Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[CH:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1>C(O)(=O)C.CCO>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH:12]=[N:9][NH:8][C:6](=[O:7])[C:5]2[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][CH:4]=2)=[CH:14][CH:15]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NNC(=O)c1ccc(O)cc1
Solvent: CCO
Solvent: CC(=O)O
Product: COc1ccc(C=NNC(=O)c2ccc(O)cc2)cc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
To a solution of 4-hydroxybenzhydrazide (0.3 g, 0.002 mol) and p-anisaldehyde (0.27 g, 0.002 mol) in abs. EtOH (10 mL) was added 1 drop of acetic acid. The reaction mixture was refluxed for 4 hours. The reaction mixture was cooling to room temperature and concentrated to remove solvent. The resulting residue was solidified by EtOAc to give white solid 0.51 g, in 93% yield, mp: 209.0° C. 1H NMR (CD3OD) δ 8.23 (s, 1H), 7.82 (d, 2H), 7.76 (d, 2H), 6.97 (d,2H), 6.87 (d, 2H), 3.82 (s, 3H). 13C NMR (CD3OD) δ 166.8, 163.2, 162.7, 149.8, 130.8, 130.4, 128.2, 124.8, 116.3, 115.2, 55.9. Anal. Calcd for C15H14N2O3: C, 66.66; H, 5.22; N, 10.36. Found: C, 66.82; H, 5.28; N, 10.38.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[N:22]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.CCOC(C)=O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]([OH:3])[CH3:2])=[CH:9][CH:8]=2)(=[O:12])=[O:11])=[C:15]([N:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[N:22]2)[CH:16]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To 4-acetyl-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-benzene-sulfonamide (synthesized according to general procedures F and G, 500 mg, 1.17 mmol) in MeOH (5 mL) was added NaBH4 (144 mg, 3.81 mmol) at 0° C. and the mixture was stirred for one hour at room temperature. The reaction mixture was then diluted with EtOAc (50 mL) and the organics were washed with saturated aqueous NH4Cl (50 mL), water (50 mL), and brine (50 mL). The organics were subsequently dried (Na2SO4), concentrated in vacuo, and purified by automated flash chromatography to obtain the title compound as foamy white solid (424 mg) in 84% yield: MS (ES) M+H expected 430.1, found 430.1.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[C:9]([C:11](Cl)=[O:12])[S:8][C:7]=2[CH:14]=1.[NH:17]1[CH2:20][CH:19]([N:21]2[CH2:26][CH2:25][N:24]([C:27](=[O:32])[C:28]([F:31])([F:30])[F:29])[CH2:23][CH2:22]2)[CH2:18]1>C(Cl)Cl>[F:31][C:28]([F:29])([F:30])[C:27]([N:24]1[CH2:23][CH2:22][N:21]([CH:19]2[CH2:20][N:17]([C:11]([C:9]3[S:8][C:7]4[CH:14]=[C:3]([C:2]([F:16])([F:15])[F:1])[CH:4]=[CH:5][C:6]=4[CH:10]=3)=[O:12])[CH2:18]2)[CH2:26][CH2:25]1)=[O:32]
Reactant: O=C(N1CCN(C2CNC2)CC1)C(F)(F)F
Reactant: O=C(Cl)c1cc2ccc(C(F)(F)F)cc2s1
Solvent: ClCCl
Product: O=C(c1cc2ccc(C(F)(F)F)cc2s1)N1CC(N2CCN(C(=O)C(F)(F)F)CC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 6-(trifluoromethyl)benzo[b]thiophene-2-carbonyl chloride (2.03 mmol, 537 mg) in CH2Cl2 (5 mL) was added to a solution of 1-(4-azetidin-3-yl-piperazin-1-yl)-2,2,2-trifluoro-ethanone (2.26 mmol, 700 mg) and TEA in CH2Cl2 (15 mL) at 0° C. The resulting mixture was allowed to warm to room temperature and was stirred for 2 h. Following workup and extraction, the residue was purified by flash column chromatography (silica gel, 3% methanol/CH2Cl2) to yield 2,2,2-trifluoro-1-(4-(1-(6-(trifluoromethyl)benzo[b]thiophene-2-carbonyl)azetidin-3-yl)piperazin-1-yl)ethanone.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:23])[N:4]2[C:16](=[CH:17][C:18]=1[C:19](=[O:22])[CH2:20][CH3:21])[C:7]1=[N:8][C:9]3[C:14]([CH:15]=[C:6]1[CH2:5]2)=[CH:13][CH:12]=[CH:11][CH:10]=3.Cl[Al](CC)CC.Br[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33].[K].C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>O1CCCC1.[Zn].C([O-])(=O)C.[Ag+].C(O)C>[OH:22][C:19]([C:18]1[CH:17]=[C:16]2[N:4]([CH2:5][C:6]3[C:7]2=[N:8][C:9]2[C:14]([CH:15]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3](=[O:23])[C:2]=1[CH3:1])([CH2:20][CH3:21])[CH2:31][C:32]([O:34][CH2:35][CH3:36])=[O:33]
Reactant: CCC(=O)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Reactant: CCOC(=O)CBr
Agent: [Ag+]
Agent: CC(=O)[O-]
Agent: CC[Al](Cl)CC
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC(O)(CC)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.6 %

