Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1)=[O:4].[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][OH:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.CCOC(/N=N/C(OCC)=O)=O>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][O:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=1
Reactant: OCCCCCO
Reactant: COC(=O)c1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OCCCCCO)cc1
Reaction time: 16 h
Yield: 68 %

Procedure:
To a solution of methyl p-hydroxybenzoate (3.38 g), 1,5-pentanediol (2.30 g) and triphenylphosphine (5.96 g) in tetrahydrofuran (100 mL), diethylazodicarboxylate (2.2N toluene solution, 10 mL) was slowly added under ice cooling. The reaction mixture was stirred under ice cooling for 16 hours. The reaction mixture was concentrated and the residue was washed with n-hexane-ethyl acetate solution (n-hexane:ethyl acetate=1:1). The reaction mixture was concentrated and then purified by silica gel chromatography (n-hexane:ethyl acetate=64:36→45:55) to obtain the title compound (3.58 g) having the following physical properties.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](Cl)=[CH:6][N:5]=1)([O-:3])=[O:2].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=1.[OH-].[Li+].CN(C=O)C>O>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:18][C:15]2[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=2)=[CH:6][N:5]=1)([O-:3])=[O:2]
Reactant: Sc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Cl)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(Sc2ccc(Cl)cc2)cn1

Procedure:
2-Nitro-5-chloropyridine (9.5 grams), 4-chlorothiophenol (8.7 grams), and lithium hydroxide (4 grams) were mixed in 100 ml. of DMF and the reaction mixture was stirred overnight (about 18 hours) at room temperature. The reaction mixture was then poured into water and the product separated by filtration and crystallized from ethanol-hexanes, yield, 10.0 grams, m.p., 96°-98° C.
Reaction SMILES: Cl[C:2]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:4]([C:5]([NH:7][C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[O:6])[CH:3]=1.[CH2:20]([NH2:22])[CH3:21]>>[CH2:20]([NH:22][C:2]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[N:13]=[C:4]([C:5]([NH:7][C:8]2[NH:12][N:11]=[N:10][N:9]=2)=[O:6])[CH:3]=1)[CH3:21]
Reactant: CCN
Reactant: O=C(Nc1nnn[nH]1)c1cc(Cl)c2ccccc2n1
Product: CCNc1cc(C(=O)Nc2nnn[nH]2)nc2ccccc12

Procedure:
4-Chloro-N(1H-tetrazol-5-yl)quinaldamide (1 g) and aqueous ethylamine (20 ml., 70% w/w) were heated to 100° in an autoclave for 10 hours. The mixture was evaporated, the residue was dissolved in water (10 ml) and the solution was acidified with hydrochloric acid to pH 1. The solid was collected and dissolved in aqueous dimethylaminoethanol (20 ml., 5%) and the solution was warmed to 60° and acidified with dilute hydrochloric acid. 4-Ethylamino-N(1H-tetrazol-5-yl)quinaldamide was collected and dried, m.p. 237° (d).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12].[CH3:15][N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]1[CH3:25].[Cl-].[Al+3].[Cl-].[Cl-].C(O)(C)C>ClC(Cl)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:18]2[C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]([CH3:15])[C:17]=2[CH3:25])=[O:7])=[CH:4][C:3]=1[S:11](=[O:14])(=[O:13])[NH2:12]
Reactant: NS(=O)(=O)c1cc(C(=O)Cl)ccc1Cl
Reactant: Cc1cc2ccccc2n1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: CC(C)O
Product: Cc1c(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)c2ccccc2n1C

Procedure:
is obtained as described in Example 10 (a) from 10 g 4-chloro-3-sulfamoylbenzoyl chloride and 6.53 g 1,2-dimethylindole in dichloro-ethane in the presence of 12 g aluminum chloride. After treatment with isopropanol, crystals having a melting point of 247°-249° C. are obtained.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:9].[C:10]([O-])([O-])=O.[K+].[K+].IC>CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[O:9][CH3:10]
Reactant: Oc1cccc(F)c1F
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 75.4 %

