Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:10]([OH:12])=O)[CH:3]=[CH:2]1.CCN(CC)CC.CCN=C=NCCCN(C)C.[Cl:31][C:32]1[CH:45]=[CH:44][C:35]([CH2:36][N:37]2[CH2:42][CH2:41][CH:40]([NH2:43])[CH2:39][CH2:38]2)=[CH:34][C:33]=1[O:46][CH2:47][CH3:48]>CN(C=O)C>[Cl:31][C:32]1[CH:45]=[CH:44][C:35]([CH2:36][N:37]2[CH2:42][CH2:41][CH:40]([NH:43][C:10]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[NH:1][CH:2]=[CH:3]4)=[O:12])[CH2:39][CH2:38]2)=[CH:34][C:33]=1[O:46][CH2:47][CH3:48]
Reactant: CCOc1cc(CN2CCC(N)CC2)ccc1Cl
Reactant: O=C(O)c1cccc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOc1cc(CN2CCC(NC(=O)c3cccc4cc[nH]c34)CC2)ccc1Cl
Yield: 29.1 %

Procedure:
Indole-7-carboxlic acid (19 mg, 0.12 mmol), Et3N (20 μL, 0.15 mmol), EDCI (25 mg, 0.13 mmol) and 1-(4-chloro-3-ethoxy-benzyl)piperidin-4-ylamine (27 mg, 0.1 mmol) were shaken in DMF (1.0 ml) for 16 h, after which time the solvent was evaporated and the residue purified by reversed phase HPLC (MeCN:H2O) affording the title compound (12 mg, 29%). MS: 412.4 (MH+)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:19])[N:6]3[CH2:20][CH2:21][N:22]=[C:5]3[C:4]=2[CH:3]=1.[C:23](Cl)(=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26]>>[C:23]([NH:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:7](=[O:19])[N:6]3[CH2:20][CH2:21][N:22]=[C:5]3[C:4]=2[CH:3]=1)(=[O:28])[CH2:24][CH:25]([CH3:27])[CH3:26]
Reactant: CC(C)CC(=O)Cl
Reactant: Nc1ccc2c(c1)C1=NCCN1C(=O)N2Cc1ccccc1
Product: CC(C)CC(=O)Nc1ccc2c(c1)C1=NCCN1C(=O)N2Cc1ccccc1

Procedure:
Preparation analogously to Example 37 from 9-amino-5-oxo-6-benzyl-2,3,5,6-tetrahydroimidazo-[1,2-c]-quinazoline and isovaleric acid chloride.
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]1([CH3:30])[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[NH:16][CH:17]1[CH2:22][CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18]1>C(Cl)Cl>[C:10]1([CH3:15])[CH:11]=[C:12]([CH3:14])[CH:13]=[C:8]([CH3:30])[C:9]=1[NH:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1
Reactant: Cc1cc(C)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c(C)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(NC2CCNCC2)c(C)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 91.3 %

Procedure:
After adding trifluoroacetic acid (10 mL) to a solution of tert-butyl 4-(mesitylamino)piperidine-1-carboxylate (5.71 g, 17.9 mmol) in methylene chloride (30 mL), the mixture was stirred at room temperature for 22 hours and then concentrated under reduced pressure. The residue was dissolved in methanol (10 mL), toluene (20 mL) was added, and concentration under reduced pressure was repeated. The residue was purified by silica gel column chromatography (75 g NH silica Chromatorex DM2035, hexane:ethyl acetate=4:1-1:1-chloroform:methanol=10:1) to obtain the title compound as a brown solid (3.57 g) (65% yield, 2 steps).
Reaction SMILES: [ClH:1].[NH2:2][OH:3].[C:4]1([C:10]#[C:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:19]=2)[C:17]#[N:18])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>>[ClH:1].[OH:3][NH:2][C:17](=[NH:18])[C:16]1[CH:19]=[C:12]([C:11]#[C:10][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:13]=[N:14][CH:15]=1
Reactant: NO
Reactant: N#Cc1cncc(C#Cc2ccccc2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: N=C(NO)c1cncc(C#Cc2ccccc2)c1
Temperature: 25 °C

