Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([OH:45])=O)=[O:39])([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].Cl.CN(C)CCCN=C=NCC.[NH2:58][CH2:59][C:60]([NH:62][CH2:63][C:64]([O:66][CH2:67][C:68]1[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=1)=[O:65])=[O:61].CC1C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl.CCN(CC)CC>[N:1]([C:38]([CH2:40][O:41][CH2:42][C:43]([NH:58][CH2:59][C:60]([NH:62][CH2:63][C:64]([O:66][CH2:67][C:68]1[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=1)=[O:65])=[O:61])=[O:45])=[O:39])([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: NCC(=O)NCC(=O)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)C(=O)COCC(=O)NCC(=O)NCC(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of (C18H37)2NCOCH2OCH2COOH (1.0 g, 1.5 mmol) in CH2Cl2 (30 mL) was added 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (0.31 g, 1.6 mmol) and the reaction was stirred at room temperature. After 0.5 h Gly-Gly-OCH2Ph.TsOH (0.62 g, 1.5 mmol) and Et3N (0.6 mL) were added and the mixture was stirred overnight. The reaction mixture washed with water (20 mL), 0.5 M aqueous HCI (20 mL), water (20 mL), 10% aqueous Na2CO3 (20 mL), and brine (20 mL) then dried over MgSO4, evaporated and the residue crystallized from MeOH to yield (C18H37)2NCOCH2OCH2CO-Gly-Gly-OCH2Ph as a deliquescent white solid (1.32 g, 94%). 1H-NMR (300 MHz, 6, CDCl3) 0.87 (6H, t, J=6.9 Hz), 1.24 (64H, m), 1.48 (4H, bs), 3.05 (2H, t, J=7.5 Hz), 3.22 (2H, t, J=7.5 Hz), 4.06–4.10 (6H, m), 4.28 (2H, s), 5.15 (2H, s), 7.33 (5H, m), 7.51 (1H, t, J=5.7 Hz), 8.23 (1H, t, J=5.7 Hz). 13C-NMR (75 MHz, 6, CDCl3): 14.2, 2.8, 27.0, 27.1, 27.6, 29.5, 29.7, 29.8, 32.0, 41.3, 42.8, 46.9, 67.1, 69.9, 72.2, 128.5, 128.7, 128.9, 135.6, 168.7, 169.9, 170.9.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH2:6])=[O:5])#[N:2].[C:7](O)(=O)C.N1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O)(=O)C>O>[CH:13]([C:14]1[NH:6][C:4](=[O:5])[C:3]([C:1]#[N:2])=[CH:16][CH:15]=1)([CH3:7])[CH3:12]
Reactant: CC(=O)O
Reactant: C1CCNCC1
Reactant: N#CCC(N)=O
Solvent: O
Product: CC(C)c1ccc(C#N)c(=O)[nH]1
Temperature: 25 °C
Yield: 68 %

Procedure:
To a solution of the product of Example 12A (5.35 g, 0.0393 mol) and 2-cyanoacetamide (3.47 g, 0.0413 mol) in water (35 mL) was stirred at room temperature for 10 minutes. To this mixture was added 2.5 mL of a stock piperidine acetate solution (prepared from 9.8 mL of piperidine, 6 mL of acetic acid and 10 mL of water), and the solution was heated under reflux for 2 hours. The mixture was then cooled to room temperature and taken to pH 4 by the addition of glacial acetic acid. The resulting light yellow solid was isolated by vacuum filtration, rinsed with water (2×30 mL), and dried under vacuum to provide the title product (4.36 g, 68%).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:36]=[CH:35][C:18]([CH2:19][NH:20][O:21][C@H:22]4[C@H:27]([O:28][CH3:29])[C@H:26]([O:30][CH3:31])[C@@H:25]([O:32][CH3:33])[C@H:24]([CH3:34])[O:23]4)=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[C:39]1(=[O:45])[O:44][C:42](=[O:43])[CH2:41][CH2:40]1>N1C=CC=CC=1.CCOC(C)=O>[F:38][C:2]([F:1])([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:36]=[CH:35][C:18]([CH2:19][N:20]([O:21][C@H:22]4[C@H:27]([O:28][CH3:29])[C@H:26]([O:30][CH3:31])[C@@H:25]([O:32][CH3:33])[C@H:24]([CH3:34])[O:23]4)[C:39](=[O:45])[CH2:40][CH2:41][C:42]([OH:44])=[O:43])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1
Reactant: O=C1CCC(=O)O1
Reactant: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ONCc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)[C@@H]1OC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CO[C@@H]1[C@@H](OC)[C@H](C)O[C@@H](ON(Cc2ccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)cc2)C(=O)CCC(=O)O)[C@@H]1OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 39 %

