Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:5]([CH2:28][CH3:29])[C:6]1[C:7]2[C:15]([CH3:17])([CH3:16])[CH:14]([OH:18])[N:13]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[C:8]=2[N:9]=[C:10]([CH3:12])[N:11]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH3:32]I>C1COCC1>[CH2:1]([N:5]([CH2:28][CH3:29])[C:6]1[C:7]2[C:15]([CH3:16])([CH3:17])[CH:14]([O:18][CH3:32])[N:13]([C:19]3[C:24]([CH3:25])=[CH:23][C:22]([CH3:26])=[CH:21][C:20]=3[CH3:27])[C:8]=2[N:9]=[C:10]([CH3:12])[N:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CI
Reactant: CCCCN(CC)c1nc(C)nc2c1C(C)(C)C(O)N2c1c(C)cc(C)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCN(CC)c1nc(C)nc2c1C(C)(C)C(OC)N2c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of 4-(butyl-ethyl-amino)-2,5,5-trimethyl-7-(2,4,6-trimethylphenyl)-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-6-ol] (20 mg, 0.05 mmol) in 1 ml of dry THF was treated with sodium hydride (60% in oil, 4 mg, 0.1 mmol) and then methyl iodide (0.3 ml) was added at room temperature. After stirring at room temperature for 2.5 hours, the mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 26 mg of crude material. After silica gel column purification with 10% ethyl acetate in hexane, 19 mg of a colorless oil of the title compound was obtained. 1H NMR (CDCl3) δ6.92 (s, 1H), 6.89 (s, 1H), 4.48 (s, 1H), 3.1-3.3 (m, 4H), 3.11 (s, 3H), 2.32 (s, 3H), 2.28 (s, 3H), 2.20 (s, 3H), 2.19 (s, 3H), 1.45 (s, 3H), 1.44 (s, 3H), 1.4-1.52 (m, 2H), 1.2-1.4 (m, 2H), 1.10 (t, 3H), 0.90 (t, 3H) ppm.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][SH:6].[OH-].[Na+].Br[CH2:11][CH2:12][OH:13]>C(O)C>[CH3:2][N:3]([CH3:7])[CH2:4][CH2:5][S:6][CH2:11][CH2:12][OH:13]
Reactant: CN(C)CCS
Reactant: OCCBr
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)CCSCCO

Procedure:
2-(Dimethylamino)ethanethiol hydrochloride (Aldrich) is treated with NaOH (0.2N) in ethanol (95%). To this slurry, 2-bromoethanol (1.2 eq.) is added and the mixture is refluxed for 2 hours. The reaction mixture is cooled, filtered and concentrated. The resultant residue is purified by silica gel flash column chromatography to give the title compound.
Reaction SMILES: Cl.[CH3:2][C:3]1[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:5]([CH2:12][NH2:13])[CH:6]=[C:7]([N+:9]([O-:11])=[O:10])[CH:8]=1.Br[CH2:21][CH2:22][CH2:23][CH2:24]Br.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH3:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([CH2:12][N:13]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:4]=1[N:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1
Reactant: BrCCCCBr
Reactant: Cc1cc([N+](=O)[O-])cc(CN)c1N1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc([N+](=O)[O-])cc(CN2CCCC2)c1N1CCOCC1
Temperature: 60 °C
Yield: 58.5 %

Procedure:
A mixture of [3-Methyl-2-(morpholin-4-yl)-5-nitrophenyl]methanamine hydrochloride (160 mg, 0.56 mmol), 1,4-dibromobutane (80 μL, 0.67 mmol) and K2CO3 (542 mg, 3.92 mmol) in 10 mL of acetonitrile was heated at 60° C. for 48 h. After filtration and evaporation of the filtrate, the residue was purified by flash chromatography (DCM/MeOH/NH4OH//9/1/0.1) to yield expected compound as a pale yellow oil (100 mg, 58% yield); m/z (ESI) 306.3 [M+H]+.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]([OH:13])[CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[O:15][C:16](=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH2:23]Br)[CH:18]=1>>[C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH2:23][C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=2)[C:16]([OH:25])=[O:15])[CH:8]=1
Reactant: Oc1cccc(-c2ccccc2)c1
Reactant: COC(=O)c1cccc(CBr)c1
Product: O=C(O)c1cccc(COc2cccc(-c3ccccc3)c2)c1

