Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:15]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:22]([O:26][C:27](=[O:30])[CH:28]=[CH2:29])([CH3:25])([CH3:24])[CH3:23].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CC#N>CCOC(C)=O.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:15]1(=[C:8]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:5]2[CH:6]=[CH:7][C:2](/[CH:29]=[CH:28]/[C:27]([O:26][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:30])=[CH:3][CH:4]=2)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Brc1ccc(C(=C2CCCCCC2)c2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)/C=C/c1ccc(C(=C2CCCCCC2)c2ccccc2)cc1
Reaction time: 2 h
Yield: 103.4 %

Procedure:
A stirred suspension of 1 (0.77 g, 2.24 mmol), TEA (1.86 mL, 13.4 mmol), t-butylacrylate (1.96 mL, 13.4 mmol), Pd(OAc)2 (0.12 g, 0.50 mmol), P(o-tolyl)3 (0.28 g, 0.90 mmol) and CH3CN were stirred at reflux under N2. Heating was discontinued after 2 h and the reaction diluted with EtOAc (50 mL) and water (50 mL). The mixture was filtered through a celite pad and the filtrate transferred to a separatory funnel. The organic fraction was washed with 50 mL brine (50 mL), dried (MgSO4), filtered and concentrated to 1.39 g of an amber oil. The crude product was purified by flash chromatography on silica gel with a hexanes to 5% EtOAc:hexanes gradient. The product, 2, was isolated as a colorless, viscous oil (900 mg, 100%). 1H NMR (300 MHz, DMSO-d6): δ 1.52 (s, 9H), 1.59 (s, 8H), 2.31 (br, 4H), 6.51 (d, J=16 Hz, 1H), 7.19-7.38 (m, 7H), 7.56 (d, J=16 Hz, 1H), 7.66 (d, J=8.1 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[C:9]([O:12][CH3:13])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[CH:14]([C:17]1[N:18]=[C:19]([C:22](O)=[O:23])[S:20][CH:21]=1)([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[C:4]([C:3]1[C:2]([NH:1][C:22]([C:19]2[S:20][CH:21]=[C:17]([CH:14]([CH3:16])[CH3:15])[N:18]=2)=[O:23])=[C:10]([CH3:11])[C:9]([O:12][CH3:13])=[CH:8][CH:7]=1)(=[O:5])[NH2:6]
Reactant: CC(C)c1csc(C(=O)O)n1
Reactant: COc1ccc(C(N)=O)c(N)c1C
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: COc1ccc(C(N)=O)c(NC(=O)c2nc(C(C)C)cs2)c1C
Reaction time: 8 h
Yield: 84.5 %

Procedure:
To a stirred mixture of 2-amino-4-methoxy-3-methyl-benzamide (2.0 g, 11 mmol), 4-isopropyl-thiazole-2-carboxylic acid (2.4 g, 14 mmol) and Hobt-hydrate (2.2 g, 14 mmol) in dry DMF (80 ml) was added EDAC (2.88 g, 15 mmol) and TEA (2.1 ml, 15 mmol) and the mixture was stirred overnight. A 5% aqueous solution of citric acid was added and the mixture was extracted three times with ethyl acetate. The organic phase was washed with saturated sodium hydrogen carbonate solution (two times) and brine, dried with sodium sulfate and evaporated under reduced pressure which gave the title compound (3.1 g).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([CH2:37][O:38]C(=O)C)=[O:36]>>[OH:38][CH2:37][C:35]([NH:1][C@@H:2]1[CH2:3][CH2:4][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH2:31][O:32][CH3:33])[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)=[O:36]
Reactant: CC(=O)OCC(=O)Cl
Reactant: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c[nH]c13)OCO2
Product: COCCOc1ccc2c(c1-c1ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)CO)CC4)c[nH]c13)OCO2