Procedure:
A suspension of zinc (1.25 g, 19.1 mmol), 8-methyl-7-propionylindolizino[1,2-b]quinoline-9-(11H)-one (500 mg, 1.43 mmol, as obtained by Kingsburry, W. D., Tetrahedron Lett. 29:6847 (1988)) and silver acetate (250 mg, 1.50 mmol) in anhydrous tetrahydrofuran (10 ml) is agitated at ambient temperature under an argon atmosphere. After 10 minutes, the reaction mixture is activated by the dropwise addition of a molar solution of chlorodiethylaluminium (10 ml, 10 mmol), then ethyl bromoacetate (1.25 ml, 11.3 mmol) is added dropwise and the resultant mixture is left to react for another 5 hours. The reaction is stopped by the successive addition of ethyl alcohol (10 ml) and a saturated solution of potassium and sodium tartrate (10 ml). The resultant mixture is agitated for another hour, filtered and concentrated under reduced pressure. The residue is taken up in dichloromethane (30 ml), washed with water, dried, concentrated and purified by column chromatography (SiO2, CH2Cl2/MeOH:98/2), which produces 93 mg (1.5%) of desired product in the form of a pale yellow solid, m.p. 185–188° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([CH:11]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)(=O)C1C(=CC=CC=1)O.C1(C)C(C)=CC=CC=1.[OH-].[Ca+2:45].[OH-]>O.CO>[CH3:12][CH:11]([C:8]1[CH:7]=[C:3]([C:4]([O-:6])=[O:5])[C:2]([OH:1])=[CH:10][CH:9]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].[Ca+2:45].[CH3:12][CH:11]([C:8]1[CH:7]=[C:3]([C:4]([O-:6])=[O:5])[C:2]([OH:1])=[CH:10][CH:9]=1)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCC(C)c1ccc(O)c(C(=O)O)c1
Agent: O=C(O)c1ccccc1O
Agent: [Ca+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: Cc1ccccc1C
Product: CCCCCCCCCCCCCC(C)c1ccc(O)c(C(=O)[O-])c1

Procedure:
The title compound in 4 g of base oil XOMAPE 150 (9.12 g, Basicity Index 1.21) was prepared as outlined in Example 4 by employing 5-(pentadecy-2-yl)salicylic acid (Example 9, 3.33 g), a commercial lower alkyl (i.e. less than C20) salicylic acid (Infineum M7103, obtainable from Infineum UK Limited, 3.70 g), xylene (203.33 g), calcium hydroxide (1.56 g), and a promoter (methanol:water (97%:3%), 23.37 ml).
Reaction SMILES: [C:1]([NH2:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[CH2:34]([O:36][C:37]([N:39]1[C:43]2[S:44][C:45]([C:47](O)=[O:48])=[CH:46][C:42]=2[C:41]([NH:50][C:51](=[O:64])[C:52]2[CH:57]=[CH:56][C:55]([N:58]3[CH2:63][CH2:62][O:61][CH2:60][CH2:59]3)=[CH:54][CH:53]=2)=[N:40]1)=[O:38])[CH3:35].CCN(C(C)C)C(C)C>CN(C)C=O.O>[CH3:2][C:1]([NH:10][C:47]([C:45]1[S:44][C:43]2[N:39]([C:37]([O:36][CH2:34][CH3:35])=[O:38])[N:40]=[C:41]([NH:50][C:51](=[O:64])[C:52]3[CH:57]=[CH:56][C:55]([N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)=[CH:54][CH:53]=3)[C:42]=2[CH:46]=1)=[O:48])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(C)(N)c1ccccc1
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCOCC3)cc2)c2cc(C(=O)O)sc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCOCC3)cc2)c2cc(C(=O)NC(C)(C)c3ccccc3)sc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.2 %

