Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.[C:10]([O:18][CH2:19][CH3:20])(=[O:17])[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([CH:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:10]([O:18][CH2:19][CH3:20])=[O:17])=[N:6][CH:7]=1
Reactant: Fc1cc(Cl)cnc1F
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ncc(Cl)cc1F
Temperature: 110 °C
Reaction time: 4.5 h
Yield: 78.2 %

Procedure:
A mixture of 3.85 g of 5-chloro-2,3-difluoropyridine, 8.80 g of diethyl malonate, 25 ml of dimethyl sulfoxide and 17.9 g of cesium carbonate was stirred for 4.5 hours at 110° C. under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature, then, to this was added ice water, and extracted with ethyl acetate. The organic layer was washed with saturated brine twice, and dried over anhydrous magnesium sulfate, then, concentrated under reduced pressure, to obtain 5.83 g of diethyl (5-chloro-3-fluoro-2-pyridyl)malonate.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][NH:4][C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH2:8][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6]1.C(N(C(C)C)CC)(C)C.Cl[C:37](=[O:43])[C:38]([O:40][CH2:41][CH3:42])=[O:39]>CC(N(C)C)=O>[CH2:41]([O:40][C:38](=[O:39])[C:37]([N:4]([CH2:3][CH:2]([CH3:26])[CH3:1])[C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH2:8][N:7]([C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[CH2:6]1)=[O:43])[CH3:42]
Reactant: CC(C)CN[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: CCOC(=O)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: CCOC(=O)C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of tert-butyl (3S,5R)-3-[(2-methylpropyl)amino]-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (9.24 g) and diisopropylethylamine (10.5 ml) in DMA (100 ml) was added dropwise ethyl chloroglyoxylate (3.4 ml) at 0° C. The reaction mixture was stirred at room temperature for 15 hr, and the reaction mixture was concentrated. An aqueous sodium bicarbonate solution was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (10.3 g).
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][O:5][C:6]1[C:7]2[C:16]([C:17](=[O:21])[C:18]([NH2:20])=[O:19])=[C:15]([CH2:22][CH3:23])[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:33])[F:32])[C:8]=2[N:9]=[C:10]([S:12][CH3:13])[N:11]=1.[OH-].[Na+]>CO>[CH3:13][S:12][C:10]1[N:11]=[C:6]([O:5][CH2:4][C:3]([OH:35])=[O:2])[C:7]2[C:16]([C:17](=[O:21])[C:18]([NH2:20])=[O:19])=[C:15]([CH2:22][CH3:23])[N:14]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]([F:34])([F:32])[F:33])[C:8]=2[N:9]=1
Reactant: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)OC)nc(SC)nc2n1Cc1ccccc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1c(C(=O)C(N)=O)c2c(OCC(=O)O)nc(SC)nc2n1Cc1ccccc1C(F)(F)F
Temperature: 25 °C
Yield: 78.1 %

Procedure:
A mixture of 66 mg (0.129 mmol) of [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-[[2-(trifluoromethyl)phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy)acetic acid methyl ester and 10 mL of methanol was treated with 0.10 mL of 2M sodium hydroxide and stirred at reflux for 4 hours. The reaction was cooled to ambient temperature. The product precipitated upon addition of lMHCland was collected by filtration. The solids were dried in vacuo to provide 50 mg (79%) of [[2-(methylthio)-5-(aminooxoacetyl)-6-ethyl-7-[[2-(trifluoromethyl)phenyl]methyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]oxy]acetic acid as a solid. nmr(300 MHz,dmso-d6) δ0.99 (t,3H), 2.36 (s,3H), 2.82 (q,2H), 4.86 (s,2H),5.62 (s,2H), 6.48 (d, 1H), 751 (m,2H),7.64 (s, 1H), 7.84 (d 1H), 8.05 (s, 1H)
