Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[S:2][CH:3]=[C:4]2[C:10]=1[C:9](=[O:11])[NH:8][C:7]1[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=1[S:5]2.S(Cl)([Cl:19])(=O)=O>C(Cl)Cl>[Cl:19][C:3]1[S:2][CH:1]=[C:10]2[C:9](=[O:11])[NH:8][C:7]3[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=3[S:5][C:4]=12
Reactant: O=C1Nc2ccccc2Sc2cscc21
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: O=C1Nc2ccccc2Sc2c1csc2Cl

Procedure:
A suspension of 1.16 g. of thieno[3,4-b][1,5]-benzothiazepin-10(9H)-one in 20 ml. of methylene chloride was treated with 0.81 g of sulfuryl chloride as in Example 12 to give 3-chlorothieno[3,4-b][1,5]benzothiazepin-10(9H)-one as a white crystal, m.p. 287°-288° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](C2N=C(C(O)=O)SC=2C2C=C(F)C=C(Cl)C=2)[CH:5]=[CH:6][C:7]=1[F:8].Br[C:26]1[S:30][C:29]([C:31]([O:33]CC)=[O:32])=[N:28][C:27]=1[C:36]1[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:26]2[S:30][C:29]([C:31]([OH:33])=[O:32])=[N:28][C:27]=2[C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CCOC(=O)c1nc(-c2cccc(Cl)c2)c(Br)s1
Reactant: O=C(O)c1nc(-c2ccc(F)c(Cl)c2)c(-c2cc(F)cc(Cl)c2)s1
Product: O=C(O)c1nc(-c2cccc(Cl)c2)c(-c2ccc(F)c(Cl)c2)s1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 8A starting with the compound from Example 5A. 59.0 mg (56% of theory) of the title compound are obtained.
Reaction SMILES: C([O:3][C:4](=[O:46])[CH2:5][CH2:6][CH2:7][N:8]([C:38]1[CH:43]=[C:42]([CH3:44])[CH:41]=[C:40]([CH3:45])[CH:39]=1)[CH2:9][C:10]1[CH:37]=[CH:36][C:13]2[N:14]=[C:15]([NH:26][CH2:27][CH2:28][CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[N:16]([CH2:17][C:18]3[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([CH3:25])[N:19]=3)[C:12]=2[CH:11]=1)C.[Li+].[OH-].O>O1CCCC1.O>[CH3:44][C:42]1[CH:43]=[C:38]([N:8]([CH2:9][C:10]2[CH:37]=[CH:36][C:13]3[N:14]=[C:15]([NH:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:16]([CH2:17][C:18]4[C:23]([OH:24])=[CH:22][CH:21]=[C:20]([CH3:25])[N:19]=4)[C:12]=3[CH:11]=2)[CH2:7][CH2:6][CH2:5][C:4]([OH:46])=[O:3])[CH:39]=[C:40]([CH3:45])[CH:41]=1
Reactant: CCOC(=O)CCCN(Cc1ccc2nc(NCCCN3CCOCC3)n(Cc3nc(C)ccc3O)c2c1)c1cc(C)cc(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)cc(N(CCCC(=O)O)Cc2ccc3nc(NCCCN4CCOCC4)n(Cc4nc(C)ccc4O)c3c2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56 %

