Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C@H:6]([C:10]([NH:12][CH:13]([CH:21]([OH:44])[CH:22]([OH:43])[CH:23]([NH:31][C:32](=[O:42])[C@H:33]([CH:39]([CH3:41])[CH3:40])[NH:34][C:35](=[O:38])[CH2:36]Br)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4].[SH:45][C:46]1[NH:47][CH:48]=[CH:49][N:50]=1>>[NH:47]1[CH:48]=[CH:49][N:50]=[C:46]1[S:45][CH2:2][C:3]([NH:5][C@H:6]([C:10]([NH:12][CH:13]([CH:21]([OH:44])[CH:22]([OH:43])[CH:23]([NH:31][C:32](=[O:42])[C@H:33]([CH:39]([CH3:41])[CH3:40])[NH:34][C:35]([CH2:36][S:45][C:46]1[NH:47][CH:48]=[CH:49][N:50]=1)=[O:38])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH:7]([CH3:9])[CH3:8])=[O:4]
Reactant: Sc1ncc[nH]1
Reactant: CC(C)[C@H](NC(=O)CBr)C(=O)NC(Cc1ccccc1)C(O)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)CBr)C(C)C
Product: CC(C)[C@H](NC(=O)CSc1ncc[nH]1)C(=O)NC(Cc1ccccc1)C(O)C(O)C(Cc1ccccc1)NC(=O)[C@@H](NC(=O)CSc1ncc[nH]1)C(C)C
Yield: 47.5 %

Procedure:
The resultant compound of Example 251 (150 mg, 0.2 mmol) was reacted with 2-mercaptoimidazole (40.6 mg) by the procedure described in Example 252 and similarly purified to afford the title compound (74 mg, 47%). 1H NMR (DMSO-d6, 300 MHz) δ 0.63 (m, 12H), 1.84 (m, 2H), 2.25-2.80 (m, 4H), 3.05-3.82 (m, 12H), 4.44 (m, 2H), 7.14 (m, 14H), 7.48 (bd, 2H), 8.07 (bd, 2H). MS (FAB) m/e 779 (M+H)+.
Reaction SMILES: C(N1C2C=CC=CC=2N(C(NCC2CC[N:20]([CH2:23][C:24]3([C:30]([OH:32])=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)CC2)=O)C1=O)(C)C>CO.[Ni]>[NH2:20][CH2:23][C:24]1([C:30]([O:32][C:24]([CH3:29])([CH3:25])[CH3:23])=[O:31])[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: CC(C)n1c(=O)n(C(=O)NCC2CCN(CC3(C(=O)O)CCOCC3)CC2)c2ccccc21
Agent: [Ni]
Solvent: CO
Product: CC(C)(C)OC(=O)C1(CN)CCOCC1
Yield: 165.8 %

Procedure:
A mixture of tert-butyl 4-cyanotetrahydro-2H-pyran-4-carboxylate (18.95 g, 0.0897 mol, step 1) and Raney Ni (1.00 g) in methanol (200 mL) was hydrogenated (3 atm) at room temperature for 12 h. Then, the mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to give 16.01 g (83%) of the title compound as a yellow syrup.
Reaction SMILES: [CH3:1][C:2](=[O:9])[C:3](=[N:7]O)[C:4](=O)[CH3:5].[N:10]1[CH:15]=[CH:14][C:13]([CH2:16][NH2:17])=[CH:12][CH:11]=1>CN(C)C=O>[CH3:5][C:4]1[NH:17][C:16]([C:13]2[CH:14]=[CH:15][N:10]=[CH:11][CH:12]=2)=[N:7][C:3]=1[C:2](=[O:9])[CH3:1]
Reactant: NCc1ccncc1
Reactant: CC(=O)C(=NO)C(C)=O
Solvent: CN(C)C=O
Product: CC(=O)c1nc(-c2ccncc2)[nH]c1C
Temperature: -10 °C
Reaction time: 4 h
Yield: 39.8 %