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:35]=[CH:34][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[C:17](=[O:33])[CH2:16]2)=[O:14])=[CH:11][CH:10]=1.C=O.[C:38](O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([N:15]2[CH2:21][C:20]3[CH:22]=[CH:23][CH:24]=[CH:25][C:19]=3[N:18]([CH2:26][CH:27]3[CH2:28][CH2:29][N:30]([CH3:38])[CH2:31][CH2:32]3)[C:17](=[O:33])[CH2:16]2)=[O:14])=[CH:34][CH:35]=1
Reactant: O=C(c1ccc(Cl)cc1)N1CC(=O)N(CC2CCNCC2)c2ccccc2C1
Reactant: CC(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
0.08 mmol of 4-(4-chlorobenzoyl)-1-(4-piperidinylmethyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on trifluoroacetate obtained in Example 140 and 5 mg (0.17 mmol) of paraformaldehyde were dissolved in 3 ml of dichloromethane. 12 mg (0.20 mmol) of acetic acid was added to the obtained solution. After stirring at room temperature for 30 minutes, 53 mg (0.25 mmol) of sodium triacetoxyborohydride was added to the obtained mixture, and they were stirred at room temperature overnight. After the treatment with dichloromethane as the extracting solvent by an ordinary method, the obtained crude product was treated in the same manner as in step 3 in Example 1 to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])=[CH:4][CH:3]=1.B1([C:23]2[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=2)OCCCO1>>[CH3:15][N:14]([CH2:13][CH2:12][CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[CH:10]=2)[CH:6]=[CH:7]1)[CH3:16]
Reactant: c1cncc(B2OCCCO2)c1
Reactant: CN(C)CCCn1ccc2ccc(Br)cc21
Product: CN(C)CCCn1ccc2ccc(-c3cccnc3)cc21

Procedure:
(9.8 mg, 13%); from 6-bromo-1-(3-(N,N-dimethylamino)propyl) indole (75.0 mg, 0.267 mmol) and pyridine-3-boronic acid 1,3-propanediol cyclic ester (87.0 mg, 0.534 mmol).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1F)#[N:2].[Cl:18][C:19]1[CH:38]=[CH:37][C:22]([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[NH:33][N:32]=[CH:31]3)=[O:27])=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O.CCOC(C)=O.C(=O)([O-])[O-].[Na+].[Na+]>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH2:24][NH:25][C:26]([C:28]2[CH:29]=[C:30]3[C:34](=[CH:35][CH:36]=2)[N:33]([C:8]2[CH:7]=[CH:6][C:5]([CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:4][C:3]=2[C:1]#[N:2])[N:32]=[CH:31]3)=[O:27])=[CH:37][CH:38]=1
Reactant: CC(C)(C)OC(=O)Cc1ccc(F)c(C#N)c1
Reactant: O=C(NCCc1ccc(Cl)cc1)c1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)Cc1ccc(-n2ncc3cc(C(=O)NCCc4ccc(Cl)cc4)ccc32)c(C#N)c1
Temperature: 90 °C
Yield: 22 %

Procedure:
To a stirred solution of tert-butyl 2-(3-cyano-4-fluorophenyl)acetate (110 mg, 0.468 mmol) and N-(4-chlorophenethyl)-1H-indazole-5-carboxamide (168 mg, 0.561 mmol) in DMSO (2 ml) was added K2CO3 (77.5 mg, 0.561 mmol). The reaction was heated to 90° C. overnight via an oil bath. The reaction was diluted with EtOAc and 10% aqueous sodium carbonate. The aqueous phase was extracted with EtOAc and the combined organic layers were washed with brine, dried over MgSO4, and concentrated. The crude product was purified over silica gel on a Biotage Horizon high-performance FLASH chromatography system (25+M silica gel cartridge) eluting with a gradient of 5% ethyl acetate/hexanes to 70% ethyl acetate/hexanes to provide tert-butyl 2-(4-(5-((4-chlorophenethyl)carbamoyl)-1H-indazol-1-yl)-3-cyanophenyl)acetate (0.241 g, 0.103 mmol, 22%).
