Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:12])[CH:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]#[CH:11])[CH2:5][CH2:4]1.[F:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[O:21][C:22]1[CH:27]=[CH:26][N:25]=[C:24]2[CH:28]=[C:29](I)[S:30][C:23]=12)[NH2:17]>>[NH2:17][C:16]1[CH:18]=[CH:19][C:20]([O:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[CH:28]=[C:29]([C:11]#[C:10][CH2:9][N:6]4[CH2:5][CH2:4][CH:3]([N:2]([CH3:12])[CH3:1])[CH2:8][CH2:7]4)[S:30][C:23]=23)=[C:14]([F:13])[CH:15]=1
Reactant: Nc1ccc(Oc2ccnc3cc(I)sc23)c(F)c1
Reactant: C#CCN1CCC(N(C)C)CC1
Product: CN(C)C1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Temperature: 50 °C

Procedure:
Prepared from N,N-dimethyl-1-(prop-2-ynyl)piperidin-4-amine (32 mg, 0.19 mmol) and 3-fluoro-4-(2-iodothieno[3,2-b]pyridin-7-yloxy)benzenamine (Example 6, Step A; 50 mg, 0.13 mmol) according to the procedure described for Example 6, Step B, except the reaction was heated at 50° C. for 7 hours. The crude was partially purified by preparative TLC [5% MeOH (containing 7N NH3) in CH2Cl2]. The product was obtained as a waxy solid (34 mg, 31%; 50% purity by 1H NMR), and carried forward without further purification. LRMS (APCI pos) m/e 425 (M+1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[N:3]=1.O.[NH2:24][NH2:25]>N1C=CC=CC=1.O>[Cl:1][C:2]1[N:3]=[C:4]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[C:6]([NH:24][NH2:25])[N:7]=1
Reactant: NN
Reactant: Clc1ccc(-c2nc(Cl)nc(Cl)c2-c2ccc(Cl)cc2)cc1
Solvent: c1ccncc1
Solvent: O
Product: NNc1nc(Cl)nc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
2,4-Dichloro-5,6-bis(4-chlorophenyl)pyrimidine (1.8 g, 4.86 mmol) was dissolved in pyridine (5 mL) and hydrazine monohydrate (0.26 mL, 5.36 mmol) was added. The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was then diluted with water (10 mL) and extracted with EtOAc (10 mL×2). The combined organic extracts were washed with water, followed by saturated aqueous NaCl, dried (MgSO4), and concentrated at reduced pressure to obtain 1.7 g of the title compound, as a mixture with its regioisomer, as a yellow solid. HPLC/MS: title compound retention time=3.261 min, [M+H]30 =365; regioisomer retention time 3.385 min.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][OH:9])[CH3:2].[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([N+]([O-])=O)[C:14]=1[C:15]#[N:16])([O-:12])=[O:11]>>[CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][C:17]1[CH:18]=[CH:19][CH:20]=[C:13]([N+:10]([O-:12])=[O:11])[C:14]=1[C:15]#[N:16])[CH3:2]
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: CCOCCOCCO
Product: CCOCCOCCOc1cccc([N+](=O)[O-])c1C#N
Yield: 66 %