Procedure:
A mixture of 4-{(3,5-dimethyl-phenyl)-[3-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-2-(3-morpholin-4-yl-propylamino)-3H-benzoimidazol-5-ylmethyl]-amino}-butyric acid ethyl ester (Compound 71), prepared as described for compounds n-4, (0.000175 mol) and LiOH/H2O (0.00035 mol) in tetrahydrofuran (8 ml) and H2O (8 ml) was stirred at room temperature for 12 hours. The tetrahydrofuran was evaporated and a 1N solution of NaOH in water was added. The solution was extracted with CH2Cl2/CH3OH (95/5). The organic layer was separated, dried (over MgSO4), filtered and the solvent was evaporated. The residue was taken up in H2O. The precipitate was filtered off and dried, yielding 0.059 g of 4-{(3,5-dimethyl-phenyl)-[3-(3-hydroxy-6-methyl-pyridin-2-ylmethyl)-2-(3-morpholin-4-yl-propylamino)-3H-benzoimidazol-5-ylmethyl]-amino}-butyric acid (Compound 62, 56%, melting point: 121° C.).
Reaction SMILES: [ClH:1].[NH:2]=[C:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][O:9]C(=O)C)[NH:4]1.N>CO>[ClH:1].[NH:2]=[C:3]1[CH2:7][CH2:6][C@@H:5]([CH2:8][OH:9])[NH:4]1
Reactant: CC(=O)OC[C@@H]1CCC(=N)N1
Agent: Cl
Agent: N
Solvent: CO
Product: N=C1CC[C@@H](CO)N1
Reaction time: 3 h
Yield: 51.1 %

Procedure:
A solution of 15 mg (0.078 mmol) of 2-imino-5-(S)-acetyloxymethylpyrrolidine hydrochloride prepared in example 7 in 3 mL of methanol was saturated with NH3 and the solution was stirred for 3 h. The reaction mixture was concentrated and the residual solid was suspended in Et2O-EtOAc, filtered and washed with Et2O and dried to isolate 6 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[C:9](#[N:12])[CH:10]=[CH2:11]>CC([O-])=O.CC([O-])=O.[Cu+2]>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:11][CH2:10][C:9]#[N:12])[CH:5]=[CH:6][CH:7]=1
Reactant: C=CC#N
Reactant: Nc1cccc(Cl)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Product: N#CCCNc1cccc(Cl)c1
Yield: 56.1 %

Procedure:
To a solution of 3-chlorobenzenamine (10 g, 0.079 mol) and acrylonitrile (5.0 g, 0.095 mol), Cu(OAc)2 (0.5 g, 5% by weight of 3-chlorobenzenamine), were heated under reflux, beginning at about 95° C. The reaction is heated at reflux for 3 h with the temperature rising to ˜130° C. Upon completion of the reaction, the acrylonitrile was stripped under reduced pressure. The residue was purified by column chromatography to afford the pure product 3-(3-chlorophenylamino)propanenitrile (8 g, yield 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][N:16]=[C:17]2[C:20]2([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)[CH2:23][CH2:22][CH2:21]2)=[CH:12][CH:11]=1)=[O:5].[BH4-].[Na+].CO>O>[Cl:1][C:2]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][O:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][NH:16][CH:17]2[C:20]2([C:24]3[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[CH2:23][CH2:22][CH2:21]2)=[CH:12][CH:11]=1)=[O:5]
Reactant: O=C(NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)=NCC2)c1ccc(Cl)cc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: O=C(NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2)c1ccc(Cl)cc1Cl
Yield: 73.3 %