Reaction SMILES: C(OC)(OC)OC.[CH2:8]([C@H:11]([NH2:15])[C:12]([OH:14])=[O:13])[CH2:9][NH2:10].Cl.[C:17](#N)[CH3:18]>CO>[CH3:17][C:18]1[NH:10][CH2:9][CH2:8][C@@H:11]([C:12]([OH:14])=[O:13])[N:15]=1
Reactant: CC#N
Reactant: NCC[C@H](N)C(=O)O
Agent: Cl
Solvent: COC(OC)OC
Solvent: CO
Product: CC1=N[C@H](C(=O)O)CCN1

Procedure:
60 ml of trimethyl orthoformate are dissolved in 400 ml of methanol, and reacted with 30 g of L-diaminobutyric acid×2 HCl at 55° C. with constant stirring. After a reaction time of 2 hours, the solvent is evaporated under reduced pressure, the crude product which remains is dissolved in 50 ml of demineralized water, and the solution is neutralized using NaOH. The compound is subsequently purified on an ion retardation column type BIORAD® AG11A8 (Bio-Rad Laboratories GmbH, Munich, Germany) using demineralized water as the eluent, and the product is dried and recrystallized from methanol. The compound obtained can be identified by means of high-pressure liquid chromatography (HPLC); (for example E. Merck, Darmstadt, Germany, LiChroCART® 125-NH2 5μ, eluent: 80% acetonitrile), and is characterized by the following 13C-NMR data:
Reaction SMILES: [OH-].[Na+:2].[CH3:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]4[CH:28]=[N:29][CH:30]=[C:31]([CH:36]=4)[C:32]([O:34]C)=[O:33])=[O:25])[CH2:20][CH2:19]3)[CH2:12][CH2:11]2)[CH:7]=[CH:6][CH:5]=1>C1COCC1>[CH3:3][C:4]1[N:9]=[C:8]([N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][CH2:17][CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]4[CH:28]=[N:29][CH:30]=[C:31]([CH:36]=4)[C:32]([O-:34])=[O:33])=[O:25])[CH2:20][CH2:19]3)[CH2:14][CH2:15]2)[CH:7]=[CH:6][CH:5]=1.[Na+:2]
Reactant: COC(=O)c1cncc(OC(=O)N2CCC(CCC3CCN(c4cccc(C)n4)CC3)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cccc(N2CCC(CCC3CCN(C(=O)Oc4cncc(C(=O)[O-])c4)CC3)CC2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
An aqueous 1 M sodium hydroxide solution (0.45 ml) was added to a THF (5 ml) solution of methyl 5-{[(4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidin-1-yl)carbonyl]oxy}nicotinate (208 mg), followed by stirring overnight at room temperature. The reaction liquid was concentrated to obtain sodium 5-{[(4-{2-[1-(6-methylpyridin-2-yl)piperidin-4-yl]ethyl}piperidin-1-yl)carbonyl]oxy}nicotinate (158 mg).
