Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.[C:3]([BH3-])#[N:4].[Na+].[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:28])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C:12](=[O:34])[C:11]2([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[Cl:50])[NH:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42]N[CH2:40][CH2:39]1.C(=O)([O-])[O-].[K+].[K+]>CO.CC(O)=O.Cl.O>[Cl:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([S:17]([C:20]1[CH:21]=[CH:22][C:23]([NH:26][C:27]([N:29]([CH2:32][CH3:33])[CH2:30][CH3:31])=[O:28])=[CH:24][CH:25]=1)(=[O:18])=[O:19])[C:12](=[O:34])[C:11]2([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[Cl:50])[NH:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][N:4]([CH3:3])[CH2:40][CH2:39]1
Reactant: [BH3-]C#N
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(NCCN3CCNCC3)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Agent: C=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)N2C(=O)C(NCCN3CCN(C)CC3)(c3ccccc3Cl)c3cc(Cl)ccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
0.03 g of paraformaldehyde and 0.02 g of sodium cyanoborohydride are added in portions in 4 hours to a solution of 0.16 g of the compound obtained in EXAMPLE 201 in 4 ml of MeOH and 1 ml of AcOH. The mixture is stirred overnight at RT, 5 drops of concentrated HCl are added, water is then added after 10 minutes and the reaction mixture is rendered alkaline by the addition of potassium carbonate. The organic solvents are concentrated under vacuum, the residue is extracted with DCM and dried over sodium sulfate and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/MeOH mixture (88/12; v/v) as the eluent to give 0.099 g of the expected product after crystallization from a DCM/hexane/iso ether mixture.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([F:20])[C:15]=1B(O)O.O.CCOC(C)=O>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:1][C:2]1[C:3]([C:9]([O:11][CH3:12])=[O:10])=[N:4][C:5]([C:15]2[C:14]([F:13])=[CH:19][CH:18]=[CH:17][C:16]=2[F:20])=[C:6]([F:8])[CH:7]=1
Reactant: COC(=O)c1ncc(F)cc1N
Reactant: OB(O)c1c(F)cccc1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2c(F)cccc2F)c(F)cc1N
Temperature: 140 °C

Procedure:
To a solution of methyl 3-amino-5-fluoropicolinate (1.0 equiv.) in DME/2M Na2CO3 (3:1, 0.05 M) equipped with microwave vial was added 2,6-difluorophenylboronic acid (3.0 equiv.) and Pd(dppf)Cl2-DCM (0.1 equiv.). The reaction mixture was heated to 140° C. for 10 min in microwave reactor. After 2,6-difluorophenylboronic acid (3.0 equiv.) was added more, the reaction mixture was heated once more to 140° C. for 10 min in microwave reactor. After the reaction mixture was cooled to room temperature, H2O and EtOAc were added and the organic phase was washed with brine, then dried with Na2SO4, and concentrated. The crude material was purified via preparative HPLC. The pure methyl 3-amino-6-(2,6-difluorophenyl)-5-fluoropicolinate was obtained after the pure fractions were neutralized with NaHCO3, extracted with EtOAc, and concentrated (34%). The methyl 3-amino-6-(2,6-difluorophenyl)-5-fluoropicolinate (1.0 equiv.) was dissolved in THF and MeOH (2:1, 0.2 M) followed by addition of LiOH (1.8 equiv., 1 M aqueous solution). After the reaction mixture was stirred for 1.5 h at room temperature, the reaction mixture was quenched with 1 N HCl solution (1.8 equiv.) and extracted with EtOAc. The organic phase was washed with brine, then dried with Na2SO4, and concentrated. The crude 3-amino-6-(2,6-difluorophenyl)-5-fluoropicolinic acid was used for the next step without further purification (88%). LCMS (m/z): 269.0 (MH+); LC Rt=3.26 min.
Reaction SMILES: [CH:1]([C:4]1[N:5]=[C:6]([CH2:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:11])[NH:7][CH:8]=1)([CH3:3])[CH3:2].[C:18](O)(=[O:21])[C:19]#[CH:20].N1(C(N2C=CN=C2)=O)C=CN=C1>>[C:10]([C:9]1[CH:20]=[CH:19][C:18](=[O:21])[N:7]2[CH:8]=[C:4]([CH:1]([CH3:3])[CH3:2])[NH:5][C:6]=12)(=[O:11])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C#CC(=O)O
Reactant: CC(C)c1c[nH]c(CC(=O)c2ccccc2)n1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)c1cn2c(=O)ccc(C(=O)c3ccccc3)c2[nH]1