Procedure:
2,4-dichloro-N-(2-{1-[1-(4-chloro-phenyl)-cyclobutyl]-3,4-dihydro-isoquinolin-7-yloxy}-ethyl)-benzamide (80.0 mg, 0.15 mmol) and sodium borohydride (12.0 mg, 0.32 mmol) were dissolved in H2O (10 ml) and MeOH (0.5 ml) and stirred for 14 h at RT. Water was added and the mixture was extracted with ethyl acetate. The organic layers were washed with water and saturated NaCl solution, dried with MgSO4, and the solvent was removed. The residue was transferred into the hydrochloride salt using HCl dissolved in isopropanole (6 molar solution). Crystallization gave 2,4-Dichloro-N-(2-{1-[1-(4-chloro-phenyl)-cyclobutyl]-1,2,3,4-tetrahydro-isoquinolin-7-yloxy}-ethyl)-benzamide (60.0 mg, 0.11 mmol, 70%) as white solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23](O)=[O:24])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:26][C:27]1[S:31][C:30]([C:32](=[N:34]O)[NH2:33])=[CH:29][CH:28]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:24][N:34]=[C:32]([C:30]4[S:31][C:27]([F:26])=[CH:28][CH:29]=4)[N:33]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: NC(=NO)c1ccc(F)s1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccc(F)s4)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 35 mg (0.22 mmol, 1.1 eq.) of 5-fluoro-N′-hydroxythiophene-2-carboximidamide were reacted according to the General Method 1. Yield: 51 mg (54% of theory)
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH:14]([OH:16])[CH3:15])[N:11]=[CH:10][N:9]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C:8]1[N:9]=[CH:10][N:11]=[C:12]([CH:14]([OH:16])[CH3:15])[CH:13]=1
Reactant: CC(O)c1cc(NC(=O)OC(C)(C)C)ncn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(O)c1cc(N)ncn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
A solution of [6-(1-hydroxyethyl)-pyrimidin-4-yl)-bis-carbamic acid tert-butyl ester and [6-(1-hydroxyethyl)-pyrimidin-4-yl)-carbamic acid tert-butyl ester (200 mg+198 mg, 1.45 mmol) in DCM (6.0 mL) was cooled to 0° C. and TFA (6.0 mL) was added. The reaction mixture was stirred at 0° C. for 15 minutes, then at room temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue was partitioned between saturated aqueous sodium bicarbonate solution and 2-methyltetrahydrofuran (×2). The aqueous layer was then extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-20% methanol in DCM) to afford the title compound as a colorless oil (195 mg, 96% yield). 1H NMR (300 MHz, DMSO-d6): δ 8.60 (s, 1H), 8.54 (br s, 2H), 6.67 (s, 1H), 4.73-4.65 (m, 1H), 1.37 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]([NH2:13])[CH:7]=1.C[O:16][C:17](=O)[CH:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])[C:19](=O)[CH2:20][CH3:21].O1CCOCC1>O>[CH3:1][O:2][C:3](=[O:14])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([F:12])=[C:8]2[C:7]=1[C:17](=[O:16])[C:18]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1[F:31])=[C:19]([CH2:20][CH3:21])[NH:13]2
Reactant: CCC(=O)C(Cc1ccc(Cl)cc1F)C(=O)OC
Reactant: COC(=O)COc1ccc(F)c(N)c1
Solvent: C1COCCO1
Solvent: O
Product: CCc1[nH]c2c(F)ccc(OCC(=O)OC)c2c(=O)c1Cc1ccc(Cl)cc1F
Temperature: 120 °C

Procedure:
A mixture of (3-amino-4-fluorophenoxy)acetic acid methyl ester (0.80 g), 2-(4-chloro-2-fluorobenzyl)-3-oxopentanoic acid methyl ester (1.4 g), polyphosphoric acid (5 g) and dioxane (10 mL) was heated at 120° C. for 23 hours. The reaction mixture was cooled to room temperature, diluted with water and extracted with ethyl acetate. The combined extracts were washed with water, dried over magnesium sulfate and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel, eluting with a mixture of ethyl acetate and cyclohexane (3:7 to 7:10 by volume) to afford title compound, 0.20 g.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[NH:3][CH:2]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([NH:13][C:10]([C:8]2[CH:7]=[CH:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH:9]=2)=[O:12])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccc2nc[nH]c2c1
Product: O=C(Nc1ccccc1)c1ccc2[nH]cnc2c1
Yield: 28.4 %

