Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]3[CH2:24][O:23]C(C)(C)[O:21]3)[N:15]=2)=[O:12])[C:7](=[O:35])[CH:6]=1.Cl.ClC1C=CC=CC=1OC1CN([C@@H](CC2C=CC(Cl)=CC=2)C(NC2C=CN(C[C@@H](O)CO)N=2)=O)C(=O)C=1>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:39]=[CH:38][CH:37]=[CH:36][C:3]=1[O:4][C:5]1[CH2:9][N:8]([C@@H:10]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[C:11]([NH:13][C:14]2[CH:18]=[CH:17][N:16]([CH2:19][C@@H:20]([OH:21])[CH2:24][OH:23])[N:15]=2)=[O:12])[C:7](=[O:35])[CH:6]=1
Reactant: CC1(C)OC[C@@H](Cn2ccc(NC(=O)[C@H](Cc3ccccc3Cl)N3CC(Oc4ccccc4Cl)=CC3=O)n2)O1
Agent: Cl
Agent: O=C(Nc1ccn(C[C@@H](O)CO)n1)[C@H](Cc1ccc(Cl)cc1)N1CC(Oc2ccccc2Cl)=CC1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(Nc1ccn(C[C@@H](O)CO)n1)[C@H](Cc1ccccc1Cl)N1CC(Oc2ccccc2Cl)=CC1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(4-chlorophenyl)-propionic acid [1-((R)-2,2-dimethyl-[1,3]dioxolan-4-yl-methyl)-1H-pyrazol-3-yl]-amide (prepared as in Example 188, 0.151 g, 0.259 mmol) in tetrahydrofuran (3 mL) was treated with 2N aqueous hydrochloric acid solution (3 mL). The reaction mixture was stirred at 25° C. for 3 h. The reaction mixture was diluted with ethyl acetate, washed with water, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The organic layer was concentrated to afford, (S)-2-[4-(2-chloro-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-3-(4-chlorophenyl)-N-[1-((R)-2,3-dihydroxy-propyl)-1H-pyrazol-3-yl]-propionamide (0.110 g, 80%) as a white powder: HR-ES-MS m/z calculated for C25H24Cl2N4O5 [M+H]+ 531.1196, observed 531.1197; 1H NMR (300 MHz, DMSO-d6); 1H NMR (300 MHz, DMSO-d6) δ ppm 3.19-3.30 (m, 4H), 3.74 (br. s., 1H), 3.80-3.91 (m, 1H), 4.07 (dd, J=13.6, 3.6 Hz, 1H), 4.25 (d, J=18.2 Hz, 1H), 4.39 (d, J=18.2 Hz, 1H), 4.65-4.71 (m, 1H), 4.72 (s, 1H), 4.93 (d, J=5.1 Hz, 1H), 5.18 (t, J=7.5 Hz, 1H), 6.43 (d, J=1.5 Hz, 1H), 7.18-7.30 (m, 2H), 7.30-7.47 (m, 5H), 7.53 (d, J=1.5 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 10.76 (s, 1H).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[C:18]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]4[CH3:25])=[N:17][C:16]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][C@@H:27]4[CH3:32])=[N:15][C:14]=3[N:33]=2)=[CH:6][C:5]=1OC.CC(N(C)C)=O.[CH2:43]([NH2:46])[CH2:44][NH2:45].CC(N(C)C)=O>C(N)CN>[CH3:32][C@H:27]1[CH2:28][O:29][CH2:30][CH2:31][N:26]1[C:16]1[N:17]=[C:18]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][C@@H:20]2[CH3:25])[C:13]2[CH:12]=[CH:11][C:10]([C:7]3[CH:8]=[CH:9][C:4]4[C:3](=[O:2])[NH:46][CH2:43][CH2:44][NH:45][C:5]=4[CH:6]=3)=[N:33][C:14]=2[N:15]=1
Reactant: NCCN
Reactant: COC(=O)c1ccc(-c2ccc3c(N4CCOC[C@@H]4C)nc(N4CCOC[C@@H]4C)nc3n2)cc1OC
Solvent: CC(=O)N(C)C
Product: C[C@H]1COCCN1c1nc(N2CCOC[C@@H]2C)c2ccc(-c3ccc4c(c3)NCCNC4=O)nc2n1