Procedure:
Starting from cis-4-[5-(2-methoxy-ethoxy)-benzo[1,3]dioxol-4-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A186) and acetic acid chlorocarbonyl-methyl ester the title compound was obtained as colorless solid.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[NH:3][C:4]([C:6]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].C(O)(=O)C.O.O.[ClH:25].[C:26]([N:34]1[CH2:39][CH2:38][O:37][C:36]([C:58]2[CH:63]=[CH:62][C:61]([F:64])=[C:60]([F:65])[CH:59]=2)([CH2:40][CH2:41]N2CCC(C3C=CC=CC=3)(NC(N)=O)CC2)[CH2:35]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([BH3-])#N.[Na+]>CO>[ClH:25].[ClH:25].[C:26]([N:34]1[CH2:39][CH2:38][O:37][C:36]([C:58]2[CH:63]=[CH:62][C:61]([F:64])=[C:60]([F:65])[CH:59]=2)([CH2:40][CH2:41][N:9]2[CH2:8][CH2:7][C:6]([C:4](=[O:5])[NH:3][N:2]([CH3:18])[CH3:1])([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:11][CH2:10]2)[CH2:35]1)(=[O:33])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CN(C)NC(=O)C1(c2ccccc2)CCNCC1
Reactant: NC(=O)NC1(c2ccccc2)CCN(CCC2(c3ccc(F)c(F)c3)CN(C(=O)c3ccccc3)CCO2)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: CN(C)NC(=O)C1(c2ccccc2)CCN(CCC2(c3ccc(F)c(F)c3)CN(C(=O)c3ccccc3)CCO2)CC1
Yield: 145 %

Procedure:
This compound is prepared by the procedure described in step B of EXAMPLE 68 from 1.55 g of 4-(3,3- dimethylcarbazoyl)-4-phenylpiperidine (free base) and 0.38 ml of acetic acid in 26 ml of MeOH, and then 2.4 g of the compound obtained in step A of EXAMPLE 68 in 26 ml of MeOH and 0.47 g of sodium cyanoborohydride in 26 ml of MeOH. This gives 1.82 g of the expected product.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].[CH2:12]([Sn](CCCC)(CCCC)CC=C)[CH2:13][CH2:14]C.CN(C)C=O.[F-].[K+]>C(N(CC)CC)C>[CH2:14]([C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11])[CH:13]=[CH2:12]
Reactant: O=C1CCc2c(Br)cccc21
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCc1cccc2c1CCC2=O
Temperature: 20 °C

Procedure:
15 g of 4-bromo-1-indanone, 24 ml of tributyl allyl stannane, 150 ml of dimethylformamide, 0.82 g of tetrakis triphenyl phosphine palladium and 7.89 g of triethylamine are taken to 120° C. for one hour. After cooling to 20° C., the reaction mixture is poured over 300 ml of an aqueous solution of potassium fluoride, agitated, and filtered on celite; the filtrate is extracted with isopropyl ether. The insoluble part is taken up with ethyl acetate and filtered on celite. The reunited organic phases are washed with water saturated with sodium chloride, dried and brought to dryness under reduced pressure. The residue is chromatographed on silica with hexane-ethyl acetate (9-1) and 11.84 g of expected product is recovered.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:23].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[C:25]1([O:24][C:22](=[O:23])[NH:1][CH2:2][C:3]2[C:12](=[O:13])[C:11]3[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=3)[N:5]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:4]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 10 mL round-bottomed flask, 3-(aminomethyl)-7-chloro-1-phenylquinolin-4(1H)-one intermediate D (0.05 g, 0.176 mmol), phenyl chloroformate (27.5 mg, 0.176 mmol) and N,N-diisopropylethylamine (68.1 mg, 92.0 μL, 0.527 mmol) were combined with CH2Cl2 (3 mL). The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated, then the crude product was purified using preparative reverse-phase HPLC to provide (7-chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-carbamic acid phenyl ester. MS calcd. for C24H18ClN5O [(M+H)+] 405.1, obsd. 404.9.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[CH:23]=[C:22]([CH2:24][CH3:25])[S:21][C:12]=2[N:13]=[C:14]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[O:20]1[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[CH:23]=[C:22]([CH2:24][CH3:25])[S:21][C:12]=3[N:13]=2)=[CH:17][CH:18]=[N:19]1
Reactant: CCc1cc2c(Cl)nc(-c3ccno3)nc2s1
Reactant: NCc1ccccc1
Product: CCc1cc2c(NCc3ccccc3)nc(-c3ccno3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(isoxazol-5-yl)-6-ethyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-benzylamino-6-ethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][CH2:10][CH2:11][C:5]2=[N:4][N:3]=1.[CH3:16][C:17]1[CH:34]=[CH:33][CH:32]=[CH:31][C:18]=1[C:19]([NH:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)=[O:20].C(N(CC)CC)C>ClCCl>[CH3:1][C:2]1[N:6]2[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[N:9]([C:26]([C:25]3[CH:24]=[CH:23][C:22]([NH:21][C:19](=[O:20])[C:18]4[CH:31]=[CH:32][CH:33]=[CH:34][C:17]=4[CH3:16])=[CH:30][CH:29]=3)=[O:27])[CH2:10][CH2:11][C:5]2=[N:4][N:3]=1
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)Cl)cc1
Reactant: Cc1nnc2n1-c1ccccc1NCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCc3nnc(C)n3-c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 5 mmol of 5,6-dihydro-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine in 20 ml of dichloromethane is added 5.5 mmol of 4-[(2-methylbenzoyl)amino]benzoyl chloride and 7.5 mmol of triethylamine. The mixture is stirred at room temperature for 8 hours and then washed with water, aqueous NaHCO3 and brine. The organic layer is dried (Na2SO4) and the solvent removed in vacuo to give a solid. The solid is purified by chromatography on silica gel with ethyl acetate-hexane as solvent to give the desired product.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1B(O)O>>[Cl:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][C:11]=1[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)cc1
Reactant: COc1ccc(Cl)c(B(O)O)c1
Product: COc1ccc(Cl)c(-c2ccc(N)cc2)c1
Yield: 75.7 %