Procedure:
In a procedure analogous to example 20, reaction of benzimidazole-5-carboxylic acid (400 mg, 5.50 mmol) and aniline (510 mg, 5.50 mmol) furnished the product (370 mg, 63%).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([OH:10])=[C:4]([F:11])[CH:3]=1.CCN(C(C)C)C(C)C.[CH3:21][Si:22]([CH2:25][CH2:26][O:27][CH2:28]Cl)([CH3:24])[CH3:23]>C(Cl)Cl>[Br:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([O:10][CH2:28][O:27][CH2:26][CH2:25][Si:22]([CH3:24])([CH3:23])[CH3:21])=[C:4]([F:11])[CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CCc1cc(O)c(F)cc1Br
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCc1cc(OCOCC[Si](C)(C)C)c(F)cc1Br
Temperature: 25 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
To a solution of 4-bromo-5-ethyl-2-fluoro-phenol (Preparation 3, 80 g, 365 mmol) in DCM (1 L) was added DIPEA (70 mL, 401 mmol) and SEM-Cl (71 mL, 401 mmol). The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was washed with water (1 L), dried over MgSO4 and concentrated in vacuo to yield the crude product. This material was purified by silica gel chromatography eluting with 30% DCM in heptane to give the title compound as a pale yellow oil (109.8 g, 86%).
Reaction SMILES: [Br:1][C:2]1[C:15]2[C:14](=O)[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][C:12]=3[Br:17])[C:7](=O)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+]>CO>[Br:1][C:2]1[C:15]2[C:6](=[CH:7][C:8]3[C:13]([CH:14]=2)=[C:12]([Br:17])[CH:11]=[CH:10][CH:9]=3)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2cccc(Br)c2C(=O)c2c(Br)cccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Brc1cccc2cc3cccc(Br)c3cc12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
23.6 g (65 mmol) of 1,8-dibromoanthraquinone were suspended in 250 ml of methanol. At 10° C., 9.9 g (260 mmol) of NaBH4 were added slowly and the mixture was subsequently stirred at 0° C. for 2 hours. The mixture was poured onto 800 ml of ice, stirred and filtered under reduced pressure. The solid was subsequently suspended in 400 ml of 18% strength hydrochloric acid and stirred at 70° C. for 5 hours, after which it was once again filtered off under reduced pressure, washed until neutral and dried. The solid was stirred with 14.8 g of NaBH4 in 250 ml of isopropanol at 85° C. (reflux) for 3 hours, brought to a pH of 7 by addition of dilute hydrochloric acid, filtered off with suction and washed with water. 1,8-Dibromoanthracene was obtained in a yield of 16.2 g (74% of theory).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1B(O)O>>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: OB(O)c1cccs1
Product: FC(F)(F)c1ccc(-c2cccs2)cc1

Procedure:
4-Bromobenzotrifluoride and thiophene-2-boronic acid were treated in a manner similar to Reference Example 20-(1) to give 2-(4-trifluoromethylphenyl)thiophene as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22].Br[CH2:26][C:27]#[C:28][Si:29]([CH3:32])([CH3:31])[CH3:30]>C1CCCCC1.C(Cl)Cl>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([CH2:26][C:27]#[C:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][C:21]([O:23][CH3:24])=[O:22]
Reactant: C[Si](C)(C)C#CCBr
Reactant: COC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Solvent: ClCCl
Solvent: C1CCCCC1
Product: COC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(CC#C[Si](C)(C)C)(c1ccccc1)C2
Yield: 74 %

Procedure:
Reaction of methyl (6,7-dichloro-1-oxo-2-phenyl-5-indanyloxy)acetate with 1-bromo-3-(trimethylsilyl)-2-propyne according to Example 1, STEP (b), affords the title compound, m.p. 125.5°-127° (from cyclohexane-methylene chloride) in 74% yield.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([Br:10])=[CH:4][C:3]=1[NH2:11].O.O.[C:14](O)(=[O:18])[C:15](O)=[O:16]>Cl.[OH-].[Na+]>[Br:10][C:5]1[CH:4]=[C:3]2[C:2]([NH:1][C:14](=[O:18])[C:15](=[O:16])[NH:11]2)=[C:7]([CH2:8][CH3:9])[CH:6]=1
Reactant: O=C(O)C(=O)O
Reactant: CCc1cc(Br)cc(N)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 62.5 °C
Yield: 31.9 %