Procedure:
A solution of 4-[2,4-bis-((S)-3-methyl-morpholin-4-yl)-pyrido[2,3-d]pyrimidin-7-yl]-2-methoxy-benzoic acid methyl ester (1 equiv) in ethylenediamine (0.35 M) was stirred at room temperature for 24 hours. DMA was added to the solution (ethylenediamine/DMA 1:1.25). The reaction vessel was sealed and exposed to microwave radiation (180° C., medium absorption setting) for 1 hour. The reaction mixture was diluted with CH2Cl2 and extracted with water and washed with brine. The organic layer was dried with magnesium sulphate, filtered and concentrated in vacuo to yield a yellow solid which was then purified by preparative HPLC to give the desired product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[N:14]1[NH:15][C:16]([CH2:23][CH2:24][C:25](O)=O)=[C:17]2[C:22]=1[CH2:21][CH2:20][CH2:19][CH2:18]2.Cl[C:29]1C=CC(C2CCNCC2)=CC=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:25][CH2:24][CH2:23][C:16]3[NH:15][N:14]=[C:22]4[CH2:21][CH2:20][CH2:19][CH2:18][CH2:29][C:17]=34)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: Clc1ccc(C2CCNCC2)cc1
Reactant: O=C(O)CCc1[nH]nc2c1CCCC2
Product: Fc1ccc(N2CCN(CCCc3[nH]nc4c3CCCCC4)CC2)cc1

Procedure:
In the same manner as in Example 102 except that 3-(2,4,5,6,7,8-hexahydrocycloheptapyrazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 5 and 1-(4-fluorophenyl)piperazine were used instead of 3-(4,5,6,7-tetrahydro-2H-indazol-3-yl)propionic acid obtained in Starting Material Synthesis Example 1 and 4-(4-chlorophenyl)piperidine, 3-(3-(4-(4-fluorophenyl)piperazin-1-yl)propyl)-2,4,5,6,7,8-hexahydrocycloheptapyrazole was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:27]=[CH:26][C:6]2[C:7](=[O:25])[CH2:8][CH2:9][CH2:10][N:11]([C:16]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:24])[CH3:23])=[O:17])[C:12](=[O:15])[CH2:13][CH2:14][C:5]=2[CH:4]=1.[O:28]1CCCC1>>[C:22]([NH:21][CH2:20][CH2:19][CH2:18][C:16]([NH:11][CH2:10][CH2:9][CH2:8][C:7]([C:6]1[CH:26]=[CH:27][C:3]([Cl:2])=[CH:4][C:5]=1[CH2:14][CH2:13][C:12]([OH:28])=[O:15])=[O:25])=[O:17])(=[O:24])[CH3:23]
Reactant: C1CCOC1
Reactant: CC(=O)NCCCC(=O)N1CCCC(=O)c2ccc(Cl)cc2CCC1=O
Agent: Cl
Product: CC(=O)NCCCC(=O)NCCCC(=O)c1ccc(Cl)cc1CCC(=O)O
Temperature: 25 °C
Reaction time: 192 h

Procedure:
120 ml of 2N hydrochloric acid are added to a solution of 23.8 g (0.06 ml) of N-[3-[(11-chloro-2,3,5,6,7,8-hexahydro-3,8-dioxo-4-benzazecin-4(1H)-yl)-carbonyl]propyl]acetamide in 240 ml of tetrahydrofuran and the mixture is stirred at room temperature for 8 days. The solution is concentrated, extracted with methylene chloride/water, dried with magnesium sulfate and the solvent is distilled in a vacuum. Recrystallization from methanol/ether gives 2-[4-(4-acetamidobutyramido)butyryl]-5-chlorohydrocinnamic acid as beige crystals with melting point 108°.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH:8]([NH2:14])[CH2:9]2.[C:15]([O-])(=O)[CH3:16].[Na+].[C:20](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+].Cl>O1CCCC1.C(O)(=O)C>[ClH:1].[CH3:2][O:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C@H:8]([NH:14][CH2:20][CH2:15][CH3:16])[CH2:9]2
Reactant: COc1cccc2c1CCC(N)C2
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCN[C@H]1CCc2c(cccc2OC)C1
Temperature: 0 °C
Yield: 78 %