Procedure:
To a solution of N-{4-[1-(4-trifluoromethoxyphenyl)-1H-[1,2,4]triazol-3-yl]-benzyl}-O-((2S,3R,4R,5S,6S)-3,4,5-trimethoxy-6-methyl-tetrahydropyran-2-yl)-hydroxylamine (3; 140 mg, 0.26 mmol) in pyridine (5 mL) was added succinic anhydride (large excess), and the mixture stirred at room temperature for 3.5 h. The mixture was diluted with EtOAc and washed with 1 N HCl. The aqueous fraction was extracted with EtOAc (2×). The organic fractions were combined, washed with brine, dried with anhydrous MgSO4 and evaporated at room temperature under vacuum. The resulting crude material was purified by silica gel chromatography (eluting with 80% EtOAc in Hexane going to 100% EtOAc over a short gradient). The title product (64 mg, 39%) was isolated as a white solid: mp 61-75° C.; 1H NMR (300 MHz, CDCl3) δ 8.63 (s, 1H), 8.16 (d, J=8.3 Hz, 2H), 7.93-7.68 (m, 2H), 7.40 (d, J=8.4 Hz, 4H), 5.40-5.10 (m, 2H), 4.76 (d, J=16.1 Hz, 1H), 3.73-3.25 (m, 13H), 3.15 (dd, J=9.1, 7.9 Hz, 1H), 3.04-2.60 (m, 4H), 1.27 (dd, J=9.8, 4.3 Hz, 3H); ESIMS m/z 639 (M+H), 638 (M+).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH:29]=O>>[NH:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[CH2:29][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: O=Cc1nc2ccccc2[nH]1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4nc5ccccc5[nH]4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 1H-benzimidazole-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(1H-benzimidazol-2-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[NH:22][S:23]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)(=[O:25])=[O:24].[C:32]1([CH3:44])[CH:37]=[C:36]([CH3:38])[CH:35]=[C:34]([CH3:39])[C:33]=1[S:40]([Cl:43])(=[O:42])=[O:41]>>[ClH:43].[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:40]([C:33]3[C:34]([CH3:39])=[CH:35][C:36]([CH3:38])=[CH:37][C:32]=3[CH3:44])(=[O:42])=[O:41])=[C:3]([NH:22][S:23]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)(=[O:25])=[O:24])[CH:4]=2)[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCCN(c2ccc(N)c(NS(=O)(=O)c3ccccc3)c2)CC1
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Product: Cc1cc(C)c(S(=O)(=O)Nc2ccc(N3CCCNCC3)cc2NS(=O)(=O)c2ccccc2)c(C)c1
Product: Cl

Procedure:
The compound was synthesized from of N-{2-amino-5-(4-t-butyloxycarbonyl-1,4-diazepan-1-yl)-phenyl}benzenesulfonamide and 2-mesitylenesulfonylchloride (59 mg, 0.27 mmol) to give 56 mg as purple solid. M+1 529.3 Calcd 529.70. 1HNMR δ 7.80-7.47 (m, 5H), 6.93 (s br, 2H), 6.64 (d, 1H), 6.46-6.39 (m, 2H), 3.60 (app t, 2H), 3.39 (app t, 2H), 3.21 (app t, 2H), 3.12 (app t, 2H), 2.36 (s, 6H), 2.26 (s, 3H), 2.08-2.00 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[C:14](=[O:26])[N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]([CH3:19])[C:17]=1[CH3:18])=[O:12].CC([O-])(C)C.[K+].Cl[C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH2:42])=[O:41])[CH:35]=1.O>CN(C=O)C>[Cl:1][C:2]1[C:3]([NH:10][C:11]([C:13]2[C:14](=[O:26])[N:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:16]([CH3:19])[C:17]=2[CH3:18])=[O:12])=[CH:4][C:5]([F:9])=[C:6]([CH:7]=1)[O:8][C:34]1[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH2:42])=[O:41])[CH:35]=1
Reactant: Cc1c(C(=O)Nc2cc(F)c(O)cc2Cl)c(=O)n(-c2ccccc2)n1C
Reactant: NC(=O)c1cc(Cl)ccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(C(N)=O)c3)cc2Cl)c(=O)n(-c2ccccc2)n1C
Temperature: 120 °C
Reaction time: 15 h
Yield: 29.2 %