Procedure:
A mixture of 6.5 g (0.05 mole) of 2,3,4-pentanetrione 3-oxime and 6.0 g (0.055mole) of 4-pyridylmethylamine in 75 ml of N,N-dimethylformamide was stirred at the reflux temperature for 4 hours. The solvent was removed in vacuo and 100 ml of acetonitrile was added to the residual oil. The mixture was boiled then was cooled at -10° C. to yield precipitate. The precipitate was collected, washed with 50 ml of cold acetonitrile and air dried. The material was recrystallized from 150 ml of boiling acetonitrile after treatment with activated charcoal and filtration by cooling at -10° C. The product of the Example was collected by filtration, washed with 50 ml of cold acetonitrile and dried to give 4.0 g of a tan solid, mp 181°-183° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([C:13](Cl)=[O:14])=[CH:10][CH:9]=1.[NH2:16][C:17]1[O:18][C:19]([C:22]2[O:23][CH:24]=[CH:25][CH:26]=2)=[N:20][N:21]=1.CO>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([C:13]([NH:16][C:17]2[O:18][C:19]([C:22]3[O:23][CH:24]=[CH:25][CH:26]=3)=[N:20][N:21]=2)=[O:14])=[CH:10][CH:9]=1
Reactant: Nc1nnc(-c2ccco2)o1
Reactant: O=C(Cl)c1ccc(-c2ccccc2F)o1
Solvent: c1ccncc1
Solvent: CO
Product: O=C(Nc1nnc(-c2ccco2)o1)c1ccc(-c2ccccc2F)o1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 69.7 %

Procedure:
Commercially available 5-(2-fluorophenyl)-2-furancarbonyl chloride (93 mg, 0.41 mmol) was added to a solution of commercially available 2-amino-5-(2-furyl)-1,3,4-oxadiazole (50 mg, 0.33 mmol) in pyridine (1.3 mL) under ice-cooling, followed by stirring at room temperature for 2.5 hr and then at 60° C. for 2 hr. Methanol was added to the reaction solution. The solvent was distilled off, and water was added to the residue. The precipitated crystals were collected by filtration, washed with water, methanol, and ethyl acetate sequentially, and then dried to obtain the title compound (77 mg, 0.23 mmol) (yield: 70%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]([O:25]CCCC)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:32][CH2:33][CH2:34][CH3:35])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[O:19][C:20]([CH2:30][CH3:31])=[C:21]([C:23]([OH:25])=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:32][CH2:33][CH2:34][CH3:35])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCCC)C2)oc1CC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCO[C@@H]1CN(c2nc(C(=O)O)c(CC)o2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Yield: 67.2 %

Procedure:
The same operation as in Example (91d) was performed using butyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-propoxypiperidin-1-yl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (113i) (0.2 g, 0.39 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (3 mL) and THF (5 mL), to obtain 119 mg of the title compound as a colorless solid (67%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][C:9](=[O:12])[CH2:8][CH2:7]2.Cl[C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=1.C([O-])([O-])=O.[K+].[K+]>>[O:12]=[C:9]1[CH2:10][C:11]2[C:2]([O:1][C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][N:15]=3)=[CH:3][CH:4]=[CH:5][C:6]=2[CH2:7][CH2:8]1
Reactant: O=C1CCc2cccc(O)c2C1
Reactant: NC(=O)c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)c1ccc(Oc2cccc3c2CC(=O)CC3)nc1
Yield: 24.2 %

