Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Al](CC)CC)[CH3:2].Br[C:9]1[CH:10]=[C:11]2[CH:17]=[N:16][NH:15][C:12]2=[CH:13][N:14]=1.[NH4+].[Cl-]>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([C:9]1[CH:10]=[C:11]2[CH:17]=[N:16][NH:15][C:12]2=[CH:13][N:14]=1)[CH3:2]
Reactant: CC[Al](CC)CC
Reactant: Brc1cc2cn[nH]c2cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1cc2cn[nH]c2cn1
Temperature: 65 °C
Reaction time: 60 h

Procedure:
Triethylaluminum (21.7 mL, 40.4 mmol, 25 wt % solution in toluene) was added to a vigorously stirred solution of 5-bromo-1H-pyrazolo[3,4-c]pyridine [929617-35-6] (4.00 g, 20.2 mmol) and Pd(PPh3)4 (1.17 g, 1.01 mmol) in THF (100 mL) under argon. The reaction mixture was stirred at 65° C. for 60 h. The mixture was cooled to RT and poured into sat. aq. NH4Cl. The resulting suspension was filtered, the solid was washed with water and discarded. The filtrate and combined washings were extracted with EtOAc (3×). The combined organic extracts were washed with brine, then dried (Phase separator) and concentrated under reduced pressure. The residual oil was purified by flash column chromatography on silica gel (EtOAc/c-hexane 50:50, then 75:25, then 100:0). TLC, Rf (c-hexane/EtOAc 1:3)=0.22; MS (LC-MS): 148 [M+H]+, tR (HPLC conditions k): 0.71 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[C:15]([O:18][CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)(=[O:17])[CH3:16].C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1.C(OCC)(=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:15]([O:18][CH:19]1[CH2:24][CH2:23][N:22]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([O:11][CH:12]([CH3:14])[CH3:13])[CH:3]=2)[CH2:21][CH2:20]1)(=[O:17])[CH3:16]
Reactant: CC(C)Oc1cc(Br)ccc1[N+](=O)[O-]
Reactant: CC(=O)OC1CCNCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OC1CCN(c2ccc([N+](=O)[O-])c(OC(C)C)c2)CC1
Yield: 42.8 %

Procedure:
A mixture of 1 g of 4-bromo-1-nitro-2-(propan-2-yloxy)benzene, 1.19 g of piperidin-4-yl acetate, 5.01 g of caesium carbonate, 86 mg of palladium acetate and 334 mg of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, in 50 ml of dioxane, is refluxed for 3 hours. The mixture is diluted with ethyl acetate and water. The aqueous phase is extracted with ethyl acetate (2×). The combined organic phases are dried over magnesium sulfate and concentrated under vacuum. The residue is purified on silica, elution being carried out with cyclohexane/ethyl acetate (80/80 to 50/50), so as to give 530 mg 1-[4-nitro-3-(propan-2-yloxy)phenyl]piperidin-4-yl acetate in the form of a brown solid.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:7][C:8]([C:10]1[N:11]=[N:12][C:13]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[C@@H:24]([CH:29]([CH2:31][CH3:32])[CH3:30])[CH2:23]2)=[O:21])=[CH:14][C:15]=1[CH2:16][CH:17]([CH3:19])[CH3:18])=O)[CH:4]([CH3:6])[CH3:5].CCN(S(F)(F)F)CC.C([O-])([O-])=O.[K+].[K+].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:29]([C@@H:24]1[N:25]([CH3:28])[CH2:26][CH2:27][N:22]([C:20]([C:13]2[N:12]=[N:11][C:10]([C:8]3[O:1][CH2:2][C@H:3]([CH:4]([CH3:5])[CH3:6])[N:7]=3)=[C:15]([CH2:16][CH:17]([CH3:18])[CH3:19])[CH:14]=2)=[O:21])[CH2:23]1)([CH2:31][CH3:32])[CH3:30]
Reactant: CCC(C)[C@H]1CN(C(=O)c2cc(CC(C)C)c(C(=O)N[C@H](CO)C(C)C)nn2)CCN1C
Agent: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CCC(C)[C@H]1CN(C(=O)c2cc(CC(C)C)c(C3=N[C@@H](C(C)C)CO3)nn2)CCN1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 64.7 %