Procedure:
2,3-Difluorophenol (4.55 g) was dissolved in DMF (25 mL) and was treated with powdered K2CO3 (6.0 grams) and the mixture was stirred at an ambient temperature for 10 minutes under nitrogen atmosphere. The mixture was treated with iodomethane (9.0 grams), and was stirred at room temperature for 18 hours. The reaction mixture was quenched with water and was extracted with ether. The ether extract was washed with water, dried (Na2SO4) and concentrated to afford 3.8 grams of title compound as amber oil. 1HNMR(CDCl3): δ 6.97(m, 1H), 6.78(m, 2H), 3.90(s, 3H). Step 2: 2,3-Difluoro-4-methoxybenzaldehyde.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=O)[CH2:3]1.[C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])(=[O:15])[NH:13][NH2:14].O>CN(C=O)C>[CH3:1][C:2]1([CH3:11])[CH2:7][C:6]([CH3:9])([CH3:8])[CH2:5][C:4](=[N:14][NH:13][C:12]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:3]1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: CC(C)(C)OC(=O)NN
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)CC(=NNC(=O)OC(C)(C)C)CC(C)(C)C1

Procedure:
3,3,5,5-Tetramethylcyclohexanone (7.7 g, 0.05 moles) was dissolved in DMF (50 mL) and t-butyl carbazate (6.6 g, 0.05 moles) was added to give a clear solution. Left to stand over the weekend. Poured into water and extracted into ethyl acetate. Washed with water and dried over anhydrous magnesium sulphate. Evaporated to give a white solid. Triturated with ether and dried in a desiccator to give the product as a white solid. (10.4 g, 78%). 1H NMR (300 MHz DMSO-d6) mixture of isomers 9.5 and 7.95 (brs, 1H), 2.95 (s, 1H), 2.75 (s, 1H), 2.1 (s, 2H), 1.95 (s, 2H), 1.4 (s, 9H), 0.9 (2s, 12H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[C:25]([C:35]#[N:36])=[N:26][C:27]([CH3:34])=[C:28]([O:31][CH2:32][CH3:33])[C:29]=1[CH3:30])=[N+]=[N-].O1CCCC1>O>[CH2:32]([O:31][C:28]1[C:29]([CH3:30])=[C:24]2[CH2:23][N:20]=[C:35]([NH2:36])[C:25]2=[N:26][C:27]=1[CH3:34])[CH3:33]
Reactant: CCOc1c(C)nc(C#N)c(CN=[N+]=[N-])c1C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCOc1c(C)nc2c(c1C)CN=C2N
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 68.7 %

Procedure:
Triphenylphosphine (170 mg, 0.648 mmol) was added to a solution of the 3-(azidomethyl)-5-ethoxy-4,6-dimethyl-2-pyridinecarbonitrile (113 mg, 0.489 mmol) in a tetrahydrofuran (3 ml) —H2O (0.15 ml) mixed solvent while cooling on ice, and the mixture was stirred at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure and the residue was purified by silica gel column chromatography (solvent: ethyl acetate-methanol-29% NH3(aq)) to yield the title compound (69 mg, 69%) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[Cl:26][S:27](O)(=[O:29])=[O:28]>C(Cl)Cl>[Cl:1][C:2]1[C:3]([NH:12][CH2:13][C:14]2([C:20]3[CH:25]=[CH:24][C:23]([S:27]([Cl:26])(=[O:29])=[O:28])=[CH:22][CH:21]=3)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=1
Reactant: O=S(=O)(O)Cl
Reactant: FC(F)(F)c1cnc(NCC2(c3ccccc3)CCCCC2)c(Cl)c1
Solvent: ClCCl
Product: O=S(=O)(Cl)c1ccc(C2(CNc3ncc(C(F)(F)F)cc3Cl)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
185 mg of (3-Chloro-5-trifluoromethyl-pyridin-2-yl)-(1-phenyl-cyclohexylmethyl)-amine were dissolved in 15 ml of methylenchloride and 0.14 ml of chlorosulfonic acid were added. The reaction mixture was stirred at room temperature for 4 days and than poured on ice water (20 ml). The organic layer was separated, washed twice with 50 ml of brine and then dried over MgSO4. The solvent was removed in vacuo to obtain 194 mg g of the crude product.
Reaction SMILES: ClC1C=CC=CC=1[C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]([NH:15][C:16]1[CH:21]=[C:20]([C:22](=[O:27])[NH:23][CH:24]2[CH2:26][CH2:25]2)[CH:19]=[CH:18][C:17]=1[CH3:28])=[O:14].[B:29]1(B2OC(C)(C)C(C)(C)O2)[O:33]C(C)(C)C(C)(C)[O:30]1.CC([O-])=O.[K+]>CN(C=O)C>[CH:24]1([NH:23][C:22]([C:20]2[CH:19]=[CH:18][C:17]([CH3:28])=[C:16]([NH:15][C:13]([C:9]3[S:10][C:11]([B:29]([OH:33])[OH:30])=[CH:12][CH:8]=3)=[O:14])[CH:21]=2)=[O:27])[CH2:26][CH2:25]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1sccc1-c1ccccc1Cl
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1NC(=O)c1ccc(B(O)O)s1
Temperature: 90 °C
Yield: 178.3 %