Procedure:
A mixture of 1,2-diamino-4-bromo-6-ethylbenzene (40 mg, 0.14 mmol) and oxalic acid dihydrate (25 mg, 0.20 mmol, used as received) in 4 N HCl (1.5 mL) was refluxed at 120-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the liquid layer was removed. The yellow solid was washed with cold water (2×1 mL), collected by filtration, and dried at 60° C. under reduced pressure for 2 h, affording 40 mg of crude product (80%) as a yellow powder. The crude product was dissolved in 1N NaOH (2 mL) and filtered. The filtrate was acidified to pH=5, affording 12 mg of pure title compound; mp:>350° C. (dec. from 300° C.); IR (KBr, cm-1):3410, 3164, 2919, 1740, 1705, 1600. 1H NMR (DMSO-d6): δ 1.099 (t, 3 H, J=6 Hz), 2.741 (q, 2 H, J=7.2 Hz), 7.117 (d, 1 H, J=1.8 Hz), 7.138 (d, 1 H, J=1.8 Hz); 11.343 (s, 1H); 11.958 (s, 1H). HRMS: calcd for C10H9BrN2O2 (M+) m/z: 267.9846; found 267.9853.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7]C(=O)C(C)(C)C.[F:14][C:15]([F:24])([F:23])[CH:16]1[CH2:21][CH2:20][C:19](=O)[CH2:18][CH2:17]1.C(Cl)Cl>C(Cl)Cl.CO>[F:14][C:15]([F:24])([F:23])[CH:16]1[CH2:21][CH2:20][C:19]([C:3]2[C:2]([NH2:7])=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:18][CH2:17]1
Reactant: CC(C)(C)C(=O)Nc1ccccn1
Reactant: O=C1CCC(C(F)(F)F)CC1
Solvent: ClCCl
Solvent: CO
Product: Nc1ncccc1C1=CCC(C(F)(F)F)CC1
Yield: 26 %

Procedure:
Prepared in analogy to example 262 step a-b), starting from N-(pyridin-2-yl)pivalamide and 4-(trifluoromethyl)cyclohexanone. 3-(4-Trifluoromethyl-cyclohex-1-enyl)-pyridin-2-ylamine was obtained after column chromatography on silica gel using a gradient from CH2Cl2 to CH2Cl2/MeOH 19:1 (v/v) as eluent as a white solid (yield: 26% over 2 steps).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[O:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:22]Br>C(O)(=O)C>[Br:22][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9][C:10]=2[C:2]=1[CH3:1]
Reactant: Cc1cccc2nc(-c3ccccc3)oc12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1c(Br)ccc2nc(-c3ccccc3)oc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.55 g (7.41 mmol) 7-methyl-2-phenyl-benzoxazole are dissolved in 5 ml glacial acetic acid, then 0.74 g (9.02 mmol) sodium acetate and 1.25 g (7.82 mmol) bromine are added. The mixture is stirred overnight at RT, then the solv. is eliminated by rotary evaporation in vacuo, the residue is dissolved with petroleum ether and extracted with water. The org. phase is dried on magnesium sulphate and evaporated down to ¼. The precipitated solid is suction filtered cold.
Reaction SMILES: C([N:8]1[CH:13]([CH2:14][F:15])[CH2:12][N:11](CC2C=CC=CC=2)[CH2:10][CH:9]1[CH2:23][F:24])C1C=CC=CC=1.Cl.[H][H]>CO.[Pd]>[F:24][CH2:23][CH:9]1[CH2:10][NH:11][CH2:12][CH:13]([CH2:14][F:15])[NH:8]1
Reactant: FCC1CN(Cc2ccccc2)CC(CF)N1Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: FCC1CNCC(CF)N1
Yield: 137.6 %

