Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].Br[C:33]([CH3:39])([CH3:38])[C:34](C#N)=[O:35]>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:25][C:33]([CH3:39])([CH3:38])[C:34](=[O:35])[C:16]=2[C:17]2[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(Br)C(=O)C#N
Reactant: COc1ccc(CC(=O)c2ccc(OCc3ccccc3)cc2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(C2=C(c3ccc(OCc4ccccc4)cc3)OC(C)(C)C2=O)cc1
Reaction time: 0.5 h
Yield: 4.1 %

Procedure:
To a pre-cooled 0° C. solution of 1-(4-(benzyloxy)phenyl)-2-(4-methoxyphenyl)-ethanone (2 g, 6.02 mmol) in THF (20 mL) under an inert atmosphere was added t-BuOK (8 mL, 1.0 N solution in THF). The mixture was then stirred for 30 minutes. 2-Bromo-2-methylpropanoyl cyanide (2 g, 12 mmol) was then added to then reaction mixture and stirring was continued for an additional 16 h. The reaction mixture was then quenched with cold water (10 mL) and extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), and then dried over Na2SO4 concentrated and purified via silica gel column chromatography (10-15% Ethyl acetate in hexanes) to afford 5-(4-(benzyloxy)phenyl)-4-(4-methoxyphenyl)-2,2-dimethylfuran-3(2H)-one (100 mg) as a white solid.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[F:6][C:7]([F:19])([F:18])[C:8]1[CH:9]=[C:10]([CH2:14][C:15](O)=[O:16])[CH:11]=[CH:12][CH:13]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C.C(Cl)Cl.C(N(CC)CC)C>[CH3:5][O:4][N:3]([CH3:2])[C:15](=[O:16])[CH2:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([C:7]([F:19])([F:18])[F:6])[CH:9]=1
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1
Reactant: CNOC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CON(C)C(=O)Cc1cccc(C(F)(F)F)c1
Reaction time: 0.08 h

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (1.577 g, 16.2 mmol) in DMF (25 mL) and CH2Cl2 (25 mL) at 0° C. was added triethylamine (2.25 mL). After stirring for 5 minutes, 3-trifluoromethylphenyl acetic acid (3.0 g, 14.7 mmol), HOBT (3.177 g, 23.5 mmol), and EDC (3.10 g, 16.2 mmol) were added. The reaction mixture was stirred at room temperature for 18 h and was concentrated in vacuo. The residue was diluted with EtOAc and the organic solution was washed consecutively with 1N NaOH (2 times), water, and brine. The organic solution was dried (MgSO4), filtered and concentrated in vacuo. Medium pressure chromatography (20% EtOAc in hexanes to 50% EtOAc in hexanes) provided N-methoxy-N-methyl-2-(3-trifluoromethyl-phenyl)-acetamide.
Reaction SMILES: [OH:1][OH:2].FC(F)(F)C(F)(F)C([O:8][C:9](=O)[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=O>FC(F)(F)C(F)(F)C(O)=O>[F:15][C:10]([F:16])([C:11]([F:12])([F:13])[F:14])[C:9]([O:1][O:2][C:9](=[O:8])[C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])=[O:8]
Reactant: O=C(OC(=O)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F
Reactant: OO
Agent: O=C(O)C(F)(F)C(F)(F)F
Product: O=C(OOC(=O)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)F

Procedure:
In a manner similar to that of Example 1, H2O2 (>95%) was combined with pentafluoropropionic anhydride to give bis(pentafluoropropanoyl) peroxide (δ−85.1, −121.3) in pentafluoropropionic acid.
Reaction SMILES: CC(C)(S([NH:6][C:7]1([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[CH2:21]3)=[O:19])=[CH:13][CH:12]=2)[CH2:10][O:9][CH2:8]1)=O)C.Cl.O1CCOCC1>CO>[NH2:6][C:7]1([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([N:20]3[CH2:28][C:27]4[CH:26]=[CH:25][N:24]=[CH:23][C:22]=4[CH2:21]3)=[O:19])=[CH:15][CH:16]=2)[CH2:10][O:9][CH2:8]1
Reactant: CC(C)(C)S(=O)NC1(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)COC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: NC1(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)COC1
Reaction time: 2 h