Procedure:
3-(Biphenyl-3-yloxymethyl)-benzoic acid was prepared using general procedure A from 3-phenylphenol (available from Aldrich, Milwaukee, Wis.) and 3-(bromomethyl)benzoic acid methyl ester (available from Lancaster Synthesis Ltd., Morcambe, Lancashire, UK). Yield: 76 mg. Mass spectrum (ES) MH+=305.
Reaction SMILES: [C:1]1([C:7]2[NH:11][CH:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[O:31]1[C:36]2[CH:37]=[CH:38][C:39]([S:41](Cl)(=[O:43])=[O:42])=[CH:40][C:35]=2[O:34][CH2:33][CH2:32]1>>[O:31]1[C:36]2[CH:37]=[CH:38][C:39]([S:41]([N:11]3[C:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[CH:8][C:9]([CH:12]=[O:13])=[CH:10]3)(=[O:43])=[O:42])=[CH:40][C:35]=2[O:34][CH2:33][CH2:32]1
Reactant: O=Cc1c[nH]c(-c2ccccc2)c1
Reactant: O=S(=O)(Cl)c1ccc2c(c1)OCCO2
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: O=Cc1cc(-c2ccccc2)n(S(=O)(=O)c2ccc3c(c2)OCCO3)c1
Yield: 69.9 %

Procedure:
Using 5-phenyl-1H-pyrrole-3-carbaldehyde (171 mg), sodium hydride (60% in oil, 72 mg), 15-crown-5 (330 mg) and 2,3-dihydro-1,4-benzodioxine-6-sulfonyl chloride (352 mg), a procedure as in Reference Example 219 was performed to give the title compound as a pale-yellow oil (yield 258 mg, 70%).
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][CH2:5][CH:4](C)[C:3]1=[O:9].Cl[CH2:12]C=CCCl.N.O>C1COCC1>[CH3:12][CH:7]1[CH2:6][CH2:5][CH2:4][C:3](=[O:9])[C:2]1([CH3:1])[CH3:10]
Reactant: ClCC=CCCl
Reactant: CC1CCCC(C)(C)C1=O
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: CC1CCCC(=O)C1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 19.6 %

Procedure:
28 g of 2,2,6-trimethyl-cyclohexanone are added dropwise to a suspension of Na vinylacetylide (prepared from 25 g of 1,4-dichlorobut-2-ene and 15 g of Na in liquid ammonia) in 200 ml of THF, whilst cooling, and the reaction mixture is stirred overnight at room temperature. 50 ml of water are then added, the aqueous phase is extracted with ether and the resulting organic phase is dried and concentrated. Subsequent fractional distillation gives 5.5 g of unconverted trimethylcyclohexanone and 20.7 g (corresponding to 68% of theory, based on ketone converted) of 2,2,6-trimethyl-1-(but-1'-yn-3'-en-1'-yl)-cyclohexanol of boiling point 62°-63° C/0.3 mm Hg and refractive index nD25 = 1.4982. Fragrance note: fresh, tart-woody, coniferous.
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH2:9][CH2:10][CH2:11][CH2:12]Cl)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[I-:15].[Na+]>CC(C)=O>[CH3:1][Si:2]([CH3:14])([CH2:9][CH2:10][CH2:11][CH2:12][I:15])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: [I-]
Reactant: C[Si](C)(CCCCCl)c1ccccc1
Agent: [Na+]
Solvent: CC(C)=O
Product: C[Si](C)(CCCCI)c1ccccc1
Yield: 92.6 %