Procedure:
A 2 L reactor with double jacket temperature control was charged with 5-methoxy-2-aminotetraline hydrochloride (Xa) (161 g), sodium acetate (62 g), and tetrahydrofuran (750 mL). The suspension was stirred at 0° C. To that suspension were added glacial acetic acid (22 mL), sodium triacetoxyborohydride (200 g) and propionalhedyde (XIa) (48 g diluted with 50 mL of tetrahydrofuran via a dropping funnel maintaining the mass temperature below 10° C. The resulting suspension was stirred overnight at 0° C. To that suspension was slowly added a 25% solution of sodium hydroxide (250 mL) at 0° C. and the resulting mixture was let to warm up to room temperature under stirring for 30 minutes. The aqueous layer was discarded and the organic layer was washed with a 6.25% solution of sodium hydroxide (200 mL). The aqueous layer was discarded and the organic layer was heated at 50° C. To this solution concentrated hydrochloric acid (77 mL) was added over 20 minutes and the resulting thick suspension was diluted with 150 mL of tetrahydrofuran. The suspension is maintained at 50° C. for 30 minutes then rapidly cooled to 10° C. and stirred at 10° C. for 30 minutes. The product was isolated by filtration, washed 2 times with cold THF (2×200 mL) and dried under vacuum at 40° C. until constant weight to give N-Propyl MAT.HCl salt as an white solid with 78% yield.
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:11])[C:7]2[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=2[N:5]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:4](=[O:34])[CH2:3]1.[CH2:35]([N:42]1[C:46]([CH2:47]Br)=[CH:45][C:44]([CH3:49])=[N:43]1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C.C1(C)C=CC=CC=1>[CH2:35]([N:42]1[C:46]([CH2:47][CH:3]2[C:2](=[O:1])[N:8]([CH2:9][C:10]([N:12]([CH:21]([CH3:23])[CH3:22])[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[O:11])[C:7]3[CH:24]=[CH:25][CH:26]=[CH:27][C:6]=3[N:5]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C:4]2=[O:34])=[CH:45][C:44]([CH3:49])=[N:43]1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: Cc1cc(CBr)n(Cc2ccccc2)n1
Reactant: COc1ccc(N(C(=O)CN2C(=O)CC(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3cc(C)nn3Cc3ccccc3)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.08 h
Yield: 60 %