Procedure:
In a 20 mL vial was added N-(4-(3-(1,1-dimethylethylsulfinamido)oxetan-3-yl)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide (253 mg, 0.610 mmol) and methanol (6.1 ml). 4N HCl in dioxane (229 μl, 0.916 mmol) was added and the reaction was stirred for 2 hours. The mixture was concentrated under vacuum to give the title compound which was used without further purification.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](B2OC(C)(C)C(C)(C)O2)[CH:4]=[N:3]1.N1C2C(=CC=CC=2)C=C(B(O)O)C=1.BrC1C=CC=C2C=1C1(C3=CC4OCOC=4C=C3OC1)C(=O)N2C.Br[C:53]1[CH:61]=[CH:60][CH:59]=[C:58]2[C:54]=1[C:55]1([C:87]3[C:78](=[CH:79][C:80]4[O:85][CH2:84][CH2:83][O:82][C:81]=4[CH:86]=3)[O:77][CH2:76]1)[C:56](=[O:75])[N:57]2[CH:62](C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:62][N:57]1[C:58]2[C:54](=[C:53]([C:5]3[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=3)[CH:61]=[CH:60][CH:59]=2)[C:55]2([C:87]3[C:78](=[CH:79][C:80]4[O:85][CH2:84][CH2:83][O:82][C:81]=4[CH:86]=3)[O:77][CH2:76]2)[C:56]1=[O:75]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Agent: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(Br)cccc21
Agent: OB(O)c1cnc2ccccc2c1
Product: CN1C(=O)C2(COc3cc4c(cc32)OCCO4)c2c(-c3cnn(C)c3)cccc21

Procedure:
Following the procedure as described in EXAMPLE 2.46 and making non-critical variations using 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to replace quinolin-3-ylboronic acid, and 4′-bromo-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 1′-methyl-4′-(1-methyl-1H-pyrazol-4-yl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (58%) as a colorless solid: mp 220-222° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) 7.32 (dd, J=7.9, 7.9 Hz, 1H), 7.16 (s, 1H), 6.99 (d, J=7.8 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.42 (s, 1H), 6.31 (s, 1H), 4.66 (d, J=9.1 Hz, 1H), 4.48 (d, J=9.1 Hz, 1H), 4.23-4.09 (m, 4H), 3.75 (s, 3H), 3.25 (s, 3H); 130 NMR (75 MHz, CDCl3) δ 178.0, 155.6, 144.8, 144.2, 138.7, 138.0, 130.8, 129.3, 129.1, 127.8, 125.2, 122.7, 119.0, 111.5, 107.0, 99.4, 76.7, 64.6, 64.0, 58.3, 38.9, 26.8; MS (ES+) m/z 390.0 (M+1).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][CH:5]([CH2:6][CH2:7]1)[CH:4]([N:10]1[CH:23]=[CH:22][C:13]3[N:14]([CH3:21])[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:12]=3[C:11]1=[O:24])[CH2:3]2>C(O)(=O)C.[OH-].[OH-].[Pd+2]>[N:2]12[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9]1)[CH:4]([N:10]1[CH2:23][CH2:22][C:13]3[N:14]([CH3:21])[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:12]=3[C:11]1=[O:24])[CH2:3]2
Reactant: Cn1c2ccccc2c2c(=O)n(C3CN4CCC3CC4)ccc21
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CC(=O)O
Product: Cn1c2c(c3ccccc31)C(=O)N(C1CN3CCC1CC3)CC2
Reaction time: 20 h
Yield: 164.9 %

Procedure:
(RS)-2-(1-azabicyclo[2.2.2]oct-3-yl)-1,2-dihydro-5-methyl-1-oxopyrido[4,3-b]indole hydrochloride (0.3 g, 0.98 mmol), from Example 3, in acetic acid (5 ml, containing 3 drops of 70% perchloric acid) was reduced with 20% palladium hydroxide on carbon (0.1 g) at 80° C. and 350 kPa for 20 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue was dissolved in water (10 ml), basified with ammonium hydroxide solution and extracted with ethyl acetate. The ethyl acetate was dried over anhydrous potassium carbonate, filtered and evaporated. The residue was purified by column chromatography (10% methanol in dichloromethane +1% ammonium hydroxide; silica; Rf. 0.3) to afford 0.5 g (16% yield) of (RS)-2-(1-azabicyclo[2.2.2]oct-3-yl)-1,2,3,4-tetrahydro-5-methyl-1-oxopyrido[4,3-b]indole.
Reaction SMILES: [Br:1][Si](C)(C)C.[CH3:6][O:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:20]=1[CH:19]=[C:18]([CH2:21]O)[CH:17]=[CH:16]2>C(Cl)(Cl)Cl>[Br:1][CH2:21][C:18]1[CH:19]=[C:20]2[C:15]([CH:14]=[CH:13][CH:12]=[C:11]2[O:10][CH2:9][CH2:8][O:7][CH3:6])=[CH:16][CH:17]=1
Reactant: C[Si](C)(C)Br
Reactant: COCCOc1cccc2ccc(CO)cc12
Solvent: ClC(Cl)Cl
Product: COCCOc1cccc2ccc(CBr)cc12
Reaction time: 1 h

