H-1,2,4-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (2.72 g) and cesium carbonate (powder: 9.7 g) were added to N,N-dimethylformamide (150 ml), and the mixture was heated at 80° C. with stirring for 9.5 hours. After cooling, the reaction mixture was diluted with ethyl acetate (400 ml). Ice water (150 ml) was added thereto to separate the ethyl acetate layer. The aqueous layer was extracted with ethyl acetate (100 ml). The ethyl acetate layers were combined and washed with 0.5N-sodium hydroxide (100 ml), 1N-hydrochloric acid (100 ml×2) and a saturated aqueous solution of sodium chloride (50 ml) successively. The ethyl acetate layer was dried over anhydrous magnesium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (eluent:ethyl acetate/acetone=2/1) to give 1-[(1R,2R)-2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-3-[4-(1H-1,2,4-triazol-1-yl)phenyl]-2(1H,3H)-imidazolone (Compound 9; 1.03 g) as a pale yellow powder.
Reaction SMILES: C(C1C=CC(N2CC[C@H](N[C@@H](C3C4C(=CC=CC=4)C=CC=3)C)C2)=CC=1)(=O)C.Cl[C:29]([N:31]([C@@H:44]([C:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48][CH:47]=1)[CH3:45])[C@H:32]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33]1)=[O:30].[C:56]([OH:60])([CH3:59])([CH3:58])[CH3:57]>>[C:56]([O:60][C:29]([N:31]([C@@H:44]([C:46]1[C:55]2[C:50](=[CH:51][CH:52]=[CH:53][CH:54]=2)[CH:49]=[CH:48][CH:47]=1)[CH3:45])[C@H:32]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:38])[CH2:33]1)=[O:30])([CH3:59])([CH3:58])[CH3:57]
Reactant: C[C@H](c1cccc2ccccc12)N(C(=O)Cl)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)(C)O
Agent: CC(=O)c1ccc(N2CC[C@H](N[C@H](C)c3cccc4ccccc34)C2)cc1
Product: C[C@H](c1cccc2ccccc12)N(C(=O)OC(C)(C)C)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 48 h

Procedure:
To a solution of 14.9 g of triphosgene dissolved in 400 ml of methylene chloride was added dropwise a solution containing 25.68 g of tert-butyl (R)-3-[1-(naphthalen-1-yl)ethylamino]pyrrolidine-1-carboxylate (the compound obtained in the above-mentioned Reference example 1.005 (1)) and 31.5 ml of triethylamine in 100 ml of methylene chloride at −20° C. Further, 7.5 g of triphosgene was added to the same, and the mixture was stirred at room temperature for 30 minutes. Water was added to the reaction mixture, the mixture was stirred and the liquids were separated. The organic layer was dried, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=6:1→2:1) to obtain 10.63 g of tert-butyl (S)-3-[chlorocarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate and 9.22 g of tert-butyl (R)-3-[chlorocarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate shown in the following Reference example Table, respectively. (2) To 18.52 g of tert-butyl (S)-3-[chlorocarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate was added 1.0 liter of tert-butanol, and the mixture was stirred at 60° C. for 2 days. The reaction mixture was concentrated, and then, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain 9.24 g of tert-butyl (S)-3-[tert-butoxycarbonyl-[(R)-1-(naphthalen-1-yl)ethyl]amino]pyrrolidine-1-carboxylate (the following Reference example 1.006(a)).
Reaction SMILES: BrC1C=CC(C2N([C:13]3C=C[C:16]([S:19](N)(=O)=O)=[N:17][CH:18]=3)N=C(C(F)(F)F)C=2)=CC=1C(F)(F)F.Br[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[N:42]([C:43]3[CH:44]=[CH:45][C:46]([S:49]([NH2:52])(=[O:51])=[O:50])=[N:47][CH:48]=3)[N:41]=[C:40]([C:53]([F:56])([F:55])[F:54])[C:39]=2Cl)=[CH:34][CH:33]=1>>[S:19]1[CH:13]=[C:18]([C:32]2[CH:33]=[CH:34][C:35]([C:38]3[N:42]([C:43]4[CH:44]=[CH:45][C:46]([S:49]([NH2:52])(=[O:50])=[O:51])=[N:47][CH:48]=4)[N:41]=[C:40]([C:53]([F:56])([F:55])[F:54])[CH:39]=3)=[CH:36][C:37]=2[C:53]([F:56])([F:55])[F:54])[N:17]=[CH:16]1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(Br)cc2)cn1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)c(C(F)(F)F)c2)cn1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3cscn3)c(C(F)(F)F)c2)cn1