Procedure:
Following the same procedure as in Example 44 Step A, 5 g (19 mmol) of dimethyl-(4-chlorobutyl)-phenylsilane in 50 ml of acetone are refluxed for 60 hours with 17 g (114 mmol) of sodium iodide to afford 5.6 g (83%) of expected dimethyl-(4-iodobutyl)-phenylsilane.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]3[O:23][C:24]4[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=4[N:26]=3)[S:21][C:14]=12>>[O:23]1[C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=[C:22]1[C:20]1[S:21][C:14]2[C:15](=[N:16][CH:17]=[CH:18][C:13]=2[NH:11][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[NH:3][C:2]([CH3:1])=[CH:10]3)[CH:19]=1
Reactant: Clc1ccnc2cc(-c3nc4ccccc4o3)sc12
Reactant: Cc1cc2cc(N)ccc2[nH]1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5nc6ccccc6o5)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-5-aminoindole and 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-benzooxazole by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.18 (d, 1H), 8.10 (s, 1H), 7.70 (m, 2H), 7.40 (m, 4H), 6.98 (d, 1H), 6.68 (d, 1H), 6.14 (s, 1H), 2.43 (s, 3H); RP18-HPLC RT: 6.13 minutes; API MS 397 (M+1).
Reaction SMILES: [CH3:1][O-].[Na+].Cl[CH2:5][CH2:6][CH2:7][C:8]([NH:10][C:11]1[CH:16]=[C:15]([O:17][C:18]2[C:19]([NH2:25])=[N:20][C:21](N)=[N:22][CH:23]=2)[C:14]([CH:26]([CH3:28])[CH3:27])=[CH:13][C:12]=1[O:29][CH3:30])=[O:9]>CO>[NH2:25][C:19]1[C:18]([O:17][C:15]2[C:14]([CH:26]([CH3:28])[CH3:27])=[CH:13][C:12]([O:29][CH3:30])=[C:11]([N:10]3[CH2:5][CH2:6][CH2:7][C:8]3=[O:9])[CH:16]=2)=[CH:23][N:22]=[C:21]([CH3:1])[N:20]=1
Reactant: COc1cc(C(C)C)c(Oc2cnc(N)nc2N)cc1NC(=O)CCCCl
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cc(C(C)C)c(Oc2cnc(C)nc2N)cc1N1CCCC1=O
Yield: 47 %

Procedure:
To a solution of 5 ml 1.9 M NaOMe in MeOH was added 4-Chloro-N-[5-(2,4-diamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-butyramide (0.495 g, 1.3 mmol). After 6 h the solution was concentrated in vacuo. The residue was taken up in ethyl acetate, washed with H2O, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo to give 1-[5-(4-amino-2-methyl-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-phenyl]-pyrrolidin-2-one (0.230 g, 47%) as white solid; [MH]+=358; mp (HCl salt)>300° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+:13].O>CO>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([O-:11])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3].[Na+:13]
Reactant: CC(C)(C)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)c1ccc([O-])cc1

Procedure:
In 2500 cc of methanol was dissolved 2000 g of p-t-butylphenol. Separately, 520 g of sodium hydroxide was added to a mixed solvent comprising 2100 cc of methanol and 400 cc of water. Both the liquids were mixed together with stirring in a 10-liter separable flask, and sodium p-t-butylphenolate was formed with generation of heat. Methanol and water were removed by distillation, and the residue was dried in vacuum at 120° C. to isolate sodium p-t-butylphenolate in the form of a yellow powder having a melting point higher than 400° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)=[N:3][CH:4]=1
Reactant: C1COCCN1
Reactant: Clc1ccc(I)cn1
Product: Ic1ccc(N2CCOCC2)nc1

Procedure:
Prepared from 2-chloro-5-iodopyridine and morpholine by the method of Example 9 (d).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([SH:9])[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[O:17][CH:16]=[C:15]([C:18]([OH:20])=[O:19])[CH:14]=1>>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:4]=[C:5]([S:9][C:13]2[O:17][CH:16]=[C:15]([C:18]([OH:20])=[O:19])[CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1coc(Br)c1
Reactant: FC(F)(F)c1cccc(S)c1
Product: O=C(O)c1coc(Sc2cccc(C(F)(F)F)c2)c1