Procedure:
To a stirring solution of 300 mg (0.66 mmol) of 2-(2,4-Dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 4, in 5 mL of DMF at 0° C. is added 1.57 mL (0.79 mmol, 1.2 equiv) of a 0.5M solution of KN(TMS)2 in toluene. The resulting solution is stirred 5 min, and a solution of 190 mg (0.72 mmol, 1.1 equiv.) of 1-Benzyl-5-bromomethyl-3-methyl-1H-pyrazole, prepared as in Intermediate 56, in 2 mL of DMF is added. The resulting solution is stirred for 18 h at RT then quenched with 5 mL of H2O. The reaction mixture is poured into 50 mL of EtOAc and extracted with H2O (2×50 mL). The organic layer is separated, dried (MgSO4), and the solvents removed in vacuo. Purification by silica gel flash column chromatography using hexane/EtOAc 1/2 as eluent afforded 254 mg of the title compound as a white solid: mp 117°-120° C.; 1H NMR (CDCl3, 400 MHz) δ7.37-7.02 (m, 15H), 6.94 (m, 2H), 6.85 (d, 1H, J=7.4), 5.80(s, 1H), 5.30 (dd, 2H, J=16.1, 30.9), 4.98 (m, 1H), 4.19 (dd, 2H, J=15.6, 76.0), 3.83 (s, 3H), 3.43 (t, 1H, J=6.7), 3.25 (ddd, 1H, J=7.1, 16.0, 40.5), 2.20 (s, 3H), 1.06 (m, 6H); low resolution MS (FAB)m/e 642 (MH+), 641 (M+); Anal. (C39H39N5O4) Calcd. C, 72.99; H, 6.13; N, 10.91 Found C, 72.86; H, 6.11; N, 10.96.
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[O:7][C@@H:8]([CH2:23][CH2:24][CH3:25])[C@@H:9]([OH:22])[CH2:10]OS(C1C=CC(C)=CC=1)(=O)=O.[Cl-].[NH4+]>O1CCOCC1>[ClH:3].[Cl:3][C:4]1[CH:5]=[C:6]([CH:26]=[C:27]([Cl:29])[CH:28]=1)[O:7][C@@H:8]([CH2:23][CH2:24][CH3:25])[C@@H:9]([OH:22])[CH2:10][NH:2][CH3:1]
Reactant: CCC[C@H](Oc1cc(Cl)cc(Cl)c1)[C@@H](O)COS(=O)(=O)c1ccc(C)cc1
Reactant: CN
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1COCCO1
Product: CCC[C@H](Oc1cc(Cl)cc(Cl)c1)[C@@H](O)CNC
Product: Cl
Temperature: 50 °C
Yield: 73 %

Procedure:
Add methyl amine (5 mL, 40% wt in water) to a solution of (2S, 3S)-toluene-4-sulfonic acid 3-(3,5-dichloro-phenoxy)-2-hydroxy-hexyl ester (306 mg, 0.706 mmol) in 1,4-dioxane (10 mL) in a heavy walled screw top sealed tube, seal the tube, and heat at 50° C. overnight. The mixture is cooled and concentrated under reduced pressure. Purification by medium pressure liquid chromatography eluting with 0-10% of 2N NH3/MeOH in dichloromethane is followed by HCl salt formation by dissolving in methanol (10 mL), adding solid ammonium chloride (32 mg, 0.598 mmol) and sonicating for 15 minutes. The mixture is concentrated under reduced pressure and the residue is dissolved in water, frozen at −78° C., and freeze dried to afford the title compound as a colorless solid (170 mg, 73%): δH (CD3OD, 400 MHz): 0.94 (dd, 3H, J=7, 7 Hz), 1.31-1.55 (m, 2H), 1.60-1.79 (m, 2H), 2.72 (s, 3H), 3.11 (dd, 1H, J=13, 10 Hz), 3.22 (dd, 1H, J=13, 3 Hz), 3.97-4.05 (m 1H), 4.37-4.45 (m, 1H), 7.00-7.04 (m, 3H). Exact Mass cacld. for C13H19O2NCl2 (M+ free base): 292.0871; found: 292.0879.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH:9]1([CH:15]=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.O>CS(C)=O>[CH:9]1([CH:15]2[O:16][CH2:4]2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=CC1CCCCC1
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C1CCC(C2CO2)CC1
Temperature: 55 °C
Reaction time: 0.5 h
Yield: 61.6 %