Procedure:
The title compound was prepared according to the procedure of step 3, 4 in the example 4 using 5-{5-[4-bromo-3-(trifluoromethyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl}-2-pyridinesulfonamide, instead of 5-[5-(4-bromophenyl)-4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([F:20])[CH:18]=3)[C:13](=[O:22])[C:12]([C:23]([O:25]CC)=[O:24])=[CH:11]2)[C:5]([F:9])=[CH:6][C:7]=1[F:8].Cl>C(O)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[C:17]([F:20])[CH:18]=3)[C:13](=[O:22])[C:12]([C:23]([OH:25])=[O:24])=[CH:11]2)[C:5]([F:9])=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1cn(-c2cc(N)c(F)cc2F)c2cc(F)c(F)cc2c1=O
Agent: Cl
Solvent: CC(=O)O
Product: Nc1cc(-n2cc(C(=O)O)c(=O)c3cc(F)c(F)cc32)c(F)cc1F
Yield: 89.6 %

Procedure:
Ethyl 1-(3-amino-4,6-difluorophenyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (1 g) was added to 8 ml of acetic acid and 2 ml of hydrochloric acid. The solution was heated at reflux overnight. After cooling down, the solution was concentrated in vacua. Ethanol was added to the residue whereupon the solid was collected by filtration and washed with diethyl ether to give 830 mg of the title compound.
Reaction SMILES: Cl.[F:2][C:3]([F:27])([F:26])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[N:18]=[CH:19][C:20]([C:23](O)=[O:24])=[N:21][CH:22]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[NH2:58][CH:59]1[CH2:64][CH2:63][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:61][CH2:60]1>CN(C)C=O>[F:26][C:3]([F:2])([F:27])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[N:18]=[CH:19][C:20]([C:23]([NH:58][CH:59]4[CH2:60][CH2:61][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:63][CH2:64]4)=[O:24])=[N:21][CH:22]=3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: O=C(O)c1cnc(OC2CCN(c3ccc(C(F)(F)F)cc3)CC2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)c2cnc(OC3CCN(c4ccc(C(F)(F)F)cc4)CC3)cn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.7 %

Procedure:
To a stirred mixture of 5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyrazine-2-carboxylic acid hydrochloric acid salt (0.10 g, 0.25 mmol) in anhydrous N,N-dimethylformamide (3 mL) was added triethylamine (0.56 g, 0.55 mmol), 1-hydroxybenzotriazole hydrate (0.04 g, 0.3 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.06 g, 0.3 mmol), and tert-butyl 4-aminopiperidine-1-carboxylate (0.06 g, 0.3 mmol). The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue obtained was purified by flash chromatography (silica gel, ethyl acetate/hexanes=1/1) to afford tert-butyl 4-(5-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)pyrazine-2-carboxamido)piperidine-1-carboxylate (compound 19) as a white solid (0.06 g, 44%). 1H-NMR (CDC3, 300 MHz): δ 8.89 (m, 1H), 8.06 (m, 1H), 7.50 (m, 3H), 6.96 (m, 2H), 5.33 (m, 1H), 4.10 (m, 3H), 3.64 (m, 2H), 3.25 (m, 2H), 2.95 (m, 2H), 2.15 (m, 2H), 1.97 (m, 4H), 1.56 (m, 2H), 1.47 (s, 9H) ppm; MS (ESI): 550.7 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]=2[NH:19][C:20]2[C:21]3[CH:29]=[CH:28][CH:27]=[N:26][C:22]=3[N:23]=[CH:24][N:25]=2)=[CH:5][CH:4]=1.[NH2:30][C:31]1[CH:39]=[CH:38][C:34]([CH2:35][C:36]#[N:37])=[CH:33][CH:32]=1.NC1C=C(O)C(C)=CC=1.C(C1C=CC2C(NC3C=C(C=CC=3SC3C=CC(OC)=CC=3)C(Cl)=O)=NC=NC=2N=1)(C)C>CO>[C:36]([CH2:35][C:34]1[CH:38]=[CH:39][C:31]([NH:30][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][C:10]([S:9][C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[C:11]([NH:19][C:20]3[C:21]4[CH:29]=[CH:28][CH:27]=[N:26][C:22]=4[N:23]=[CH:24][N:25]=3)[CH:12]=2)=[CH:32][CH:33]=1)#[N:37]
Reactant: N#CCc1ccc(N)cc1
Reactant: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3ncccc23)cc1
Agent: COc1ccc(Sc2ccc(C(=O)Cl)cc2Nc2ncnc3nc(C(C)C)ccc23)cc1
Agent: Cc1ccc(N)cc1O
Solvent: CO
Product: COc1ccc(Sc2ccc(C(=O)Nc3ccc(CC#N)cc3)cc2Nc2ncnc3ncccc23)cc1

