Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)[CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:15]([N:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[F:30])[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=O)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(O[N:49]1N=NC2C=[CH:53][CH:54]=[CH:55][C:50]1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.N1CCCC1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([C:15](=[O:16])[N:17]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH2:18][CH2:19][CH2:20][C:21](=[O:23])[N:49]2[CH2:50][CH2:55][CH2:54][CH2:53]2)[CH:31]=[C:32]([Cl:34])[CH:33]=1)[C:35]1[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCC(=O)O)c2ccccc2F)c1)c1ccncc1
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCC(=O)N2CCCC2)c2ccccc2F)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.5 %

Procedure:
To a stirred solution of 4-({3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoyl}-(2-fluoro-phenyl)-amino)-butyric acid (0.025 g), TBTU (0.028 g) and HOBt (0.012 g) in DMF (1 ml) was added DIPEA (0.015 ml) followed by pyrrolidine (0.007 ml) after 10 min. The reaction mixture was stirred at room temperature for 16 h and then concentrated under reduced pressure. The residue was subjected to preparative hplc and the title compound (0.025 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18]([OH:20])=[O:19])=[O:15])[CH:5]=[CH:4][C:3]1=2.S(=O)(=O)(O)O.[CH2:31](O)[CH3:32]>>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([C:14]([C:16]3[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=3[C:18]([O:20][CH2:31][CH3:32])=[O:19])=[O:15])[CH:5]=[CH:4][C:3]1=2
Reactant: CCO
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)c3ccccc3C(=O)O)ccc21
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccccc1C(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C

Procedure:
A solution of 8.41 g (0.025 mole) of 2-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) carbonyl]benzoic acid, described in Example I, in 300 cm3 of ethyl alcohol containing 0.4cm3 of 98% sulfuric acid is heated for 14 hours at reflux. The solution is then concentrated under reduced pressure and the resulting crude ester is dissolved in 300 cm3 of ethyl ether. The ether solution is washed with sodium bicarbonate and then with water, dried on sodium sulfate and evaporated to dryness. After drying, 7.9 g of ethyl 2-[(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-2-naphthyl) carbonyl]benzoate are obtained in the form of a colorless oil which slowly crystallizes at ambient temperature to give a white solid whose melting point is 58°-59° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19]Br)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[N:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][NH2:28])[CH:22]=1>C(O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][CH2:19][NH:28][CH2:27][C:23]3[CH:22]=[N:21][CH:26]=[CH:25][CH:24]=3)[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(OCCCBr)c2c1C
Reactant: NCc1cccnc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)c1oc2cccc(OCCCNCc3cccnc3)c2c1C
Temperature: 50 °C

Procedure:
4-(3-bromo-propoxy)-3-methyl-benzofuran-2-carboxylic acid ethyl ester (Example 5-a: 180 mg) and 3-picolylamine (500 μl) were dissolved in ethanol (2 ml) and heated at 50° C. for 16 hours. The reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution and water. The organic solvent was dried over anhydrous sodium sulfate and evaporated to dryness. The residue was purified by silica gel column chromatography (dichloromethane-MeOH) to afford 3-methyl-4-{3-[(pyridin-3-ylmethyl)-amino]-propoxy}-benzofuran-2-carboxylic acid ethyl ester (150 mg) as a colorless oil. EI-MS: m/z 368 (M+); 1H-NMR (CDCl3): δ 1.44 (3H, t, J=7 Hz), 2.07 (2H, quintet, J=6.5 Hz), 2.67 (3H, s), 2.89 (2H, t, J=7 Hz), 3.84 (2H, s), 4.17 (2H, t, J=6 Hz), 4.44 (2H, q, J=7 Hz), 6.62 (1H, d, 8 Hz), 7.12 (1H, d, J=8 Hz), 7.21 (1H, dd, J1=8 Hz, J2=5 Hz), 7.30 (1H, t, J=8 Hz), 7.66 (1H, dd, J1=8 Hz, J2=2 Hz), 8.49 (1H, dd, J1=5 Hz, J2=2 Hz), 8.57 (1H, d, J=2 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH:9][CH:10]([C:12]1[N:17]=[N:16][C:15]([NH:18][C:19]2[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=2)=[N:14][CH:13]=1)[CH3:11])=O.N1C=NC=N1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:18][C:19]3[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=3)=[N:16]2)=[C:10]([CH3:11])[N:9]=1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3sccc3Br)nn2)cc(OC)c1OC
Agent: c1nc[nH]n1
Solvent: c1ccncc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2ncc3c(C)nc(-c4sccc4Br)n3n2)cc(OC)c1OC
Yield: 14.7 %

