Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:10]3([CH2:15][CH2:16][CH2:17][CH:18]=2)[O:14][CH2:13][CH2:12][O:11]3)O1.Br[C:21]1[CH:26]=[C:25]([Cl:27])[N:24]=[N:23][C:22]=1[NH2:28].C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:27][C:25]1[N:24]=[N:23][C:22]([NH2:28])=[C:21]([C:9]2[C:10]3([CH2:15][CH2:16][CH2:17][CH:18]=2)[O:11][CH2:12][CH2:13][O:14]3)[CH:26]=1
Reactant: Nc1nnc(Cl)cc1Br
Reactant: CC1(C)OB(C2=CCCCC23OCCO3)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Nc1nnc(Cl)cc1C1=CCCCC12OCCO2
Yield: 42.9 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 39a by using the 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4-dioxaspiro[4.5]dec-6-ene (0.64 g, 2.40 mmol) prepared in Example 82a, 4-bromo-6-chloropyridazin-3-amine (0.50 g, 2.40 mmol), tetrakis(triphenylphosphine)palladium (0) (0.14 g, 0.12 mmol), cesium carbonate (1.72 g, 5.29 mmol), dioxane (8.0 mL) and water (4.0 mL), to yield the title compound (275.7 mg, 43%) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22]C)=[O:21])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl>[OH-].[Na+].CO.CS(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([OH:22])=[O:21])=[C:14]([CH3:17])[CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COC(=O)C(C)(C)Cc1cc2cnn(-c3ccc(F)cc3)c2cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: CO
Product: Cc1cc2c(cnn2-c2ccc(F)cc2)cc1CC(C)(C)C(=O)O
Yield: 77.7 %

Procedure:
Methyl 3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2,2-dimethylpropanoate (121 mg, 0.355 mmol) was heated to 100 C overnight in a mixture of 2 M NaOH/MeOH/DMSO (1:1:1). The next day, the reaction was cooled, acidified to pH 5 with HCl and extracted 2×EtOAc. The organic layers were washed with water×2, dried over MgSO4, filtered, and concentrated in vacuo to give 90 mg (80% yield) of acid 3-(1-(4-fluorophenyl)-6-methyl-1H-indazol-5-yl)-2,2-dimethylpropanoic acid. MS found: (M+H)+=327.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])[C:3]=1[CH3:21].[O:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:33]([NH2:34])=[CH:32][C:31]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[CH:30][N:29]=2)[CH2:24][CH2:23]1>C1(C)C=CC=CC=1>[N:25]1([C:28]2[C:33]([NH:34][C:2]3[C:11]4[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=4[F:12])[N:5]=[C:4]([N:14]4[CH2:19][CH2:18][CH2:17][CH2:16][C:15]4=[O:20])[C:3]=3[CH3:21])=[CH:32][C:31]([N:35]3[CH2:36][CH2:37][O:38][CH2:39][CH2:40]3)=[CH:30][N:29]=2)[CH2:24][CH2:23][O:22][CH2:27][CH2:26]1
Reactant: Nc1cc(N2CCOCC2)cnc1N1CCOCC1
Reactant: Cc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Cl
Solvent: Cc1ccccc1
Product: Cc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Nc1cc(N2CCOCC2)cnc1N1CCOCC1

Procedure:
Prepared according to Procedure H using 1-(4-chloro-5,7-difluoro-3-methylquinolin-2-yl)piperidin-2-one (35.0 mg, 0.113 mmol) and 2,5-dimorpholinopyridin-3-amine in toluene to give 1-(4-((2,5-di-4-morpholinyl-3-pyridinyl)-amino)-5,7-difluoro-3-methyl-2-quinolinyl)-2-piperidinone. 1H NMR (CDCl3) δ ppm 8.01 (1H, br. s.), 7.60 (1H, d, J=2.5 Hz), 7.47 (1H, d, J=9.8 Hz), 6.99 (1H, ddd, J=13.7, 8.6, 2.5 Hz), 6.51 (1H, br. s.), 4.33 (1H, br. s.), 3.83-4.01 (4H, m), 3.77-3.83 (4H, m), 3.48-3.59 (1H, m), 3.41 (2H, br. s.), 3.16 (4H, br. s,), 2.89-3.07 (2H, m), 2.50-2.61 (2H, m), 1.88-2.19 (7H, m). Mass Spectrum (ESI) m/e=539.2 (M+1).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]2[O:13][C:12]([CH3:15])([CH3:14])[C:11]([CH3:17])([CH3:16])[O:10]2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[NH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1>CCOCC>[CH3:16][C:11]1([CH3:17])[C:12]([CH3:15])([CH3:14])[O:13][B:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)=[CH:4][CH:5]=2)[O:10]1
Reactant: C1CCNC1
Reactant: CC1(C)OB(c2ccc(CBr)cc2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC1(C)OB(c2ccc(CN3CCCC3)cc2)OC1(C)C
Temperature: 80 °C