Procedure:
β-Hydroxy amide 16 (8 mg, 0.018 mmol) was dissolved in 500 μL DCM and cooled to −78° C. DAST (3 μL, 0.020 mmol, 3.2 mg) was added slowly and the reaction mixture was stirred for 1 hour at −78° C. The reaction was quenched with the addition of ca. 4 mg K2CO3 (0.027 mmol) and allowed to warm to room temperature. Saturated sodium bicarbonate was added (1 mL), the product was extracted with DCM (3×1 mL), washed with brine (1×1 mL), dried over magnesium sulfate and evaporated to give a yellow oil. The product was purified by prep plate chromatography (250 μm×20 cm×20 cm; 9.8:0.2:0.1% DCM-MeOH-Et3N, Rf=0.20) to give 5 mg (65%) of a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[CH3:8][C:9]1[N:14]=[C:13]([SH:15])[N:12]=[C:11]([OH:16])[CH:10]=1.C(N(CC)CC)C>C(O)C>[CH3:8][C:9]1[N:14]=[C:13]([S:15][CH2:2][C:3]2[CH:7]=[CH:6][S:5][CH:4]=2)[N:12]=[C:11]([OH:16])[CH:10]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: BrCc1ccsc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(O)nc(SCc2ccsc2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 19.7 %

Procedure:
A mixture of 3-(bromomethyl)thiophene (360 mg, 2.0 mmol), 6-methyl-2-sulfanylpyrimidin-4-ol (242 mg, 1.7 mmol), and triethylamine (280 μL, 2.0 mmol) in absolute ethanol (10 mL) was stirred at room temperature for 2 days. The solid residue was removed by filtration. The filtrate was recovered and evaporated under reduced pressure. The solid product was suspended in water (20 mL). The solid material was recovered by filtration, washed with water (2×15 mL) and hexanes (3×15 mL), and dried in vacuo, affording the title compound (80 mg, 20% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.21 (s, 3H), 4.39 (s, 2H), 6.02 (s (br), 1H), 7.12 (dd, 1H, J=1.3 Hz, 3.5 Hz), 7.47 (m, 2H); M+239; HPLC purity: 96.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.O.ON1C2C=CC=CC=2N=N1.Cl.[NH2:35][C:36]1([C:39]2[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=2)[CH2:38][CH2:37]1.C(N(CC)CC)C>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=3)[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:35][C:36]1([C:39]2[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=2)[CH2:38][CH2:37]1)=[O:9]
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Oc2cccc(F)c2)C1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Oc4cccc(F)c4)C3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 89 %

Procedure:
A mixture of 5-chloro-2-(3-(3-fluorophenoxy)azetidin-1-yl)nicotinic acid (D103) (30 g, 0.0929 mol), 1-Hydroxybenzotriazole hydrate (14.2 g, 0.0929 mol) 1-Ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (26.7 g, 0.1394 mol) in dimethylformamide (230 ml) was stirred 40 min at room temperature. A solution of methyl 4-(1-aminocyclopropyl)benzoate (D7) (21.16 g, 0.0929 mol) and triethylamine (12.94 ml, 0.0929 mol) in dimethylformamide (75 ml) was added and the resulting mixture was stirred 3 hours at room temperature. Water (500 ml) was added and the formed precipitate was filtered off and washed with water. After drying it afford the title compound (D151) (41 g)
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[O:11])=[N:6][C:5]=1[C:18]1[O:19][CH:20]=[CH:21][CH:22]=1)([OH:3])=O.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C.O>[O:19]1[CH:20]=[CH:21][CH:22]=[C:18]1[C:5]1[N:6]=[C:7]([NH:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[O:11])[S:8][C:4]=1[C:1]([N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1)=[O:3]
Reactant: C1COCCN1
Reactant: O=C(Nc1nc(-c2ccco2)c(C(=O)O)s1)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: O=C(Nc1nc(-c2ccco2)c(C(=O)N2CCOCC2)s1)c1ccncc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 31.8 %