Procedure:
Sodium hydride (4.5 g, 187.5 mmol) and trimethylsulfoxonium iodide (41.25 g, 187.5 mmol) were combined in a 3-neck flask equipped with a mechanical stirrer and an addition funnel. Dimethyl sulfoxide (DMSO) was added slowly over a 30 min period, until 200 mL had been added. Gas was evolved throuqhout the addition. A solution of cyclohexane carboxaldehyde (21.8 mL, 180 mmol) in 50 mL of DMSO was added dropwise to the reaction mixture over a 15 min period. The reaction mixture was heated to 55° C. and stirred at 55° C. for 30 min. The reaction mixture was cooled to ambient temperature and poured into 500 mL of water. The aqueous solution was extracted with 3×100 mL of diethyl ether. The combined ether extracts were washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The crude product was distilled (44° C., 0.1 mm) to give 14 g (62% yield) of 1-cyclohexyl ethylene oxide as a clear colorless liquid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[C:16]([F:17])=[CH:15][C:14]([F:18])=[C:13]([F:19])[C:9]=1[C:10](O)=[O:11].C(O)C.O>CCOCC>[F:7][C:8]1[C:16]([F:17])=[CH:15][C:14]([F:18])=[C:13]([F:19])[C:9]=1[CH2:10][OH:11]
Reactant: O=C(O)c1c(F)c(F)cc(F)c1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: OCc1c(F)c(F)cc(F)c1F
Reaction time: 3 h
Yield: 46.7 %

Procedure:
Lithium aluminium hydride (4.6 g) was added in small portions to a stirred solution of 2,3,5,6-tetrafluorobenzoic acid (30.0 g) in dry ether (600 ml) at the ambient temperature, and stirring continued for a period of 3 hours. After decomposition of the excess lithium aluminium hydride with ethyl alcohol, water was added in excess and the ethereal phase separated, washed with water, and concentrated to yield crude 2,3,5,6-tetrafluorobenzyl alcohol (13.0 g) as a colourless oil.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[CH2:10][CH2:9]2)C=CC=CC=1.CO.Cl.[H][H]>[Pd].O>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:10][CH2:9]1
Reactant: [H][H]
Reactant: c1ccc(CN2CCC(Nc3cccnc3)CC2)cc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: O
Product: c1cncc(NC2CCNCC2)c1

Procedure:
A mixture of 20 parts of N-[1-(phenylmethyl)-4-piperidinyl]-3-pyridinamine, 160 parts of methanol, 30 parts of water and 12 parts of a concentrated hydrochloric acid solution is hydrogenated at normal pressure and at a temperature between 22°-39° C., in the presence of 7 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, hydrogenation is stopped. The catalyst is filtered off and the filtrate is evaporated. The oily residue is dissolved in water. This solution is rendered alkaline with ammonium hydroxide, saturated with solid potassium carbonate and then extracted with methylbenzene. The extract is dried over potassium carbonate and evaporated. The solid residue is recrystallized from a mixture of 40 parts of benzene and 32 parts of 1,1'-oxybisethane, yielding 3 parts of N-(4-piperidinyl)-3-pyridinamine; mp. 127°-129° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH:20]=[CH:19]3)[CH:5]=[C:6]([Br:9])[C:7]=1[NH2:8].[OH:27]O>>[Br:1][C:2]1[CH:3]=[C:4]([S:10]([CH2:11][CH2:12][CH2:13][CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[CH:20]=[CH:19]3)=[O:27])[CH:5]=[C:6]([Br:9])[C:7]=1[NH2:8]
Reactant: Nc1c(Br)cc(SCCCCOc2ccc3[nH]c(=O)ccc3c2)cc1Br
Reactant: OO
Product: Nc1c(Br)cc(S(=O)CCCCOc2ccc3[nH]c(=O)ccc3c2)cc1Br

Procedure:
Prepared analogous to Example 123 from 6-[4-(3,5-dibromo-4-amino-phenylmercapto)-butoxy]-carbostyril and hydrogen peroxide.
Reaction SMILES: [OH:1][P:2]([O-:5])([O-:4])=[O:3].[Ca+2:6].C(=O)([O-])[O-].[Ca+2]>[Pt].O>[O-:3][P:2]([O-:5])([O-:4])=[O:1].[O-:3][P:2]([O-:5])([O-:4])=[O:1].[Ca+2:6].[Ca+2:6].[Ca+2:6]
Reactant: O=P([O-])([O-])O
Agent: [Pt]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: O=P([O-])([O-])[O-]
Temperature: 1400 °C
Reaction time: 72 h