Procedure:
A solution of 1.0 g (2.64 mmol) of 5-bromo-N-(5-(cyclopropylcarbamoyl)-2-methylphenyl)thiophene-2-carboxamide (Example 136, Step B), bis(pinacolato)diborane (1.0 g, 3.95 mmol) and KOAc (1.30 g, 13.2 mmol) in DMF (15 mL) was purged with argon and Pd(dppf)2Cl2/CH2Cl2 complex (65 mg, 0.08 mmol) was added followed by heating at 90° C. for 16 h. After cooling to rt, the mixture was partitioned between EtOAc (250 mL) and water (50 mL) and the layers were separated. The organic portion was washed with additional water, then brine, then dried over anhyd Na2SO4, filtered, and concentrated under vacuum to afford 1.62 g of a brown semi-solid as the crude product mixture. This material was triturated with EtOAc and filtered to afford 626 mg of the compound a containing ˜10% of the boronate ester. This material was used as is without any further purification. HPLC Ret time=2.36 min. LCMS [M+H]+ 345.2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([CH3:14])([NH2:13])[CH3:12])=[CH:2]1.[F:15][C:16]1[CH:17]=[C:18](/[CH:25]=[CH:26]/[C:27]([O:29][CH3:30])=[O:28])[CH:19]=[C:20]([F:24])[C:21]=1[CH:22]=O>C(O)(=O)C>[CH3:12][C:11]1([CH3:14])[NH:13][CH:22]([C:21]2[C:20]([F:24])=[CH:19][C:18](/[CH:25]=[CH:26]/[C:27]([O:29][CH3:30])=[O:28])=[CH:17][C:16]=2[F:15])[C:2]2[NH:1][C:9]3[C:4]([C:3]=2[CH2:10]1)=[CH:5][CH:6]=[CH:7][CH:8]=3
Reactant: CC(C)(N)Cc1c[nH]c2ccccc12
Reactant: COC(=O)/C=C/c1cc(F)c(C=O)c(F)c1
Solvent: CC(=O)O
Product: COC(=O)/C=C/c1cc(F)c(C2NC(C)(C)Cc3c2[nH]c2ccccc32)c(F)c1
Temperature: 80 °C
Yield: 95 %

Procedure:
1-(1H-Indol-3-yl)-2-methylpropan-2-amine (807 mg, 4.29 mmol) and (E)-methyl 3-(3,5-difluoro-4-formylphenyl)acrylate (obtained as described in Example 1, preparation of starting materials) (970 mg, 4.29 mmol) were combined in acetic acid (15 ml) and the mixture heated to 80° C. for 2 hours. The reaction mixture was purified by ion exchange chromatography, using an SCX-2 column. The desired product was eluted from the column using 2M NH3 in methanol and product-containing fractions were evaporated to dryness to afford (E)-methyl 3-(4-(3,3-dimethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)-3,5-difluorophenyl)acrylate (1610 rag, 95%) as a yellow foam. 1H NMR (500 MHz, DMSO, 20° C.) δ 1.15 (3H, s), 1.27 (3H, s), 2.23 (1H, s), 2.61 (2H, s), 3.75 (3H, s), 5.46 (1H, s), 6.84 (1H, d), 6.97 (2H, dtd), 7.18 (1H, d), 7.39 (1H, d), 7.58 (2H, s), 7.67 (1H, d), 10.60 (1H, s). m/z: ES− [M−H]− 395.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C@H:11]2[C@@H:17]([CH2:18][NH:19][C:20](=[O:24])[CH2:21][O:22][CH3:23])[O:16][CH2:15][CH2:14][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10].[CH3:32]I.O>CN(C=O)C>[Cl:3][C:4]1[CH:5]=[C:6]([C@H:11]2[C@@H:17]([CH2:18][N:19]([C:20](=[O:24])[CH2:21][O:22][CH3:23])[CH3:32])[O:16][CH2:15][CH2:14][N:13]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10]
Reactant: COCC(=O)NC[C@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCC(=O)N(C)C[C@H]1OCCN(C(=O)OC(C)(C)C)C[C@H]1c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.8 %