Procedure:
A mixture of cumylamine (1.43 g, 10.6 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU, 3.40 g, 10.6 mmol), 1-(ethoxycarbonyl)-3-[(4-morpholin-4-ylbenzoyl)amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid hydrochloride (3.40 mg, 7.07 mmol) and N,N′-diisopropylethylamine (12.1 mL, 7.07 mmol) in 80 mL of dimethylformamide was stirred at room temperature for 20 hours. Afterward the reaction mixture was diluted with water and extracted with dichloromethane. Volatiles were removed by evaporation under reduced pressure and the residue was triturated with ethyl acetate, filtered, extensively washed with diethyl ether and dried under vacuum at 40° C., to give 3.7 g of the title compound, used in the next step without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.[CH:12]([N:14]1[C:20]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=2[C:18]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[N:17][CH2:16][CH2:15]1)=O.[Al]>O>[CH3:12][N:14]1[C:20]2[CH:21]=[CH:22][C:23]([Cl:25])=[CH:24][C:19]=2[CH:18]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:17][CH2:16][CH2:15]1
Reactant: O=CN1CCN=C(c2ccccc2)c2cc(Cl)ccc21
Agent: [Al+3]
Agent: [Al]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CN1CCNC(c2ccccc2)c2cc(Cl)ccc21
Temperature: 55 °C
Reaction time: 1 h

Procedure:
To a suspension of 400 mg. of lithium aluminum hydride in 10 ml. of tetrahydrofuran is added a solution of 600 mg. of 1-formyl-5-phenyl-7-chloro-2,3-dihydro-1H-1,4-benzodiazepine in 40 ml. of tetrahydrofuran at a room temperature. After the reaction mixture is stirred for one hour at 55° C., water is added thereto carefully. The addition of water is stopped when an aluminum compound begin to precipitate on the bottom of the flask, and the precipitate is removed by filtration. The filtrate is concentrated under a reduced pressure to a solidal substance. The solidal substance is recrystallized from a solvent mixture of benzene and n-hexane to give 400 mg. of 1-methyl-5-phenyl-7-chloro-1,2,4,5-tetrahydro-1H-benzodiazepine, melting point 128°-129° C.
Reaction SMILES: N([O-])=O.[Na+].C(O)(=[O:7])C.N[C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:20][C:19]3[CH2:21][N:22]([C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:23][C:18]=3[CH2:17]2)=[N:14][CH:15]=1>S(=O)(=O)(O)O.C(O)(=O)C>[OH:7][C:10]1[CH:11]=[CH:12][C:13]([N:16]2[CH2:20][C:19]3[CH2:21][N:22]([C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:23][C:18]=3[CH2:17]2)=[N:14][CH:15]=1
Reactant: Nc1ccc(N2CC3=C(CN(C(=O)c4ccccc4C(F)(F)F)C3)C2)nc1
Reactant: CC(=O)O
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(c1ccccc1C(F)(F)F)N1CC2=C(C1)CN(c1ccc(O)cn1)C2
Reaction time: 1 h

Procedure:
Sodium nitrite (106.1 mg, 1.537 mmol) was dissolved at 0° C. in 1.84 ml of conc. sulfuric acid. Subsequently, [5-(5-aminopyridin-2-yl)-3,4,5,6-tetrahydro-1H-pyrrolo[3,4-c]pyrrol-2-yl](2-trifluoromethylphenyl)methanone acetate (523 mg, 1.2 mmol), dissolved in 8 ml of acetic acid, was added dropwise, the cooling bath was removed and stirring was continued for 1 h. The reaction solution was added dropwise to 50 ml of boiling water and stirred under reflux for 5 h. After cooling, the mixture was admixed with ethyl acetate and filtered off from the residue, the water phase was adjusted to pH 4 with sodium hydrogencarbonate solution, and the organic phase was removed and concentrated. Yield: 181 mg (40%), M+H+: 376.11.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@@H:13]2[O:18][C:17]3[CH:19]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:21]=[C:22]([F:23])[C:16]=3[O:15][CH2:14]2)(=O)=O)=CC=1.[CH2:28]([NH2:30])[CH3:29].Cl>C(#N)C>[F:23][C:22]1[C:16]2[O:15][CH2:14][C@H:13]([CH2:12][NH:30][CH2:28][CH3:29])[O:18][C:17]=2[CH:19]=[C:20]([S:24]([CH3:27])(=[O:25])=[O:26])[CH:21]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3c(F)cc(S(C)(=O)=O)cc3O2)cc1
Reactant: CCN
Agent: Cl
Solvent: CC#N
Product: CCNC[C@H]1COc2c(F)cc(S(C)(=O)=O)cc2O1