Procedure:
Using a method similar to Intermediate 1, using 8-hydroxy-2-tetralone (J. Med. Chem. (1978), 21(9), 913-22) (1.55 g, 9.55 mmol), 6-chloronicotinamide (1.49 g, 9.55 mmol) and K2CO3 (1.98 g, 14.3 mmol) gives the title compound (652 mg), after purification on silica gel (50% THF/DCM), as an yellow foam. Mass spectrum (ion spray): m/z=283 (M+1); 1HNMR (CDCl3): 8.52 (s, 1H), 8.18 (d, 1H), 7.30 (t, 1H), 7.17 (d, 1H), 7.02 (m, 2H), 5.92 (broad, 2H), 3.42 (s, 2H), 3.15 (t, 2H), 2.61 (t, 2H).
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14](O)=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH3:4].Cl[S:24]([C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=1)(=[O:26])=[O:25]>>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10]([C:11]1[CH:16]=[CH:15][C:14]([S:24]([C:27]2[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([OH:36])[CH:28]=2)(=[O:26])=[O:25])=[CH:13][CH:12]=1)=[O:18])[CH2:2][CH2:3][CH3:4]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccc(O)cc1
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(S(=O)(=O)c2ccc(C(=O)O)c(O)c2)cc1
Yield: 11.4 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using commercial 2-n-butyl-3-(4-hydroxybenzoyl)benzofuran (1.00 g, 3.40 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (1.61 g, 6.79 mmol). Purification on :2% H3PO4/MeOH treated silica gel, eluting with EtOAc/hexane gave 0.185 g (11%) of the title compound as an off white solid, mp 143-145° C. 1H NMR (DMISO-d6) δ0.76 (t, 3 H), 1.12-1.22 (m, 2 H), 1.60 (quintet, 2 H), 2.69 (t, 2 H), 7.21-7.38 (m, 7 H), 7.61 (d, 1 H), 7.76 (d, 2 H), 7.98 (d, 1 H). IR (KBr) 2950, 1690, 1600, 1380 and 1150 cm−1. mass spectrum (+ESI) m/z 495 (M+H). Anal. Calcd. for C26H22O8S. 0.2H2O: C, 62.24; H, 4.58; N, 0.00. Found: C, 62.38; H, 4.59; N, 0.13.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](SC)=[CH:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1.[CH3:17][NH2:18]>CCO>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([NH:18][CH3:17])=[CH:11][N+:12]([O-:14])=[O:13])=[CH:4][CH:3]=1
Reactant: CN
Reactant: CSC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1
Solvent: CCO
Product: CNC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1
Yield: 53.8 %

Procedure:
In 100 ml of EtOH was dissolved 1.2 g (4.6×10-3 mole) of 1-(6-chloro-3-pyridylmethyl)amino-1-methylthio-2-nitroethylene and on reflux, a solution of 0.84 g of 40% aqueous methylamine in 30 ml EtOH was added dropwise over 1 hour. After cooling, the reaction mixture was concentrated under reduced pressure to about 50 ml and the resulting crystals were collected by filtration and dried to give 0.6 g of the title compound as pale yellow needles.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH2:9][CH2:10][CH2:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.B(F)(F)F.[CH3:17]COCC.[Li]C.Cl>CCOC(C)=O.O>[F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:17])[CH2:9][CH2:10][CH2:11][NH:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOCC
Reactant: Fc1cccc(C2=NCCC2)c1
Agent: Cl
Agent: FB(F)F
Agent: [Li]C
Solvent: O
Solvent: CCOC(C)=O
Product: CC1(c2cccc(F)c2)CCCN1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
A solution of 5-(3-fluorophenyl)-3,4-dihydro-2H-pyrrole (6.1 g, 37.4 mmol) in 100 mL THE was cooled to −78° C., and boron trifluoride diethyl etherate (9.47 mL, 74.8 mmol) was added drop-wise over 5 minutes. The resulting cloudy reaction mixture was stirred at −78° C. for 40 minutes. MeLi (1.6 M in diethyl ether, 46.7 mL, 74.8 mmol) was added drop-wise over 10 minutes. The mixture was stirred at −78° C. for another 2 hours, then warmed up to ambient temperature overnight. For workup, water and EtOAc were added to the reaction mixture, and the aqueous layer was acidified with HCl solution. After separating and discarding the organic layer, the aqueous layer was basified with NaOH (6 N, aq.) to pH=12 and extracted twice with EtOAc. The combined organic extracts was dried over Na2SO4 and concentrated to get a mixture of the desired product (2-(3-fluorophenyl)-2-methylpyrrolidine) and starting material (4.3 g, 1.3:1 of the desired product:starting material, 37% yield). The crude product was used in the next step without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([OH:25])=O)=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[NH2:64][CH2:65][C:66]1[CH:67]=[CH:68][C:69]2[C:73]([CH2:76][CH3:77])([CH2:74][CH3:75])[O:72][B:71]([OH:78])[C:70]=2[CH:79]=1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:28])([F:27])[F:29])[O:13][N:12]=[C:11]([C:14]3[N:15]4[C:19]([C:20]([C:23]([NH:64][CH2:65][C:66]5[CH:67]=[CH:68][C:69]6[C:73]([CH2:74][CH3:75])([CH2:76][CH3:77])[O:72][B:71]([OH:78])[C:70]=6[CH:79]=5)=[O:25])=[CH:21][CH:22]=3)=[CH:18][CH:17]=[CH:16]4)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CCC1(CC)OB(O)c2cc(CN)ccc21
Reactant: O=C(O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)n2cccc12
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: CCC1(CC)OB(O)c2cc(CNC(=O)c3ccc(C4=NOC(c5cc(Cl)cc(Cl)c5)(C(F)(F)F)C4)n4cccc34)ccc21
Reaction time: 0.17 h