Procedure:
Sodium hydride (60% in oil, 16 mg) was added to a solution of tert-butyl (6R,7S)-6-(3,4-dichlorophenyl)-7-{[(methoxyacetyl)amino]methyl}-1,4-oxazepane-4-carboxylate (180 mg) in DMF (5 ml), and the mixture was stirred at room temperature for 20 min. Methyl iodide (57 mg) was added dropwise to the reaction mixture, and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (170 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]([OH:40])=[O:39])[CH2:34][CH2:33]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[CH:15][N:16]=[CH:17][CH:18]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:25]=[CH:26][C:27]([CH2:28][N:32]4[CH2:37][CH2:36][CH:35]([C:38]([OH:40])=[O:39])[CH2:34][CH2:33]4)=[CH:30][CH:31]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: O=C(O)C1CCNCC1
Product: O=C(O)C1CCN(Cc2ccc(-c3noc(-c4nnn(-c5ccccc5F)c4-c4ccncc4)n3)cc2)CC1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (100 mg; 0.24 mmol) and piperidine-4-carboxylic acid (62.6 mg; 0.48 mmol) to give Example 128 as a white solid. 1H NMR: (DMSO-d6, 400 MHz) δ 8.75 (2H, d, J=5.3 Hz), 7.97-7.88 (3H, m), 7.73 (1H, q, J=6.9 Hz), 7.61 (2H, d, J=5.4 Hz), 7.55-7.48 (4H, m), 3.56 (2H, s), 2.78 (2H, d, J=10.9 Hz), 2.27-2.18 (1H, m), 2.05 (2H, m), 1.81 (2H, m), 1.61 (2H, m). LC/MS (Method C): 526 (M+H)+. HPLC (Method E) Rt 2.20 min (Purity: 97.7%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[N:3]=1.C([Li])CCC.[O:18]1[CH2:21][C:20](=[O:22])[CH2:19]1>O1CCCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[N:3]=[C:2]([C:20]2([OH:22])[CH2:21][O:18][CH2:19]2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1COC1
Reactant: Brc1cccc(C2OCCO2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC1(c2cccc(C3OCCO3)n2)COC1
Reaction time: 0.5 h
Yield: 26.9 %

Procedure:
To a solution of 2-bromo-6-(1,3-dioxolan-2-yl)pyridine (2.49 g, 10.8 mmol) in anhydrous tetrahydrofuran (40 mL) was added a solution of n-butyllithium (2.5 M, 4.3 mL, 10.8 mmol) at −78° C. After stirring for 30 min., a solution of oxetan-3-one (0.6 g, 8.32 mmol) in anhydrous tetrahydrofuran (12 mL) was added slowly and the mixture was stirred at that temperature for 1 h. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure to afford the crude compound. The crude material was purified via preparative TLC eluting with 35% ethyl acetate in petroleum ether to afford 3-(6-(1,3-dioxolan-2-yl)pyridin-2-yl)oxetan-3-ol (500 mg, 27%). MS (ES+) (M+H) 224.20; LCMS retention time: 2.76 minutes (Method S).
Reaction SMILES: [C:1](Cl)(=[O:5])[CH2:2][CH2:3][CH3:4].[NH2:7][C:8]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11].[OH-].[Na+].Cl>C(OCC)(=O)C.C1COCC1>[C:1]([NH:7][C:8]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:9]=1[C:10]([NH2:12])=[O:11])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: NC(=O)c1cc(Cl)ccc1N
Reactant: CCCC(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1ccc(Cl)cc1C(N)=O
Yield: 92 %