Procedure:
Add hydroxylamine hydrochloride (0.55 g, 7.8 mmol) to a suspension of 5-phenylethynylnicotinonitrile (0.20 g, 0.98 mmol) and potassium carbonate (0.68 g, 4.9 mmol) and heat at reflux for 2 h. Cool the reaction mixture to room temperature, filter away any solids and concentrate. Purify by silica gel chromatography, eluting with 40:60 ethyl acetate:hexanes, to obtain the free base of the title compound as a white solid. Dissolve the free base in diethyl ether, add a 1 M solution of hydrogen chloride in diethyl ether (1.1 eq) and collect the resulting precipitated solids by filtration to give the title compound (0.1 g, 37%).
Reaction SMILES: [C:1]([NH2:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:12][CH2:13][C:14]([CH2:16]Cl)=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:12][CH2:13][C:14]1[N:11]=[C:1](/[CH:2]=[CH:3]/[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:10][CH:16]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)C=Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: ClCc1coc(/C=C/c2ccccc2)n1
Temperature: 130 °C
Reaction time: 1 h
Yield: 46.7 %

Procedure:
A mixture of cinnamamide (25.3 g) and 1,3-dichloroacetone (20.9 g) was stirred for one hour at 130° C. The reaction mixture was diluted with water, neutralized with potassium carbonate, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO4), and concentrated under reduced pressure. The residue was subjected to a silica gel column chromatography. From the fraction eluted with diethyl ether-hexane, 4-chloromethyl-2-[(E)-2-phenylethenyl]oxazole (16.9 g, 47%) was obtained. Recrystallization from diethyl ether-hexane gave colorless needles, mp 72-73° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7](Br)[CH:8]=[CH2:9].[CH2:11]([O:13][C:14](=[O:33])[C:15]([OH:32])([C:28]([F:31])([F:30])[F:29])[CH2:16][C:17]([C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[OH:27])([CH3:19])[CH3:18])[CH3:12]>CN(C=O)C>[CH2:11]([O:13][C:14](=[O:33])[C:15]([OH:32])([C:28]([F:29])([F:30])[F:31])[CH2:16][C:17]([C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[O:27][CH2:9][CH:8]=[CH2:7])([CH3:19])[CH3:18])[CH3:12]
Reactant: C=CCBr
Reactant: CCOC(=O)C(O)(CC(C)(C)c1cc(F)ccc1O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc(F)cc1C(C)(C)CC(O)(C(=O)OCC)C(F)(F)F
Temperature: 0 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
Potassium carbonate (4.15 g, 30 mmol) and allyl bromide (2.16 ml, 25 mmol) are added to a solution of 4-(5-fluoro-2-hydroxyphenyl)-2-hydroxy-4-methyl-2-trifluoromethyl-valeric acid ethyl ester (5.36 g, 15.84 mmol) in DMF (50 ml) while being cooled with ice. After 2 hours at 2° C. and after 2 hours at room temperature, the batch is poured into ice water and extracted with hexane-ether 2:1. The combined organic extracts are dried (Na2SO4) and concentrated by evaporation in a vacuum. Column chromatography on silica gel with hexane-ethyl acetate yields 5.7 g of the product.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([N+:12]([O-])=O)[C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=1>CCO.[Pd]>[NH2:12][C:4]1[C:5]2[O:9][C:8](=[O:10])[NH:7][C:6]=2[CH:11]=[CH:2][CH:3]=1
Reactant: O=c1[nH]c2cc(Cl)cc([N+](=O)[O-])c2o1
Agent: [Pd]
Solvent: CCO
Product: Nc1cccc2[nH]c(=O)oc12
Reaction time: 18 h