Procedure:
A solution of 5-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)indolizine-8-carboxylic acid (0.24 mmol) and DIPEA (151 mg, 1.17 mmol) in DMF (5.0 mL) can be stirred at rt for 5 min and then HATU (180 mg, 0.47 mmol) was added. The mixture can be stirred for 10 min prior to the addition of 6-(aminomethyl)-3,3-diethylbenzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (63 mg, 0.25 mmol). And the resulting mixture can be stirred at rt overnight. It can be then concentrated under vacuum, and the residue can be partitioned between 1N HCl and ethyl acetate. The organic layer separated can be concentrated under vacuum, and the residue can be purified by column chromatography and prep-HPLC to provide the final title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][C:22]#[CH:23])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1.I[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][O:20][CH2:21][C:22]#[C:23][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1
Reactant: Ic1ccccc1
Reactant: C#CCOCCn1c(CCOC)nc2cnc3ccccc3c21
Product: COCCc1nc2cnc3ccccc3c2n1CCOCC#Cc1ccccc1
Reaction time: 0.75 h
Yield: 346.4 %

Procedure:
Using the general method of Example 12 Part A, 2-(methoxyethyl)-1-[2-(prop-2-ynyloxy)ethyl]-1H-imidazo[4,5-c]quinoline (2.72 g, 1.79 mmol) was reacted with iodobenzene (1.1 mL, 9.67 mmol) at ambient temperature. After 45 minutes the reaction was judged complete. The volatiles were removed under reduced pressure and the resulting oil partitioned between dichioromethane and 5% aqueous sodium bicarbonate. The aqueous layer was extracted with dichloromethane. The organic fractions were combined, washed with brine, dried with anhydrous sodium sulfate, and then concentrated under reduced pressure to leave a brown solid. The solid was purified by chromatography over silica gel (95/5 (dichloromethane/methanol) and trituration with hexane to provide 2.39 g of 2-(methoxyethyl)-1-{2-[(3-phenylprop-2-ynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinoline as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:5][CH:4]=1.Cl.Cl.[NH2:23][CH:24]1[CH2:31][CH:30]2[N:32]([CH3:33])[CH:26]([CH2:27][CH2:28][CH2:29]2)[CH2:25]1>>[CH3:33][N:32]1[CH:26]2[CH2:27][CH2:28][CH2:29][CH:30]1[CH2:31][CH:24]([NH:23][C:18]([C:17]1[C:11]3[O:10][C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[N:13][C:12]=3[CH:14]=[CH:15][CH:16]=1)=[O:20])[CH2:25]2
Reactant: CN1C2CCCC1CC(N)C2
Reactant: COc1ccc(-c2nc3cccc(C(=O)O)c3o2)cc1
Agent: Cl
Product: COc1ccc(-c2nc3cccc(C(=O)NC4CC5CCCC(C4)N5C)c3o2)cc1
Yield: 36 %