Procedure:
By the procedure of Example 13, m-trifluoromethylthiophenol (5.59 g., 31.4 mmoles) was reacted with 5-bromofuran-3-carboxylic acid. Isolation according to Example 16 gave crude product (1.0 g.) as a gummy solid. The latter was chromatographed on silica gel with ethyl acetate-1/hexane-5/5% acetic acid as eluant. Clean middle fractions were combined and evaporated to solid product (550 mg.). Recrystallization from hexane gave purified 5-(3-trifluoromethylphenylthio)furan-3-carboxylic acid (310 mg., m.p. 99°-101° C., m/e 288).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[NH:11][C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[S:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[CH:14][CH:13]=4)=[CH:4][CH:3]=1.I[C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>[Cu].C1(C)C=CC=CC=1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[C:12]4[C:17]([C:18]=3[CH:19]=2)=[CH:16][C:15]([C:20]2[S:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[CH:14][CH:13]=4)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc3[nH]c4ccc(-c5ccc(C)s5)cc4c3c2)s1
Reactant: COc1ccc(I)cc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COc1ccc(-n2c3ccc(-c4ccc(C)s4)cc3c3cc(-c4ccc(C)s4)ccc32)cc1
Temperature: 100 °C
Yield: 42.1 %

Procedure:
The obtained 3,6-bis(5-methylthiophen-2-yl)carbazole (8.07 g, 22.4 mmol), 4-iodoanisole (21.00 g, 89.7 mmol), copper powder (0.71 g) and potassium carbonate (12.40 g) were mixed together. The mixture was refluxed in a nitrogen atmosphere for 6 hours and cooled to 100° C. Next, toluene (80 mL) was added thereto, and the resultant mixture was filtrated using a filtration aid to remove insoluble matter. Thereafter, the solvent was evaporated under reduced pressure. The residue was dissolved in methylene chloride, and the solution was washed with water and dried to obtain a brown liquid. Next, the obtained liquid was purified through silica gel column chromatography using as an eluent a solvent mixture of methylene chloride/hexane (3/7 by volume), to thereby obtain 4.39 g of 3,6-bis(5-methylthiophen-2-yl)-9-(4-methoxyphenyl)carbazole.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][N:11]([C:18]1[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=1)[C:12](=[O:17])[CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][N:26]([CH3:50])[C:27]([C:29]1[N:38]([C:39]2[CH:44]=[CH:43][C:42]([C:45]([C:48]#[N:49])([CH3:47])[CH3:46])=[CH:41][CH:40]=2)[C:32]2[N:33]=[C:34](Cl)[N:35]=[CH:36][C:31]=2[CH:30]=1)=[O:28]>>[C:48]([C:45]([C:42]1[CH:41]=[CH:40][C:39]([N:38]2[C:32]3[N:33]=[C:34]([NH:24][C:21]4[N:20]=[CH:19][C:18]([N:11]5[C:12](=[O:17])[CH2:13][CH:14]6[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:9]([CH2:16][CH2:15]6)[CH2:10]5)=[CH:23][CH:22]=4)[N:35]=[CH:36][C:31]=3[CH:30]=[C:29]2[C:27](=[O:28])[N:26]([CH3:25])[CH3:50])=[CH:44][CH:43]=1)([CH3:47])[CH3:46])#[N:49]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1-c1ccc(C(C)(C)C#N)cc1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CN(c1ccc(N)nc1)C(=O)C2
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CC5CCC(CC4=O)N5C(=O)OC(C)(C)C)cn3)nc2n1-c1ccc(C(C)(C)C#N)cc1
Yield: 89 %