Procedure:
To a solution of 5-chloro-7-nitro-1,3-benzoxazol-2(3H)-one from Step A (1.10 g, 5.13 mmol) in EtOH (50 mL) was added 10% Pd/C (300 mg). The reaction mixture was shaken in a Parr aparatus under a hydrogen atmosphere (40 p.s.i.) for 18 h, then filtered through a Celite pad, washing with EtOH, and the filtrate was concentrated under reduced pressure to give the title compound. MS: m/z=151 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][CH2:23][NH:22][NH:21][CH2:20]3)[S:17][CH:18]=2)[CH2:10]1.[CH3:25][C:26]1[N:30]([CH2:31][C:32](O)=[O:33])[N:29]=[C:28]([C:35]([F:38])([F:37])[F:36])[CH:27]=1>ClCCl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[CH:9]1[O:13][N:12]=[C:11]([C:14]2[N:15]=[C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:32](=[O:33])[CH2:31][N:30]4[C:26]([CH3:25])=[CH:27][C:28]([C:35]([F:38])([F:37])[F:36])=[N:29]4)[NH:21][CH2:20]3)[S:17][CH:18]=2)[CH2:10]1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)O
Reactant: Fc1cccc(F)c1C1CC(c2csc(C3CCNNC3)n2)=NO1
Solvent: ClCCl
Product: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(C3=NOC(c4c(F)cccc4F)C3)cs2)CN1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 4-[4-[5-(2,6-difluorophenyl)-4,5-dihydro-3-isoxazolyl]-2-thiazolyl]hexahydropyridazine (i.e. the product of Step H) (0.29 g, 0.83 mmol), 5-methyl-3-(trifluoromethyl)-1H-pyrazole-1-acetic acid (0.19 g, 0.91 mmol) and N,N-dicyclohexylcarbodiimide (0.19 g, 0.91 mmol) in dichloromethane (5 mL) was stirred at room temperature for 48 h. More dichloromethane was added to the reaction mixture, the mixture was filtered, washing thoroughly with dichloromethane. The filtrate was concentrated under reduced pressure and loaded onto a chromatotron plate (4 mm). The plate was eluted with dichloromethane, followed by a gradient of 0.5% to 2% methanol in dichloromethane. Fractions containing product material were further purified by HPLC using an Alltima C18 column (250×22 mm), monitored at wavelength 225 nm and eluted with 60% methanol and 0.1% 2,2,2-trifluoroacetic acid in water to provide the title compound (69 mg), a compound of the present invention.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:9][CH:8]2[C@H:4]([C@@H:5]([CH2:19]I)[O:6][C@H:7]2[N:10]2[C:15](=[O:16])[N:14]=[C:13]([NH2:17])[C:12]([F:18])=[CH:11]2)[O:3]1.[H][H]>CO.C(N(CC)CC)C.[Pd]>[CH3:19][C@H:5]1[O:6][C@@H:7]([N:10]2[C:15](=[O:16])[N:14]=[C:13]([NH2:17])[C:12]([F:18])=[CH:11]2)[C@@H:8]2[O:9][C:2]([CH3:1])([CH3:21])[O:3][C@@H:4]12
Reactant: [H][H]
Reactant: CC1(C)OC2[C@@H](O1)[C@@H](CI)O[C@H]2n1cc(F)c(N)nc1=O
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: C[C@H]1O[C@@H](n2cc(F)c(N)nc2=O)[C@@H]2OC(C)(C)O[C@H]21