Procedure:
The compound is prepared as described in example 15 with 105 mg (0.46 mmol) of 2-(4-isopropyl-1H-imidazol-2-yl)-1-phenylethanone (example X, 48.3 mg (0.69 mmol) of propiolic acid and 134 mg (0.83 mmol) of 1-(1H-imidazol-1-yl-carbonyl)-1H-imidazole.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:17]1([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:26]3[CH2:27][CH2:28][CH:23]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH2:24][CH2:25]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCC(N3CCC(c4ccccc4)CC3)CC2)cc1

Procedure:
3.0 g of 1-(4-nitrophenyl) -4-piperidone and 2.2 g of 4-phenylpiperidine were reacted as in Example 1. The product contained 1/6 mol of water of crystallization.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:16])([F:15])[CH:8]([CH2:12][CH2:13][OH:14])[CH2:9][CH2:10][OH:11].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:1][S:2]([O:11][CH2:10][CH2:9][CH:8]([C:7]([F:15])([F:16])[F:6])[CH2:12][CH2:13][O:14][S:2]([CH3:1])(=[O:4])=[O:3])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCC(CCO)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OCCC(CCOS(C)(=O)=O)C(F)(F)F
Temperature: 0 °C

Procedure:
With stirring at 0° C., 63 ml of methylsulfonyl chloride in 40 ml of toluene are added dropwise to a solution of 69.3 g of 3-trifluoromethyl-1,5-pentanediol and 140 ml of triethylamine in 150 ml of toluene. After 12 hours' stirring at room temperature, the solid portions are filtered off and the toluene solution is concentrated in vacuo to give in almost quantitative yield 1,5-bismethanesulfonyloxy-3-trifluoromethylpentane; m.p. 40°-45° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH3:14])=[C:6]([CH3:15])[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:23](Cl)(Cl)=[S:24]>C(Cl)(Cl)Cl.ClCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:9][CH2:10][CH2:11][N:12]([CH2:13][CH3:14])[C:23]2=[S:24])=[C:6]([CH3:15])[CH:5]=[CH:4][CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: CCNCCCNc1c(C)cccc1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCN1CCCN(c2c(C)cccc2Cl)C1=S
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 59.5 %

Procedure:
To an ice-cold solution of the diamine of Step A (3.4 g) and triethylamine (4.0 mL) in dry chloroform (50 mL) was added thiophosgene (1.7 mL). After 20 minutes at ambient temperature, the reaction was quenched with water and extracted with dichloromethane. The extracts were combined, dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude material was dissolved in dichloromethane and absorbed onto a column of Merck-60 flash silica gel. Elution with 11% ethyl acetate in hexane provided an orange solid which was triturated with diethyl ether to give the title product (2.4 g, 59.5%) as a white solid, m.p. 88-90° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[N:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:34]1[CH2:39][CH2:38][C:37]([C:41]([F:44])([F:43])[F:42])([OH:40])[CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:23][C:20]1[N:21]=[CH:22][C:17]([C:3]2[CH:4]=[CH:5][C:6]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([N:34]3[CH2:39][CH2:38][C:37]([C:41]([F:44])([F:42])[F:43])([OH:40])[CH2:36][CH2:35]3)(=[O:32])=[O:33])=[CH:7][C:2]=2[F:1])=[N:18][CH:19]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)cn3)c(F)c2)OC1(C)C
Reactant: O=S(=O)(c1ccccc1Br)N1CCC(O)(C(F)(F)F)CC1
Product: Nc1cnc(-c2ccc(-c3ccccc3S(=O)(=O)N3CCC(O)(C(F)(F)F)CC3)cc2F)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 448 using 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-pyrazin-2-amine and 1-((2-bromophenyl)sulfonyl)-4-(trifluoromethyl)piperidin-4-ol. MS (ESI): mass calcd. for C22H20F4N4O3S, 496.12; m/z found, 497.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.38 (s, 1H), 8.23 (d, J=1.1, 1H), 8.15-8.11 (m, 1H), 7.94 (m, 1H), 7.75-7.67 (m, 1H), 7.64-7.58 (m, 1H), 7.45-7.41 (m, 1H), 7.35-7.27 (m, 2H), 3.29-3.22 (m, 2H), 2.79-2.64 (m, 2H), 1.65-1.48 (m, 4H).
Reaction SMILES: C([O:3][C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[O:19][CH3:20])[N:11]([CH2:21][CH2:22][F:23])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[F:23][CH2:22][CH2:21][N:11]1[C:10]2[CH2:9][CH2:8][CH2:7][CH:6]([C:4]([OH:5])=[O:3])[C:18]=2[C:17]2[C:12]1=[CH:13][CH:14]=[CH:15][C:16]=2[O:19][CH3:20]
Reactant: CCOC(=O)C1CCCc2c1c1c(OC)cccc1n2CCF
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cccc2c1c1c(n2CCF)CCCC1C(=O)O
Yield: 99.3 %