Procedure:
The title compound (154 mg) was prepared from 4-bromoaniline (150 mg, 0.87 mmol) and 2-chloro-5-methoxyphenyl boronic acid (211 mg, 1.13 mmol) as a colourless viscous liquid.
Reaction SMILES: [CH:1]1([CH:7]([C:9](C(Br)C2CCCCC2)=O)Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]([NH2:22])=[S:21]>C(O)C>[NH2:22][C:20]1[S:21][CH:9]=[C:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[N:19]=1
Reactant: NC(N)=S
Reactant: O=C(C(Br)C1CCCCC1)C(Br)C1CCCCC1
Solvent: CCO
Product: Nc1nc(C2CCCCC2)cs1
Temperature: 25 °C

Procedure:
Cyclohexylbromomethylketone (49 g., 0.24 mole) was added to a slurry of thiourea (20.1 g., 0.26 mole) in 250 ml. of ethanol and the mixture heated to reflux. The resulting solution was refluxed for 2 hours, cooled to room temperature and evaporated in vacuo to an oil. The oil was taken up in 100 ml. of water, the solution made basic with concentrated ammonium hydroxide and crude product recovered in two crops by filtration. Crude product was recrystallized from cyclohexane to yield purified 2-amino-4-cyclohexylthiazole (20.4 g.; m.p. 141°-143° C.).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][O:21]C(=O)C)=[CH:16][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:25]=1.[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH2:29].P>C1(C)C=CC=CC=1.C(O)(C)(C)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH:29][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][OH:21])=[CH:16][C:9]=3[CH2:8][CH2:7][C:6]=2[CH:25]=1
Reactant: CC(=O)OCCCOc1ccc2c(c1)CCc1cc(Cl)ccc1C2=O
Reactant: Nc1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: P
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: O=C1c2ccc(Nc3ccc(F)cc3F)cc2CCc2cc(OCCCO)ccc21
Yield: 42 %

Procedure:
In accordance with general method O, 0.65 g (1.8 mmol) of acetic acid 3-(8-chloro-5-oxo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-2-yloxy)-propyl ester, 0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.04 g of Pd(OAc)2, 0.17 g of phosphine ligand and 0.74 g (7.7 mmol) of Na—O-tert-butylate are reacted in 10 ml of toluene and 2 ml of tert-BuOH. Yield: 42%; m.p.: 154° C.
Reaction SMILES: [Cl:1][CH2:2][C:3](=O)[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[C:11]1([CH:18]=CC=[C:14](O)[CH:13]=1)[OH:12]>S(=O)(=O)(O)O>[Cl:1][CH2:2][C:3]1[C:9]2[C:8](=[CH:18][C:11]([OH:12])=[CH:13][CH:14]=2)[O:7][C:5](=[O:6])[CH:4]=1
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)CC(=O)CCl
Agent: O=S(=O)(O)O
Product: O=c1cc(CCl)c2ccc(O)cc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.3 %