Procedure:
A solution of 5'-deoxy-5'-iodo-2',3'-O-isopropylidene-5-fluorocytidine (48g, 116.5 mmol) in methanol (500 ml) and triethylamine (20ml) was treated with hydrogen at atmospheric pressure in the presence of palladium on carbon (5%, 25g) for 30 min. at room temperature. During this time the suspension was agitated using a "VIBROMIX" vibrator. The catalyst removed by filtration through celite, and the filtrate was evaporated to dryness and triturated with ethyl acetate (200 ml). After storage overnight the crystals were removed by filtration, and the filtrate was evaporated to approximately 100 ml and again stored overnight. A second batch of crystals was removed by filtration, and the filtrate was evaporated to dryness, pumped in vacuo, to give 5'-deoxy-2',3'-O-isopropylidene-5-fluorocytidine as a foam 31g (93%). This material was characterized by formation of a crystalline picrate salt, mp 168°-170°. uv (CH3OH) λ max 237-238 mμ(ε 20,700), λmax 282 mμ(ε 9,400), λ max 353-354mμ(ε 15,300). NMR ((CH3)2SO-d6) δ 8.58 (S, 2, picrate) δ 8.29 (d, 1, J = 7 Hz, CHCF) δ5.72 (d,J= 4 Hz, C'1) δ1.47, 1.28 (S, 3, (CH3)2C) δ 1.31 (d, 3, J = 6 Hz, CH3CH).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[CH2:3][NH:4][C:5](=[O:22])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:7]=1[OH:21].C[O-].[Na+].[CH2:28](Br)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[F:24][C:2]([F:1])([F:23])[CH2:3][NH:4][C:5](=[O:22])[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]([NH:13][C:14](=[O:20])[CH2:15][O:16][C:17](=[O:19])[CH3:18])[C:7]=1[O:21][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CC(=O)OCC(=O)Nc1cc(F)cc(C(=O)NCC(F)(F)F)c1O
Reactant: BrCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)OCC(=O)Nc1cc(F)cc(C(=O)NCC(F)(F)F)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
7.75 g (22 mmol) of 3-acetoxyacetamido-5-fluoro-2-hydroxy-benzoic acid-(2,2,2,-trifluoro-ethyl)amide (Example 37d) is dissolved in 50 ml of dry THF. 1.35 g (25 mmol) of sodium methylate is added, stirred for 15 minutes at room temperature, 4.27 g (25 mmol) of benzylbromide is added and refluxed for 1 hour. The reaction solution is then cooled to room temperature, NaBr is filtered off, the filtrate is concentrated by evaporation in a vacuum and the residue is chromatographed on silica gel 60 with ethyl acetate/hexane. 5.2 g=53.4% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[O:5][CH2:6][C:7]([O:9]CC)=[O:8].[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH3:15])[CH:14]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)COc1cc(C)cc(C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C)cc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
Referring to FIG. 37, to a solution of ethyl 2-(3,5-dimethylphenoxy)acetate (19 g, obtained from the previous step) in methanol (150 mL) was added NaOH solution (6 N, 50 mL). The reaction mixture was stirred at room temperature for 4 h and then adjusted to pH=1˜2 with 2 N HCl solution. The resulting mixture was extracted with ethyl acetate (150 mL×2). The combined extracts were washed with brine, dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a solid, which was washed with ethyl acetate/hexane (1:15, 40 mL) to give product (14 g, 95% yield over two steps); 1H NMR (CDCl3, 300 MHz): δ 6.69 (s, 1H), 6.58 (s, 2H), 4.68 (s, 2H), 2.31 (s, 6H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[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[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N: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[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=2)=[O:24])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCNCc1ccc2ccccc2n1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Product: CCN(Cc1ccc2ccccc2n1)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-2-ylmethyl-amine
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:12][CH2:11]3)[C:7](=[S:9])[NH:8][C:4]=2[CH:3]=1.I[CH3:32].C[O-].[Na+]>CO>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[N:6]([CH:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]4[C:23]5[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=5[NH:21][C:20]4=[O:28])[CH2:12][CH2:11]3)[C:7]([S:9][CH3:32])=[N:8][C:4]=2[CH:3]=1
Reactant: CI
Reactant: O=c1[nH]c2ccccc2n1CCCN1CCC(n2c(=S)[nH]c3cc(Cl)ccc32)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CSc1nc2cc(Cl)ccc2n1C1CCN(CCCn2c(=O)[nH]c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2.21 parts of 1-{3-[4-(5-chloro-2,3-dihydro-2-thioxo-1H-benzimidazol-1-yl)-1-piperidinyl]propyl}-1,3-dihydro-2H-benzimidazol-2-one, 0.71 parts of iodomethane, 0.28 parts of sodium methanolate and 40 parts of methanol is stirred overnight at room temperature. The reaction mixture is evaporated. The residue is stirred with water and the product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 4-methyl-2-pentanone. The product is filtered off and dried, yielding 1.1 parts of 1-[3-{4-[5-chloro-2-(methylthio)-1H-benzimidazol-1-yl]-1-piperidinyl}propyl]-1,3-dihydro-2H-benzimidazol-2-one; mp. 196.1° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]2=[CH:11][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.C1C=CC=CC=1.[C:45]([C:47]1[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][CH:48]=1)#[CH:46]>C1C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:47]1([C:45]#[C:46][C:2]2[CH:3]=[C:4]3[C:9](=[O:10])[O:8][C:6](=[O:7])[C:5]3=[CH:11][CH:12]=2)[C:56]2[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=2)[CH:50]=[CH:49][CH:48]=1
Reactant: C#Cc1cccc2ccccc12
Reactant: O=C1OC(=O)c2cc(Br)ccc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: O=C1OC(=O)c2cc(C#Cc3cccc4ccccc34)ccc21
Reaction time: 1 h
Yield: 36.2 %