Procedure:
The product from Example 260B was reacted with 4-aminobenzyl cyanide according to the procedure from Example 137C substituting 4-aminobenzyl cyanide for 5-amino-o-cresol and substituting the product from Example 260B for the product from Example 137B to provide the title compound as an off white solid after trituration of the reaction product from methanol (54.7 mg, 64%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 10.60 (s, 1 H), 10.26 (s, 1 H), 9.09 (s, 1 H), 8.95 (s, 1 H), 8.65 (s, 1 H), 7.98 (s, 1 H), 7.64-7.89 (m, J=8.46 Hz, 4 H), 7.36-7.47 (m, 2 H), 7.31 (d, J=8.82 Hz, 2 H), 6.91-7.07 (m, 3 H), 3.99 (s, 2 H), 3.78 (s, 3 H); MS (ESI+) m/z 519.4 (M+H)+, (ESI−) m/z 517.1 (M−H)−.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]=2[N:3]=1.Br[CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:27]1([O:20][C:17]2[CH:16]=[CH:15][C:14]([CH2:13][CH2:12][C:8]3[CH:9]=[N:10][C:11]4[C:6]([CH:7]=3)=[C:5]3[CH:21]=[CH:22][C:23]([CH3:25])=[CH:24][C:4]3=[N:3][C:2]=4[NH2:1])=[CH:19][CH:18]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: BrC1CCCC1
Reactant: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(O)cc3)cc12
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OC4CCCC4)cc3)cc12

Procedure:
2-(4-(Cyclopentyloxy)phenethyl)-8-methylbenzo[f][1,7]naphthyridin-5-amine was prepared from 4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenol (from Example 170) following the procedure described for Example 136, but using bromocyclopentane. 1H NMR (Acetone-d6): δ 8.75 (d, 2H), 8.30 (d, 1H), 7.45 (s, 1H), 7.20 (d, 1H), 7.14 (d, 2H), 6.79 (d, 2H), 4.73-4.81 (m, 1H), 3.22 (t, 2H), 3.05 (t, 2H), 2.47 (s, 3H), 1.85-1.96 (m, 2H), 1.70-1.79 (m, 4H), 1.56-1.64 (m, 2H). LRMS [M+H]=398.2
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH:6]2[CH2:7][CH2:8][C:3]1([CH2:13][S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[CH2:19][CH2:18]1)(=[O:16])=[O:15])[C:4]([C:9]([O:11]C)=[O:10])=[CH:5]2.[OH-].[K+].Cl>CO>[CH3:1][C:2]1([CH3:30])[CH:6]2[CH2:7][CH2:8][C:3]1([CH2:13][S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[CH3:29])[CH2:19][CH2:18]1)(=[O:16])=[O:15])[C:4]([C:9]([OH:11])=[O:10])=[CH:5]2
Reactant: COC(=O)C1=CC2CCC1(CS(=O)(=O)N1CCN(c3ccccc3C)CC1)C2(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1N1CCN(S(=O)(=O)CC23CCC(C=C2C(=O)O)C3(C)C)CC1
Reaction time: 18 h

Procedure:
To a stirred solution of 1-((7,7-dimethyl-2-methoxycarbonyl-bicyclo(2.2.1)hept-2-en-1-yl)methanesulfonyl)-4-(2-methylphenyl)-piperazine (1.0 g; 2.3 mmol) in MeOH (10 mL) was added a solution of 4M aqueous KOH (2.0 mL; 8.0 mmol). After 18 h, the reaction was brought to pH 1 with 5% aqueous HCl, and the solvents were removed under reduced pressure. The residue was taken up in chloroform (50 mL) and washed with water (25 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give the hydrochloride salt of the title compound as a white foam.