Procedure:
A suspension of 2-(4-(bromomethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (5.18 g, 17.44 mmol), potassium carbonate (2.89 g, 20.93 mmol) and N,N-dimethylformamide (75 mL) was treated with pyrrolidine (1.875 mL, 22.67 mmol), and the reaction was heated to 80° C. for 1 hour. The reaction was cooled to ambient temperature, diluted with ether (115 mL), and filtered. The filtrate was concentrated to dryness to provide the title compound. MS ESI(+) m/z 288.2 [M+H]+.
Reaction SMILES: C(OC([N:8]([CH3:33])[C:9]1[CH:32]=[CH:31][C:12]2[N:13]=[C:14]([C:16]3[CH:17]=[CH:18][C:19](CNC(=O)OC(C)(C)C)=[N:20][CH:21]=3)[S:15][C:11]=2[CH:10]=1)=O)(C)(C)C.[CH3:34][NH:35]C1N=CC(C2SC3C=C(N)C=CC=3N=2)=CC=1>>[CH3:33][NH:8][C:9]1[CH:32]=[CH:31][C:12]2[N:13]=[C:14]([C:16]3[CH:21]=[N:20][C:19]([NH:35][CH3:34])=[CH:18][CH:17]=3)[S:15][C:11]=2[CH:10]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc2nc(-c3ccc(CNC(=O)OC(C)(C)C)nc3)sc2c1
Reactant: CNc1ccc(-c2nc3ccc(N)cc3s2)cn1
Product: CNc1ccc2nc(-c3ccc(NC)nc3)sc2c1

Procedure:
tert-Butyl (5-{6-[(tert-butoxycarbonyl)(methyl)amino]-1,3-benzothiazol-2-yl}pyridin-2-yl)methylcarbamate (53 mg, 0.11 mmol) was reacted according to the procedure used for the preparation of 2-(6-methylaminopyridin-3-yl)benzothiazol-6-amine. This gave the title compound (20 mg) as a yellow solid. 1H NMR δ 8.56 (d, 1H) 7.91 (dd, 1H) 7.63 (d, 1H) 7.12 (br q, 1H) 7.00 (d, 1H) 6.75 (dd, 1H) 6.55 (d, 1H) 5.99 (br q, 1H) 2.84 (d, 3H) 2.73 (d, 3H); MS m/z (M+H) 271.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].F[C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=1.O>CN(C=O)C>[N+:19]([C:16]1[CH:17]=[CH:18][C:13]([O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:14][CH:15]=1)([O-:21])=[O:20]
Reactant: O=Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(Oc2ccc([N+](=O)[O-])cc2)cc1
Yield: 72.4 %

Procedure:
A solution of 61 g (0.5 mole) of 4-hydroxybenzaldehyde in 20 mL of dry DMF was added to a suspension of 0.5 mole of sodium hydride (from 24 g of 50% sodium hydride washed free of oil with hexane) in 500 mL of DMF. When the sodium hydride had completely dissolved, a solution of 53 mL (0.55 mole) of 4-fluoronitrobenzene was added and the reaction mixture was heated to 70°-80° C. for 2 hr. The mixture was then poured into water, the solid collected and recrystallized from iso-propanol. The solid was recrystallized again from ethanol to give 88 g (85% yield) of the title compound as a yellow solid, mp=101°-104° C.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:17]([CH2:18][CH2:19][C@:3]12[CH3:4])[C:16]1[CH:15]=[CH:14][C:13]([OH:20])=[CH:12][C:11]=1[CH2:10][CH2:9]3.[C:21](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.O>C(O)C>[CH3:21][O:20][C:13]1[CH:14]=[CH:15][C:16]2[C@@H:17]3[C@H:8]([C@H:5]4[C@@:3]([CH2:19][CH2:18]3)([CH3:4])[C:2](=[CH2:1])[CH2:7][CH2:6]4)[CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: C=C1CC[C@H]2[C@@H]3CCc4cc(O)ccc4[C@H]3CC[C@]12C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: O
Solvent: CCO
Product: C=C1CC[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]12C
Yield: 68.5 %