Procedure:
Preparation according to Example 5 using [(2R)-5-fluoro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl 4-methylbenzenesulfonate (0.56 g, 1.33 mmol), ethanamine (1 ml, 70% in water) and ACN (3 ml). Yield: 0.32 g, 83%. The amine was converted to the hydrochloric acid salt and crystallized from MeOH/Et2O. M.p. 274° C. MS m/z (rel. intensity, 70 eV) 289 (M+, 3), 70 (3), 59 (4), 58 (bp), 56 (3). [α]=−58° (MeOH).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[C:5](=O)[NH:4][CH2:3]1>C1COCC1>[CH3:1][C:2]1([CH3:16])[C:11]2[C:6](=[CH:7][C:8]([N+:12]([O-:14])=[O:13])=[CH:9][CH:10]=2)[CH2:5][NH:4][CH2:3]1
Reactant: CC1(C)CNC(=O)c2cc([N+](=O)[O-])ccc21
Solvent: C1CCOC1
Product: CC1(C)CNCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4,4-Dimethyl-7-nitro-3,4-dihydro-2H-isoquinolin-1-one (230 mg) was dissolved in THF (10 ml) and BH3Me2S (400 ul) was added and the reaction was stirred overnight at RT. The reaction was quenched with MeOH (10 ml) and NaOH (200 mg) and heating at reflux for 20 min. The mixture was extracted with EtOAc, washed with sat'd NH4Cl, extracted with 10% HCl (20 ml). The acidic solution was treated with 5N NaOH (15 ml), extracted with EtOAc (30 ml) dried, filtered and evaporated to give the compound as a yellow solid. M+H 207.2, Calc'd 206.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1.NC1C=C[C:16]2[O:17]CCOC=2C=1.COC(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[F:1][C:2]1[C:11]([CH:16]=[O:17])=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: Fc1ccc2c(c1)OCCO2
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: COC(Cl)Cl
Solvent: ClCCl
Product: O=Cc1cc2c(cc1F)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 6-fluoro-2,3-dihydro-benzo[1,4]dioxine (prepared from 6-amino-2,3-dihydro-benzo[1,4]dioxine according to the procedure of V. Daukas, P. Gaidelis, R. Martinkus, S. Urboniene, Chemija, 1999, 10 (1), 59), (154 mg, 1 mmol) in dichloromethane (0.5 ml) was treated with dichloromethyl methyl ether (0.25 ml) at 0° C. under argon. Titanium tetrachloride (0.45 ml) in dichloromethane (0.5 ml) was added over 0.25 hours. The cooling bath was removed and the mixture was stirred at ambient temperature for 1 hour before being quenched with water and extracted with ether. The ether extract was washed with aqueous sodium bicarbonate and brine. Drying and evaporation afforded a brown oil which was purified by chromatography on silica (ethyl acetate/hexane) affording a clear oil (0.12 g).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH:7]1([NH:10][C:11](=[O:38])[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N:19]3[CH:24]=[CH:23][NH:22][CH:21]([N:25]4[CH2:29][CH2:28][CH2:27][CH:26]4[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[OH:36])[C:20]3=[O:37])[CH:13]=2)[CH2:9][CH2:8]1.Cl[CH2:40][CH2:41][N:42]([CH3:53])[C:43](=[O:52])[O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1.C(Cl)Cl>C(#N)C.O>[CH:7]1([NH:10][C:11]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[C:14]([N:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:29][CH2:28][CH2:27][CH:26]4[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[O:36][CH2:40][CH2:41][N:42]([CH3:53])[C:43](=[O:52])[O:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:20]3=[O:37])[CH:13]=2)=[O:38])[CH2:9][CH2:8]1
Reactant: CN(CCCl)C(=O)OCc1ccccc1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1N1C=CNC(N2CCCC2c2ccccc2O)C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ccnc(N2CCCC2c2ccccc2OCCN(C)C(=O)OCc2ccccc2)c1=O
Temperature: 90 °C
Yield: 47.2 %