Procedure:
A mixture of a suspension of 5.03 g (0.015 mole) of 1,4-dibenzyl-2,6-bis(fluoromethyl)piperazine isomer B [prepared as described in step (b) above] in 130 ml of methanol and 6 ml of concentrated aqueous hydrochloric acid was stirred vigorously under a stream of hydrogen at room temperature for 1 hour in the presence of 0.6 g of 20% w/w palladium-on-carbon. At the end of this time, the catalyst was removed by filtration, and the filtrate was concentrated by evaporation under reduced pressure. The residue was mixed with 50 ml of water, and the resulting insoluble materials were removed by filtration. The filtrate was concentrated by evaporation under reduced pressure, and the residue was washed with ethanol, to afford 3.10 g of 2,6-bis(fluoromethyl)piperazine (isomer B) dihydrochloride as a colorless powder, melting at 207°-225° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]2[N:18]=[CH:17][CH:16]=[CH:15][C:12]=2[CH:13]=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[N:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33](OC)=[O:34])=[CH:21][CH:20]=1.[Li+].CC([N-]C(C)C)C>CN(C=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[C:11]3[C:12](=[CH:15][CH:16]=[CH:17][N:18]=3)[CH:13]=[C:32]([CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][C:22]3[CH:21]=[CH:20][N:19]=[CH:24][CH:23]=3)[C:33]2=[O:34])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=Cc1cccnc1Nc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CCCCCCCCc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: O=c1c(CCCCCCCc2ccncc2)cc2cccnc2n1-c1cccc([N+](=O)[O-])c1

Procedure:
The procedure of Example 1 was repeated using 2-(3-nitrophenylamino)nicotinaldehyde (1.0 eq.), methyl 9-(pyridin-4-yl)nonanoate (1.5 eq., prepared in Synthetic Example 16) and LDA (1.5 eq.) to obtain 1-(3-nitrophenyl)-3-[7-(pyridin-4-yl)heptyl]-1,8-naphthyridin-2(1H)-one, mp 189 to 192° C./DMF, wherein the product was purified through silica gel column chromatography and recrystallization.
Reaction SMILES: [C:1](=[O:23])([O:21][CH3:22])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:4]=1[C:16]1[CH2:20][CH2:19][CH2:18][CH:17]=1>C(O)C.[Pd]>[C:1](=[O:23])([O:21][CH3:22])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:5][C:4]=1[CH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(C(C)(C)C)cc1C1=CCCC1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)Oc1cc(N)c(C(C)(C)C)cc1C1CCCC1
Reaction time: 3 h
Yield: 92.2 %

Procedure:
To a flask charged with 10% Pd/C (132 mg) under inert atmosphere was added a solution of 4-tert-butyl-2-cyclopentenyl-5-nitrophenyl methyl carbonate (660 mg, 2.07 mmol) in ethanol (20 mL). The reaction was stirred under H2 atmosphere for 3 h, then filtered and dried down to provide 5-amino-4-tert-butyl-2-cyclopentylphenyl methyl carbonate as an off-white crystalline solid (556 mg, 92% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 6.97 (s, 1H), 6.38 (s, 1H), 4.81 (s, 2H), 3.80 (s, 3H), 2.84 (m, 1H), 1.87-1.80 (m, 2H), 1.72-1.66 (m, 2H), 1.62-1.56 (m, 2H), 1.47-1.39 (m, 2H), 1.32 (s, 9H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][C@:27]1([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[CH:48]=[CH2:49])=[CH:38][CH:37]=2)[CH2:31][NH:30][C@H:29]([C:32]([O:34][CH3:35])=[O:33])[CH2:28]1.[CH3:50][C:51]([CH3:66])([CH3:65])[C@H:52]([NH:56][C:57]([O:59][CH2:60][CH2:61][CH2:62][CH:63]=[CH2:64])=[O:58])[C:53](O)=[O:54].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:50][C:51]([CH3:66])([CH3:65])[C@H:52]([NH:56][C:57]([O:59][CH2:60][CH2:61][CH2:62][CH:63]=[CH2:64])=[O:58])[C:53]([N:30]1[CH2:31][C@:27]([O:26][CH3:25])([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[CH:48]=[CH2:49])=[CH:38][CH:37]=2)[CH2:28][C@H:29]1[C:32]([O:34][CH3:35])=[O:33])=[O:54]
Reactant: C=Cc1ccccc1-c1ccc([C@@]2(OC)CN[C@H](C(=O)OC)C2)cc1
Reactant: C=CCCCOC(=O)N[C@H](C(=O)O)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCOC(=O)N[C@H](C(=O)N1C[C@](OC)(c2ccc(-c3ccccc3C=C)cc2)C[C@H]1C(=O)OC)C(C)(C)C
Temperature: 25 °C
Yield: 75.2 %