Procedure:
In a similar manner as described for Example 9, 3-bromo-N-(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)thiophene-2-carboxamide (Intermediate 19) (0.23 g, 0.47 mmol) and 1,2,4-triazole (100 mg, 1.5 mmol) in pyridine (4 mL) and phosphorus oxychloride (0.070 mL, 0.75 mmol) gave 7-(3-bromothien-2-yl)-5-methyl-N-(3,4,5-trimethoxyphenyl)imidazo[5,1-f][1,2,4]triazin-2-amine (0.033 g) as a yellow solid. 1H NMR (CDCl3): δ8.82 (s, 1H), 7.47 (d, J=5.3 Hz, 1H), 7.13 (s, 1H), 7.10 (d, J=5.3 Hz, 1H), 6.89 (s, 2H), 3.80 (s, 3H), 3.75 (s, 6H), 2.63 (s, 3H). MS m/z 476, 478 (M+1, M+3).
Reaction SMILES: [H-].[Na+].[C:3]([O:9][CH3:10])(=[O:8])[CH2:4][C:5]([CH3:7])=[O:6].C([Li])CCC.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:32]3[C:31](=[O:33])[NH:30][C:29](=[O:34])[NH:28][C:27]=3[N:26]=[C:25]([CH:35]([CH3:37])[CH3:36])[C:24]=2/[CH:38]=[CH:39]/[CH:40]=[O:41])=[CH:19][CH:18]=1>>[F:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:32]3[C:31](=[O:33])[NH:30][C:29](=[O:34])[NH:28][C:27]=3[N:26]=[C:25]([CH:35]([CH3:37])[CH3:36])[C:24]=2/[CH:38]=[CH:39]/[CH:40]([OH:41])[CH2:7][C:5](=[O:6])[CH2:4][C:3]([O:9][CH3:10])=[O:8])=[CH:21][CH:22]=1
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)c1nc2[nH]c(=O)[nH]c(=O)c2c(-c2ccc(F)cc2)c1/C=C/C=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Product: COC(=O)CC(=O)CC(O)/C=C/c1c(C(C)C)nc2[nH]c(=O)[nH]c(=O)c2c1-c1ccc(F)cc1

Procedure:
0.28 g (9.3 mmol) of 80% strength sodium hydride, 0.97 g (8.4 mmol) of methyl acetoacetate, 8.6 ml (14 mmol) of 15% strength butyllithium and 0.99 g (2.88 mmol) of the compound from Example 27 are reacted analogously to the procedure for Example 7.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([NH2:6])[CH2:4]O.[OH-].[Na+].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.O>COC(C)(C)C>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([N:6]2[CH2:4][C@H:3]2[CH2:2][CH3:1])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: CCC(N)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COC(C)(C)C
Product: CC[C@@H]1CN1S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C