Procedure:
N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-(4-methoxyphenyl)benzoxazole-7-carboxamide was prepared from 2-(4-methoxyphenyl)benzoxazole-7-carboxylic acid and 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride using the method outlined in Step C of Example 14. This compound was obtained in 36% yield as a off-white solid: mp 160-162° C.; 1H NMR (500 MHz, CD3OD) δ 8.22 (dt, J=9.7, 2.8 Hz, 2H), 7.82 (dd, J=7.9, 1.0 Hz, 1H), 7.72 (dd, J=7.7, 1.0 Hz, 1H), 7.46 (t, J=7.8 Hz, 1H), 7.14 (dt, J=9.7, 2.8 Hz, 2H), 4.61 (m, 1H), 3.90 (s, 3H), 3.16 (m, 2H), 2.59 (m, 2H), 2.55 (s, 3H), 2.14 (m, 1H), 2.08 (m, 2H), 1.61 (m, 3H), 1.99 (m, 2H); MS (ESI) m/z 406 [M+H]+.
Reaction SMILES: CO[CH:3](OC)[CH2:4][NH:5][C:6]([C:8]1[NH:12][N:11]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:9]=1)=[O:7].FC(F)(F)C(O)=O>ClCCl>[F:14][C:13]([F:16])([F:15])[C:10]1[CH:9]=[C:8]2[C:6](=[O:7])[NH:5][CH:4]=[CH:3][N:12]2[N:11]=1
Reactant: COC(CNC(=O)c1cc(C(F)(F)F)n[nH]1)OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=c1[nH]ccn2nc(C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 267 mg (1 mmol) of N-(2,2-dimethoxyethyl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide, 1.6 mL of trifluoroacetic acid, and 1.6 mL of dichloromethane was stirred at room temperature overnight and then concentrated. The residue was suspended in polyphosphoric acid (enough to cover it) and heated at 145° C. for 4.5 h. The cooled mixture was treated with ice, and the pH was adjusted to 8-9 by addition of concentrated ammonium hydroxide solution. The mixture was transferred to a separatory funnel and shaken with dichloromethane. The organic phase was separated, and the aqueous phase was extracted twice more with dichloromethane. The combined organic fractions were dried over sodium sulfate, filtered, and concentrated to yield the title compound as a solid.
Reaction SMILES: [CH2:1](Br)[C:2]#[CH:3].[SH:5][C:6]1[NH:10][N:9]=[C:8]([CH:11]([CH3:13])[CH3:12])[N:7]=1>C[O-].[Na+]>[CH:11]([C:8]1[N:7]=[C:6]([S:5][CH2:3][C:2]#[CH:1])[NH:10][N:9]=1)([CH3:13])[CH3:12]
Reactant: C#CCBr
Reactant: CC(C)c1n[nH]c(S)n1
Agent: C[O-]
Agent: [Na+]
Product: C#CCSc1nc(C(C)C)n[nH]1

Procedure:
11.9 g. Prop-2-ynyl bromide was added to a solution of 14.3 g. 5-mercapto-3-isopropyl-1,2,4-triazole in sodium methoxide solution (2.3 g. sodium dissolved in 200 ml. methanol). Then the solution was boiled under reflux for 2 1/2 hours. The solvent was evaporated under reduced pressure from the steam bath and the residual solid triturated with 500 ml. cold water, filtered off and dried under vacuum to give 3-isopropyl-5-prop-2-ynylthio-1,2,4-triazole which was purified by recrystallisation in the presence of charcoal, from petroleum ether (boiling point 80°-100° C.). The melting point of the product was 91°-92° C.
Reaction SMILES: [C:1]([OH:6])(=[O:5])/[CH:2]=[CH:3]/[CH3:4].[CH3:7][Si:8]([CH3:11])([CH3:10])Cl.N1C=CC=CC=1>C(OCC)C>[C:1]([O:6][Si:8]([CH3:11])([CH3:10])[CH3:7])(=[O:5])/[CH:2]=[CH:3]/[CH3:4]
Reactant: C[Si](C)(C)Cl
Reactant: C/C=C/C(=O)O
Solvent: CCOCC
Solvent: c1ccncc1
Product: C/C=C/C(=O)O[Si](C)(C)C
Temperature: 38 °C
Reaction time: 0.08 h
Yield: 61.9 %

Procedure:
To a single-neck reaction flask (250 mL) were added of crotonic acid (10.750 g, 0.125 mol), anhydrous ethyl ether (125 mL) and trimethyl chlorosilane (19 mL, 0.150 mol). The mixture was stirred for 5 min. Pyridine (12 mL, 0.150 mol) was dropwise added into the resulting mixture under stirring at the temperature of 35° C. After the addition finished, the mixture was warmed up to the temperature of 38° C. and stirred under relux for 3 hr. The white solid was filtered in vacuo. Ethyl ether was evaporated under atmospheric pressure. The resultant was distilled under reduced pressure to collect the fraction under 10 mmHg at the temperature of 46° C.-48° C. to give (E)-trimethylsilyl 2-butenoate as a colorless liquid (12.242 g). Yield: 62.0%.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[C:18]1([S:24]([N:27]2[CH:31]=[CH:30][CH:29]=[C:28]2[CH:32]=O)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:32][C:28]3[N:27]([S:24]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)(=[O:26])=[O:25])[CH:31]=[CH:30][CH:29]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1cccn1S(=O)(=O)c1ccccc1
Solvent: CCO
Solvent: C1CCNCC1
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1cccn1S(=O)(=O)c1ccccc1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in EtOH and 1-(phenylsulfonyl)-1H-pyrrole-2-carbaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[O:26]1[CH2:31][CH:30]=[C:29](OS(C(F)(F)F)(=O)=O)[CH2:28][CH2:27]1>>[O:26]1[CH2:27][CH:28]=[C:29]([C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[N:8]([CH3:25])[C:9](=[O:24])[C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=2)[CH2:30][CH2:31]1
Reactant: O=S(=O)(OC1=CCOCC1)C(F)(F)F
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1C1=CCOCC1