Procedure:
0.198 ml of bromotrimethylsilane are added dropwise at room temperature to a solution of 0.23 g of [8-(2-methoxyethoxy)naphthalen-2-yl]methanol in 5 ml of chloroform. After 1 hour, the reaction mixture is concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60F).
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@H:11]([N:13]4[CH2:17][CH2:16][CH2:15][C@H:14]4C)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.N1C=C(B(O)O)C=NC=1>>[CH3:21][O:22][C:23]1[N:28]=[CH:27][C:26]([C:2]2[CH:20]=[CH:19][C:5]3[N:6]=[C:7]([C@H:9]4[CH2:10][C@H:11]([N:13]5[CH2:14][CH2:15][CH2:16][CH2:17]5)[CH2:12]4)[S:8][C:4]=3[CH:3]=2)=[CH:25][CH:24]=1
Reactant: C[C@@H]1CCCN1[C@H]1C[C@H](c2nc3ccc(Br)cc3s2)C1
Reactant: COc1ccc(B(O)O)cn1
Agent: OB(O)c1cncnc1
Product: COc1ccc(-c2ccc3nc([C@H]4C[C@H](N5CCCC5)C4)sc3c2)cn1

Procedure:
The title compound was prepared according to the procedure described in Example 1F, substituting the product of Example 62A for the product of Example 1E and substituting 6-methoxy-3-pyridineboronic acid for pyrimidine-5-boronic acid. 1H NMR (300 MHz, CDCl3) δ ppm 8.43 (d, J=2.37 Hz, 1H) 8.03 (d, J=8.48 Hz, 1H) 7.97 (s, 1H), 7.83 (dd, J=8.65, 2.54 Hz, 1H) 7.61 (dd, J=8.48, 2.03 Hz, 1H) 6.85 (d, J=9.15 Hz, 1H) 4.01-4.10 (m, J=6.78 Hz, 1H) 4.00 (s, 3H) 3.35-3.70 (m, 1H) 2.68 (s, 6H) 1.93 (s, 2H) 1.93 (s, 4H) 1.46-1.65 (m, 2H). MS: (M+H)+=366.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[N:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:17])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][N:18]=3)=[CH:31][CH:30]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(-c2cnccn2)cc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CN)c1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3cnccn3)cc2)c1

Procedure:
The title compound of Step A was prepared from (3-aminomethyl-phenoxy)-acetic acid tert-butyl ester, of Preparation 20, and 4-pyrazin-2-yl-benzaldehyde, of Preparation 27, using the method described in Example 3, Step A, except no triethylamine was used. 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 8.60 (m, 1H), 8.47 (d, 1H), 7.96 (d, 2H), 7.62 (m, 1H), 7.47 (d, 2H), 7.22 (m, 1H), 6.94 (m, 1H), 6.76 (dd, 1H), 4.50 (s, 2H), 3.85 (s 2H), 3.78 (s, 2H), 1.46 (s, 9H); MS 406 (M+1).
Reaction SMILES: [I:1]/[CH:2]=[CH:3]/[CH:4]([OH:10])[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH2:11]([C:20](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1>N1C=CC=CC=1>[I:1]/[CH:2]=[CH:3]/[CH:4]([O:10][C:20]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: COc1ccc(CC(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCCCC(O)/C=C/I
Solvent: c1ccncc1
Product: CCCCCC(/C=C/I)OC(Cc1ccc(OC)cc1)(c1ccccc1)c1ccccc1