Procedure:
To a 250 mL RB flask fitted with magnetic stirrer was charged with Ethyl 4-chloroacetoacetate (22.12 g, 134.9 mmol) was dissolved in concentrated sulfuric acid (48 mL) at 0° C., and resorcinol (14.0 g, 127.3 mmol) was added portionwise. The mixture was stirred at room temperature for 2 h. The reaction mixture was poured into ice-water, and the resulting solid was collected by filtration, washed with water, and dried to give 4-(chloromethyl)-7-hydroxy-2H-chromen-2-one (21.0 g, 75.6%) as a beige solid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:15]([O:19][C:20]1[C:23](=[O:24])[C:22](=[O:25])[C:21]=1[NH:26][CH2:27][CH2:28][CH2:29]Br)[CH2:16][CH2:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].COCCOCCN(CCOCCOC)CCOCCOC>ClCCl>[CH2:15]([O:19][C:20]1[C:23](=[O:24])[C:22](=[O:25])[C:21]=1[NH:26][CH2:27][CH2:28][CH2:29][O:14][C:10]1[CH:11]=[CH:12][CH:13]=[C:8]([CH2:7][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH:9]=1)[CH2:16][CH2:17][CH3:18]
Reactant: Oc1cccc(CN2CCCCC2)c1
Reactant: CCCCOc1c(NCCCBr)c(=O)c1=O
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCCCOc1c(NCCCOc2cccc(CN3CCCCC3)c2)c(=O)c1=O
Temperature: 20 °C
Reaction time: 40 h
Yield: 94.2 %

Procedure:
A mixture of 3-piperidinomethyl phenol (0.876 kg; 4.582 moles), 1-butoxy-2-(3-bromopropylamino)-1-cyclobutene-3,4-dione [prepared in Example 10] (1 kg; 3.446 moles), finely powdered (pulverized) potassium carbonate (0.633 kg; 4.582 moles), tris[2-(2-methoxyethoxy)ethyl]amine (0.234 kg; 0.725 mole) in dichloromethane (17.23L) was stirred at 20° C. for 40 hours. The mixture was washed with 3% aqueous sodium hydroxide (2×3L) and then the organic phase was concentrated to dryness under reduced pressure to an oil. The concentrate was diluted with toluene (10L), washed with water (3×2.5L), then extracted with 3N hydrochloric acid (2×2.5L). The cooled aqueous acidic phase was basified with 30% sodium hydroxide then extracted with dichloromethane (2×2.5L). The organic phase was treated with charcoal, stirred for 15 minutes, dried (over magnesium sulfate), filtered through diatomaceous earth and the pad washed with dichloromethane (3×0.25L). The combined filtrate was concentrated to dryness under reduced pressure to give 1300 g (94% yield) of the title compound as a yellowish oil.
Reaction SMILES: Br[CH2:2][CH:3]1[O:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4]1.[NH:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[CH2:14]1.Br>C(#N)C>[O:8]1[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][CH:3]1[CH2:2][N:13]1[CH2:18][CH2:17][CH2:16][CH:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[OH:25])[CH2:14]1
Reactant: BrCC1COc2ccccc2O1
Reactant: Oc1ccccc1C1CCCNC1
Agent: Br
Solvent: CC#N
Product: Oc1ccccc1C1CCCN(CC2COc3ccccc3O2)C1

Procedure:
A mixture of 2-bromomethyl-2,3-dihydrobenzo[1,4]dioxine (54 mg, 0.24 mmol), 2-(piperidin-3-yl)phenol.HBr (61 mg, 0.24 mmol) and KHCO3 (84 mg, 0.84 mmol) in acetonitrile (2 mL) was heated in a microwave reactor at 160° C. for 5.5 h. The mixture was absorbed on silica and purified by flash chromatography using a gradient of DCM and MeOH (1% triethylamine) as eluent to give 11 mg of the title compound.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])[C:5]([NH2:18])=[CH:4][CH:3]=1.[CH3:19][N:20]1[CH:24]=[C:23]([S:25](Cl)(=[O:27])=[O:26])[N:22]=[C:21]1[CH3:29]>>[F:8][C:7]1[C:6]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:11]=2[F:17])=[C:5]([NH:18][S:25]([C:23]2[N:22]=[C:21]([CH3:29])[N:20]([CH3:19])[CH:24]=2)(=[O:27])=[O:26])[CH:4]=[CH:3][C:2]=1[F:1]
Reactant: Nc1ccc(F)c(F)c1Nc1ccc(I)cc1F
Reactant: Cc1nc(S(=O)(=O)Cl)cn1C
Product: Cc1nc(S(=O)(=O)Nc2ccc(F)c(F)c2Nc2ccc(I)cc2F)cn1C