Procedure:
Compound 95 (410 mg, 1.30 mmol), morpholine (0.141 mL, 1.60 mmol), EDC hydrochloride (500 mg, 2.60 mmol), 1-hydroxybenzotriazole monohydrate (400 mg, 2.60 mmol) and triethylamine (0.36 mL, 2.60 mmol) were dissolved in DMF (5 mL), followed by stirring at room temperature for 3 hours. Water was added to the reaction mixture, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from ethanol to afford the entitled Compound 96 (159 mg, 34%) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]2[N:6]=[C:7]([C:9]3[CH:28]=[CH:27][C:12]([C:13]([NH:15][CH:16]4[CH2:21][C:20]([CH3:23])([CH3:22])[N:19]([CH3:24])[C:18]([CH3:26])([CH3:25])[CH2:17]4)=[O:14])=[CH:11][C:10]=3[O:29][CH3:30])[NH:8][C:4]=2[CH:3]=1.[OH-].[K+].I[CH3:37]>CC(C)=O>[Cl:1][C:2]1[C:32]([Cl:33])=[CH:31][C:5]2[N:6]([CH3:37])[C:7]([C:9]3[CH:28]=[CH:27][C:12]([C:13]([NH:15][CH:16]4[CH2:21][C:20]([CH3:23])([CH3:22])[N:19]([CH3:24])[C:18]([CH3:25])([CH3:26])[CH2:17]4)=[O:14])=[CH:11][C:10]=3[O:29][CH3:30])=[N:8][C:4]=2[CH:3]=1
Reactant: CI
Reactant: COc1cc(C(=O)NC2CC(C)(C)N(C)C(C)(C)C2)ccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COc1cc(C(=O)NC2CC(C)(C)N(C)C(C)(C)C2)ccc1-c1nc2cc(Cl)c(Cl)cc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 132.4 %

Procedure:
A mixture of 4-(5,6-dichlorobenzimidazol-2-yl)-N-(1,2,2,6,6-pentamethylpiperidin-4-yl)-3-methoxybenzamid (0.16 g, 0.33 mmol), prepared as described in Example 4, and KOH (0.0185 g, 0.33 mmol) in acetone (8 ml) was stirred for 1 h at room temperature. Iodomethane (0.047 g, 0.033 mmol) was added and stirring was continued for 24 h. Solvent was removed under reduced pressure and the residue was partitioned between water and ethyl acetate. the organic layer was washed with brine, dried over Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified by column chromatography eluting with CH2Cl2/MeOH/NH4OH 95:5:0.2. Fraction containing the desired product were collected, evaporated to dryness under reduced pressure and the solid was triturated with diisopropyl ether to give 0.022 g of the title compound (yield 13%), mp=178–180° C.
Reaction SMILES: C[O:2][CH2:3][PH:4]([C:6](=[O:13])[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:5].[Li:14]>[I-].[Li+].C(C(C)=O)C(C)C>[Li:14].[OH:2][CH2:3][PH:4]([C:6](=[O:13])[CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:5]
Reactant: COC[PH](=O)C(=O)CCC(=O)OC
Agent: [I-]
Agent: [Li+]
Agent: [Li]
Solvent: CC(=O)CC(C)C
Product: COC(=O)CCC(=O)[PH](=O)CO
Reaction time: 2 h

Procedure:
The product of step (a) (16.0 g) was dissolved in a 0.5 M solution of anhydrous lithium iodide in methyl isobutyl ketone (170 ml) and the solution heated under reflux with stirring for 2 hours. After cooling the crude lithium salt was filtered off, washed with acetone and dried. The product (12.0 g) was dissolved in methanol (50 ml) and diluted with acetone (500 ml). The precipitated impurities were filtered off and the filtrate was evaporated to dryness to give the title product as a deliquescent, pale yellow solid (9.5 g). The salt has no sharp melting point and gradually softens and decomposes above 195° C. Elemental analysis indicates the monohydrate:
Reaction SMILES: Br[CH:2]([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CN(C)C=O.C(OCC)(=O)C>[N:10]1([CH2:9][CH2:2][CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNCC1
Reactant: CCOC(=O)CC(C)Br
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCN1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 81.2 %

Procedure:
To a solution of ethyl 3-bromobutanoate (6.0 mL, 42 mmol) in N,N-dimethylformamide (20 mL) at 0° C. was added piperidine (8.0 mL, 80 mmol) and the mixture was warmed to room temperature then stirred 16 h. The reaction mixture was diluted with ethyl acetate (200 mL) and washed with a solution of brine and 2.0M aqueous sodium hydroxide (4:1 v/v). The organic phase was then dried over anhydrous sodium sulfate, filtered and concentrated to give ethyl 4-piperidin-1-ylbutanoate (6.8 g, 81% yield) as brown oil. MS (EI) for C11H21NO2: 200 (MH+).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28].Cl.[NH2:31][CH:32]1[CH2:37][CH:36]2[CH2:38][CH:33]1[CH2:34][CH2:35]2.C(N(CC)CC)C>CN(C=O)C>[CH:33]12[CH2:38][CH:36]([CH2:35][CH2:34]1)[CH2:37][CH:32]2[NH:31][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[CH:16][CH:15]=2)=[O:13])(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:27]([O-:29])=[O:28]
Reactant: NC1CC2CCC1C2
Reactant: O=C(NS(=O)(=O)c1ccc(Cl)c([N+](=O)[O-])c1)c1ccc(-c2ccc(F)cc2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NS(=O)(=O)c1ccc(NC2CC3CCC2C3)c([N+](=O)[O-])c1)c1ccc(-c2ccc(F)cc2)cc1
Reaction time: 16 h