Procedure:
Prepared as in Example 215c from 2-(2-ethoxyethoxy)ethanol and 2,6-dinitrobenzonitrile in 66% yield. MS 281 (MH+).
Reaction SMILES: CN(C(O[N:9]1N=N[C:11]2C=CC=[N:15][C:10]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Cl:25][C:26]1[CH:34]=[C:33]([C:35]2[CH:36]=[CH:37][C:38]3[N:39]([C:41]([CH2:44][O:45][C:46]4[C:55]5[C:50](=[CH:51][C:52]([O:56][CH3:57])=[CH:53][CH:54]=5)[N:49]=[CH:48][CH:47]=4)=[N:42][N:43]=3)[N:40]=2)[CH:32]=[CH:31][C:27]=1[C:28](O)=[O:29].O/N=C(\N)/C>CN(C=O)C.O>[Cl:25][C:26]1[CH:34]=[C:33]([C:35]2[CH:36]=[CH:37][C:38]3[N:39]([C:41]([CH2:44][O:45][C:46]4[C:55]5[C:50](=[CH:51][C:52]([O:56][CH3:57])=[CH:53][CH:54]=5)[N:49]=[CH:48][CH:47]=4)=[N:42][N:43]=3)[N:40]=2)[CH:32]=[CH:31][C:27]=1[C:28]1[O:29][N:15]=[C:10]([CH3:11])[N:9]=1
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)O)c(Cl)c5)nn34)ccnc2c1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C/C(N)=N/O
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(OCc3nnc4ccc(-c5ccc(-c6nc(C)no6)c(Cl)c5)nn34)ccnc2c1
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
HATU (0.370 g, 0.974 mmol) and 2-chloro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)benzoic acid (0.300 g, 0.650 mmol) were taken up in DMF (5 mL). Added Hunig'sBase (0.339 ml, 1.95 mmol). Stirred for 10 min. Added (Z)-N′-hydroxyacetamidine (0.289 g, 3.90 mmol). Stirred for an additional 30 min. Removed DMF in vacuo. Suspended in water. Isolated product by filtration. The resulting solid was allowed to try under vacuum. Split into 3 portions and separately took up in dioxane (4 mL) in a microwave tube and heated for 12 min at 150° C. Combined all 3 reactions. Concentrated. Purified on RPHPLC. Took fractions containing product and made basic with 9% sodium carbonate. Removed volatiles in vacuo. Product crashed out and was isolated by filtration. MS m/z=500.0 [M+1]+. Calc'd for C25H18ClN7O3: 499.1.
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].[CH2:22]([O:29][C@@H:30]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C@@H:36](O)[C@@H:35]([CH2:47][O:48][CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[O:34][C@@H:31]1[O:32][CH3:33])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(O[C@@H]1[C@@H](OCC2C=CC=CC=2)[C@@H](OC(F)(F)F)[C@@H](C(=S(=O)=O)OCC2C=CC=CC=2)O[C@@H]1OC)C1C=CC=CC=1.OS(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH2:22]([O:29][C@@H:30]1[C@@H:37]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[C@@H:36]([O:12][S:9]([C:8]([F:21])([F:20])[F:7])(=[O:11])=[O:10])[C@@H:35]([CH2:47][O:48][CH2:49][C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[O:34][C@@H:31]1[O:32][CH3:33])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: CO[C@H]1O[C@H](C(OCc2ccccc2)=S(=O)=O)[C@H](OC(F)(F)F)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@H](OS(=O)(=O)C(F)(F)F)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a solution of dry pyridine (0.46 mL) in methylene chloride (17.5 mL) cooled to -15° C. was added trifluoromethane sulfonic anhydride (0.87 mL). The mixture was stirred during 15 min at -10° C., then methyl 2,3,6-tri-O-benzyl-α-D-galactopyranoside (1.2 g, 2.58 mmol) in methylene chloride (5 mL) was added (N. Morishima, S. Koto, M. Oshima, A. Sugimoto and S. Zen, Bull. Chem. Soc. Jpn, 56, 2849 (1983)). The mixture was washed with water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford an oil which was the expected triflate methyl 2,3,6-tri-O-benzyl-4-O-trifluoromethyl-sulfonyl-α-D -galactopyranoside (1.43 g, 93%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[F:20][CH:21]([F:24])[CH2:22][NH2:23].CO>C1COCC1>[F:20][CH:21]([F:24])[CH2:22][NH:23][CH2:15][C:13]1[N:14]=[C:10]([NH:9][C:7]([NH:6][CH2:5][C:4]2[CH:17]=[CH:18][CH:19]=[C:2]([F:1])[CH:3]=2)=[O:8])[S:11][CH:12]=1
Reactant: NCC(F)F
Reactant: O=C(NCc1cccc(F)c1)Nc1nc(CI)cs1
Solvent: C1CCOC1
Solvent: CO
Product: O=C(NCc1cccc(F)c1)Nc1nc(CNCC(F)F)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(4-Iodomethyl-thiazol-2-yl)-3-(3-fluorobenzyl)-urea (Intermediate 7, 1 eq.) was taken up in THF (0.3 M) and 2,2-difluoroethanamine (20 eq.) was added. The reaction was stirred overnight at ambient temperature. Some of the starting material, Intermediate 7 remained. Added additional 2,2-difluoroethanamine (10 equivalents). The reaction was complete after 2-4 hours. Removed solvent; coevaporated twice with MeOH. Crude is a 1:1 mixture of title compound and bis addition impurity. (used as is in subsequent step).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:12]=2[C:13]#[N:14])=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].BrBr.S(Cl)([Cl:29])(=O)=O>C(O)(=O)C>[Cl:29][C:11]1[C:12]([C:13]#[N:14])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[NH:9][C:10]=1[C:15]([F:18])([F:16])[F:17]
Reactant: N#Cc1cc(C(F)(F)F)[nH]c1-c1ccc(Cl)cc1
Reactant: O=S(=O)(Cl)Cl
Agent: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: N#Cc1c(-c2ccc(Cl)cc2)[nH]c(C(F)(F)F)c1Cl
Reaction time: 1 h
Yield: 84 %