Procedure:
To a stirred suspension of 17-methylenestra-1,3,5(10)-trien-3-ol (5.37 g, 20.0 mmol) and potassium carbonate (50.82 g, 0.3678 mol) at reflux in 90% ethanol (500 mL) was added dimethyl sulfate (5.0 mL, 53 mmol). After 1/2 h reflux additional dimethyl sulfate (36 mL, 0.38 mol, in three 12 mL aliquots) was added over the period of 1 h. See FIG. 17. The reaction was refluxed a further hour, following which 360 mL of water were added and the mixture was placed in the refrigerator overnight. The resulting suspension was filtered and washed with 80 mL of 60% methanol+three 80 mL portions of 5% (w/w) sodium hydroxide+three 80 mL portions of water. The residue was recrystallized from aqueous methanol to give white crystals (3.88 g, 13.7 mmol, 69%), m.p. 59°-62° C. TLC (20% ethyl acetate/hexanes on silica gel) showed product (Rf 0.63) with trace contaminants at Rf 0.37 and at the origin. (NA-1994A-247)
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[CH:8]=[CH:9][CH:10]=1.CC(C)([O-])C.[K+].Cl.Cl[CH2:28][CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][N:31]1[CH3:35]>CC(N(C)C)=O>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[O:19][CH2:28][CH2:29][CH:30]2[CH2:34][CH2:33][CH2:32][N:31]2[CH3:35])[CH:8]=[CH:9][CH:10]=1
Reactant: COCOc1cccc(CCc2ccccc2O)c1
Reactant: CN1CCCC1CCCl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COCOc1cccc(CCc2ccccc2OCCC2CCCN2C)c1
Yield: 55.2 %

Procedure:
Following a procedure similar to that described in Example 35(a), 2.37 g of 2-[2-(3-methoxymethoxyphenyl)ethyl]phenol (prepared as described in Preparation 21), 1.03 g of potassium t-butoxide and 1.69 g of 2-(2-chloroethyl)-1-methylpyrrolidine hydrochloride were reacted in 50 ml of dimethylacetamide. The reaction mixture was then worked up as described in Example 35(a), and the crude product was purified by column chromatography through silica gel, using a 20:1 by volume mixture of methylene chloride and methanol as the eluent, to give 1.87 g (yield 62%) of the title compound as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[C:18]2[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=2[NH:16][C:15]1=[O:32])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:34][C:35]([O:37][CH3:38])=[O:36].C(O)(=O)C>CN(C)C=O.O>[CH2:3]([O:10][C:11]([NH:13][CH:14]1[N:20]=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[F:27])[C:18]2[CH:28]=[CH:29][CH:30]=[CH:31][C:17]=2[N:16]([CH2:34][C:35]([O:37][CH3:38])=[O:36])[C:15]1=[O:32])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: O=C(NC1N=C(c2ccccc2F)c2ccccc2NC1=O)OCc1ccccc1
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: COC(=O)CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(c2ccccc2F)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.8 %