Procedure:
A solution of Example 1D (50 mg, 0.12 mmol), 2-aminonorbornane hydrochloride (106 mg, 0.58 mmol), and triethylamine (0.08 ml, 0.58 mmol) in DMF (2 mL) were heated to 120° C. in a sealed vial with shaking for 16 hours, then concentrated. The concentrate was dissolved in 1:1/DMSO:methanol (1.0 ml) and purified by reverse phase preparative HPLC with 0.1% TFA in H2O/CH3CN to provide the desired product. MS (APCI(+)) m/e 510 (M+H)+; 1H NMR (500 MHz, DMSO-d6) δ 12.45 (br s, 1H), 8.67 (d, 1H), 8.48 (d, 1H), 7.99 (dd, 1H), 7.95 (d, 2H), 7.78 (2d, 4H), 7.32 (t, 2H), 7.24 (d, 1H), 4.04 (m, 1H), 2.58 (m, 1H), 2.27 (m, 1H), 2.24-2.21 (m, 1H), 1.59-1.29 (m, 6H), 0.97 (dt, 1H).
Reaction SMILES: C(OC([N:8]1[CH2:12][C@@H:11]([CH2:13][NH:14][C:15](=[O:29])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])=[O:23])[CH:17]=2)[CH2:10][C@H:9]1[C:30]([N:32]1[CH2:36][CH2:35][S:34][CH2:33]1)=[O:31])=O)(C)(C)C.Cl.O1CCOCC1>CO>[CH3:28][S:25]([NH:24][C:22]([C:18]1[CH:17]=[C:16]([CH:21]=[CH:20][CH:19]=1)[C:15]([NH:14][CH2:13][C@H:11]1[CH2:10][C@@H:9]([C:30]([N:32]2[CH2:36][CH2:35][S:34][CH2:33]2)=[O:31])[NH:8][CH2:12]1)=[O:29])=[O:23])(=[O:26])=[O:27]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)c2cccc(C(=O)NS(C)(=O)=O)c2)C[C@H]1C(=O)N1CCSC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CS(=O)(=O)NC(=O)c1cccc(C(=O)NC[C@@H]2CN[C@H](C(=O)N3CCSC3)C2)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of Example 32C (372.1 mg, 0.69 mmol) in methanol (5 mL) was slowly added a solution of 4 M HCl in dioxane (1.6 mL, 6.4 mmol) at 0° C. over 10 minutes via addition funnel. The mixture was allowed to stir for 5 hours at room temperature and then was concentrated under reduced pressure to provide the titled compound. MS (ESI) m/e 441 (M+H)+, 439 (M−H)−; 1H NMR (400 MHz, CD3OD) δ ppm 1.80 (m, 1 H), 2.74 (m, 1 H), 2.84 (m, 1 H), 3.09 (m, 1 H), 3.16 (t, 1 H), 3.24 (m, 1 H), 3.52 (dd, 2 H), 3.55 (m, 1 H), 3.74 (m, 1 H), 3.88 (m, 1 H), 4.51 (m, 1 H), 4.65 (d, 1 H), 4.70 (d, 1 H), 7.63 (m, 1 H) 8.06 (d, 1 H) 8.10 (d, 1 H) 8.39 (s, 1 H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]=[C:10]=[O:11].[OH:12][C:13]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:15][N:14]=1>O1CCCC1>[CH3:8][NH:9][C:10]([N:14]1[C:13](=[O:12])[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[S:15]1)=[O:11]
Reactant: CN=C=O
Reactant: Oc1nsc(-c2ccccc2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNC(=O)n1sc(-c2ccccc2)nc1=O
Temperature: 20 °C