Procedure:
8-chloro-9-(2-Fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid ethyl ester (16) (380 mg, 1.2 mmol) was dissolved in ethanol (4 mL). A solution of sodium hydroxide (580 mg, 14.5 mmol) dissolved in 6 mL of water, was added. The reaction mixture was heated to reflux overnight. The solvent was removed in vacuo and the crude mixture diluted with water, acidified with 2 N HCl until acidic, and washed with dichloromethane. The organics were combined and dried over magnesium sulfate and concentrated in vacuo to give 347 mg (quantitative) of 9-(2-Fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid (17) as an off white solid which was used crude into the next step. The structure was confirmed by 13C NMR (75 MHz; CDCl3): δC 20.4, 21.9, 27.2, 39.9, 43.3 (d, JCF=23 Hz), 55.1, 81.9 (d, JCF=173 Hz), 100.3, 102.8, 106.2, 117.1, 122.2, 135.6, 137.8, 153.3, and 180.8.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH2:12][O:13][C:14]1[CH:29]=[CH:28][C:17]3[O:18][CH2:19][C:20]4[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=4[CH:22](O)[C:16]=3[CH:15]=1)[CH:8]=[CH:7]2.[SH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34]>>[C:33]([CH2:32][CH2:31][S:30][CH:22]1[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[CH2:19][O:18][C:17]2[CH:28]=[CH:29][C:14]([O:13][CH2:12][C:9]3[CH:8]=[CH:7][C:6]4[C:11](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=4)[N:10]=3)=[CH:15][C:16]1=2)([OH:35])=[O:34]
Reactant: OC1c2ccccc2COc2ccc(OCc3ccc4cccc(F)c4n3)cc21
Reactant: O=C(O)CCS
Product: O=C(O)CCSC1c2ccccc2COc2ccc(OCc3ccc4cccc(F)c4n3)cc21

Procedure:
2-(8-Fluoroquinolin-2-yl)methoxy-11-hydroxy-6,11-dihydrodibenz[b,e]oxepine and 3-mercaptopropionic acid were used and reacted in the same manner as in Example 1 to obtain the title compound.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[OH:9][CH:10]1[CH2:14][C:13](=O)[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:11]1[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CO>[OH:9][CH:10]1[CH2:14][C:13](=[N:2][OH:3])[C:12]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=[O:23])=[C:11]1[CH:25]=[CH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NO
Reactant: O=C(O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CO
Product: O=C(O)CCCCCCC1=C(C=Cc2ccccc2)C(O)CC1=NO
Reaction time: 48 h

Procedure:
To a solution of 6.95 parts of hydroxylamine hydrochloride and 16.4 parts of sodium acetate dissolved in 80 parts by volume of 50% aqueous methanol is added a solution of 6.5 parts of 3-hydroxy-5-oxo-2-styrylcyclopent-1-eneheptanoic acid and 0.8 parts of sodium hydroxide in 30 parts by volume of 50% aqueous methanol. That mixture is allowed to stand for 48 hours. After that time, the reaction mixture is acidified with citric acid and filtered to yield crystals which, when recrystallized from 50 parts by volume of methanol, gives 3-hydroxy-5-hydroxyimino-2-styrylcyclopent-1-eneheptanoic acid. That compound melts at about 164° and displays, in methanol, an ultraviolet absorption spectrum with a peak at about 321 millimicrons with a molecular extinction coefficient of about 44,700. That compound is represented by the following structural formula ##SPC10##
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([O:9]C)=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[CH3:17].[OH-].[K+]>C1COCC1.O>[Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][C:3]=1[C:11]1[N:15]([CH3:16])[N:14]=[CH:13][C:12]=1[CH3:17]
Reactant: COC(=O)c1cc(-c2c(C)cnn2C)c(Cl)s1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cnn(C)c1-c1cc(C(=O)O)sc1Cl
Temperature: 50 °C
Yield: 94.3 %