Procedure:
To a suspension of N-(2-chloro-5-fluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (751.6 mg, 2 mmol) and t-BuOK (224.4 mg, 2 mmol) in DMF (4 mL) and was added 4-chloropicolinamide (313.2 mg, 2 mmol). The reaction was warmed up to 120° C. and stirred for 15 hours. After the mixture cooling to rt, H2O (40 mL) was added and the resulted mixture was stirred at rt overnight. Filtered and the filter cake was purified by a silica gel column chromatography (DCM/CH3OH (v/v)=50/1) to give the title compound as a light yellow solid (290 mg, 60.5%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[O:26]1[CH2:31][CH2:30][CH:29]([NH2:32])[CH2:28][CH2:27]1>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:32][CH:29]3[CH2:30][CH2:31][O:26][CH2:27][CH2:28]3)[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NC1CCOCC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NC3CCOCC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and tetrahydro-2H-pyran-4-ylamine. MS obsd. (ESI+) [(M+H)+] 438, 1H NMR (400 MHz, DMSO-d6) δ ppm 7.89 (dd, J=6.95, 3.41 Hz, 2 H), 7.78 (s, 1 H), 7.59 (t, J=7.07 Hz, 1 H), 7.47 (t, J=7.58 Hz, 1 H), 7.31 (d, J=8.59 Hz, 1 H), 7.23 (d, J=8.59 Hz, 1 H), 6.33 (d, J=8.08 Hz, 1 H), 6.09 (s, 1 H), 5.09 (brs, 2 H), 4.44 (brs, 1 H), 3.99 (d, J=9.85 Hz, 2 H), 3.94-3.82 (m, 1 H), 3.69-3.52 (m, 4 H), 2.36 (s, 3 H), 1.85 (d, J=11.87 Hz, 2 H), 1.69-1.44 (m, 2 H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[Mg+].[C:24]([O:30][CH2:31][CH3:32])(=[O:29])[CH2:25]C([O-])=O.Cl>O1CCCC1.O.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH2:25][C:24]([O:30][CH2:31][CH3:32])=[O:29])[CH:8]=[CH:9][CH:10]=1
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(O)c1cccc(F)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Mg+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 173.8 %

Procedure:
To a solution of 3-fluorobenzoic acid (25.5 g, 182 mmol) in tetrahydrofuran (300 ml) was added 1,1′-carbonylbis-1H-imidazole (32.4 g, 200 mmol) and the mixture was stirred at room temperature for 30 min. Monoethyl malonate magnesium salt (27.1 g, 94.7 mmol) was added to the reaction solution and the mixture was heated under reflux for 30 min. Ethyl acetate (50 ml) and water (50 ml) were added to the reaction solution, and conc. hydrochloric acid was added until the aqueous layer showed acidic pH. The reaction solution was extracted with ethyl acetate (200 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) to give ethyl 3-(3-fluorophenyl)-3-oxopropionate (34.6 g, 91%) as a colorless oil.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]3[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[N:13]=3)=[CH:10][NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[CH:30]([CH3:32])[CH3:31].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH3:31][CH:30]([N:8]1[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[C:11]([C:12]2[C:17](=[O:18])[CH:16]=[CH:15][N:14]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=3)[N:13]=2)[CH:10]=[N:9]1)[CH3:32]
Reactant: CC(C)I
Reactant: O=c1ccn(-c2cccc(C(F)(F)F)c2)nc1-c1c[nH]nc1-c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)n1ncc(-c2nn(-c3cccc(C(F)(F)F)c3)ccc2=O)c1-c1ccccc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A suspension of 3-(3-phenyl-1H-pyrazol-4-yl)-1-[3-(trifluoromethyl)phenyl]pyridazin-4(1H)-one (325 mg, 0.85 mmol), 2-iodopropane (0.130 mL, 1.3 mmol), and K2CO3 (235 mg, 1.7 mmol) in DMF (3 mL) was stirred overnight at 50° C. The reaction mixture was poured into water and extracted with AcOEt. The extract was washed with water and brine, dried over MgSO4, and concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography eluting with AcOEt followed by separation by preparative HPLC to give the title compounds.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].F[C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[C:10](C)(C)[NH:9]2.C(N(CC)CC)C>C1COCC1>[C:1]([N:9]1[C:8]2[C:13](=[CH:14][CH:15]=[CH:6][CH:7]=2)[NH:12][C:11](=[O:16])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC1(C)Nc2cc(F)ccc2NC1=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CC(=O)Nc2ccccc21
Reaction time: 1 h