Procedure:
To a solution of 4-bromophthalic anhydride (4.54 g, 20.0 mmol), triphenylphosphine (520 mg, 2.0 mmol), cuprous iodide (190 mg, 1.0 mmol), bis(triphenylphosphine)palladium dichloride (280 mg, 0.4 mmol) in 2:1 triethylamine/benzene (75 mL) was added 1-ethynylnaphthalene (4.94 g, 32.5 mmol) in benzene (25 mL) by cannula transfer and the mixture was heated at reflux for 2 h. The cooled solution was filtered and the precipitate was added to water (150 mL), filtered and washed with water (3×5 mL). The crude yellow solid was recrystallized from toluene, filtered and washed with hexanes (3×5 mL). The product was then added to 0.15 M NaHCO3(aq), stirred vigorously for 1 h and filtered. The yellow solid was dried at reduced pressure to constant weight to yield 4-(1-naphthylethynyl)phthalic anhydride (2.16 g, 36.2%). mp 220-222° C.; 1H NMR (CDCl3, 300 MHz) δ7.48-7.68 (m, 3H), 7.82 (d, J=7.2 Hz, 1H), δ7.92 (t, J=8.1 Hz, 2H), δ7.99 (d, J=7.8 Hz, 1H), δ8.07 (d, J=8.0 Hz, 1H), δ8.20 (s, 1H), δ8.35 (d, J8.1 Hz, 1H); 13 C NMR (CDCl3, 300 MHz) δ92.0, 94.6, 119.3, 125.5, 125.8, 125.9, 127.0, 127.6, 128.4, 128.8, 129.7, 130.6, 131.7, 131.9, 132.2, 133.3, 133.4, 138.7, 162.3, 162.3. Anal. Calcd for C20H10O3: C, 80.53;H, 3.38. Found: C, 80.37;H, 3.36.
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.CC(C)([O-])C.[K+].[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1)=[CH2:17]>C(O)(=O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[CH2:16][CH2:17][C:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]=1
Reactant: C1=Cc2ccccc2C1
Reactant: C=Cc1ccccn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: C1=C(CCc2ccccn2)c2ccccc2C1

Procedure:
This compound is prepared as described by Dressler and Kurland J.O.C. 29, 175 (1964). Under nitrogen gas, 500 g. indene plus 5 g. potassium t-butoxide are stirred and heated to 130°. 2-vinyl pyridine (220 g., 2.0 M) is added dropwise over a period of 1 hour keeping the temperature at 135°-145° C. during addition and for 2 hours after addition is completed. The reaction mixture is cooled and 25 ml. acetic acid is added, followed by filtration. A flash distillation yields 395 g. (84%) crude product boiling 160°-175°/0.3 mm. This is redistilled to give 353 g. (75%) of oil (3-[2(pyridyl)ethyl]indene) boiling point 135°-140°/0.1 mm.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:13]([OH:21])[CH2:14]CCCCCC.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:13]([O:11][C:10](=[O:12])[C@H:2]([CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[NH2:1])(=[O:21])[CH3:14]
Reactant: CCCCCCCCO
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(=O)OC(=O)[C@@H](N)Cc1ccccc1
Yield: 93.3 %

Procedure:
L-Phenylalanine (5.0 g, 0.03 mol), 1-octanol (3.9 g, 0.03 mol) and p-toluenesulfonic acid monohydrate (6.3 g, 0.038 mol) were suspended in toluene (200 ml) in a flask equipped with a Dean-Stark trap and refluxed for 20 h., resulting in a clear solution. Subsequently, the solvent was removed in vacuo and the remaining white solid was dissolved in CHCl3 (150 ml). This solution was extracted with 10% sodium carbonate, water and brine and dried over MgSO4. Evaporation of the solvent in vacuo yielded a colourless oil (7.7 g, 0.028 mol, 92%). 1H NMR (CDCl3): δ=7.19 (m, 5H), 4.04 (t, 2H, 3J=6.59 Hz), 3.67 (dd, 1H, 3JAB=5.5 Hz, 3JAB=7.7 Hz), 3.03 (dd, 1H, 2JAB=13.6 Hz, 3JAB=5.5 Hz), 2.81 (dd, 1H, 2JAB=13.6 Hz, 3JAB=7.7 Hz), 1.54 (m, 2H), 1.47 (s, 2H), 1.22 (a, 10H), 0.83 (t, 3H, 3J=6.8 Hz); 13C NMR (CDCl3): δ=175.1, 137.15, 129.15, 128.40, 126.65, 65.02, 55.75, 41.06, 31.65, 29.06, 28.41, 25.74, 22.51, 13.97.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[C:18]([OH:24])[N:17]=2)=[CH:12][CH:11]=1.C1COCC1>CO>[Br:1][C:23]1[C:16]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)=[N:17][C:18]([OH:24])=[C:19]([CH:22]=1)[C:20]#[N:21]
Reactant: N#Cc1ccc(-c2ccc(F)cc2)nc1O
Reactant: O=C1CCC(=O)N1Br
Solvent: CO
Solvent: C1CCOC1
Product: N#Cc1cc(Br)c(-c2ccc(F)cc2)nc1O
Yield: 94.6 %