Procedure:
To a solution of methyl 5-chloro-4-(1,4-dimethyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (7.6 g, 28.1 mmol) in THF/H2O (30 mL/5 mL) was added KOH (4.72 g, 84 mmol). The reaction mixture was heated to 50° C. for 1 h. After the mixture was concentrated and diluted with H2O, the pH was adjusted to 3. The mixture was extracted with DCM (50 mL×3). The collected organic layers were concentrated under vacuum to give the crude acid (6.8 g, 94%), which was used directly in the next step without further purification: LCMS (ES) m/z 257 (M+H)+.
Reaction SMILES: [C@H:1]1([N:9]2[CH:16]=[C:15]([F:17])[C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:6][C@@H:5]([CH2:7][OH:8])[CH2:4][C@H:2]1[OH:3].[Si:18](Cl)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19].C(=O)([O-])O.[Na+].CO>N1C=CC=CC=1.C(Cl)Cl>[Si:18]([O:8][CH2:7][C@@H:5]1[O:6][C@H:1]([N:9]2[CH:16]=[C:15]([F:17])[C:13]([NH2:14])=[N:12][C:10]2=[O:11])[C@H:2]([OH:3])[CH2:4]1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Nc1nc(=O)n([C@H]2O[C@@H](CO)C[C@H]2O)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](O)[C@@H](n2cc(F)c(N)nc2=O)O1
Temperature: 25 °C
Reaction time: 10 h
Yield: 86 %

Procedure:
To a solution of 18 (1.38 g, 5.63 mmol) in dry pyridine (30 mL) was added dropwise under argon atmosphere t-butyldimethylsilyl chloride (1.10 g, 7.32 mmol) and the mixture was stirred for 10 h at room temperature. Then the mixture was poured onto a saturated aqueous sodium hydrogen carbonate solution (100 mL) and extracted with chloroform (3×150 mL). Combined extracts were washed with water (2×200 mL) and then dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (2-10%) in methylene chloride] to give pure 19 (1.74 g, 86% yield) as a white solid: mp 202-204° C.; UV (ethanol): λmax 241 nm (ε 7800), 284 nm (ε 7800), λmin 226 nm (ε 6600), 263 nm (ε 5400); 1H NMR (DMSO-d6): δ 7.77 (d, 1H, H-6, J6-F5=7.1 Hz), 7.7-7.3 (br d, 2H, NH2), 6.88 (dd, 1H, H-1′, J1′-2′=4.9 Hz and J1′-F5=1.9 Hz), 5.24 (d, 1H, OH-3′, JOH-3′=4.6 Hz), 4.4 (m, 1H, H-2′), 4.0 (m, 1H, H-4′), 3.8-3.7 (m, 2H, H-5′ and H-5″), 2.2 (m, 1H, H-3′), 1.7 (m, 1H, H-3″), 0.84 (s, 9H, (CH3)3C—Si), 0.06 (s, 6H, (CH3)2Si); MS (matrix GT): FAB>0 m/z 1437 (4M+H)+, 1078 (3M+H)+, 719 (2M+H)+, 360 (M+H)+, 231 (S)+, 130 (BH2)+, 115 (TBDMS)+; FAB<0 m/z 1076 (3M−H)−, 717 (2M−H)−, 358 (M−H)−, 128 (B)−; [α]D20=−107 (c, 0.88 DMSO).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[CH:8]=2)[C:3]=1[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22](O)=[O:23].S(Cl)(Cl)=O.[NH2:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1>COCCOC.ClCCl>[OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([OH:18])[CH:13]=3)[CH:8]=2)[C:3]=1[C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=1)[C:22]([NH:32][C:33]1[S:34][CH:35]=[CH:36][N:37]=1)=[O:23]
Reactant: O=C(O)c1cccc(-c2c(O)ccc3cc(-c4cccc(O)c4)ccc23)c1
Reactant: Nc1nccs1
Solvent: COCCOC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Nc1nccs1)c1cccc(-c2c(O)ccc3cc(-c4cccc(O)c4)ccc23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 13 %