Procedure:
A mixture of 2-(p-chloropheny1)-5-(trifluoromethyl)pyrrole-3-carbonitile (8.12 g, 0.03 mol) and sodium acetate (0.25 g, 0.003 mol) in acetic acid at 70° C. is treated dropwise with bromine (0.48 g, 0.003 mol). When the color has disappeared, the reaction mixture is treated dropwise with sulfuryl chloride (6.1 g, 0.045 mol) over a 1 hour period, held at 70° C. for 1 hour, concentrated in vacuo and diluted with water. The reaction mixture is filtered, the filter cake is washed with water and dried to yield the title product as a white solid, 7.7 g (84% yield), mp 242°-243° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:52])([CH2:41][CH2:42][CH2:43][O:44][Si](CC)(CC)CC)[CH2:3][CH2:4][C:5]1[C:17]2[CH2:16][N:15]3[C:10](=[CH:11][C:12]4[C:22]([O:25][C:26](=[O:35])[O:27][CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)([CH2:23][CH3:24])[C:21](=[O:36])[O:20][CH2:19][C:13]=4[C:14]3=[O:18])[C:9]=2[N:8]=[C:7]2[CH:37]=[CH:38][CH:39]=[CH:40][C:6]=12.F.N1C=CC=CC=1>C(#N)C>[CH2:23]([C:22]1([O:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:12]2[CH:11]=[C:10]3[N:15]([C:14](=[O:18])[C:13]=2[CH2:19][O:20][C:21]1=[O:36])[CH2:16][C:17]1[C:5]([CH2:4][CH2:3][Si:2]([CH2:41][CH2:42][CH2:43][OH:44])([CH3:52])[CH3:1])=[C:6]2[CH:40]=[CH:39][CH:38]=[CH:37][C:7]2=[N:8][C:9]3=1)[CH3:24]
Reactant: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCO[Si](CC)(CC)CC
Agent: F
Solvent: CC#N
Solvent: c1ccncc1
Product: CCC1(OC(=O)OCc2ccccc2)C(=O)OCc2c1cc1n(c2=O)Cc2c-1nc1ccccc1c2CC[Si](C)(C)CCCO
Temperature: 21 °C
Reaction time: 14 h
Yield: 48 %