Procedure:
Acetyl chloride (0.36 ml) is added to 1,2,3,4-tetrahydroquinoxalin-2-one (IV, EXAMPLE 1, 0.676 g) and triethylamine (0.76 ml) in THF (8 ml) at 0°. After stirring for 1 hr, the solvent is removed under reduced pressure and the residue is partitioned between dichloromethane and aq. sodium bicarbonate. The layers are separated, the organic phase is filtered through sodium sulfate and concentrated. The concentrate is crystallized from methanomethylene chloride/hexane to give the title compound, mp 164°-165°; NMR (CDCl3) 2.28, 4.54, 7.00, 7.11, 7.21 and 9.19 δ.
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17]([CH:25]=O)=[CH:18][N:19]2[CH3:24].CN1C2C(=CC=CC=2)C(C)=C1C=O>>[Cl:14][C:15]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:16]=1[C:17]([CH2:25][NH:6][CH3:5])=[CH:18][N:19]2[CH3:24]
Reactant: COC(=O)CNc1ccc(Br)cn1
Reactant: Cn1cc(C=O)c2c(Cl)cccc21
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1cn(C)c2cccc(Cl)c12
Yield: 78 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 4-chloro-1-methyl-1H-indole-3-carboxaldehyde for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (1.75 g, 78%) was obtained as a yellow solid: MS (ES) m/e 209.0 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=1[Br:24].[CH3:25][CH2:26]N=C=NCCCN(C)C.Cl.O>CN(C=O)C>[Br:24][C:15]1[CH:16]=[C:17]([CH2:20][C:21]([O:23][CH2:25][CH3:26])=[O:22])[CH:18]=[CH:19][C:14]=1[NH:13][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:12]
Reactant: Nc1ccc(CC(=O)O)cc1Br
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(NC(=O)c2c[nH]c3ccccc23)c(Br)c1
Temperature: 25 °C
Yield: 26.6 %

Procedure:
In DMF (20 ml) were dissolved indole-3-carboxylic acid (1.00 g, 6.21 mmol) and 4-amino-3-bromophenylacetic acid (1.60 g, 6.21 mmol). To the resulting solution was added EDC HCl (1.43 g, 7.45 mmol) under stirring at room temperature. After the reaction mixture was stirred at room temperature for 4 hours, water was added thereto, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from ethyl acetate eluate fractions, ethyl (3-bromo-4-((3-indolylcarbonyl)amino)phenyl)acetate (664 mg, 27%) was obtained as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([O:23]C)=[O:22])=[CH:17][CH:16]=2)=[C:11]([O:25][CH3:26])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[O-].[K+].Cl>C1COCC1.C(OCC)(=O)C.O>[C:1]([O:5][C:6](=[O:27])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([OH:23])=[O:22])=[CH:19][CH:20]=2)=[C:11]([O:25][CH3:26])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(-c2ccc(CCC(=O)OC(C)(C)C)cc2OC)cc1
Agent: C[Si](C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(CCC(=O)OC(C)(C)C)ccc1-c1ccc(C(=O)O)cc1