Procedure:
R-(−)-2-amino-1-butanol (99.96 g, 105 mL) and tert-butyl methyl ether (TBME) (277 g, 366 mL) are combined under a nitrogen atmosphere. This mixture is stirred for several minutes and 10 N aqueous sodium hydroxide (449 mL) is added over a period of about 10 minutes. The reaction mixture is cooled to below 10° C. and a solution of p-toluene sulfonyl chloride (TsCl) (464 g) in TBME (711 g) is added over a period of about 50 minutes, maintaining the temperature of the reaction mixture at or below 32° C. After the addition is complete, the mixture is stirred for about 30 minutes at 40° C., and water (900 mL) is added while cooling the mixture to 25° C. The layers are separated and the organic layer washed sequentially with water (150 g) and 25% aqueous sodium chloride solution (300 g). Toluene (450 g) is added to the organic layer, and the mixture distilled under reduced pressure, maintaining the temperature of the mixture at or below 45° C., until the water content of the mixture is below about 0.1%. The resulting solution is used, without further treatment, for the preparation described in Example 2.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([SH:7])=[N:4][N:3]=1.Br[CH2:9][C:10]1([CH3:36])[CH:14]([C:15]([O:17][CH2:18][C:19]([Cl:22])([Cl:21])[Cl:20])=[O:16])[N:13]2[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:12]2[S:11]1>P([O-])([O-])([O-])=O.CC(C)=O>[CH3:1][C:2]1[S:6][C:5]([S:7][CH2:9][C:10]2([CH3:36])[CH:14]([C:15]([O:17][CH2:18][C:19]([Cl:20])([Cl:21])[Cl:22])=[O:16])[N:13]3[C:23](=[O:35])[CH:24]([NH:25][C:26](=[O:34])[CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C@H:12]3[S:11]2)=[N:4][N:3]=1
Reactant: CC1(CBr)S[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OCC(Cl)(Cl)Cl
Reactant: Cc1nnc(S)s1
Agent: O=P([O-])([O-])[O-]
Solvent: CC(C)=O
Product: Cc1nnc(SCC2(C)S[C@@H]3C(NC(=O)Cc4ccccc4)C(=O)N3C2C(=O)OCC(Cl)(Cl)Cl)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 15.2 %

Procedure:
5-Methyl-1,3,4-thiadiazole-2-thiol (0.16 g) was dissolved in a mixture of pH 6.5 phosphate buffer (5 ml) and acetone (10 ml). To this solution was added 2,2,2-trichloroethyl 2-bromomethyl-2-methyl-6-(2-phenylacetamido)penam-3-carboxylate (0.54 g) and the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure and acetone was distilled off and thereafter the residue was extracted with ethyl acetate. The ethyl acetate layer was washed with sodium bicarbonate aqueous solution and then with water and thereafter dried over magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography on silica gel using chloroform as developing solvent to give oily 2,2,2-trichloroethyl 2-(5-methyl-1,3,4-thiadiazol-2-yl)thiomethyl-2-methyl-6-(2-phenylacetamido)-penam-3-carboxylate (0.09 g) from the second and third fractions each of which was separated into about 30 ml.
Reaction SMILES: [Br:1][C:2]1[CH:43]=[CH:42][C:5]([O:6][CH2:7][C:8]([NH:10][CH2:11][C@H:12]([OH:41])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[C:15]([N:28]([S:37]([CH3:40])(=[O:39])=[O:38])[CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[CH:14]=2)=O)=[CH:4][CH:3]=1.N(CCO)(CCO)CCO.O>O1CCCC1>[Br:1][C:2]1[CH:43]=[CH:42][C:5]([O:6][CH2:7][CH2:8][NH:10][CH2:11][C@@H:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])=[C:15]([N:28]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[S:37]([CH3:40])(=[O:39])=[O:38])[CH:14]=2)[OH:41])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCOc1ccc([C@@H](O)CNC(=O)COc2ccc(Br)cc2)cc1N(COCC[Si](C)(C)C)S(C)(=O)=O
Solvent: O
Solvent: OCCN(CCO)CCO
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCOc1ccc([C@@H](O)CNCCOc2ccc(Br)cc2)cc1N(COCC[Si](C)(C)C)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 85.4 %