Procedure:
Preparation D10, Step 1: Butyryl chloride (0.68 mL, 6.5 mmol, 1 eq) was slowly dripped into a mixture of 2-amino-5-chlorobenzamide (1.10 g, 6.5 mmol, 1 eq), 1.000N NaOH (6.50 mL, 6.5 mmol, 1 eq) and THF (enough to dissolve) at 0° C. More acid chloride and base were added to drive the reaction to completion. After 4 days ethyl acetate was added followed by 1N HCl. The layers were separated and the organic layer washed with 1N HCl (2×), saturated sodium bicarbonate (1×), and brine (1×). The organic layer was dried (MgSO4) and stripped to yield 2-butyramido-5-chlorobenzamide (1.44 g) as a white powder. Mass Spec (ESI) (M+H)+=241.0.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[N:7]=[C:6]([C:27](O)=[O:28])[CH:5]=1)[CH2:2][CH3:3].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.CN(C=O)C.[NH2:68][C@H:69]([CH2:74][C:75]1[CH:80]=[CH:79][CH:78]=[CH:77][C:76]=1[Cl:81])[CH2:70][C:71]([OH:73])=[O:72].Cl>>[Cl:81][C:76]1[CH:77]=[CH:78][CH:79]=[CH:80][C:75]=1[CH2:74][C@@H:69]([NH:68][C:27]([C:6]1[CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:8]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][N:25]=[N:24][N:23]=3)=[CH:14][CH:15]=2)[N:7]=1)=[O:28])[CH2:70][C:71]([OH:73])=[O:72]
Reactant: N[C@@H](CC(=O)O)Cc1ccccc1Cl
Reactant: CCCc1cc(C(=O)O)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(C(=O)N[C@@H](CC(=O)O)Cc2ccccc2Cl)nn1Cc1ccc(-c2ccccc2-c2nnn[nH]2)nc1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A solution of 5-propyl-1-{6-[2-(1H-tetrazol-5-yl)phenyl]pyridin-3-ylmethyl}-1H-pyrazole-3-carboxylic acid (20 mg, 0.05 mmol), HATU (19.5 mg, 0.0514 mmol) and DIPEA (44.7 uL, 257 μmol) in DMF (1.59 mL, 20.5 mmol) was stirred to pre-activate the acid. After 30 minutes, (R)-3-amino-4-(2-chlorophenyl)butanoic acid.HCl (12.8 mg, 0.0514 mmol)) was added. The resulting solution was stirred overnight. The mixture was concentrated, re-dissolved in water/MeCN/TFA and purified using reverse phase liquid chromatography to yield the title compound (20.5 mg; 100% purity) as a TFA salt. MS m/z: [M+H]+ calcd for C30H29ClN8O3, 585.21; found 585.4.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].Br.[Cl:16][C:17]1[CH:18]=[C:19]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[O:20][C:21]1[C:22]([CH3:28])=[N:23][NH:24][C:25]=1[CH2:26][NH2:27].[F:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>C(O)(=O)C.ClCCl>[Cl:16][C:17]1[CH:18]=[C:19]([CH:29]=[C:30]([Cl:32])[CH:31]=1)[O:20][C:21]1[C:22]([CH3:28])=[N:23][NH:24][C:25]=1[CH2:26][NH:27][CH2:38][C:37]1[CH:40]=[CH:41][C:34]([F:33])=[CH:35][CH:36]=1
Reactant: Cc1n[nH]c(CN)c1Oc1cc(Cl)cc(Cl)c1
Reactant: O=Cc1ccc(F)cc1
Agent: Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1n[nH]c(CNCc2ccc(F)cc2)c1Oc1cc(Cl)cc(Cl)c1
Reaction time: 3 h
Yield: 19.7 %