Procedure:
To a suspension of sodium hydride (0.294g of a 60 % dispersion in mineral oil (7.36 mmol) in N,N-dimethylformamide (20 ml) was added slowly (3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-(2-fluorophenyl)-1H-1,4-benzodiazepin-2-one (2.70 g) under cooling in an ice-bath. The mixture was stirred at the same temperature for 0.5 hour and at ambient temperature for 1 hour. To the mixture was added dropwise a solution of methyl bromoacetate (1.13 g) in N,N-dimethylformamido (5 ml) under cooling in an ice-bath. The mixture was stirred at ambient temperature overnight. To the reaction mixture was added acetic acid (1 ml) and stirred for 0.5 hour. The resultant was poured into water (100 ml) and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford (3RS)-3-benzyloxycarbonylamino-2,3-dihydro-5-(2-fluoro-phenyl)-1-(methoxycarbonylmethyl)-1H-1,4-benzodiazepin-2-one (3.4 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[C:32]([F:36])=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:11][C@@H:10]([C:37](O)=[O:38])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH4+].[N:41]1(O)C2C=CC=CC=2N=N1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:37]([C@@H:10]1[CH2:11][C@H:12]([N:14]([C:19]([C:21]2[N:25]([CH2:26][CH2:27][CH2:28][CH2:29][O:30][CH3:31])[C:24]3[C:32]([F:36])=[CH:33][CH:34]=[CH:35][C:23]=3[N:22]=2)=[O:20])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])[CH2:9]1)(=[O:38])[NH2:41]
Reactant: On1nnc2ccccc21
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)O)CN(C(=O)OC(C)(C)C)C2)nc2cccc(F)c21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(N)=O)CN(C(=O)OC(C)(C)C)C2)nc2cccc(F)c21
Temperature: 50 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
(3R,5S)-1-(tert-Butoxycarbonyl)-5-[{[7-fluoro-1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]piperidine-3-carboxylic acid (360 mg), 1H-1,2,3-benzotriazol-1-ol ammonium salt (250 mg) and triethylamine (360 μl) were dissolved in DMF (10 ml), WSC.HCl (315 mg) was added, and the mixture was stirred at 50° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, diluted with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (3:7)-ethyl acetate-ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object product (263 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1([O:18][CH2:19][CH2:20]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]12[CH2:7][N:8]([CH2:9][CH2:10]1)[CH2:20][CH2:19][O:18]2
Reactant: Cc1ccc(S(=O)(=O)OCCOC2(c3nccs3)CCN(C(=O)OC(C)(C)C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: c1csc(C23CCN(CCO2)C3)n1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To an ambient solution of tert-butyl 3-(thiazol-2-yl)-3-(2-(tosyloxy)ethoxy)pyrrolidine-1-carboxylate (2.3 g, 4.91 mmol) in dichloromethane (24.54 ml) was added trifluoroacetic acid (0.378 mL, 4.91 mmol). The reaction was stirred for 2 hours and was then concentrated under reduced pressure. The residue was dissolved in dichloromethane (10 mL), and the solution was added slowly to an ambient mixture of potassium carbonate (6.78 g, 49.1 mmol) in dichloromethane (50 mL). The mixture was heated to 50° C. for 1 hour and then cooled to room temperature. The reaction was diluted with water (100 mL). The layers were separated, and the aqueous layer was extracted with additional dichloromethane (2×). The combined organics were dried with anhydrous sodium sulfate, filtered and dried under reduced pressure, to give the title compound, which was used without further purification. MS ESI(+) m/z 197.1 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]2[C:13](=O)[CH2:14][O:15][C:11]=2[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:22].CN([CH:26]=[O:27])C>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:12]2[C:26](=[O:27])[C:14]([CH3:13])([CH3:22])[O:15][C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CI
Reactant: O=C1COc2cc(OCc3ccccc3)ccc21
Agent: [H-]
Agent: [Na+]
Product: CC1(C)Oc2cc(OCc3ccccc3)ccc2C1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 47 %

Procedure:
To a solution of 6-(benzyloxy)benzofuran-3(2H)-one (Adams, J. L., et al., J. Med. Chem. (1996), 39(26):5035-46) (1.60 g, 6.67 mmol) in DMF (50.0 mL) were added sodium hydride (0.59 g, 14.7 mmol) and iodomethane (1.46 mL, 23.3 mmol) at 0° C. The reaction mixture was stirred at ambient temperature for 16 h and quenched with saturated ammonium chloride (50.0 mL). The aqueous mixture was extracted with ethyl acetate (3×50.0 mL). The combined organic layers was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/10) to give the title compound (0.85 g, 47%): 1H NMR (300 MHz, CDCl3) δ 7.55 (d, 1H), 7.44-7.30 (m, 5H), 6.69 (dd, 1H), 6.54 (d, 1H), 5.10 (s, 2H), 1.43 (s, 6H); MS (ES+) m/z 269.5 (M+1).
Reaction SMILES: C[C:2]1[N:6]=[C:5](C2CCCNC2)[O:4][N:3]=1.[C:13]([OH:22])(=[O:21])[C@H:14]([C@@H:16]([C:18]([OH:20])=[O:19])[OH:17])[OH:15].C(#N)C>CO>[C:18]([C@H:16]([C@@H:14]([C:13]([O-:22])=[O:21])[OH:15])[OH:17])([O-:20])=[O:19].[O:4]1[CH:5]=[N:6][CH:2]=[N:3]1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Reactant: Cc1noc(C2CCCNC2)n1
Solvent: CO
Solvent: CC#N
Product: O=C([O-])[C@@H](O)[C@H](O)C(=O)[O-]
Product: c1ncon1
Temperature: 25 °C