Procedure:
A mixture of Compound 52 (1.70 g, 2.3 mmol), hydrofluoric acid (48% in water, 1.8 mL, 46 mmol), and pyridine (4.5 mL, 55 mmol) in 20 mL of acetonitrile was stirred at 21° C. for 14 hours. The reaction was quenched with saturated sodium bicarbonate solution, and aqueous layer was extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated to afford yellow oil, which was chromatographed to give the desired product (Yield: 48%).
Reaction SMILES: [CH3:1][O:2][CH:3]=[CH:4][C:5]1[C:10]([F:11])=[CH:9][C:8](Br)=[CH:7][C:6]=1[F:13].[Li]CCCC.[CH3:19][C:20]([CH3:22])=[O:21].O>C(OC)(C)(C)C>[F:13][C:6]1[CH:7]=[C:8]([C:20]([OH:21])([CH3:22])[CH3:19])[CH:9]=[C:10]([F:11])[C:5]=1[CH:4]=[CH:3][O:2][CH3:1]
Reactant: CC(C)=O
Reactant: COC=Cc1c(F)cc(Br)cc1F
Agent: [Li]CCCC
Solvent: O
Solvent: COC(C)(C)C
Product: COC=Cc1c(F)cc(C(C)(C)O)cc1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled (−78° C.) solution of 2-(4-bromo-2,6-difluorophenyl)vinyl methyl ether (45 g, 0.18 mol) in methyl tert-butyl ether (300 mL) was added n-BuLi (75 mL of 2.5M in hexanes, 0.19 mol), and the mixture was stirred at −78° C. for one hour. A solution of acetone (13.6 g, 0.24 mol) in methyl tert-butyl ether (100 mL) was added dropwise to the reaction mixture and the resulting solution was stirred at −78° C. for two hours. Water (90 ml) was added to quench the reaction. The resulting biphasic mixture was extracted with ethyl acetate (2×). The organic layers were dried and concentrated in vacuo. Purification via flash chromatography afforded the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1Cl)([O-:3])=[O:2].Cl.[CH2:16]([O:18][NH2:19])[CH3:17].C(N(CC)CC)C>CO>[N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([N+:11]([O-:13])=[O:12])[C:5]=1[NH:19][O:18][CH2:16][CH3:17])([O-:3])=[O:2]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: CCON
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCONc1c([N+](=O)[O-])cc(C)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
A suspension of 10.0 g. (0.046 mole) of 2,6-dinitro-4-methylchlorobenzene in 100 ml. of methanol was prepared, and to the suspension there was added 7.6 g. (0.092 mole) of ethoxyamine hydrochloride, and 13.9 g. (0.138 mole) of triethylamine. The reaction mixture was stirred for about 30 minutes at room temperature and then heated and stirred for about 30 minutes at about 50° C., after which an additional 16.7 g. (0.20 mole) of ethoxyamine hydrochloride was added, and the reaction mixture was stirred and refluxed for about 24 hours. An NMR spectrum of the reaction mixture indicated the presence of the desired product in about 70 percent yield. The reaction product mixture was poured over a mixture of ice and water, and the aqueous mixture filtered. The solid obtained was recrystallized from petroleum ether (b.p. 60°-71° C.) to yield 5.5 g. of product having a melting point of about 64°-66° C. The product was identified by its NMR spectrum as 2,6-dinitro-N-ethoxy-p-toluidine.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH:10]=O)[CH:8]=1)([O-:3])=[O:2].[NH:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>CC#N>[N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][N:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: c1ccc2c(c1)CCN2
Reactant: O=CCn1cc([N+](=O)[O-])cn1
Solvent: CC#N
Product: O=[N+]([O-])c1cnn(CCN2CCc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-(4-nitro-1H-pyrazol-1-yl)acetaldehyde (1.02 g, 4.97 mmol) in MeCN (18.0 mL), indoline (0.56 mL, 4.95 mmol) dissolved in MeCN (6 mL) was added. The resulting orange solution was stirred at rt for 5 min, then STAB (2.10 g, 9.90 mmol) was added in portions. After stirring at rt for 1 h, the reaction mixture was quenched with water and extracted with DCM (2×). The combined org. layers were concentrated and purification was performed by FC (EtOAc/toluene 2:8) to yield 1-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)indoline as a brown solid. LC-MS conditions A: tR=0.85 min, [M+H]+=259.14.
Reaction SMILES: [CH2:1]([N-]CC)C.[Li+].[C:7]([O:11][C:12]1[CH:17]=[C:16]([F:18])[N:15]=[C:14]([F:19])[C:13]=1[F:20])([CH3:10])([CH3:9])[CH3:8].CI>C1COCC1>[C:7]([O:11][C:12]1[C:17]([CH3:1])=[C:16]([F:18])[N:15]=[C:14]([F:19])[C:13]=1[F:20])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)Oc1cc(F)nc(F)c1F
Reactant: CC[N-]CC
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1c(F)nc(F)c(F)c1OC(C)(C)C
Reaction time: 0.83 h

Procedure:
A freshly prepared solution of lithium diethylamide (LDA) (58.21 mmol) in 30 mL of THF at -78° C. was added to 10.0 g (48.74 mmol) of 4-t-butoxy-2,3,6-trifluoropyridine in 50 mL of THF at -78° C, and the reaction was stirred for 50 min. To the reaction mixture was added 4.3 mL (69.07 mmol) of methyl iodide, and the mixture was stirred at -78° C. for 1 hour and stirred at ambient temperature for 16 hours. The reaction was quenched with saturated NH4Cl solution, extracted with hexane, and the extracts washed with water, dried over MgSO4 and concentrated to give 4-t-butoxy-2,3,6-trifluoro-5-methylpyridine as a pale yellow oil, which was taken directly to the next step. MS (220) (M+H)+ ; 1H NMR (CDCl3)∂: 1.47 (m, 9H), 2.12 (m, 3H). 19F NMR (CDCl3, CFCl3 as reference)∂: 75.91 (dd apparent, J1 =15.0, J2 =22.1 Hz), 93.17 (dd apparent, J1 =15.0, J2 =22.1 Hz), 156.54 (m).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][CH:5]=1)=[O:3].[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[C:33]([N:40]1[CH2:48][CH2:47][CH:43]([C:44](O)=[O:45])[CH2:42][CH2:41]1)([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].CCN(C(C)C)C(C)C>CN(C=O)C>[C:36]([O:35][C:33]([N:40]1[CH2:48][CH2:47][CH:43]([C:44](=[O:45])[NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][CH:6]=2)[CH2:42][CH2:41]1)=[O:34])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(NC(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 70.4 %