Procedure:
Sodium triacetoxyborohydride (36 mg, 0.160 mmol) was added in one portion to a stirred solution of the pyrazole of Example 109 (150 mg, 0.400 mmol), 4-fluorobenzaldehyde (11 mg, 0.080 mmol) and acetic acid (3 drops) in dichloromethane (15 ml) at room temperature under nitrogen. The reaction was stirred for 3 hours and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (90:9:1, by volume) to provide the title compound (6 mg) as a colourless oil.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:16]=[N:17][NH:18][CH:19]=3)=[N:12][CH:13]=[C:8]2[CH:7]=[N:6]1.[O-:24][C:25]#[N:26].[K+].C(=O)([O-])[O-].[Na+].[Na+]>C(#N)C.O>[F:1][C:2]1[CH:23]=[CH:22][CH:21]=[CH:20][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:19]=[N:18][N:17]([C:25]([NH2:26])=[O:24])[CH:16]=3)=[N:12][CH:13]=[C:8]2[CH:7]=[N:6]1
Reactant: Fc1ccccc1Cn1ncc2cnc(Nc3cn[nH]c3)nc21
Reactant: N#C[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: NC(=O)n1cc(Nc2ncc3cnn(Cc4ccccc4F)c3n2)cn1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2-fluorobenzyl)-N-(1H-pyrazol-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-amine (Example 88), (111 mg, 0.36 mmol) in ACN/H2O (9:1, 4 mL) was added potassium cyanate (35 mg, 1.2 eq). After 30 min at rt, the reaction mixture was neutralized with saturated sodium carbonate and the aqueous phase extracted with DCM. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative HPLC to give the title product. 1H NMR (d6-DMSO) δ 10.12 (s, 1H), 9.00 (s, 1H), 8.57 (s, 1H), 8.12 (s, 1H), 7.94 (s, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 7.41-7.28 (m, 2H), 7.26-7.14 (m, 2H), 5.58 (s, 2H); LC-MS method B, (ES+) 353.0, RT=7.75 min.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.Br[CH2:22][CH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH:23]1([CH2:22][N:15]2[CH2:16][C:17](=[O:18])[N:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:20])[CH:12]=3)[C:14]2=[O:19])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Reactant: BrCC1CCCCC1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CC3CCCCC3)C2=O)cn1
Yield: 20 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and bromomethylcyclohexane. Yield: 20%. 1H NMR (DMSO-d6, 400 MHz): δ0.88 (q, J=10.4 Hz, 2H), 1.09-1.19 (m, 3H), 1.58-1.65 (m, 6H), 2.12 (s, 3H), 2.38 (s, 3H), 3.13 (d, J=7.2 Hz, 2H), 4.06 (s, 2H), 5.17 (s, 2H), 7.75 (s, 1H), 8.14 (s, 1H). MS M+H calculated 372.2. found 372.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.28 μM.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[C:15]([C:19]4([CH3:26])[NH:24][C:23](=O)[CH2:22][O:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:36])=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([NH:12][C:13]3[CH:14]=[C:15]([C:19]4([CH3:26])[NH:24][C:23](=[S:36])[CH2:22][O:21][CH2:20]4)[CH:16]=[CH:17][CH:18]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: Cn1nc(Nc2cccc(C3(C)COCC(=O)N3)c2)c2ccc(Br)cc21
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cn1nc(Nc2cccc(C3(C)COCC(=S)N3)c2)c2ccc(Br)cc21
Temperature: 120 °C

Procedure:
To a suspension of 5-[3-(6-bromo-1-methyl-1H-indazol-3-ylamino)-phenyl]-5-methyl-morpholin-3-one (52.6 mg, 0.127 mmol) in toluene (3 ml) was added Lawesson's reagent (51.2 mg, 0.127 mmol) and the reaction mixture was heated at 120° C. for 2 h. The solvent was evaporated and the title compound was purified by FC (cyclohexane:EtOAc 100:0 to 80:20).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([CH2:20][C:21]([OH:23])=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH:4]=1.[NH2:26][C:27]([CH3:36])([CH3:35])[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:36][C:27]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])([CH3:35])[NH:26][C:21](=[O:23])[CH2:20][C@H:17]1[CH2:18][CH2:19][C@H:14]([C:11]2[CH:10]=[CH:9][C:8]([C:5]3[NH:6][N:7]=[C:3]([C:2]([F:25])([F:1])[F:24])[CH:4]=3)=[CH:13][CH:12]=2)[CH2:15][CH2:16]1
Reactant: CC(C)(C)OC(=O)C(C)(C)N
Reactant: O=C(O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)[nH]n3)cc2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)C(C)(C)NC(=O)C[C@H]1CC[C@H](c2ccc(-c3cc(C(F)(F)F)n[nH]3)cc2)CC1
Reaction time: 4 h

Procedure:
To a 20 mL scintillation vial was added the product from Example 28 (30 mg, 0.085 mmol), tert-butyl 2-amino-2-methylpropanoate (15.0 mg, 0.088 mmol), and N,N-dimethylformamide (0.85 mL) followed by O-(7-azabenzotriazol-1-yl)-N,N,N′N′-tetramethyluronium hexafluorophosphate (39.0 mg, 0.102 mmol) and diisopropylethylamine (30 μL, 0.176 mmol). Following 4 hours of stirring, the solvent was evaporated and the residue purified over RP-HPLC to afford the title product. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.01-1.16 (m, 2 H), 1.26-1.31 (m, 6 H), 1.35 (s, 9 H), 1.40-1.53 (m, 2 H), 1.68-1.77 (m, 1 H), 1.77-1.90 (m, 4 H), 1.93-2.02 (m, 2 H), 8.01 (s, 1 H), 13.98 (s, 1 H); MS (ESI) m/z 494 [M+H]+.