Procedure:
A 2 mol/L solution of borane dimethylsulfide complex in tetrahydrofuran (1.96 mL) was added dropwise to a solution of 2-(4-bromophenoxy)-N—((R)-2-hydroxy-2-{3-[methanesulfonyl-(2-trimethylsilylethoxymethyl)amino]-4-(2-trimethylsilylethoxymethoxy)phenyl}ethyl)acetamide (1.35 g) in tetrahydrofuran (10 mL) at room temperature under an atmosphere of argon. The mixture was stirred under ref lux for 1.5 hrs, and then cooled to room temperature. A solution of triethanolamine (0.88 g) in tetrahydrofuran (5 mL) was added dropwise to the reaction mixture. After being stirred under reflux for 5 hrs, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by medium-pressure silica gel column chromatography (eluent: ethyl acetate/ethanol=15/1) to afford the title compound (1.13 g).
Reaction SMILES: [OH:1][C@@:2]1([CH2:21]O)[CH2:7][CH2:6][CH2:5][C@@:4]([CH2:9][N:10]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)([CH3:8])[CH2:3]1.C(Cl)Cl.C(N(CC)CC)C.C([O-])([O-])=O.[K+].[K+]>CN(C1C=CN=CC=1)C.C([O-])(O)=O.[Na+]>[CH3:8][C@:4]1([CH2:9][N:10]2[C:14]3[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:13]=3[N:12]=[CH:11]2)[CH2:5][CH2:6][CH2:7][C@:2]2([O:1][CH2:21]2)[CH2:3]1
Reactant: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@](O)(CO)C1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCC[C@@]2(CO2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
To a 1 L flask was added 1-{[(1S,3S)-3-hydroxy-3-(hydroxymethyl)-1-methylcyclohexaneyl]methyl}-1H-benzimidazole-6-carbonitrile (21.2 g, 70.8 mmol) and DCM (698 mL) and the temperature was lowered to 5° C. Next DMAP (6.49 g, 53.1 mmol), tosyl-Cl (20.25 g, 106 mmol) and triethylamine (20.23 mL, 145 mmol) were added. The solution was allowed to stir and warm to RT. Stirring was continued for 18 h and then the solution was added to a separatory funnel and diluted with saturated aq NaHCO3 (1 L). The DCM was separated, and washed sequentially with saturated aq NH4Cl, then saturated aq NaHCO3. The DCM was then passed over a phase separator to remove leftover water, concentrated, and taken directly onto the next step. To the yellow residue was added methanol (698 mL) followed by K2CO3 (10.77 g, 78 mmol). The mixture was stirred at RT for 3 h. Following completion, the solution was filtered, and the solids were washed with MeOH. The mixture was then diluted with DCM (500 mL) and saturated aq NaHCO3 (1 L). The solution was added to a 3 L separatory funnel, and the aqueous layer extracted three times with DCM. The combined DCM extracts were washed with brine and then dried over Na2SO4, filtered and concentrated. The crude solid was azeotroped with EtOAc two times to give a yellow residue. The residue was dried under reduced pressure to give 1-{[(3S,5S)-5-methyl-1-oxaspiro[2.5]oct-5-yl]methyl}-1H-benzimidazole-6-carbonitrile as a yellow solid (19.9 g, 95% yield). MS (m/z) 282.2 (M+H+).
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=2)[C:8]([OH:10])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:18]O>S(=O)(=O)(O)O>[CH3:18][O:9][C:8](=[O:10])[CH:7]([C:11]1[CH:16]=[CH:15][C:14]([I:17])=[CH:13][CH:12]=1)[CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CO
Reactant: O=C(O)C(CC1CCCC1)c1ccc(I)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C(CC1CCCC1)c1ccc(I)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
A solution of 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid (13.00 g, 37.77 mmol) in methanol (94 mL) was treated slowly with concentrated sulfuric acid (5 drops). The resulting reaction mixture was heated under reflux for 67 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove methanol. The residue was diluted with ethyl acetate (300 mL). The organic phase was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 100% hexanes then 19/1 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(4-iodo-phenyl)-propionic acid methyl ester (13.18 g, 97%) as a yellow semi-solid: EI-HRMS m/e calcd for C15H19IO2 (M+) 358.0430, found 358.0434.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](=[O:8])[N:6]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)[CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1O
Product: COc1ccc(Cn2cc(Cl)cc([N+](=O)[O-])c2=O)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
The title compound was prepared in analogy to the procedure described for example 1 but using 5-chloro-3-nitropyridin-2-ol and 4-methoxybenzyl chloride. The reaction was stirred for 1 h at 80° C. The residue was purified by silica gel column chromatography (CH2Cl2/EtOAc, 8:2). tR: 0.91 min (LC-MS 4); ESI-MS: 295.2 [M+H]+ (LC-MS 4); Rf=0.59 (hexane/EtOAc, 1:1).
Reaction SMILES: C([O:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH3:18])=[CH:11][CH:10]=1)C1C=CC=CC=1.C1CCCCC1.C(O)C>C(OC(C)C)(C)C.[Pd]>[OH:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH3:18])=[CH:11][CH:10]=1
Reactant: Cn1ccc2ccc(OCc3ccccc3)cc21
Agent: [Pd]
Solvent: C1CCCCC1
Solvent: CC(C)OC(C)C
Solvent: CCO
Product: Cn1ccc2ccc(O)cc21