Procedure:
HATU (248 mg, 0.652 mmol) was added to a solution of (2S,4R)-methyl 4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (200 mg, 0.593 mmol), (S)-3,3-dimethyl-2-((pent-4-enyloxy)carbonylamino)butanoic acid (180 mg, 0.741 mmol) and DIEA (0.311 mL, 1.778 mmol) in DCM (8 mL) and stirred at r.t. 60 hours. The reaction was evaporated and purified on the Biotage (10-40% EtOAc:Hex) to give the product (2S,4R)-methyl 1-((S)-3,3-dimethyl-2-((pent-4-enyloxy)carbonylamino)butanoyl)-4-methoxy-4-(2′-vinylbiphenyl-4-yl)pyrrolidine-2-carboxylate (251 mg, 0.446 mmol, 75% yield) as white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.96-1.00 (m, 1H) 1.04-1.10 (m, 1H) 1.11-1.21 (m, 7H) 1.64-1.79 (m, 2H) 2.06-2.20 (m, 2H) 2.52 (dd, J=13.30, 8.78 Hz, 1H) 2.83-3.04 (m, 4H) 3.72-3.82 (m, 3H) 3.96-4.12 (m, 3H) 4.15-4.21 (m, 1H) 4.31-4.41 (m, 1H) 4.86-5.10 (m, 3H) 5.19-5.30 (m, 1H) 5.41 (d, J=9.79 Hz, 1H) 5.67-5.87 (m, 2H) 6.61-6.76 (m, 1H) 7.28-7.44 (m, 7H) 7.61-7.71 (m, 1H). LCMS: r.t.=2.18 min., [M+H]+=563 Phenomenex Luna S10 (3×50 mm); Solvent A=95% water—5% methanol—10 mM ammonium acetate, Solvent B=5% water—95% methanol—10 mM ammonium acetate; gradient=0% to 100% solvent B over 2 min. and then hold for 1 min.; 4 ml/min; inj. vol.=10 ul; wavelength=220 nm.
Reaction SMILES: CS([O:5][CH2:6][C:7]1[C:8]([C:16]2[CH:17]=[N:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)=[N:9][S:10][C:11]=1[C:12]([F:15])([F:14])[F:13])(=O)=O.O[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([CH3:36])[C:26]=1[CH3:37]>>[CH3:23][O:22][C:19]1[N:18]=[CH:17][C:16]([C:8]2[C:7]([CH2:6][O:5][C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[C:27]([CH3:36])[C:26]=3[CH3:37])=[C:11]([C:12]([F:15])([F:14])[F:13])[S:10][N:9]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(-c2nsc(C(F)(F)F)c2COS(C)(=O)=O)cn1
Reactant: Cc1c(O)ccc(CCC(=O)O)c1C
Product: COc1ccc(-c2nsc(C(F)(F)F)c2COc2ccc(CCC(=O)O)c(C)c2C)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1 starting following Step 5 and 6 coupling (3-(6-methoxypyridin-3-yl)-5-(trifluoromethyl)isothiazol-4-yl)methyl methanesulfonate and 3-(4-hydroxy-2,3-dimethylphenyl)propanoic acid followed by hydrolysis to afford the desired product as an off-white solid. 1H NMR (300 MHz, CD3OD) δ 8.47 (s, 1H), 7.99-8.03 (m, 1H), 6.98 (d, J=8.4 Hz, 1H), 6.87 (d, J=8.7 Hz, 1H), 6.74 (d, J=8.1 Hz, 1H), 5.11 (s, 2H), 3.99 (s, 3H), 2.91 (t, J=7.2 Hz, 2H), 2.51 (t, J=7.5 Hz, 2H), 2.23 (s, 3H), 2.03 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C20H15F5N2O4S, 467.1 (M−H). found 467.0.