Procedure:
To 3-(2-hydroxy-6-(3-hydroxyphenyl)naphthalene-1-yl)benzoic acid (79 mg, 0.22 mmol, 1 eq), which is dissolved under a nitrogen atmosphere in 2 ml of dry DME, thionyl chloride (100 μl) is added, and the mixture is stirred at RT for 2 h. After the excess thionyl chloride has been removed in vacuum on a rotary evaporator, the residue is dissolved in dry DME and added dropwise to a suspension of 2-aminothiazole (22.2 mg, 0.22 mmol, 1 eq) in dry dichloromethane cooled at 0° C. The reaction mixture is stirred at RT over night, followed by removing the solvent on a rotary evaporator. Purification of the raw product by column chromatography with dichloromethane/methanol 95/5 as the eluent yielded the desired compound in a yield of 13%, 13 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[O:9][CH2:10][CH2:11][NH:12][C:13]2[C:14]3[C:19]([N:20]=[C:21]4[C:26]=2[C:25](=[O:27])[CH2:24][CH2:23][CH2:22]4)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[O:9][CH2:10][CH2:11][NH:12][C:13]2[C:14]3[C:19]([N:20]=[C:21]4[C:26]=2[CH:25]([OH:27])[CH2:24][CH2:23][CH2:22]4)=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:6][CH:7]=1
Reactant: O=C1CCCc2nc3ccccc3c(NCCOC(c3ccc(F)cc3)c3ccc(F)cc3)c21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OC1CCCc2nc3ccccc3c(NCCOC(c3ccc(F)cc3)c3ccc(F)cc3)c21
Reaction time: 1 h

Procedure:
To a cooled solution of 5.55 g of 3,4-dihydro-9-[[2-[bis(4-fluorophenyl)methoxy]ethyl]amino]acridin-1(2H)-one in 100 ml of tetrahydofuran was added 6.5 ml of 1M solution of lithium aluminum hydride in tetrahydrofuran. This was stirred for 1 hour at ice bath temperature.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][CH2:7][C:8]([NH:17][C:18]([C:20]1[N:24]2[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH2:30][C:31]3[C:36]([F:37])=[CH:35][CH:34]=[CH:33][C:32]=3[F:38])[C:23]2=[N:22][C:21]=1[CH3:39])=[O:19])([C:10]1[N:11]=[N:12][N:13]([CH2:15][CH3:16])[N:14]=1)[CH3:9])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.C(OCC)(=O)C>C1COCC1>[F:37][C:36]1[CH:35]=[CH:34][CH:33]=[C:32]([F:38])[C:31]=1[CH2:30][O:29][C:28]1[C:23]2[N:24]([C:20]([C:18]([NH:17][C:8]([C:10]3[N:11]=[N:12][N:13]([CH2:15][CH3:16])[N:14]=3)([CH3:9])[CH2:7][OH:6])=[O:19])=[C:21]([CH3:39])[N:22]=2)[CH:25]=[CH:26][CH:27]=1
Reactant: CCn1nnc(C(C)(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)NC(=O)c2c(C)nc3c(OCc4c(F)cccc4F)cccn23)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCn1nnc(C(C)(CO)NC(=O)c2c(C)nc3c(OCc4c(F)cccc4F)cccn23)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.4 %