Procedure:
Cesium carbonate (0.274 g) was added to a solution of N-cyclopropyl-3-{3-[2-(2-hydroxyphenyl)pyrrolidin-1-yl]-2-oxo-3,4-dihydropyrazin-1(2H)-yl}-4-methylbenzamide (Example 324a, 0.18 g) and benzyl 2-chloroethyl(methyl)carbamate (0.096 g) in acetonitrile (4 mL), and the reaction was heated at 90° C. for 72 h. DCM and water were added, and the organic layer was separated, dried (Na2SO4) and the solvent removed in vacuo. Purification (SiO2 chromatography eluting with 30-50% EtOAc in DCM) gave the subtitle compound as an oil (0.122 g).
Reaction SMILES: Cl[C:2]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([O:13][CH3:14])[C:7]([CH3:16])([CH3:15])[CH2:6]1)=[O:3].[NH2:17][NH2:18]>CO>[C:2]([O:4][CH:5]1[CH2:10][C:9]([CH3:12])([CH3:11])[N:8]([O:13][CH3:14])[C:7]([CH3:16])([CH3:15])[CH2:6]1)(=[O:3])[NH:17][NH2:18]
Reactant: CON1C(C)(C)CC(OC(=O)Cl)CC1(C)C
Reactant: NN
Solvent: CO
Product: CON1C(C)(C)CC(OC(=O)NN)CC1(C)C

Procedure:
The title compound is prepared by reacting the compound of Example 27 (1 mole) with hydrazine (1.1 mole), employing methanol as the solvent.
Reaction SMILES: [CH3:1][C:2]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15](=[O:32])[NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:21][CH:20]=2)=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[CH2:40](OC(=O)C(CC1C=CC(O)=CC=1)(OC1C=CC=CC=1)CC)C>>[O:33]([C:2]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:32])[NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[CH:21][CH:20]=2)=[CH:11][CH:12]=1)([CH2:1][CH3:40])[C:3]([OH:5])=[O:4])[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: CCOC(=O)C(CC)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: CC(Cc1ccc(OCC(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)(Oc1ccccc1)C(=O)O
Product: CCC(Cc1ccc(OCC(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)(Oc1ccccc1)C(=O)O

Procedure:
The title compound was prepared using same method for 2-Methyl-2-phenoxy-3-(4-{[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-methoxy}-phenyl)-propionic acid from 2-(4-Hydroxy-benzyl)-2-phenoxy-butyric acid ethyl ester
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[OH-].[Na+].[CH2:14](Br)[C:15]#[CH:16]>C(O)(C)C>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([O:7][CH2:16][C:15]#[CH:14])=[O:6]
Reactant: C#CCBr
Reactant: O=C(O)c1ccc(O)c(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: C#CCOC(=O)c1ccc(O)c(O)c1
Yield: 68 %

Procedure:
Using the above procedure, 3,4-dihydroxybenzoic acid (0.0649 mole) and sodium hydroxide (0.0649 mole) were dissolved in 50% isopropyl alcohol (200 ml). Propargyl bromide (0.0649 mole) was added and the solution was heated to reflux for 6 hours. The solution was then cooled and the isopropyl alcohol was removed under vacuum. The residue was taken up in methylene chloride (200 ml), washed with water (200 ml), saturated sodium bicarbonate, saline and dried over magnesium sulfate. Removal of the solvent yielded crude product, which was recrystallized, from CCI4 to give the pure product. (68.0% yield) m.p. 127-129° C.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[N:9][CH:10]=[C:11]([Sn](CCCC)(CCCC)CCCC)[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:27]1[CH:31]=[CH:30][S:29][C:28]=1[C:32]([O:34][CH3:35])=[O:33]>C1COCC1.C(Cl)Cl.O.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>[CH3:35][O:34][C:32]([C:28]1[S:29][CH:30]=[CH:31][C:27]=1[C:11]1[CH:12]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[N:9][CH:10]=1)=[O:33]
Reactant: COC(=O)c1sccc1Br
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnnc(-c2ccccc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1sccc1-c1cnnc(-c2ccccc2)c1
Temperature: 150 °C
Yield: 12 %