Procedure:
For a mixture of 500 g (dry weight), 360 g dicalcium phosphate anhydrous powder, 144 g calcium carbonate powder and 220 ml deionized water were mixed for 7 minutes at 500 rpm using a laboratory stirrer. The slurry from the mixing process was immediately transferred into a high temperature stable platinum cup. The filled platinum cup was placed in a cold furnace. The furnace was heated to 1400° C. by using a heating rate of 60° C. per hour. The heating process was stopped after 72 hours by switching off the furnace. The sample was cooled down to room temperature within the furnace. The bulk sintered material (phase pure α-Ca3(PO4)2) was removed from the furnace and the platinum cup. The bulk product from the sintering process had a weight of 420 g (weight loss 16.7%). The control of phase purity was performed using powder X-ray diffraction analysis.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][CH2:15][CH2:16][O:17][CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH:20]([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CC#N.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([N:14]([CH:20]([CH3:22])[CH3:21])[CH2:15][CH2:16][O:17][CH3:18])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCNC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: COCCN(C(C)C)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 60 °C

Procedure:
Amine preparation: A mixture of 4-(2-methoxy-ethylamino)-piperidine-1-carboxylic acid tert-butyl ester (see preparation of 121) (300 mg) and 2-bromopropane (1.20 mL) in MeCN (3 mL) with potassium carbonate (192 mg) were heated at 60° C. in a sealed tube for 7 days. The reaction mixture was cooled down, diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo. The residue was purified using flash chromatography to yield 4-[isopropyl-(2-methoxy-ethyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester as an oil (131 mg). Treatment of this compound with HCl in DCM/MeOH and basic wash with aqueous sodium bicarbonate yielded the desired amine.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[C:12]([OH:14])[CH:11]=[CH:10][C:9]=1[CH:15]([CH3:34])[C:16]([C:22]1[CH:33]=[CH:32][C:25]2[N:26]([CH3:31])[C:27](=[O:30])[N:28]([CH3:29])[C:24]=2[CH:23]=1)([OH:21])[C:17]([F:20])([F:19])[F:18].Cl[C:36]1[N:45]=[CH:44][C:43]([Cl:46])=[CH:42][C:37]=1[C:38]([O:40][CH3:41])=[O:39].C(O)=O>CN(C=O)C>[CH3:41][O:40][C:38](=[O:39])[C:37]1[CH:42]=[C:43]([Cl:46])[CH:44]=[N:45][C:36]=1[O:14][C:12]1[CH:11]=[CH:10][C:9]([CH:15]([CH3:34])[C:16]([C:22]2[CH:33]=[CH:32][C:25]3[N:26]([CH3:31])[C:27](=[O:30])[N:28]([CH3:29])[C:24]=3[CH:23]=2)([OH:21])[C:17]([F:18])([F:19])[F:20])=[C:8]([Cl:7])[CH:13]=1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccc2c(c1)n(C)c(=O)n2C)C(F)(F)F
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=CO
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Cl)cnc1Oc1ccc(C(C)C(O)(c2ccc3c(c2)n(C)c(=O)n3C)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Potassium tert-butoxide (6 mg) was added to a solution of 5-[2-(2-chloro-4-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (Example 85, 20 mg) in DMF (3.6 ml). The solution was added to methyl 2,5-dichloronicotinate (CAS Reg. No. 67754-03-4, 20 mg). The resulting mixture was stirred overnight at room temperature. The mixture was acidified with HCOOH and purified by prep. HPLC (C18-column, solvent gradient 20-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (10 mg). MS (m/e)=584.3 [M+H+].
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[CH:7]=1.[F:15][C:16]([F:28])([F:27])[O:17][C:18]1[CH:23]=[CH:22][C:21](B(O)O)=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].O>CN(C=O)C>[F:15][C:16]([F:27])([F:28])[O:17][C:18]1[CH:23]=[CH:22][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=3)[CH:7]=2)=[CH:20][CH:19]=1
Reactant: FC(F)(F)c1nnc2ccc(Br)cn12
Reactant: OB(O)c1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(-c2ccc3nnc(C(F)(F)F)n3c2)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
In a 100 mL round-bottom flask 6-bromo-3-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine (2.124 g), 4-trifluoromethoxyphenylboronic acid (2.466 g), and sodium carbonate (0.635 g) were suspended in a mixture of DMF (81 mL) and deionized water (9 mL) that was degassed with nitrogen. Tetrakis(triphenylphosphine)palladium (0.462 g) was added and the reaction mixture stirred at 90° C. overnight, concentrated, the residue dissolved in ethyl acetate, and washed with water (2×) and concentrated NaHCO3. The combined organic phase dried over MgSO4 and concentrated, then subjected to gradient chromatography (ethyl acetate/hexane) to produce dark grey solid. The solid was recrystallized from ethyl acetate/hexanes mixture to produce off-white material.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH:14]=[O:15]>O>[Br:10][C:11]1[C:18]([F:19])=[CH:17][C:16]([N+:6]([O-:9])=[O:7])=[C:13]([CH:12]=1)[CH:14]=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=Cc1cc(Br)c(F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a 0° C. solution of concentrated sulfuric acid (125 mL, 2340 mmol) and nitric acid (11.79 mL, 185 mmol) was added 3-bromo-4-fluorobenzaldehyde (25.0 g, 123 mmol). The reaction was warmed to ambient temperature, during which time the solids dissolved. After 2 h, the reaction mixture was poured into a mixture of ice (500 mL) and water (250 mL). The resulting suspension was filtered through a medium frit affording 5-bromo-4-fluoro-2-nitrobenzaldehyde as a yellow solid.
Reaction SMILES: Cl.[CH3:2][C:3]1[S:7][C:6]([C:8](=[NH:10])[NH2:9])=[N:5][N:4]=1.[Br:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]=O.O=[C:22]([CH3:29])[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>>[Br:11][C:12]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:13]=1[CH:14]1[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:22]([CH3:29])[NH:9][C:8]([C:6]2[S:7][C:3]([CH3:2])=[N:4][N:5]=2)=[N:10]1
Reactant: Cc1nnc(C(=N)N)s1
Reactant: CCOC(=O)CC(C)=O
Reactant: O=Cc1ccc(F)cc1Br
Agent: Cl
Product: CCOC(=O)C1=C(C)NC(c2nnc(C)s2)=NC1c1ccc(F)cc1Br
Yield: 22.8 %