Procedure:
Methyl-5-(piperidin-3-yl)-1,2,4-oxadiazole (0.83 g, 0.0050 mol) and D-tartaric acid (0.74 g, 0.0050 mol) were dissolved in hot methanol (10 mL) and the solution was refluxed for 15 minutes. 30 mL of acetonitrile was added and the resulting solution was allowed to cool to room temperature. The crystals were filtered, washed with 10 mL of 1:3 methanol:acetonitrile, and recrystallized 3 times from methanol:acetonitrile (10 mL 20 mL) as before to give the D-tartrate salt of S-(+)-3-methyl-5-piperidin-3-yl)-1,2,4-oxadiazole (3a), 193 mg white solid. The optical purity 100% ee, as determined by HPLC analysis (Chiral Technologies Chiral-AGP, 4.0 mm×150 mm, 0.5% methanol 20 mM sodium phosphate pH=7). MS (ESI) m/z 168 [M+1]+. 1H NMR (DMSO-d6) δ 1.67-1.79 (m, 3H), 2.10-2.13 (m, 1H), 2.33 (s, 3H), 2.76-2.82 (t, 1H), 3.01-3.14 (m, 2H), 3.31-3.36 (m, 1H), 3.44-3.47 (m, 1H), 3.95 (s, 1H).
Reaction SMILES: [BH4-].[Na+].C(COC)OC.[C:9]([O:19][C:20]([C:26]([O:29][C:30]([C:36]([O:39][C:40]([C:46]([O:49][C:50]([C:56]([O:59][C:60]([C:66]([O:69][C:70]([C:76](OC)=[O:77])([C:72]([F:75])([F:74])[F:73])[F:71])([F:68])[F:67])([C:62]([F:65])([F:64])[F:63])[F:61])([F:58])[F:57])([C:52]([F:55])([F:54])[F:53])[F:51])([F:48])[F:47])([C:42]([F:45])([F:44])[F:43])[F:41])([F:38])[F:37])([C:32]([F:35])([F:34])[F:33])[F:31])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[F:21])([C:12]([C:15]([F:18])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10].Cl>O.CO>[C:9]([O:19][C:20]([C:26]([O:29][C:30]([C:36]([O:39][C:40]([C:46]([O:49][C:50]([C:56]([O:59][C:60]([C:66]([O:69][C:70]([CH2:76][OH:77])([C:72]([F:73])([F:74])[F:75])[F:71])([F:67])[F:68])([C:62]([F:63])([F:64])[F:65])[F:61])([F:58])[F:57])([C:52]([F:53])([F:54])[F:55])[F:51])([F:48])[F:47])([C:42]([F:45])([F:44])[F:43])[F:41])([F:38])[F:37])([C:32]([F:35])([F:34])[F:33])[F:31])([F:28])[F:27])([C:22]([F:25])([F:24])[F:23])[F:21])([C:12]([C:15]([F:18])([F:17])[F:16])([F:14])[F:13])([F:11])[F:10]
Reactant: COC(=O)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: COCCOC
Product: OCC(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(OC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F)C(F)(F)F
Temperature: 50 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
A stirred mixture of 30 g NaBH4 (Aldrich), 50 mL HFE, and 400 mL dry dimethoxyethane was treated over 6 hours with 1000 g C3F7O(CF(CF3)CF2O)5CF(CF3)COOCH3, resulting in an exotherm, and the mixture was stirred at 50° C. overnight. After cooling, the mixture was cautiously treated with first 50 mL MeOH and then 75 mL 5% HCl, with the first few mL of HCl causing vigorous foaming. Addition of 300 mL water, filtration of some white solid at the interphase, and stripping the lower layer gave 931 g C3F7O(CF(CF3)CF2O)5CF(CF3)CH2OH. A solution of 322 g of this and 38.9 g diisopropylethylamine (Aldrich) in 150 mL HFE was treated dropwise with 25.0 g acryloyl chloride (Aldrich), forming a white solid. This was stirred overnight at 50° C., cooled, treated with 4 mL water, 5.0 g K2CO3, and 25 g silica gel, waiting about 2 hours between each addition. The mixture was filtered and stripped to give 297.5 g of HFPO-5-DHA.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH:25]1([NH:28][C:29]([NH:31][NH2:32])=[S:30])[CH2:27][CH2:26]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>CCOC(C)=O.CCO>[F:12][C:9]([F:11])([F:10])[C:7]1[CH:6]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([NH:32][NH:31][C:29](=[S:30])[NH:28][CH:25]3[CH2:27][CH2:26]3)=[O:21])[N:14]=2)[CH:4]=[C:3]([C:2]([F:24])([F:1])[F:23])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: NNC(=S)NC1CC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)NNC(=S)NC1CC1
Temperature: -60 °C
Reaction time: 1 h
Yield: 9.1 %