Procedure:
To a solution of 137 mg of N-[1-{[tert-butyl (diphenyl)silyl]oxy}-2-(2-ethyl-2H-tetrazol-5-yl)propan-2-yl]-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide in 3 ml of THF was added 0.3 ml of a 1 M tetrabutylammonium fluoride/THF solution, followed by stirring at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography. To the obtained crude product was added ethyl acetate, and the insoluble materials were collected by filtration, washed with diisopropyl ether, and dried under reduced pressure to obtain 75 mg of 8-[(2,6-difluorobenzyl)oxy]-N-[2-(2-ethyl-2H-tetrazol-5-yl)-1-hydroxypropan-2-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]=2)=[CH:5][C:4]=1[N+:23]([O-])=O>[Pd].CO>[NH2:23][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][C:3]=1[NH:2][CH3:1])[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:9]=1
Reactant: CNc1ccc(Oc2ccnc(C(=O)OC(C)(C)C)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1ccc(Oc2ccnc(C(=O)OC(C)(C)C)c2)cc1N

Procedure:
A solution of tert-butyl 4-[4-(methylamino)-3-nitrophenoxy]pyridine-2-carboxylate (1 eq) and 10% palladium on carbon (0.1 eq) in methanol was stirred at room temperature and flushed with nitrogen. Hydrogen was flushed through the reaction for 1-2 hours or until the reaction was determined to be complete by HPLC. Nitrogen was flushed through the reaction for 15 minutes before the reaction was filtered through a celite pad. The celite pad was washed with excess methanol followed by concentration under reduced pressure to afford the product as a light yellow solid. MS: MH+=316.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:21][CH3:22])[C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([C:18]([OH:20])=[O:19])[CH2:14][CH2:13]1)[N:8]([CH2:23][C:24]([F:27])([F:26])[F:25])[CH:7]=[C:6]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:42])([F:41])[F:40])=[CH:34][C:33]=1[CH3:43])=[O:29])[C:5]2=[O:44].C(#N)C.[OH-].[OH:49][CH2:50][CH2:51][N+:52]([CH3:55])([CH3:54])[CH3:53]>O>[OH:49][CH2:50][CH2:51][N+:52]([CH3:55])([CH3:54])[CH3:53].[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:21][CH3:22])[C:11]=1[N:12]1[CH2:17][CH2:16][CH:15]([C:18]([O-:20])=[O:19])[CH2:14][CH2:13]1)[N:8]([CH2:23][C:24]([F:27])([F:25])[F:26])[CH:7]=[C:6]([C:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][C:39]([F:40])([F:41])[F:42])=[CH:34][C:33]=1[CH3:43])=[O:29])[C:5]2=[O:44]
Reactant: COc1c(N2CCC(C(=O)O)CC2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Agent: C[N+](C)(C)CCO
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: COc1c(N2CCC(C(=O)[O-])CC2)c(F)cc2c(=O)c(C(=O)NCc3ccc(OC(F)(F)F)cc3C)cn(CC(F)(F)F)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
400 mg (0.63 mmol) of 1-[6-fluoro-8-methoxy-3-({[2-methyl-4-(trifluoromethoxy)benzyl]amino}carbonyl)-4-oxo-1-(2,2,2-trifluoroethyl)-1,4-dihydroquinolin-7-yl]piperidine-4-carboxylic acid (Example 47) are suspended in 20 ml of deionized water and 20 ml of acetonitrile at RT. 140 μl (153 mg, 0.63 mmol) of β-hydroxyethyltrimethylammonium hydroxide (“choline hydroxide”) are added and the mixture is stirred at RT overnight. The resulting solution is freed from the acetonitrile on a rotary evaporator. The aqueous solution which remains was frozen and lyophilized. 494 mg (100% of theory) of residue, which is found by analysis to correspond to the title compound, are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH:9]2[CH2:22][OH:23])=[CH:4][C:3]=1[F:24].Cl.C(O)C>>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[O:14][CH2:13][CH2:12][NH:11][CH2:10][CH:9]2[CH2:22][OH:23])=[CH:4][C:3]=1[F:24]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(F)c2)C(CO)C1
Agent: Cl
Solvent: CCO
Product: OCC1CNCCOC1c1ccc(Cl)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 154.9 %

Procedure:
To tert-butyl (6RS,7SR)-7-(4-chloro-3-fluorophenyl)-6-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (229 mg) was added 2 N hydrogen chloride-ethanol solution (1.02 ml), and the mixture was stirred at room temperature for 1 hr. Further, 14.7 N hydrogen chloride-ethanol solution (2 mL) was added, and the mixture was stirred for 10 min. The oil obtained by concentration under reduced pressure was crystallized from diisopropyl ether-ethanol to give the title compound (146 mg).