Procedure:
0.5 ml of triethylamine and 10 ml of methyl isocyanate were added to a solution of 9 g of 3-hydroxy-5-phenyl-1,2,4-thiadiazole in 100 ml of tetrahydrofuran and the mixture was stirred at 20° C for an hour and then was vacuum filtered. The crystals recovered were crystallized from acetic acid to obtain 10 g of 2-(N-methylcarbamoyl)-5-phenyl-1,2,4-thiadiazole-3-one melting at 210° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.Br[CH2:16][CH2:17][CH2:18][C:19]1[CH:29]=[CH:28][CH:27]=[C:21]2[C:22]([NH:24][C:25](=[O:26])[C:20]=12)=[O:23].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH2:11][N:12]([CH2:16][CH2:17][CH2:18][C:19]3[CH:29]=[CH:28][CH:27]=[C:21]4[C:22]([NH:24][C:25](=[O:26])[C:20]=34)=[O:23])[CH2:13][CH2:14]2)=[CH:5][CH:4]=1
Reactant: O=C1NC(=O)c2c(CCCBr)cccc21
Reactant: Fc1ccc(C2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2c(CCCN3CCC(c4ccc(F)cc4)CC3)cccc21
Temperature: 97.5 °C
Reaction time: 12 h
Yield: 11.8 %

Procedure:
A mixture of 4-(4-fluorophenyl)piperidine hydrochloride (5.08 g, 23.2 mmol), 3-bromopropylphthalimide (6.22 g, 23.2 mmol), and potassium carbonate (15 g) in DMF (100 mL) was stirred at 95-100° C. for 12 h. About 80% of the solvent was evaporated under reduced pressure. The residue was diluted with ethyl acetate (200 mL) and washed with brine (3×100 mL) and dried (Na2SO4). The solvent was evaporated from the ethyl acetate solution and the residue was purified by column chromatography (1/1 hexane-ethyl acetate to 100% ethyl acetate), giving crude product (7.50 g, 88%). This crude product was crystallized from isopropanol, giving a white crystalline solid (4.50 g, 1st crop). This material was used in the next step. Concentration of the mother liquor and cooling gave the second crop of desired product (1.0 g). 1H NMR δ 1.43-1.52 (m, 2H), 1.67-1.75 (m, 2H), 1.80-1.96 (m, 4H), 2.33-2.46 (m, 3H), 2.94-2.99 (br d, 2H), 3.78 (t, J=7 Hz, 2H), 6.90-7.04 (m, 4H), 7.70-7.74 (m, 2H), 7.84-7.87 (m, 2H).
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[C:7]1([P:13]([O-:19])[S:14]CCCC)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>>[CH2:1]([O:19][P:13]([CH2:1][CH:2]1[O:6][C:4](=[O:5])[CH2:3]1)([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[S:14])[CH2:2][CH2:3][CH3:4]
Reactant: C=C1CC(=O)O1
Reactant: CCCCSP([O-])c1ccccc1
Product: CCCCOP(=S)(CC1CC(=O)O1)c1ccccc1
Temperature: 85 °C

Procedure:
A mixture of 7.4 parts of diketene and 1.2 parts of bis-(t-butylcyclohexyl)-perdicarbonate was added dropwise over 1 hour to 65.4 parts of vigorously stirred n-butyl phenylthiophosphonite which was heated at 85° C. in a nitrogen atmosphere. The mixture was then passed down a wiped wall still at 70° C. and a pressure of 0.013 mb to remove unreacted starting materials. The residue was distilled on the wiped wall still at 115° C. and a pressure of 0.013 mb and gave crude n-butyl(2-oxo-4-oxetanylmethyl)phenylthiophosphinate as a colourless oil which contained a more volatile impurity. The crude product was passed down a wiped wall still at 85° C. and a pressure of 0.013 mb and the involatile fraction was found to be pure n-butyl(2-oxo-4-oxetanylmethyl)phenylthiophosphinate which 31P NMR showed to be a mixture of diastereoisomers having chemical shifts at δ-83.7 and δ-83.2 and which had the following elemental analysis by weight.
Reaction SMILES: [F:1][CH2:2][CH:3]([OH:13])[CH:4]([N+:10]([O-])=O)[CH2:5][CH2:6][C:7]([NH2:9])=[O:8]>CO.[Ni]>[NH2:10][CH:4]([CH:3]([OH:13])[CH2:2][F:1])[CH2:5][CH2:6][C:7]([NH2:9])=[O:8]
Reactant: NC(=O)CCC(C(O)CF)[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: NC(=O)CCC(N)C(O)CF
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 6-fluoro-5-hydroxy-4-nitro-hexanoic acid amide (0.5 g, 2.58 mmol) in MeOH (20 mL) was added Raney Ni (about 200 mg), and the mixture was shaken under H2 (40-45 psi) at room temperature for 6 h. It was filtered and the catalyst was washed with MeOH (3×10 mL). The MeOH solution was evaporated and the residue oil (435 mg) was used without further purification. 1H NMR (acetone-d6): 6.85 (bs, NH, 1H), 6.15 (bs, NH, 1H), 4.70-4.25 (m, 3H), 3.65-3.50 (m, 1H), 2.86 (bs, 2H), 2.40-2.20 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(Cl)CCl.C1C=CC2N(O)N=[N:24]C=2C=1.N>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:24])=[O:13])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: On1nnc2ccccc21
Reactant: O=C(O)c1cc(Br)cc2cc[nH]c12
Agent: N
Solvent: ClCCCl
Solvent: ClCCl
Product: NC(=O)c1cc(Br)cc2cc[nH]c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.6 %