Reaction SMILES: [C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Br)=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH2:21]([N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH3:22].C(N(CC)CC)C.ClC(OC)=O>C(O)C.ClCCl>[C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([N:26]2[CH2:27][CH2:28][N:23]([CH2:21][CH3:22])[CH2:24][CH2:25]2)=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCN1CCNCC1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C1CCCC1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCN1CCN(c2cc(C3CCCC3)c(OC(=O)OC)cc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
A solution of (4-bromo-2-cyclopentyl-5-nitro-phenyl) methyl carbonate (800 mg, 2.33 mmol) and 1-ethylpiperazine (266 mg, 2.33 mmol) in ethanol (2.4 mL) was heated under microwave irradiation at 150° C. for 6 h, resulting in product formation with loss of the carbonate group. The reaction was concentrated in vacuo and the residue was redissolved in dichloromethane, washed with water, dried over Na2SO4, filtered and reconcentrated. The crude product was dissolved in triethylamine (648 μL, 4.65 mmol) and dichloromethane (2 mL), cooled to 0° C. and methyl chloroformate (180 μL, 2.32 mmol) was added dropwise. The reaction was warmed to room temperature and stirred for 2 h. The reaction was quenched with water and the aqueous layer was extracted with dichloromethane. The combined organics were dried over MgSO4, filtered and concentrated. Purification by silica gel chromatography (0-10% ethyl acetate/hexanes) provided 2-cyclopentyl-4-(4-ethylpiperazin-1-yl)-5-nitrophenyl methyl carbonate (672 mg, 76% yield). 1H NMR (400.0 MHz, DMSO-d6) δ 7.66 (d, J=8.6 Hz, 1H), 7.30 (d, J=8.6 Hz, 1H), 3.88 (s, 3H), 3.08-3.06 (m, 1H), 2.88 (s, 4H), 2.34-2.30 (m, 5H), 1.93-1.90 (m, 3H), 1.75-1.72 (m, 2H), 1.65-1.63 (m, 2H), 1.54-1.51 (m, 2H), 1.00 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[C:5]([NH2:13])[NH:4][N:3]=1.CO[CH:16](OC)[CH:17]([CH:21](OC)OC)[CH2:18][C:19]#[N:20].ClC1C=CC2N=NN(OC(=[N+](C)C)N(C)C)C=2C=1.C([O-])(O)=O.[Na+]>CS(C)=O.O.CCOC(C)=O>[NH2:13][C:5]1[C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:12])=[O:8])=[C:2]2[N:1]=[CH:16][C:17]([CH2:18][C:19]#[N:20])=[CH:21][N:3]2[N:4]=1
Reactant: C=CCOC(=O)c1c(N)n[nH]c1N
Reactant: COC(OC)C(CC#N)C(OC)OC
Agent: CN(C)C(On1nnc2ccc(Cl)cc21)=[N+](C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: C=CCOC(=O)c1c(N)nn2cc(CC#N)cnc12
Temperature: 85 °C
Reaction time: 8 h
Yield: 62.4 %

Procedure:
To a suspension of allyl 3,5-diamino-1H-pyrazole-4-carboxylate 3 (63.49 g, 348.5 mmol) in a mixture of DMSO (340 mL) and water (340 mL), was added 3-(dimethoxymethyl)-4,4-dimethoxy-butanenitrile (85 g, 418.2 mmol), followed by para-toluene Sulfonic acid hydrate (1) (11.27 g, 59.24 mmol). The reaction mixture was heated to 85° C. and stirred overnight. The reaction mixture was cooled with an ice bath. The mixture was diluted with EtOAc (680 mL) and a saturated aqueous solution of NaHCO3 (1.36 L). The precipitate was filtered and rinsed with water, then with a mixture of water and EtOAc. The brown solid was dried under vacuum to give allyl 2-amino-6-(cyanomethyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylate 4c as a brown solid (55.94 g, 62% yield).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][OH:8])=[CH:3][CH:2]=1.[Si:9](Cl)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].N1C=CN=C1.O>CN(C)C=O>[Si:9]([O:8][CH2:7][C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: OCc1ccncc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.7 %

Procedure:
Pyridin-4-ylmethanol (2.2 g, 20 mmol) was dissolved in N,N-dimethylformamide, and tert-butyldimethylsilyl chloride (3.3 g, 22 mmol) and imidazole (2.0 g, 30 mmol were added thereto. The mixture was stirred at a room temperature overnight. After the completion of the reaction was confirmed by HPLC, water was added to the mixture, and the extraction with diethyl ether was performed 3 times. The combined organic layer was washed with a saturated saline solution and dried over magnesium sulfate, and the solvent was distilled off. Thus the title compound (4.5 g, 100%) was obtained as an oily substance.