Procedure:
Following general N—C coupling procedure 1, 3-(6-Amino-pyridin-3-yl)-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester was combined with 2-Chloro-7-[4-(cyano-dimethyl-methyl)-phenyl]-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide which gave tert-butyl 3-(6-(7-(4-(2-cyanopropan-2-yl)phenyl)-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino) pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (160 mg) in 89% yield. MS m/z 664.7
Reaction SMILES: Cl[C:2]1[C:11]([N:12]([CH3:16])[CH:13]([CH3:15])[CH3:14])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:17]#[N:18])[CH:8]=2)[N:3]=1.[CH3:19][C:20]1[NH:21][C:22]2[C:27]([CH:28]=1)=[CH:26][C:25](B1OC(C)(C)C(C)(C)O1)=[CH:24][CH:23]=2.C(=O)([O-])[O-].[K+].[K+].O>COCCOC.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>[CH3:16][N:12]([CH:13]([CH3:15])[CH3:14])[C:11]1[C:2]([C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20]([CH3:19])=[CH:28]3)=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][C:7]([C:17]#[N:18])=[CH:6][CH:5]=2
Reactant: Cc1cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2[nH]1
Reactant: CC(C)N(C)c1nc2cc(C#N)ccc2nc1Cl
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1cc2cc(-c3nc4ccc(C#N)cc4nc3N(C)C(C)C)ccc2[nH]1
Temperature: 90 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a solution of 2-chloro-3-[methyl(propan-2-yl)amino]quinoxaline-6-carbonitrile (250 mg, 0.96 mmol) in DME (8 ml) was added 2-methyl-5-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (494 mg, 1.92 mmol), potassium carbonate (265 mg, 1.92 mmol), Pd(PPh3)4 (58 mg, 0.05 mmol) and water (2 ml). The resulting solution was stirred for 1 h at 90° C. under an inert atmosphere of nitrogen. Then the mixture was quenched with water (100 ml) and extracted with ethyl acetate (3×50 ml), and the organic layers combined and dried over anhydrous magnesium sulfate. The filtrate was concentrated in vacuo to give a residue, which was purified via silica gel column chromatography (10%-20% ethyl acetate in petroleum ether) to afford 3-[methyl(propan-2-yl)amino]-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carbonitrile as a yellow solid (200 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:30])[F:29])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])=[CH:17][C:9]1=2.[CH3:32][NH:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[O:41][CH3:42]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]([F:31])([F:29])[F:30])=[C:6]([CH:27]=1)[CH2:7][N:8]1[CH2:13][CH2:12][NH:11][C:10]2[N:14]=[CH:15][C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([N:33]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[O:41][CH3:42])[CH3:32])=[O:22])=[CH:17][C:9]1=2
Reactant: O=C(O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1
Reactant: CNCc1ccccc1OC
Product: COc1ccccc1CN(C)C(=O)c1cccc(-c2cnc3c(c2)N(Cc2cc(Cl)ccc2C(F)(F)F)CCN3)c1

Procedure:
3-{1-[5-chloro-2-(trifluoromethyl)benzyl]-1,2,3,4-tetrahydropyrido[2,3-b]pyrazin-7-yl}benzoic acid was reacted with N-methyl-2-methoxybenzylamine as in General Procedure 10 to give the title compound. LCMS: m/z=580.94 (M+H+); retention time=0.96 minutes.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11])=[C:4]([O:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[C:25]3C=C(C4OC(C(O)=O)=CN=4)O[C:24]3=[CH:23][C:22]=2[N:38]([CH2:43][C:44]([OH:46])=[O:45])[CH2:39][C:40]([OH:42])=[O:41])[CH:3]=1.[H][H]>C(O)(=O)C.[Pd]>[CH:7]1[CH:2]=[CH:3][C:4]([O:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N:38]([CH2:43][C:44]([OH:46])=[O:45])[CH2:39][C:40]([OH:42])=[O:41])=[C:5]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11])[CH:6]=1
Reactant: Cc1ccc(N(CC(=O)O)CC(=O)O)c(OCCOc2cc3cc(-c4ncc(C(=O)O)o4)oc3cc2N(CC(=O)O)CC(=O)O)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(O)CN(CC(=O)O)c1ccccc1OCCOc1ccccc1N(CC(=O)O)CC(=O)O