Procedure:
To a solution of 5-bromo-1H-indole-7-carboxylic acid (10.0 g, 42 mmol) in CH2Cl2 (100 mL) at room temperature, EDC (9.66 g, 50.4 mmol), HOBt (6.81 g, 50.4 mmol) and NH3 (2.0 M in MeOH, 84 mL, 168 mmol) were added. The reaction mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue partitioned between ethyl acetate (100 mL) and water (100 mL). The water layer was extracted with ethyl acetate (2×100 mL) and the combined organic phase was dried over MgSO4 and concentrated to give 10 g (98%) of the title compound as a crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14]([OH:16])=O)[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:29][O:30][C:31](=[O:43])[CH:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([NH2:41])=[C:37]([F:42])[CH:36]=1)[CH3:33]>>[CH3:29][O:30][C:31](=[O:43])[CH:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([NH:41][C:14](=[O:16])[CH:13]([N:12]2[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[C:37]([F:42])[CH:36]=1)[CH3:33]
Reactant: COC(=O)C(C)Oc1ccc(N)c(F)c1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Product: COC(=O)C(C)Oc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
This compound was prepared in analogy to example 57, intermediate, from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid and 2-(4-amino-3-fluoro-phenoxy)-propionic acid methyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C@H:12]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:13][CH2:14][C:15](O)=[O:16])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH:8]=2)[N:3]=1.ClC(OCC(C)C)=O.CN1CCOCC1.[CH3:46][C:47]([CH3:59])([CH3:58])[CH2:48][CH2:49][NH:50][CH2:51][C:52]1[N:53]([CH3:57])[CH:54]=[CH:55][N:56]=1>ClCCl.C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:11]([C@H:12]([CH:18]2[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]2)[CH2:13][CH2:14][C:15]([N:50]([CH2:49][CH2:48][C:47]([CH3:59])([CH3:58])[CH3:46])[CH2:51][C:52]2[N:53]([CH3:57])[CH:54]=[CH:55][N:56]=2)=[O:16])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:24][C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:8]=2)[N:3]=1
Reactant: Cn1ccnc1CNCCC(C)(C)C
Reactant: Nc1nc2ccc(Oc3ccccc3)cc2cc1[C@@H](CCC(=O)O)C1CCCCC1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClC(Cl)Cl
Product: Cn1ccnc1CN(CCC(C)(C)C)C(=O)CC[C@H](c1cc2cc(Oc3ccccc3)ccc2nc1N)C1CCCCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice cold solution of 4-(2-amino-6-phenoxy-quinoline-3-yl)-4-(S)-cyclohexyl-butyric acid (0.085 mg, 0.19 mmol) in dichloromethane (2.0 mL) was added isobutyl chloroformate (0.025 mL, 0.19 mmol) and N-methylmorpholine (0.021 mL, 0.019 mmol). The reaction mixture was stirred at this temperature for 0.5 h. The reaction mixture was then reacted with a solution of (3,3-dimethyl-butyl)-(1-methyl-1H-imidazole-2-ylmethyl)-amine (0.037 mg, 0.19 mmol) in dichloromethane (0.5 mL) and stirred at 0° C. for 0.5 h. To this reaction mixture was added CHCl3, and the resulting mixture was washed with H2O and saturated aqueous NaHCO3 solution. The organic layer was dried (MgSO4) and concentrated in vacuo to yield crude material. The crude material was purified by silica gel column chromatography using 4% MeOH in CHCl3 to yield 4-(2-amino-6-phenoxy-quinolin-3-yl)-4-(S)-cyclohexyl-N-(3,3-dimethyl-butyl)-N-(1-methyl-1H-imidazol-2-ylmethyl)-butyramide as a solid.