Procedure:
In a 50 mL, 3-neck round-bottom flask, (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (Example 1, Step 4; 0.5 g, 1.0 eq.) was dissolved in EtOAc:EtOH (15 mL, 2:1) and cooled to −60° C. where N-cyclopropylhydrazinecarbothioamide (0.22 g, 1.2 eq.) was introduced dropwise. T3P (50% in EtOAc) (1.69 mL, 2 eq.) was added dropwise followed by DIPEA (1 mL, 4 eq.) and the reaction mixture was stirred for 1 h at −60° C. The reaction mixture was concentrated under reduced pressure (25° C., 20 mm Hg) to afford the crude product that was purified by column chromatography (60/120 silica gel) using methanol/dichloromethane gradient (the column was packed in dichloromethane and the desired compound started eluting from 3% methanol/dichloromethane). Fractions containing the desired compounds were combined to afford (Z)-2-(3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acryloyl)-N-cyclopropylhydrazinecarbothioamide (0.06 g, yield: 9%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[S:6][CH:7]=1.[CH2:24]([NH:27][CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]>O1CCCC1>[CH2:24]([N:27]([CH2:2][C:3]1[N:4]=[C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[C:15](=[O:22])[N:14]([CH3:23])[CH2:13][C:12]=23)[S:6][CH:7]=1)[CH2:28][CH2:29][CH3:30])[CH2:25][CH3:26]
Reactant: CN1Cc2c(-c3nc(CCl)cs3)ncn2-c2ccccc2C1=O
Reactant: CCCNCCC
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1csc(-c2ncn3c2CN(C)C(=O)c2ccccc2-3)n1
Yield: 56.4 %

Procedure:
A solution of 1.0 g (0.0029 mol) of 3-(4-chloromethyl-thiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]-benzodiazepin-6-one in 60 ml of tetrahydrofuran was treated with 7.9 ml (0.058 mol) of dipropylamine. After stirring at reflux for 16 hrs. the solution obtained was completely freed from the solvents. The residue was chromatographed over silica gel with ethyl acetate and the eluent and recrystallized from hot isopropyl ether. There was obtained 0.67 g (56%) of 3-(4-dipropylaminomethyl-thiazol-2-yl)-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as white crystals; m.p. 111°-112°.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[C:5]([C:9]([O:11]CC)=[O:10])[S:6][C:7]=1[I:8])#[N:2].[OH-].[Na+]>O1CCCC1.O>[C:1]([C:3]1[C:4]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])=[C:5]([C:9]([OH:11])=[O:10])[S:6][C:7]=1[I:8])#[N:2]
Reactant: CCOC(=O)c1sc(I)c(C#N)c1-c1ccc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(I)sc(C(=O)O)c1-c1ccc(Cl)cc1Cl
Reaction time: 8 h
Yield: 111.2 %

Procedure:
To a solution of ethyl 4-cyano-3-(2,4-dichlorophenyl)-5-iodothiophene-2-carboxylate (1.44 g, 0.00318 mol) in tetrahydrofuran (20 mL) and water (10 mL) was added a solution of 1.00M sodium hydroxide in water (16 mL). The solution was allowed to stir overnight. The reaction was quenched with a solution of 1N HCl (18 mL) and extracted with ethyl acetate. The organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford the crude title compound (1.50 g, 100%) used directly in the next reaction. LCMS: (FA) ES−, 422. 1H NMR (400 MHz, d6-DMSO) δ: 7.68 (d, 1H, J=2.0 Hz), 7.46-7.34 (m, 2H).