Procedure:
3-Phenyl-5-(tri-n-butylstannyl)pyridazine (50 mg, 0.11 mmol), methyl 3-bromothiophene-2-carboxylate (30 mg) and Pd(PPh3)4 (5 mg) in THF (2 ml) were combined and heated to 150° C. for 600 seconds in a Smith Synthesizer microwave reactor. The reaction was diluted with CH2Cl2 (6 ml) and H2O (2 ml) then poured into PTFE (5 μM) fritted syringe barrels. The organic phase was collected and concentrated to leave 85 mg of crude product. Part of the sample was purified by HPLC with mass triggered collection of fractions to give the title compound (3.9 mg). δH (400 MHz, d6 DMSO) 3.73 (3H, s), 7.52-7.62 (4H, m), 8.10 (1H, d, J 8.0), 8.22 (2H, dd, J 1.6 and 8.0), 8.35 (1H, d, J 4.0), 9.33 (1H, d, J 4.0); m/z (ES+) (MH+) 297.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:5]=1[O:6][CH2:7]/[CH:8]=[C:9](\[CH3:14])/[C:10]([O:12]C)=[O:11]>O1CCCC1CO>[Cl:3][C:4]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:5]=1[O:6][CH2:7]/[CH:8]=[C:9](\[CH3:14])/[C:10]([OH:12])=[O:11]
Reactant: COC(=O)/C(C)=C/COc1ccc(Cl)cc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: OCC1CCCO1
Product: C/C(=C\COc1ccc(Cl)cc1Cl)C(=O)O
Temperature: 25 °C

Procedure:
In 20 ml of a 1:1 tetrahydrofuran-methanol mixture 0.38 g methyl (E)-4(2,4-dichlorophenoxy)-2-methyl-2-buten-1-oate is dissolved and the solution stirred under nitrogen as a 20% aqueous potassium hydroxide solution is added dropwise. The solution is then heated at reflux for about 2 hours before being evaporated to dryness. The residue is taken up in 20 ml water and filtered to remove the very small amount of insoluble material and is then acidified with dropwise addition of dilute aqueous HCl. The mixture is extracted with two 20 ml portions of methylene chloride and the extracts are combined and treated with magnesium sulfate and the mixture filtered. The filtrate is heated under a stream of nitrogen as 5 ml of hexane is added. When the volume reaches 10 ml the solution is allowed to cool to room temperature and is placed in a freezer. A white needle-like crystalline solid forms and is collected by nitrogen pressure filtration and after drying on the filter 0.11 g solid product is collected, m.p. 117°- 121.5° C.
Reaction SMILES: [CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10](Br)=[C:9]1[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:34]=[O:35]>CCCCCC.O1CCCC1>[CH2:1]([N:8]1[C:12]2=[C:13]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:14]=[N:15][CH:16]=[C:11]2[C:10]([CH:34]=[O:35])=[C:9]1[CH3:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(Br)c2cnnc(OCc3ccccc3)c2n1Cc1ccccc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(C=O)c2cnnc(OCc3ccccc3)c2n1Cc1ccccc1
Yield: 32 %

Procedure:
5.0 g (12.2 mmol) of 1-benzyl-7-benzyloxy-3-bromo-2-methylpyrrolo[2,3-d]pyridazine, 9 ml (14.7 mmol) of a 15% strength solution of n-butyllithium in hexane and 2.4 ml (29.4 mmol) of dimethylformamide are reacted in 125 ml of anhydrous tetrahydrofuran as described for Example 2a. Yield: 32%, m.p.: 147°-149° C.
Reaction SMILES: [CH2:1]([N:8]=[N+:9]=[N-:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])#[N:12]>>[CH2:1]([N:8]1[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:12][N:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: CCOC(=O)C#N
Product: CCOC(=O)c1nnnn1Cc1ccccc1
Temperature: 150 °C

Procedure:
An equimolar mixture of benzyl azide and ethyl cyanoformate is heated in a bomb under antogenous pressure at 150° C. for 4 hours. The resulting yellow oil is crystallized from hexane to give the title compound, m.p. 58°-61° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](=[O:19])[CH3:18])=[C:9]1[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:23](=O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17](=[O:19])/[CH:18]=[CH:23]/[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:9]1[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1c(C(C)C)n(Cc2ccccc2)c2ccccc12
Reactant: O=Cc1ccccc1
Product: CC(C)c1c(C(=O)/C=C/c2ccccc2)c2ccccc2n1Cc1ccccc1

Procedure:
The title compound was prepared from 1-(1-benzyl-2-isopropyl-1H-indol-3-yl)ethanone (Compound 42) and benzaldehyde by General Procedure G.