Procedure:
A mixture of Example 122K (3.5 g), and potassium trimethylsilanolate (1.70 g) in THF (250 mL) at room temperature was stirred for 18 hours, diluted with ethyl acetate (400 mL) and water (50 mL), and adjusted to pH 3 with 2N HCl. The organic phase was washed with water (150 mL) and brine (100 mL), dried (MgSO4), filtered, and concentrated to provide the desired product. MS (DCI (+)) m/e 357 (M+H)+.
Reaction SMILES: FC(F)(F)C1N=C(NC2C=CC([C@@H](C)C(O)=O)=CC=2)SC=1.[C:22]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([C@@H:32]([CH3:37])[C:33]([O:35]C)=[O:34])=[CH:28][CH:27]=1)(=[S:24])[NH2:23].Br[CH2:39][C:40](=O)[C:41]([CH3:44])([CH3:43])[CH3:42]>>[C:41]([C:40]1[N:23]=[C:22]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([C@@H:32]([CH3:37])[C:33]([OH:35])=[O:34])=[CH:28][CH:27]=2)[S:24][CH:39]=1)([CH3:44])([CH3:43])[CH3:42]
Reactant: COC(=O)[C@H](C)c1ccc(NC(N)=S)cc1
Reactant: CC(C)(C)C(=O)CBr
Agent: C[C@@H](C(=O)O)c1ccc(Nc2nc(C(F)(F)F)cs2)cc1
Product: C[C@@H](C(=O)O)c1ccc(Nc2nc(C(C)(C)C)cs2)cc1
Yield: 55 %

Procedure:
The acid was obtained following the same procedure described for (2R)-2-(4-{[4-(trifluoromethyl)-1,3-thiazol-2-yl]amino}phenyl)propanoic acid and starting from methyl (2R)-2-[4-(carbamothioylamino)phenyl]propanoate (2.0 g, 8.40 mmol) and 1-bromopinacolone (1.13 ml, 8.40 mmol). The following acid hydrolysis afforded the pure (2R)-2-{4-[(4-tert-butyl-1,3-thiazol-2-yl)amino]phenyl}propanoic acid (1.41 g, 4.62 mmol) as pale yellow oil (55%). 1H-NMR (CDCl3): δ 8.30 (bs, 1H, NH), 7.40 (d, 2H, J=7 Hz), 7.20 (d, 2H, J=7 Hz), 6.40 (s, 1H), 3.75 (q, 1H, J=7 Hz), 1.50 (d, 3H, J=7 Hz), 1.40, (s, 9H).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:10]=[C:9]3[Br:21])=[N:2]1.[C:22]1([C:28](Cl)([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>N1C=CC=CC=1.C(OCC)(=O)C>[Br:21][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[C:6]([C:3]3[N:4]=[CH:5][N:1]([C:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)([C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)[C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:2]=3)[CH:7]=2)[N:11]([CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][O:16]2)[N:10]=1
Reactant: Brc1nn(C2CCCCO2)c2ccc(-c3nc[nH]n3)cc12
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Brc1nn(C2CCCCO2)c2ccc(-c3ncn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc12
Temperature: 50 °C
Yield: 93 %