Procedure:
According to the general procedure B, 5,6-difluoro-N1-(2-fluoro-4-iodophenyl)benzene-1,2-diamine was reacted with 1,2-dimethyl-1H-imidazole-4-sulfonyl chloride to obtain the title compound. 1H NMR (300 MHz, CDCl3): δ 7.95 (br s, 1H), 7.37 (dd, J=1.8 & 10.8 Hz, 1H), 7.32-7.14 (m, 3H), 6.98 (dd, J=9.6 & 17.7 Hz, 1H), 5.87 (dt, J=4.2, 9.0 & 17.4 Hz, 1H), 5.55 (br s, 1H), 3.49 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: C([O:3][C:4](=[O:23])[CH2:5][CH:6]([C:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)C.[NH:24]([C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1)[NH2:25]>C(O)(=O)C>[C:8]1([C:7]2[C:6]([CH2:5][C:4]([OH:3])=[O:23])=[C:15]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:24]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[N:25]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)CC(C(=O)c1ccccc1)C(=O)c1ccccc1
Reactant: NNc1cccnc1
Solvent: CC(=O)O
Product: O=C(O)Cc1c(-c2ccccc2)nn(-c2cccnc2)c1-c1ccccc1
Yield: 61.2 %

Procedure:
8.7 grams 3,3-dibenzoyl-propionic acid ethyl ester, 5.0 grams 3-hydrazino-pyridine and 6.0 grams glacial acetic acid were mixed and the mixture heated to the boiling temperature under reflux for 5 hours. The reaction product was further processed by a procedure analogous to that described in Example (2a). 6.1 grams 3,5-diphenyl-1-(3-pyridyl)-pyrazol-4-acetic acid, melting at 185°-187° C., were obtained, representing a yield of 62%.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C(N(CC)CC)C.[CH2:20]1[C:33]2[C:24](=[N:25][C:26]3[C:31]([C:32]=2[NH2:34])=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:23][CH2:22][CH2:21]1>C(Cl)(Cl)Cl>[CH2:30]1[C:31]2[C:26](=[N:25][C:24]3[C:33]([C:32]=2[NH:34][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:27][CH2:28][CH2:29]1
Reactant: Nc1c2c(nc3ccccc13)CCCC2
Reactant: CCCCCCCCCC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCCCCCCC(=O)Nc1c2c(nc3ccccc13)CCCC2
Temperature: 25 °C

Procedure:
Freshly distilled decanoyl chloride, 5.18 g (0.029 mol), is slowly added to a mixture of 2.94 g (0.029 mol) of triethylamine and 5.82 g (0.029 mol) of 1,2,3,4-tetrahydro-9-acridinamine (Petrow, V., Journal of the Chemical Society, pages 634 to 637 (1947)) in 150 ml of Chloroform. The mixture is heated at reflux for two hours, cooled to room temperature, filtered, and the filtrate evaporated to afford, after repeated washing with diethyl ether, 1.67 g of N-(1,3,4,5-tetrahydro-9-acridinyl)decanamide as a yellow solid: mp 123-126° C.
Reaction SMILES: [H-].[Na+].[C:3](=[O:8])([O:6][CH3:7])OC.[C:9]1(=[O:19])[CH:18]2[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11][CH2:10]1.Cl>O1CCCC1.CCOCC>[O:19]=[C:9]1[CH:18]2[CH:13]([CH2:14][CH2:15][CH2:16][CH2:17]2)[CH2:12][CH2:11][CH:10]1[C:3]([O:6][CH3:7])=[O:8]
Reactant: O=C1CCCC2CCCCC12
Reactant: COC(=O)OC
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)C1CCC2CCCCC2C1=O