Procedure:
The mixture constituted by 0.24 mole (57 g) 6-benzyloxy-1-methylindole, 5.7 g 10% palladium-on-charcoal, 114 ml cyclohexane and 170 ml 96° ethanol is heated for 30 minutes under reflux. It is filtered hot in order to remove the catalyst. After evaporation of the filtrate under vacuum, an oil is obtained which, when dissolved in isopropyl ether, leads after evaporation to dryness to the desired product. It melts at 74° C.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][C:16]([N:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)([CH3:18])[CH3:17])[CH:9]=1>ClCCl.ClCCCl>[C:8]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][CH2:15][C:16]([N:19]2[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]2)([CH3:18])[CH3:17])[CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C(C)(C)CCc2cccc(-c3ccccc3)c2)CC1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CCc1cccc(-c2ccccc2)c1)N1CCNCC1
Reaction time: 2 h
Yield: 94.2 %

Procedure:
0.65 ml (8.4 mmol) of trifluoroacetic acid is added to a solution of 0.35 g (0.86 mmol) of 1,1-dimethylethyl 4-(3-biphenyl-3-yl-1,1-dimethylpropyl)piperazine-1-carboxylate, prepared in step 5.3., in 5 ml of dichloromethane. The mixture is stirred for 2 hours and then 0.65 ml of trifluoroacetic acid is added. It is stirred for 2 more hours and then diluted with 10 ml of 1,2-dichloroethane and evaporated to dryness. The residue is taken up in a mixture of 50 ml of dichloromethane and 20 ml of 15% aqueous sodium hydroxide solution. The phases are separated and the aqueous phase is extracted with 2 times 20 ml of dichloromethane. The organic phases are washed with 10 ml of water and then with 20 ml of saturated aqueous sodium chloride solution, dried over sodium sulphate and evaporated, to give 0.25 g (0.81 mmol) of product in the form of a yellow oil.
Reaction SMILES: [C:1]1([C:7](=[C:15]2[CH2:20][C:19]([CH3:22])([CH3:21])[CH2:18][C:17]([CH3:24])([CH3:23])[CH2:16]2)[C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36]>CC(C)=O>[C:1]1([C:7](=[C:15]2[CH2:16][C:17]([CH3:24])([CH3:23])[CH2:18][C:19]([CH3:22])([CH3:21])[CH2:20]2)[C:8]2[CH:9]=[CH:10][C:11]([O:14][CH2:32][CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC1(C)CC(=C(c2ccccc2)c2ccc(O)cc2)CC(C)(C)C1
Reactant: CCOC(=O)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)CCCOc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
An O-alkylation procedure described for 9 (example 5, step 2) employed using 32 (800 mg, 2.50 mmol), K2CO3 (1.04 g, 7.49 mmol), ethyl 4-chlorobutanoate (715 uL, 5 mmol), and acetone (30 mL). The mixture was refluxed for 15 h and cooled to RT. The mixture was filtered, concentrated, and purified to give ˜1.05 g (purity 80%) of the title product 36. This material was used as such without purification.
Reaction SMILES: Cl[C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([N:13]([CH:27]3[CH2:29][CH2:28]3)[C:14](=[O:26])[C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][CH:24]=[N:23][CH:22]=4)=[CH:17][CH:16]=3)[CH2:9][CH2:8]2)[S:4][N:3]=1.[CH:30]([OH:33])([CH3:32])[CH3:31].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[CH:27]1([N:13]([CH:10]2[CH2:11][CH2:12][N:7]([C:5]3[S:4][N:3]=[C:2]([O:33][CH:30]([CH3:32])[CH3:31])[N:6]=3)[CH2:8][CH2:9]2)[C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:25][CH:24]=[N:23][CH:22]=3)=[CH:17][CH:16]=2)[CH2:29][CH2:28]1
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(Cl)ns2)CC1
Reactant: CC(C)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: CC(C)Oc1nsc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1
Temperature: 125 °C
Reaction time: 72 h