Procedure:
N-Bromosuccinimide (3.66 g) was added to a mixture of 6-(4-fluorophenyl)-2-hydroxynicotinonitrile (4.00 g), THF (30 mL), and methanol (30 mL), and the resultant mixture was stirred at room temperature for 10 minutes. The solvent was distilled off, and the obtained residue was suspended in a mixed solvent of water, ethyl acetate, and hexane. Then, the obtained solid was washed with hexane to obtain the title compound (5.18 g).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[C:12](OCC)(OCC)([O:14][CH2:15][CH3:16])[CH3:13].C(OC(=O)C)(=O)C>[Cl-].[Zn+2].[Cl-]>[CH2:12]([O:14][C:15](=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH3:16])[CH3:13]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: CCOC(C)(OCC)OCC
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(C(=O)OCC)=C(C)OCC
Temperature: 140 °C

Procedure:
A mixture of diethyl malonate (4.8 mL), triethyl orthoacetate (17 mL), acetic anhydride (0.11 mL) and zinc chloride (1.2 g) was stirred at 140° C. To the mixture was added acetic anhydride (0.11 mL) each after 30, 90 and 120 minutes, and then stirred at the same temperature overnight. The reaction mixture was cooled to room temperature, and the insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=4/1−7/3) to give diethyl 2-(1-ethoxyethylidene)malonate (5.02 g). To a solution of diethyl 2-(1-ethoxyethylidene)malonate (4.13 g) in ethanol (15 mL) were added formamidine hydrochloride (1.73 g) and a solution of potassium hydroxide (2.21 g) in water (7.5 mL), and the mixture was stirred at room temperature for 2 days. The reaction mixture was neutralized by adding acetic acid. To the mixture was added ethyl acetate (30 mL), and the mixture was stirred at room temperature for 30 minutes. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate−ethyl acetate/methanol=9/1) to give the title compound (1.5 g).
Reaction SMILES: C(O)(=O)C.[Br:5][C:6]1[C:7]([O:14][CH3:15])=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][NH2:10].CS[C:18]1[N:19](C(OC)=O)[CH2:20][CH2:21][N:22]=1>CO>[Br:5][C:6]1[C:7]([O:14][CH3:15])=[C:8]([CH:11]=[CH:12][CH:13]=1)[CH2:9][N:10]1[CH2:21][CH2:20][N:19]=[C:18]1[NH2:22]
Reactant: COC(=O)N1CCN=C1SC
Reactant: COc1c(Br)cccc1CN
Solvent: CC(=O)O
Solvent: CO
Product: COc1c(Br)cccc1CN1CCN=C1N
Temperature: 25 °C

Procedure:
10 mL of acetic acid (HOAc) was added to a solution of 3.9 g of 3-bromo-2-methoxy-benzylamine 8 and 3.1 g of methyl 2-(methylthio)-4,5-dihydro-1H-imidazole-1-carboxylate in 100 mL of methanol. The resulting solution was heated to a gentle reflux and refluxed overnight. The solution was cooled to room temperature, quenched with sodium hydroxide and extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over magnesium sulfate. The mixture was then filtered. The solvents were removed under vacuum. The remaining residue was purified by chromatography on silica gel (10% saturated ammonia methanol in dichloromethane) to give (3-bromo-2-methoxy-benzyl-4,5-dihydro-1H-imidazol-2-yl)-amine 9.