Procedure:
A mixture of 14.92 g. (0.0588 mole) of 1-iodo-trans-1-octen-3-ol (Example 225) and 18.2 g. (0.0588 mole) of p-anisyldiphenylmethyl chloride in 165 ml. of dry pyridine is heated at 60° C. for 18 hours under an inert atmosphere. The mixture is cooled and the solvent is evaporated in vacuo. The residue is partitioned between ether and water, and the organic phase is washed with water and saturated brine, dried (MgSO4), and evaporated. The residue is chromatographed upon 300 g. of Florisil® packed in hexane and the product is eluted with hexane and 4:1 hexane-benzene to yield a colorless oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23]([OH:25])=O)[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=[CH:32][CH:31]=1)[CH3:27]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[N:33]=[CH:32][CH:31]=2)=[O:25])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Reactant: CCNCc1ccnc2ccccc12
Product: CCN(Cc1ccnc2ccccc12)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-p-tolyl-amino]-acetic acid with ethyl-quinolin-4-ylmethyl-amine
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[N:12]=[C:11](Cl)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[S-:16][C:17]#[N:18].[K+]>C(O)(=O)C>[F:1][C:2]([F:15])([F:14])[C:3]1[N:12]=[C:11]([S:16][C:17]#[N:18])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: N#C[S-]
Reactant: FC(F)(F)c1nc(Cl)c2ccccc2n1
Agent: [K+]
Solvent: CC(=O)O
Product: N#CSc1nc(C(F)(F)F)nc2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
46.5 g of 2-trifluoromethyl-4-chloro-quinazoline is added, while stirring, to a mixture of 97 g of potassiumthiocyanate and 200 ml of acetic acid. The reaction mixture is stirred for 2 hours at room temperature, the resultant light-yellow precipitate is drawn off, consecutively washed with a small amount of acetic acid and water and subsequently dried in air. The 2-trifluoromethyl-4-thiocyano-quinazoline thus obtained has a melting point of 134°-136°C.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][CH2:8][C:9](=O)[CH2:10][CH2:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C.[Pd]>[CH2:13]([NH:20][CH:9]1[CH2:8][CH2:7][C:6]2[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=2[CH2:11][CH2:10]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCc2ccccc2CC1
Reactant: NCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(CNC2CCc3ccccc3CC2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5,6,8,9-Tetrahydro-benzocyclohepten-7-one (3.00 g) and benzylamine (2.00 g) are dissolved in ethanol (50 mL). A catalytic amount of 10% palladium on charcoal is added and the reaction mixture is placed under an atmosphere of hydrogen. The reaction mixture is stirred at r.t. The reaction is shown to be complete by TLC after 24 hours. The catalyst is filtered off and the solvent is removed in vacuo. The product is not purified further. TLC (silica, n-hexane/ethyl acetate 1:2 Rf=0.50).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13](=O)[CH:14]([CH3:19])[CH2:15][C:16](O)=[O:17])=[C:9]([O:21][CH3:22])[CH:8]=2)=[N:4][N:3]=1.O.[NH2:24][NH2:25]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:14]([CH3:19])[CH2:15][C:16](=[O:17])[NH:24][N:25]=3)=[C:9]([O:21][CH3:22])[CH:8]=2)=[N:4][N:3]=1
Reactant: NN
Reactant: COc1cc(-c2nnc(C)o2)ccc1C(=O)C(C)CC(=O)O
Solvent: O
Solvent: CCO
Product: COc1cc(-c2nnc(C)o2)ccc1C1=NNC(=O)CC1C

Procedure:
10.1 g (0.033 mole) of 4-(4-(5-methyl-1,3,4-oxadiazol-2-yl)-methoxy-phenyl)-4-oxo-3-methyl-butyric acid and 2.1 ml (0.043 mole) of hydrazine hydrate are stirred in 100 ml of ethanol at 50° C. for 1 hour. After addition of a mixture of diethyl ether/ligroin until cloudiness results, the product crystallises out. After filtering off with suction, the product is recrystallised from 500 ml of isopropanol.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][C:3]=1[F:11].[Cl:12][C:13]1[C:14]([F:21])=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.[OH-].[Na+]>C(O)(C)C>[Cl:12][C:13]1[C:14]([F:21])=[C:15](/[CH:16]=[C:6](/[C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([F:11])[CH:4]=2)\[C:7]#[N:8])[CH:18]=[CH:19][CH:20]=1
Reactant: N#CCc1ccc(Cl)c(F)c1
Reactant: O=Cc1cccc(Cl)c1F
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: N#C/C(=C\c1cccc(Cl)c1F)c1ccc(Cl)c(F)c1
Temperature: 25 °C