Procedure:
To a solution of 4-aminoacetophenone (6.76 g, 50 mmol) in DMF (250 ml) were added TOTU (16.40 g, 50 mmol), boc-isonipecotic acid (11.46 g, 50 mmol) and DIPEA (8.6 ml, 50 mmol). The reaction mixture was stirred at ambient temperature for 12 h. The solvent was removed in vacuo. The residue was redissolved in ethyl acetate (250 ml) and washed with sat. sodium hydrogen carbonate solution (2×50 ml), hydrochloric acid (1 N, 50 ml) and brine (50 ml). The organic phase was dried over sodium sulfate, evaporated and recrystallized from ethyl acetate. The product was obtained as white crystalline solid (yield: 12.2 g, 70%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([CH2:17][CH2:18][CH2:19][N:20]([CH2:28][C:29]1[CH:37]=[CH:36][C:32]2[O:33][CH2:34][O:35][C:31]=2[CH:30]=1)C(OC(C)(C)C)=O)[C:7]1[S:11][N:10]=[C:9]([N:12]2[CH:16]=[CH:15][N:14]=[CH:13]2)[N:8]=1)C.[NH3:39]>CO.CCOC(C)=O>[O:33]1[C:32]2[CH:36]=[CH:37][C:29]([CH2:28][NH:20][CH2:19][CH2:18][CH2:17][N:6]([C:7]3[S:11][N:10]=[C:9]([N:12]4[CH:16]=[CH:15][N:14]=[CH:13]4)[N:8]=3)[CH2:5][C:4]([NH2:39])=[O:3])=[CH:30][C:31]=2[O:35][CH2:34]1
Reactant: N
Reactant: CCOC(=O)CN(CCCN(Cc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C)c1nc(-n2ccnc2)ns1
Solvent: CO
Solvent: CCOC(C)=O
Product: NC(=O)CN(CCCNCc1ccc2c(c1)OCO2)c1nc(-n2ccnc2)ns1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
A mixture of [[3-(benzo[1,3]dioxol-5-ylmethyl-tert-butoxycarbonyl-amino)-propyl]-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-acetic acid ethyl ester from Step 1 (115 mg, 211 μmol) and a 2.0 M solution NH3 in MeOH (10 mL) was stirred at r.t. for 24 h. The reaction mixture was concentrated to a yellow oil. The crude residue was dissolved in TFA/DCM (1:1, 3 mL) and stirred at room temperature for 30 min. The solvent was evaporated to afford an orange oil. The crude product was diluted with EtOAc (50 mL), washed with 1M NaOH (50 mL), brine (50 mL), dried over Na2SO4, filtered and concentrated to an oil. Purification was achieved using column chromatography (CH2Cl2 to 4:1 CH2Cl2/MeOH) to afford 53 mg (60%) of 2-[{3-[(benzo[1,3]dioxol-5-ylmethyl)-amino]-propyl}-(3-imidazol-1-yl-[1,2,4]thiadiazol-5-yl)-amino]-acetamide as a white solid. [M+H]+ 415.97; 1H NMR (400 MHz, d6-DMSO) δ 8.29 (s, 1H), 7.72 (s, 1H), 7.63 (br s, 1H), 7.28 (br s, 1H), 7.09 (s, 1H), 6.92 (s, 1H), 6.82 (m, 2H), 5.98 (s, 2H), 4.20 (br s, 1H), 3.60 (s, 2H), 3.33 (s, 2H), 2.54 (m, 4H), 1.80 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[C:7](=[O:14])[C:6]([C:15]([O:17]CC)=O)=[C:5]2[OH:20].[C:21]([NH:30][NH2:31])(=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH3:13])[C:7](=[O:14])[C:6]([C:15]([NH:31][NH:30][C:21](=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:17])=[C:5]2[OH:20]
Reactant: CCCCCCCC(=O)NN
Reactant: CCOC(=O)c1c(O)c2cc(Br)ccc2n(CC)c1=O
Product: CCCCCCCC(=O)NNC(=O)c1c(O)c2cc(Br)ccc2n(CC)c1=O