Procedure:
The title compound was prepared in analogy to example 73, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 98, intermediate a) and trifluoro-methanesulfonic acid 3,6-dihydro-2H-pyran-4-yl ester (CAS RN 188975-30-6). The compound was purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane:EtOAc (100:0 to 40:60). Colorless solid (56%). MS (ESI): m/z=431.177 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:27])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[NH:22][C:21](=[O:26])[CH2:20]2)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:29][C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:27])[CH2:18][CH:19]2[CH2:24][C:23](=[O:25])[N:22]([CH2:29][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[C:21](=[O:26])[CH2:20]2)[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)CC2CC(=O)NC(=O)C2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)CC2CC(=O)N(CC(=O)OCc3ccccc3)C(=O)C2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 112.6 %

Procedure:
A suspension of 4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}piperidine-2,6-dione (Example 14, 0.300 g, 0.81 mmol), benzyl bromoacetate (0.236 g, 0.97 mmol), and potassium carbonate (0.335 g, 2.42 mmol) in DMF (5 mL) was stirred at 60° C. for 16 h. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to give a pale yellow powder, which was re-crystallized from hexane and ethyl acetate to provide benzyl (4-{2-[4-(2-tert-butylphenyl)piperazin-1-yl]-2-oxoethyl}-2,6-dioxopiperidin-1-yl)acetate (0.474 g, 79%) as an off-white powder.
Reaction SMILES: [CH3:1][C:2]([OH:16])([CH3:15])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[CH3:14]>CO.[Pd]>[NH2:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([CH3:15])([OH:16])[CH3:1])=[C:6]([CH3:14])[CH:7]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1OCC(C)(C)O
Agent: [Pd]
Solvent: CO
Product: Cc1cc(N)ccc1OCC(C)(C)O
Reaction time: 18 h
Yield: 9.5 %

Procedure:
A mixture of 2-methyl-1-(2-methyl-4-nitrophenoxy)propan-2-ol (7.30 g, 314 mmol) and 10% Pd/C (0.345 g, 3.24 mmol) in MeOH (150 mL) was hydrogenated at 1 atm of H2 for 18 hours. After removal of the Pd/C by filtration, the solution was concentrated to yield 1-(4-amino-2-methylphenoxy)-2-methylpropan-2-ol (6.10 g, 29.7 mmol, 92% yield) as clear gum which was carried forward without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][CH:7]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][O:33][C:34](=[O:38])[CH2:35][CH2:36][NH2:37].CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:32][O:33][C:34](=[O:38])[CH2:35][CH2:36][NH:37][C:18](=[O:20])[C:17]1[CH:16]=[CH:15][C:14]([CH:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:24][CH:23]=2)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[CH:22][CH:21]=1
Reactant: COC(=O)CCN
Reactant: CCCCCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCC(Oc1ccc(Br)cc1)c1ccc(C(=O)NCCC(=O)OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a mixture of 4-[1-(4-bromo-phenoxyl)-heptyl]-benzoic acid (1700 mg, 4.35 mmol) in methylene chloride (43 mL) are added triethyl amine (1.82 mL, 13.4 mmol), DMAP (5.0 mg), 3-amino-propionic acid methyl ester (910 mg, 6.52 mmol) and EDCI (2507 mg, 13.04 mmol) at room temperature. The reaction mixture is stirred at room temperature overnight, loaded on silica gel, eluted with eluted with hexanes with a gradient from 0% of ethyl acetate to 100% of ethyl acetate giving racemic 3-{4-[1-(4-bromo-phenoxyl)-heptyl]-benzoylamino}-propionic acid methyl ester (1660 mg).