Procedure:
A mixture of 4-chloro-3-fluorobenzylcyanide (1.0 g, 5.92 mmol), 3-chloro-2-fluorobenzaldehyde (0.938 g, 5.92 mmol), 2 N NaOH (4 mL) and isopropyl alcohol were stirred at rt. The mixture was stirred for 10 min. to afford a solid ppt that was collected by filtration with multiple water washes. The solid was dried ON under reduced pressure to afford a white solid (Z)-3-(3-chloro-2-fluoro-phenyl)-2-(4-chloro-3-fluoro-phenyl)-acrylonitrile, 1.62 g, 89.3%;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:8](Cl)=[N:7]2.[C:18]1(B(O)O)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[Na+].[Na+]>CC#N.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>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:7]2
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(C)Nc1nc2c(Br)cccc2nc1Cl
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: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)Nc1nc2c(Br)cccc2nc1-c1ccccc1
Temperature: 80 °C
Reaction time: 17.5 h
Yield: 61.6 %

Procedure:
A suspension of 8-bromo-N-(tert-butyl)-3-chloroquinoxalin-2-amine (Example 304a (˜2.5:1 mixture with 5-bromo-N-(tert-butyl)-3-chloroquinoxalin-2-amine); 119.0 mg, 0.378 mmol), phenylboronic acid (Aldrich; 46.1 mg, 0.378 mmol), Na2CO3 (200 mg, 1.891 mmol), and Pd(PPh3)4 (Strem Chemicals, Inc.; 21.85 mg, 0.019 mmol) in a mixture of MeCN (3.0 mL) and water (1.000 mL) was stirred under argon at 80° C. for 17.5 h. The reaction mixture was cooled to RT and concentrated onto silica gel. Chromatographic purification (silica gel, 0-10% EtOAc/hexanes) furnished 8-bromo-N-(tert-butyl)-3-phenylquinoxalin-2-amine (83.0 mg, 0.233 mmol, 62% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ ppm 7.85 (1H, dd, J=4.5, 1.2 Hz), 7.83 (1H, dd, J=5.1, 1.4 Hz), 7.67-7.72 (2H, m), 7.51-7.59 (3H, m), 7.20 (1H, t, J=7.8 Hz), 5.23 (1H, br. s.), 1.57 (9H, s). m/z (ESI, +ve) 355.9/358.0 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:7]([CH3:8])[N:6]2[C:9]3[N:15]=[C:14]([C:16]([O:18]CC)=[O:17])[CH:13]=[CH:12][C:10]=3[CH:11]=[C:5]2[C:4](=[O:21])[NH:3]1.[OH-].[Na+]>C(O)C>[CH3:1][C@H:2]1[C@H:7]([CH3:8])[N:6]2[C:9]3[N:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][C:10]=3[CH:11]=[C:5]2[C:4](=[O:21])[NH:3]1
Reactant: CCOC(=O)c1ccc2cc3n(c2n1)[C@@H](C)[C@H](C)NC3=O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1NC(=O)c2cc3ccc(C(=O)O)nc3n2[C@H]1C
Temperature: 50 °C
Yield: 91.7 %

Procedure:
To a suspension of ethyl trans-8,9-dimethyl-6-oxo-6,7,8,9-tetrahydropyrido[3′,2′:4,5]pyrrolo[1,2-a]pyrazine-2-carboxylate (702 mg, 2.44 mmol) in ethanol (20 mL) is added 1M aqueous NaOH solution (6.11 mL, 6.11 mmol). The reaction mixture is heated at 50° C. for 90 min and is cooled to room temperature. The ethanol is removed in vacuo and the aqueous mixture is acidified with 1N aqueous HCl. The resulting solid is collected by filtration and dried in vacuo to afford the title compound as a white solid (580 mg, 92%). LCMS: 260.64 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(Cl)(Cl)(Cl)Cl.[Br:18]N1C(=O)CCC1=O.C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:18][CH2:12][C:3]1[C:2]([Cl:1])=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(Cl)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(Cl)c1CBr
Temperature: 90 °C
Reaction time: 3 h
Yield: 100.1 %