Procedure:
A suspension of sodium hydride (4.60 g, 115 mmol) in tetrahydrofuran (20 mL) was treated with dimethyl carbonate (8.29 mL, 99 mmol), heated to reflux under nitrogen, treated dropwise with a solution of octahydronaphthalen-1(2H)-one (Aldrich cat#115063, mixture of trans (major) and cis (minor), 5 g, 32.8 mmol) in tetrahydrofuran (20 mL) over 5 minutes, and heated to reflux overnight. The mixture was cooled, diluted with ether (300 mL) and treated with 1 M hydrochloric acid (150 mL). The layers were separated and the aqueous layer was extracted with ether (2×100 mL). The combined ether layers were washed with brine, dried (magnesium sulfate), filtered and concentrated to provide the desired product that was not purified, but used as is in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].N([O-])=O.[Na+].[N-:15]=[N+:16]=[N-].[Na+]>Cl>[N:8]([C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[N+:15]=[N-:16]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Product: [N-]=[N+]=Nc1ccc([N+](=O)[O-])cc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
To a solution of 4-nitroaniline (27.6 g) in 0.4N hydrochloric acid (500 ml) was added 1M aqueous sodium nitrite solution (200 ml) under ice-cooling, and the mixture was stirred for 30 min and then at room temperature for 20 min. An aqueous solution (100 ml) of sodium azide (13.0 g) was added to the obtained reaction mixture under ice-cooling, and the mixture was stirred for 30 min. The precipitated crystals were collected by filtration, washed with 1N hydrochloric acid and water and air-dried to give the title compound as a brown powder (28.2 g, 86%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[CH2:7][S:8][CH2:9][CH2:10][NH2:11].[C:12]([CH:14]=[C:15](OCC)[NH:16][CH3:17])#[N:13]>>[C:12]([CH:14]=[C:15]([NH:16][CH3:17])[NH:11][CH2:10][CH2:9][S:8][CH2:7][C:6]1[NH:5][CH:4]=[N:3][C:2]=1[CH3:1])#[N:13]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CCOC(=CC#N)NC
Product: CNC(=CC#N)NCCSCc1[nH]cnc1C
Reaction time: 5 h

Procedure:
4-Methyl-5-[(2-aminoethyl)thiomethyl]imidazole (3.5g) was added to a solution of 1-cyano-2-ethoxy-2-methylaminoethylene (3.1g) and the solution was stirred for 5 hours at 100°. The product was chromatographed on a column of neutral alumina with elution bychloroform/ethyl acetate (1:1) to give the title compound as a glass.
Reaction SMILES: [Si]([O:8][CH2:9][C@H:10]1[O:14][C@@H:13]([N:15]2[CH:23]=[C:21](C)[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:12][C@@H:11]1[OH:24])(C(C)(C)C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:45]1[C:49](=[O:50])[C:48]2=[CH:51][CH:52]=[CH:53][CH:54]=[C:47]2[C:46]1=[O:55].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[C:49]1(=[O:50])[N:45]([O:8][CH2:9][C@H:10]2[O:14][C@@H:13]([N:15]3[CH:23]=[CH:21][C:19](=[O:20])[NH:18][C:16]3=[O:17])[CH2:12][C@@H:11]2[OH:24])[C:46](=[O:55])[C:47]2=[CH:54][CH:53]=[CH:52][CH:51]=[C:48]12
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O2)c(=O)[nH]c1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C1c2ccccc2C(=O)N1OC[C@H]1O[C@@H](n2ccc(=O)[nH]c2=O)C[C@@H]1O
Temperature: 0 °C
Yield: 62 %

Procedure:
To a solution of 5'-O-t-butyldimethylsilylthymidine [1, 21.36 g, 60 mmol, prepared according to the procedure of Nair, et al., Org. Prep. Procedures Int. 1990, 22, 57 in dry THF (750 ml)], triphenylphosphine (17.28 g, 66 mmol) and N-hydroxyphthalimide (10.74 g, 66 mmol) were added. The solution was cooled to 0° C. and diisopropylazodicarboxylate (15.15 g, 75 mmol) was added dropwise over a period of 3 hr while stirring under nitrogen. The reaction mixture was then stirred at room temperature for 12 hr. The solution was evaporated and the residue was dissolved in CH2Cl2 (750 ml), extracted with sat. NaHCO3 (200 ml), and water (200 ml), dried (MgSO4), filtered and concentrated to furnish yellow oily residue. Silica gel column chromatography (100% hexanes, and the hexanes:Et2O gradient to 90% Et2O) of the residue gave compound 2 as a colorless glass (18.68 g, 62%); 1H NMR (CDCl3) δ [2s, 6, (CH3)2 ], 0.91 [s, 9, (CH3)3 ], 2.0 (s, 3, CH3), 2.5-2.65 (m, 2, 2'CH2), 4.05-4.2 (m, 2, 5'CH2), 4.25-4.35 (m, 1, 4'H), 5.0 (m, 1, 3'H), 6.15 (m, 1, 1'H), 8.6 (br s, 1, NH), and aromatic protons. Anal. Calcd. for C24H31N3O7Si; C, 57.46; H, 6.23; N, 8.37. found: C, 57.20; H, 6.26; N, 8.27.