Reaction SMILES: C([O:4][P:5]([CH2:11][O:12][CH2:13][C:14]([CH3:31])=[CH:15][CH2:16][C:17]1[C:18]([OH:30])=[C:19]2[C:23](=[C:24]([CH3:28])[C:25]=1[O:26][CH3:27])[CH2:22][O:21][C:20]2=[O:29])(=[O:10])[O:6]C(C)C)(C)C.N1C(C)=CC=CC=1C.C[Si](Br)(C)C>C(#N)C>[OH:30][C:18]1[C:17]([CH2:16][CH:15]=[C:14]([CH3:31])[CH2:13][O:12][CH2:11][P:5](=[O:4])([OH:10])[OH:6])=[C:25]([O:26][CH3:27])[C:24]([CH3:28])=[C:23]2[C:19]=1[C:20](=[O:29])[O:21][CH2:22]2
Reactant: COc1c(C)c2c(c(O)c1CC=C(C)COCP(=O)(OC(C)C)OC(C)C)C(=O)OC2
Agent: C[Si](C)(C)Br
Solvent: CC#N
Solvent: Cc1cccc(C)n1
Product: COc1c(C)c2c(c(O)c1CC=C(C)COCP(=O)(O)O)C(=O)OC2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid diisopropyl ester (25 mg, 0.055 mmol) and 2,6-lutidine (0.18 mL, 1.65 mmol) in acetonitrile was added trimethylsilyl bromide (0.126 mL, 1.1 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred for 4 h. The reaction was quenched with methanol at 0° C., and the resulting mixture was concentrated. The residue was purified by preparative reverse-phase HPLC to afford, after removal of the solvent, [4-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-isobenzofuran-5-yl)-2-methyl-but-2-enyloxymethyl]-phosphonic acid as an oil (17 mg, 83%); 1H NMR (300 MHz, CD3OD) δ 1.81 (s, 3H), 2.06 (s, 3H), 3.40 (d, J=6.6 Hz, 2H), 3.50 (d, 2H), 3.77 (s, 3H), 3.97 (s, 2H), 5.20 (s, 2H), 5.47 (t, J=6.6 Hz, 1H); MS (m/z) 371 [M−H]−.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[O-]S([O-])(=O)=O.[Na+].[Na+].[CH3:22]O>[Pd]>[NH2:12][C:9]1[CH:10]=[CH:11][C:2]([O:1][CH3:22])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1O
Reactant: CO
Agent: [Pd]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1cc(N)ccc1OC

Procedure:
The hydrogenation of methyl 2-hydroxy-5-nitrobenzoate (700 mg, 3.3 mmol) using 10% Pd—C (100 mg) and Na2SO4 (100 mg) in MeOH at 50 psi gave methyl 5-amino-2-methoxybenzoate (600 mg).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:7]#[CH:8].P(=O)(O)(O)O.B(F)(F)F>S(=O)(=O)(O)O.[Hg]>[C:1]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#C
Reactant: c1ccccc1
Agent: FB(F)F
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Product: CC(c1ccccc1)c1ccccc1
Yield: 65 %

Procedure:
1,1-Diphenylethane (DPE) is a valuable hydrocarbon for conversion to benzophenone, which, in turn, can be converted to the corresponding nitro and amine derivatives. Unfortunately, there are no simple methods known for its preparation in high yield. Thus, Baeyer, Ber., VI, 223 (1873) attempted to prepare 1,1-diphenylethane by reacting paraldehyde with benzene in the presence of sulfuric acid, but obtained only a resinous material. Later, in Ber. VII, 1190 (1874), he isolated some 1,1-diphenylethane from a tarry reaction product in disappointingly low yield. Spilker et al., Ber., 65B, 1686 (1932), condensed benzene with styrene in the presence of sulfuric acid and obtained a 25 percent yield of 1,1-diphenylethane. Higher yields of the same product, from 40 to 50 percent, were obtained by Reichert et al., J. Am. Chem. Soc., 45, 3090 (1923) in the mercury-catalyzed condensation of benzene with acetylene in sulfuric acid. More recently, Baeyer et al. in Ber., 94, 1717 (1961) and Ber., 95, 1989, ( 1962), reacted benzene with acetylene in the presence of phosphoric acid which has been saturated with boron trifluoride to obtain 1,1-diphenylethane in 65 percent yield, as well as some polymeric substances.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])[NH2:6].I[C:15]1[C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18]>>[CH3:13][O:12][C:8]1[CH:7]=[C:5]2[C:4](=[C:3]([O:2][CH3:1])[C:9]=1[O:10][CH3:11])[C:24](=[O:25])[C:23]1[CH:22]=[CH:21][CH:20]=[C:16]([C:17]([OH:19])=[O:18])[C:15]=1[NH:6]2