Procedure:
Reagents: Comp 36 (0.36 mmols, 0.12 g); octanoyl hydrazine (0.4 mmols, 0.06 g). Yield: 0.13 g (80%), white solid, m.p.=171° C.-172° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:22][CH2:21][C@H:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:25]=4[F:34])[C:19]3=[O:35])[CH2:14][CH2:13]2)=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](OC)=[O:8].[Li+].[BH4-]>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[C:3]([N:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:22][CH2:21][C@H:20]([NH:23][C:24]4[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:31])=[O:32])=[CH:26][C:25]=4[F:34])[C:19]3=[O:35])[CH2:16][CH2:17]2)=[N:4][CH:5]=[C:6]([CH2:7][OH:8])[CH:11]=1
Reactant: COC(=O)c1cnc(N2CCC(N3CC[C@H](Nc4ccc(S(C)(=O)=O)cc4F)C3=O)CC2)c(Cl)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(N[C@H]2CCN(C3CCN(c4ncc(CO)cc4Cl)CC3)C2=O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 11.3 %

Procedure:
To a solution of (S)-methyl 5-chloro-6-(4-(3-(2-fluoro-4-(methylsulfonyl)phenylamino)-2-oxopyrrolidin-1-yl)piperidin-1-yl)nicotinate (0.20 g, 0.38 mmol) in THF (20 mL) was added LiBH4 (2 M in THF, 0.19 mL, 0.38 mmol) and the reaction was stirred overnight at ambient temperature. The reaction was diluted with DCM (50 mL) and the organic layer was washed with water (20 mL), 1 N HCl (10 mL), 1 N NaOH (10 mL) and brine (10 mL), and the combined organic phases were dried over MgSO4, filtered and concentrated under vacuum. The crude material was purified on silica using EtOAc as eluent to yield a solid, which was further triturated with isopropanol/hexanes to give (S)-1-(1-(3-chloro-5-(hydroxymethyl)pyridin-2-yl)piperidin-4-yl)-3-(2-fluoro-4-(methylsulfonyl)phenylamino)pyrrolidin-2-one (0.021 g, 0.043 mmol, 11% yield). Mass spectrum (apci) m/z=497.0 (M+H+).
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]1([CH:18]([CH3:20])[CH3:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[CH:18]([C:12]1[CH:17]=[CH:16][C:15]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][CH:13]=1)([CH3:20])[CH3:19]
Reactant: CC(C)c1ccccc1
Reactant: O=CC(=O)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: CC(Cl)Cl
Product: CC(C)c1ccc(C(O)C(=O)c2ccccc2)cc1

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and cumene (0.56 ml, 4 mM) were dissolved in dichloroethane (4 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 4 hours. Using the same procedure as in Example 1, 4'-iso-propylbenzoin was obtained as crystal (300.6 mg, 59.6% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:4][C:3]=1[OH:12].[C:13](O)(=[O:20])[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.N1C=CC=CC=1>O>[C:8]([C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:13](=[O:20])[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[C:3]([OH:12])[CH:4]=1)([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(C)(C)c1ccc(N)c(O)c1
Reactant: O=C(O)c1ccncc1
Agent: CCN=C=NCCCN(C)C
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)c1ccc(NC(=O)c2ccncc2)c(O)c1
Temperature: 80 °C
Yield: 51.9 %

Procedure:
A mixture of 1.44 g of 2-amino-5-tert-butylphenol, 1.07 g of isonicotinic acid, 2.17 g of WSC and 15 ml of pyridine was stirred while heating at 80° C. for five hours. The reaction mixture was cooled to room temperature, and then water was poured. Precipitated solid was filtered and washed with water and diethyl ether to give 1.22 g of N-(4-tert-butyl-2-hydroxyphenyl)isonicotinamide.
Reaction SMILES: [CH2:1]([N:9]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]1=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:16]([NH2:24])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:9]1[C:10](=[O:15])[CH2:11][CH:12]([NH:24][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[C:13]1=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCN
Reactant: CCCCCCCCN1C(=O)C=CC1=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCCCCCCNC1CC(=O)N(CCCCCCCC)C1=O

Procedure:
A mixture of N-octyl maleimide (0.01 M) prepared as described in Example 10 above, octylamine (0.01 M), triethylamine [catalytic, 0.1 equivalent] in acetonitrile (25 ml) was stirred for 24 hours at room temperature. Acetonitrile was removed under vacuum to leave a residual liquid product which was flash chromatographed (25% ethyl acetate in petroleum ether) to yield a white solid as the desired product.