Procedure:
Synthesis of a BAPTA tetramethyl ester that contains a phenolic reactive group (Compound XXV). A hydroxy derivative of BAPTA (4-hydroxy-BAPTA) is synthesized by hydrogenation of one of the key intermediate in the synthesis of the Ca2+ indicator fura-2 [U.S. Pat. No. 4,603,209]. For instance 9.8 g of 4-benzyloxy-5'-methyl BAPTA tetramethyl ester is hydrogenated in 50 mL glacial acetic acid in the presence of 0.3 g 10% palladium on charcoal at 40 psi hydrogen pressure for four hours. The reaction is filtered through a pad of Celite to remove the catalyst and the yellow filtrate is evaporated under reduced pressure to give a light brown oil. This is triturated with 50 mL methanol to yield 7.2 g of 4-hydroxy BAPTA tetramethyl ester as a colorless solid (Compound XXV).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:30][O:31][CH2:32][CH2:33][OH:34]>>[CH3:30][O:31][CH2:32][CH2:33][O:34][CH2:2][C:3]1[N:4]=[CH:5][S:6][C:7]=1/[CH:8]=[CH:9]\[S:10][C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: COCCO
Reactant: ClCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COCCOCc1ncsc1/C=C\SC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
In the same manner as in step b) in Example 2, 461 mg of the title compound was prepared from 436 mg of 4-chloromethyl-5-((Z)-2-tritylthioethen-1-yl)thiazole prepared in step a) in Example 2 and 7 ml of 2-methoxyethanol.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.OS(O)(=O)=O.[NH3:17]>C(O)CCC.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH2:17])=[O:8]
Reactant: N
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: O=S(=O)(O)O
Solvent: CCCCO
Solvent: CO
Product: NC(=O)c1cc(Br)ccc1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 82 %

Procedure:
To a stirred solution of 5-Bromosalicyclic acid (30 g, 135.5 mmol) in n-butylalcohol (60 mL) was added H2SO4 (95.6%, 289 μL, 5.42 mmol) in a 100 ml round bottom flask connected by a Dean-Stark trap/reflux condenser that was filled with 12 ml of n-butylalcohol. After heated to reflux for 2 days, the reaction was cooled down to R.T. and concentrated to give a pale yellow oil. The mixture was added 50 mL MeOH, followed by NH3 in MeOH (7 N, 116 mL). The reaction was stirred at R.T. for another 2 days, monitored by HPLC. After the reaction complete, it was concentrated to give a white solid. The crude solid was washed with small amount of EtOAc and hexane to afford 24 g of the product as a white crystalline solid (82% yield). 1H NMR (CDCl3) δ 12.15 (s, 1 H), 7.54 (m, 2 H), 6.97 (d, J=12 Hz, 1 H), 6.00 (broad, 2 H).
Reaction SMILES: Br[CH2:2][CH:3]1[CH:5]([CH3:6])[O:4]1.[C:7]1([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH2:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO>[CH:13]([N:14]1[CH2:2][CH:3]([OH:4])[CH:5]1[CH3:6])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC1OC1CBr
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: CO
Product: CC1C(O)CN1C(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A 500-mL round-bottom flask was charged with 2-(bromomethyl)-3-methyloxirane (42.4 g, 280 mmol), methanol (120 mL), and diphenylmethanamine (44 mL, 260 mmol), and the resulting solution stirred overnight at 80° C. The reaction mixture was cooled to room temperature and concentrated. The residue was purified via column chromatography on silica gel (eluting with 50:1, dichloromethane/methanol) to afford 1-benzhydryl-2-methylazetidin-3-ol (25 g, 35%) as a white solid. MS (ESI, pos. ion) m/z 254 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([N+:24]([O-])=O)=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[H][H]>CO.C(Cl)Cl.[Ni]>[CH3:1][O:2][C:3](=[O:27])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3[N+](=O)[O-])CC2)cc1
Agent: [Ni]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3N)CC2)cc1
Reaction time: 4 h
Yield: 88.1 %

Procedure:
4-[1-(3-Nitro-2-pyridyl)piperazin-4-yl-carbonyl]benzoic acid methyl ester (5 g) was dissolved in a co-solvent of methanol (80 ml) and methylene chloride (60 ml) in a pressurized reactor. With the addition of about 1 g of Raney-nickel (50% slurry in water), the reaction mixture was filled with hydrogen gas and stirred at 50~60 psi for 4 hours. After completion of the reaction, reaction mixture was filtered through celite and filtrate was concentrated under reduced pressure. The concentrated residue was treated with hexane and ether for crystallization, filtered, washed and dried to give 4.05 g (yield: 88%) of the desired compound.