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: O=C(O)c1cccc(C(=O)O)c1I
Product: COc1cc2[nH]c3c(C(=O)O)cccc3c(=O)c2c(OC)c1OC

Procedure:
From 3,4,5-trimethoxyaniline (3.8 g) and 2-iodoisophthalic acid (5 g).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]=1[C:13]([NH2:15])=[O:14])([O-])=O.C(=O)(O)[O-].[Na+]>C(O)C>[NH2:1][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[O:9])=[CH:6][C:5]=1[C:13]([NH2:15])=[O:14]
Reactant: NC(=O)c1ccc([N+](=O)[O-])c(C(N)=O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: NC(=O)c1ccc(N)c(C(N)=O)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a solution of 4-nitroisophthalamide (6.0 g (28.7 mmol) in ethanol (150.0 ml), stannous chloride (20.02 g (86.1 mmol) was added and the mixture was stirred at 70° C. overnight. After cooling, the reaction mixture was neutralized with a saturated aqueous sodium bicarbonate solution, and insolubles formed were removed by filtration. The filtrate was extracted with ethyl acetate and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2.59 g (50%) of 4-aminoisophthalamide as pale yellow crystals.
Reaction SMILES: N1C=C(CCC(O)=O)N=C1.S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[C:21]([CH2:26][CH2:27][CH2:28][C:29]1[N:30]=[CH:31][NH:32][CH:33]=1)([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)CC)C.[C:41]1([C:47](Cl)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(O)C.O.CN(C)C=O>[C:41]1([C:47]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)([C:54]2[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=2)[N:32]2[CH:33]=[C:29]([CH2:28][CH2:27][CH2:26][C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:30]=[CH:31]2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CCOC(=O)CCCc1c[nH]cn1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CCc1c[nH]cn1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a reaction flask equipped for hydrogenation, 10 g of urocanic acid (72.4 mmol) are dissolved in 200 ml of water. 1 g of Pd/C (10%) are added and hydrogenation is performed at 50° C. for 4 hours. The catalyst is filtered off and the water evaporated off, giving 3-(4-imidazolyl)propionic acid which appears in the form of a white powder (8.8 g; 86%); m.p.: 209-211° C. (3-Imidazol-4-yl)propionic acid (6 g, 42 mmol) is dissolved in absolute ethanol (204 ml), and a catalytic amount of concentrated sulphuric acid (2 ml) is added. The resulting mixture is heated to reflux for 16 hours. The solvent is evaporated off, which gives an oily residue which is dissolved in 45 ml of water. The solution is neutralized with sodium hydrogencarbonate, and 4-(3-carboethoxypropyl)-1H-imidazole is extracted with ethyl acetate; an oil (5.1 g; 72%) is obtained. The 4-(3-carboethoxypropyl)-1H-imidazole (5.4 g, 32 mmol) is dissolved in 4 ml of anhydrous dimethylformamide. 3.4 g of triethylamine (33.6 mmol) and 9.3 g of triphenylmethyl chloride (33.6 mmol) are added, and the mixture is stirred at room temperature under nitrogen for 4 hours. The mixture is poured onto crushed ice (60 g), which gives a white precipitate which is recrystallized from diethyl ether (9.2 g; 70%), giving 1-(triphenylmethyl)-4-(3-carboethoxypropyl)-1H-imidazole; m.p.: 134° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[C:11]2[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:11]3[CH:16]=[C:15]([N+:17]([O-:19])=[O:18])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccc(F)cc3)nc(Cl)nc2s1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1-c1nc(NCc2ccc(F)cc2)c2cc([N+](=O)[O-])sc2n1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-nitro-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-nitro-4-(4-fluorobenzylamino)-thieno-[2,3-d]-pyrimidine.