Procedure:
A mixture of N-[1-(3-chloro-[1,2,4]thiadiazol-5-yl)-piperidin-4-yl]-N-cyclopropyl-4-oxazol-5-yl-benzamide (43 mg), isopropanol (2.0 mL), and cesium carbonate (98 mg) in N-methyl-2-pyrrolidinon (2.0 mL) is stirred at 125° C. for three days. The mixture is separated by HPLC (MeOH/H2O/TFA) to give the title compound. LC (method 5): tR=2.14 min; Mass spectrum (ESI+): m/z=454 [M+H]+.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][N:5]([CH:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13].[OH-].[Na+].Cl>CO>[C:23]([O:22][C:20]([CH:14]([C@@H:15]1[CH2:19][CH2:18][CH2:17][NH:16]1)[N:5]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])[CH2:4][C:3]([OH:27])=[O:2])=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: COC(=O)CN(Cc1ccccc1C)C(C(=O)OC(C)(C)C)[C@@H]1CCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccccc1CN(CC(=O)O)C(C(=O)OC(C)(C)C)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
N-[(t-Butyloxycarbonyl)-pyrrolidin-2(S)-ylmethyl]-(N-2-methylbenzyl)-glycine methyl ester (41.85 g, 0.111 mol) was dissolved in CH3OH (300 mL) at 0° C. and treated with 2 N NaOH solution (111 mL, 0.222 mol) and allowed to stir at ambient temperature for 3 hr. 1 N HCl (235 mL, 0.235 mol) was added, the CH3OH was removed on a rotary evaporator, and the residue was extracted with EtOAc (2×1.5 L), washed with brine, and dried (MgSO4). Filtration and concentration to dryness gave the title compound as a white solid. 1H NMR (CD3OD ) δ 7.56 (d, 1H, J=7.5 Hz), 7.15-7.36 (m, 3H), 4.70 (d, 1H, J=13 Hz), 4.27 (d, 1H, J=13 Hz), 4.1-4.2 (m, 1H), 3.73 (d, 1H, J=16 Hz), 3.59 (d, 1H, J=16 Hz), 3.15-3.5 (m, 4H), 2.49 (s, 3H), 2.1-2.2 (m, 1H), 1.7-1.9 (m, 2H), 1.6-1.7 (m, 1H), 1.46 (s, 9 h).
Reaction SMILES: Cl[CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]3[C:17]([C:5]=2[CH2:4][CH2:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=3.[N-:18]=[N+:19]=[N-:20].[Na+].O>CS(C)=O>[N:18]([CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][C:12]3[C:17]([C:5]=2[CH2:4][CH2:3]1)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1Nc2ccc3ccccc3c2CCC1Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: [N-]=[N+]=NC1CCc2c(ccc3ccccc23)NC1=O
Temperature: 60 °C

Procedure:
To a suspension of 3-chloro-4-oxo-2,3,4,5-tetrahydro-1H- naphtho-[2,1-b]azepine (16.6 g, 67.6 mmol) in DMSO (80 ml) was added sodium azide (8.8 g, 135 mmol) and the suspension was heated at 60° C. for 5 h. The hot reaction mixture was poured into water (1 L). The precipitate was isolated by filtration and washed with water. After drying in vacuo 16.3 g of 3-azido-4-oxo-2,3,4,5-tetrahydro-1H-naphtho[2,1-b]azepine was obtained.