Procedure:
5-methyl-1,3,4-thiadiazole-2-carboximidamide hydrochloride (1.8 g, 10 mmol) was reacted with 2-bromo-4-fluorobenzaldehyde (2.03 g, 10 mmol) and ethyl 3-oxobutanoate (1.56 g, 12 mmol) according to the procedure as described in Example 1, Step A to give the title compound as a yellow solid (1.0 g, 25%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1.C(N(CC)CC)C.[F:22][C:23]([F:27])([F:26])[S:24]Cl>C1(C)C=CC=CC=1>[F:14][C:2]([F:1])([F:13])[O:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][N:10]2[S:24][C:23]([F:27])([F:26])[F:22])=[CH:6][CH:5]=1
Reactant: FC(F)(F)SCl
Reactant: FC(F)(F)Oc1ccc2cn[nH]c2c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: FC(F)(F)Oc1ccc2cnn(SC(F)(F)F)c2c1

Procedure:
20.2 g (0.1 mole) of 6-trifluoromethoxyindazole and 10.1 g (0.1 mole) of triethylamine in 125 ml of toluene are heated to 80° to 85° C., and 13.6 g (0.1 mole) of trifluoromethanesulphenyl chloride are then passed in the course of one hour and the mixture is stirred for a further hour at this temperature. After cooling, the precipitated triethylamine hydrochloride is filtered off with suction and rinsed with toluene. The filtrate, combined with the wash liquor, is washed twice with water. After drying (MgSO4) the volatile constituents are removed by distillation under a water pump vacuum. The oily crude product is purified by distillation under an oil pump vacuum. Boiling point 62°/0.05 mbar. Yield: 16.2 g (46% of theory).