Procedure:
A suspension of methyl 3-chloro-2-methylbenzoate obtained in Example 10b (1 g, 5.42 mmol), carbon tetrachloride (13.3 ml), N-bromosuccinimide (1.06 g, 5.96 mmol) and benzoyl peroxide (3.5 mg, 0.0108 mmol) was heated in a 90° C. oil bath under a nitrogen stream. After three hours and 45 minutes, heating was completed, and the mixture was diluted with water, ethyl acetate and a saturated aqueous sodium bicarbonate solution. The organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (1.43 g, yield: 100%).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:13]2[C:12]3[CH2:14][CH2:15][CH2:16][CH2:17][C:11]=3[C:10](=[O:18])[O:9][C:8]=2[CH:7]=[C:6]([CH3:19])[CH:5]=1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>CS(C)=O.O>[CH3:19][C:6]1[CH:5]=[C:4]([O:3][CH2:20][CH:22]2[CH2:23][O:24]2)[C:13]2[C:12]3[CH2:14][CH2:15][CH2:16][CH2:17][C:11]=3[C:10](=[O:18])[O:9][C:8]=2[CH:7]=1
Reactant: ClCC1CO1
Reactant: Cc1cc(O)c2c3c(c(=O)oc2c1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(OCC2CO2)c2c3c(c(=O)oc2c1)CCCC3
Reaction time: 0.08 h

Procedure:
To a stirred solution of NaOH (4.0 g, 0.1 m) in dimethylsulfoxide (DMSO) (250 ml) and water (250 ml), was added 7,8,9,10-tetrahydro-1-hydroxy-3-methyl-6-oxo-6H-dibenzo[b,d]pyran (20.0 g, 0.87 m) and the mixture stirred for 5 minutes, then treated with epichlorohydrin (50 ml). After 5 hours the mixture was cooled in an ice bath for 30 minutes and the precipitated solid collection by filtration, washed with water and dried to give 7,8,9,10-tetrahydro-3-methyl-1-(oxiranylmethoxy)-6-oxo-6H-dibenzo[b,d]pyran as a white solid, mp. 164°-165° C. An analytical sample recrystallized from methanol melted at 165°-166° C.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[C:10]([C:12]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH:17]=3)[N:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(O)C.[OH-].[Pd+2].[OH-]>[C:1]1([N:7]2[CH:11]=[C:10]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]3)[N:9]=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cn(-c3ccccc3)nn2)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2cn(-c3ccccc3)nn2)CC1
Yield: 99.4 %

Procedure:
tert-Butyl 4-[1-phenyl-1H-[1,2,3]triazol-4-yl]-1,2,3,6-tetrahydropyridine-1-carboxylate (5 mg) was dissolved in 1 ml of ethanol, a catalytic amount of 20% palladium hydroxide was added and the mixture was vigorously stirred for 30 minutes in a hydrogen atmosphere. The reaction solution was filtered through Celite. The solvent was evaporated from the resulting filtrate to give 5 mg of the title compound as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:36]=[CH:35][C:7]2[N:8]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]4[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=4)(=[O:27])=[O:26])=[O:23])=[CH:15][CH:14]=3)[C:9]([CH2:11][CH3:12])=[N:10][C:6]=2[CH:5]=1)(=[O:3])[CH3:2].[CH3:37][Mg]I.O>O1CCCC1>[CH2:11]([C:9]1[N:8]([C:13]2[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH:21][C:22]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=3)(=[O:26])=[O:27])=[O:23])=[CH:17][CH:18]=2)[C:7]2[CH:35]=[CH:36][C:4]([C:1]([OH:3])([CH3:37])[CH3:2])=[CH:5][C:6]=2[N:10]=1)[CH3:12]
Reactant: C[Mg]I
Reactant: CCc1nc2cc(C(C)=O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCc1nc2cc(C(C)(C)O)ccc2n1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
A solution of N-[({2-[4-(5-acetyl-2-ethyl-1H -benzimidazol-1-yl)phenyl]ethyl}amino)carbonyl]-4-methylbenzenesulfonamide (Example 78, 100 mg, 0.19 mmol) in tetrahydrofurane (15 ml) was added MeMgI (1.2 ml, 0.99 mmol) dropwise under nitrogen at 0° C. The mixture was stirred at 0° C. for 1 h and then was stirred at rt for 30 min. The mixture was added water (10 ml) and extracted with CH2Cl2(50 ml). The organic layer was washed with brine (10 ml), then dried (Na2SO4). After removal of solvent, the crude product was purified by flash column chromatography eluting with CH2Cl2:methanol (30:1/20:1/10:1) to afford 100 mg (97%) of the title compound as white solids.