Procedure:
2-(5-(1H-1,2,4-Triazol-3-yl)-3-bromo-1H-indazolyl)perhydro-2H-pyran (15.05 g, 43.22 mmol), triphenylmethyl chloride (19.54 g, 70.09 mmol), and triethylamine (9.9 mL, 71.02 mmol) was taken up in pyridine (115 mL) and heated at 50° C. overnight. The reaction was quenched with methanol (10 mL), cooled to room temperature, and condensed. The brown oil was dissolved in ethyl acetate and washed with sodium bicarbonate (saturated aqueous). Upon sonication in a ultrasonic bath a white to yellow precipitate formed that was filtered and washed with 10% ethyl acetate in hexanes. The precipitate was dried in a vacuum oven overnight (23.80 g, 93% yield): ES-MS (m/z) 590 [M+1]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:9])[CH:5]([NH2:8])[C:6]#[N:7])[CH3:2].[C:10](OCC)(OCC)(OCC)[CH2:11][CH3:12].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(#N)C>[CH2:1]([O:3][C:4]([C:5]1[N:8]=[C:10]([CH2:11][CH3:12])[N:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:6]=1[NH2:7])=[O:9])[CH3:2]
Reactant: CCOC(CC)(OCC)OCC
Reactant: CCOC(=O)C(N)C#N
Reactant: Nc1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1nc(CC)n(-c2ccccc2)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of amino-cyano-acetic acid ethyl ester (400 mg, 3.12 mmol) and triethyl orthopropionate (629 μL, 3.12 mmol) in acetonitrile is heated at reflux for 45 minutes. After cooled down to room temperature, aniline (285 μL, 3.12 mmol) is added. After stirred at room temperature overnight, the solution is concentrated and purified with flash chromatography. A pale yellow solid is obtained as the desired product: 1H NMR (CDCl3) δ 7.56 (m, 3H), 7.29 (m, 2H), 4.77 (b, 2H), 4.37 (q, 2H), 2.49 (q, 2H), 1.40 (t, 3H), 1.11 (t, 3H); m/z 260.1 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:5]=[C:4]2[CH:15]=[CH:16][S:17][C:3]=12.[NH:18]1[CH2:26][CH2:25][CH:21]([C:22]([NH2:24])=[O:23])[CH2:20][CH2:19]1.C([O-])(=O)C.[Na+]>CN1CCCC1=O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[N:5]=[C:4]3[CH:15]=[CH:16][S:17][C:3]3=[C:2]([N:18]3[CH2:26][CH2:25][CH:21]([C:22]([NH2:24])=[O:23])[CH2:20][CH2:19]3)[CH:7]=2)=[CH:9][CH:10]=1
Reactant: NC(=O)C1CCNCC1
Reactant: Fc1ccc(-c2cc(Cl)c3sccc3n2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: NC(=O)C1CCN(c2cc(-c3ccc(F)cc3)nc3ccsc23)CC1
Temperature: 160 °C
Yield: 59.5 %

Procedure:
A mixture of 7-chloro-5-(4-fluorophenyl)thieno[3,2-b]pyridine (68 mg, 0.26 mmole), isonipecotamide (66 mg, 0.52 mmole), and sodium acetate (21 mg, 0.26) in 1-methyl-2-pyrrolidone (3 mL) is stirred and heated in an oil bath at 160° C. for 4 hours. The reaction mixture is then cooled and diluted with EtAc (15 mL), transferred to a separatory funnel, and washed with water (3×15 mL). The organic layer is dried over sodium sulfate and concentrated. The residue is recrystalized with ethyl acetate to give 1-(5-(4-fluorophenyl)thieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide (55 mg, 60% yield) as a white solid. This material is dissolved in ethyl acetate and HCl saturated ethyl acetate (2 mL) is added. The solution is concentrated to afford the HCl salt as a greasy oil. 1-(5-phenylthieno[3,2-b]pyridin-7-yl)-4-piperidinecarboxamide hydrochloride (compound 3) is precipitated out of an ether solution, collected by filtration, washed with ether, and dried in vacuo to afford the final product. m.p. 303-305° C. (dec).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20](OC1C=CC=CC=1)=[O:21].[CH3:29][C:30]1[O:34][N:33]=[C:32](C(Cl)=O)[CH:31]=1>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[N:15]([CH3:16])[C:14](=[O:17])[N:13]([CH3:18])[C:12](=[O:19])[C:11]=1[C:20]([C:32]1[CH:31]=[C:30]([CH3:29])[O:34][N:33]=1)=[O:21]
Reactant: Cc1cc(C(=O)Cl)no1
Reactant: Cn1c(Nc2ccc(I)cc2F)c(C(=O)Oc2ccccc2)c(=O)n(C)c1=O
Product: Cc1cc(C(=O)c2c(Nc3ccc(I)cc3F)n(C)c(=O)n(C)c2=O)no1

Procedure:
The title compound was synthesized following a similar procedure described in the synthesis of compound 2A by reaction of Example 1 and 5-methylisoxazole-3-carbonyl chloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.42 (s, 2H) 3.13 (s, 2H) 3.19 (s, 2H) 6.13-6.29 (m, 1H) 7.08 (t, J=8.59 Hz, 1H) 7.47 (dd, J=8.46, 1.89 Hz, 1H) 7.68 (dd, J=9.98, 1.89 Hz, 1H) 10.47 (s, 1H) [M+H] calc'd for C17H14FIN4O4, 485; found, 485.