Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:30]=[CH:29][C:8]([CH:9]=[CH:10][C:11]([NH:13][CH2:14][C:15]([N:17]([C:19]2[C:20]([Cl:28])=[C:21]([C:24]([Cl:27])=[CH:25][CH:26]=2)[CH2:22]Br)[CH3:18])=[O:16])=[O:12])=[CH:7][CH:6]=1)=[O:4].[CH2:31]([O:33][C:34]1[C:43]2[C:38](=[C:39]([OH:44])[CH:40]=[CH:41][CH:42]=2)[N:37]=[C:36]([CH3:45])[CH:35]=1)[CH3:32].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:28][C:20]1[C:19]([N:17]([CH3:18])[C:15](=[O:16])[CH2:14][NH:13][C:11](=[O:12])[CH:10]=[CH:9][C:8]2[CH:29]=[CH:30][C:5]([C:3](=[O:4])[NH:2][CH3:1])=[CH:6][CH:7]=2)=[CH:26][CH:25]=[C:24]([Cl:27])[C:21]=1[CH2:22][O:44][C:39]1[CH:40]=[CH:41][CH:42]=[C:43]2[C:38]=1[N:37]=[C:36]([CH3:45])[CH:35]=[C:34]2[O:33][CH2:31][CH3:32]
Reactant: CCOc1cc(C)nc2c(O)cccc12
Reactant: CNC(=O)c1ccc(C=CC(=O)NCC(=O)N(C)c2ccc(Cl)c(CBr)c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C)nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)C=Cc4ccc(C(=O)NC)cc4)c3Cl)cccc12
Temperature: 25 °C
Reaction time: 5 h
Yield: 90.2 %

Procedure:
To a solution of 3-[N-[4-(methylcarbamoyl)-cinnamoylglycyl]-N-methylamino]-2,6-dichlorobenzyl bromide (60 mg) and 4-ethoxy-8-hydroxy-2-methylquinoline (24.9 mg) in dimethylformamide (0.6 ml) was added potassium carbonate (48.5 mg), and the mixture was stirred for 5 hours at ambient temperature. Water was added thereto, and the mixture was extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate and concentrated. The residue was purified by preparative thin-layer chromatography (dichloromethane:methanol=15:1, V/V) to give 8-[2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]-amino]benzyloxy]-4-ethoxy-2-methylquinoline (67 mg) as an amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]([NH:9][NH2:10])=[O:8].[C:15](Cl)(Cl)=[O:16]>>[Cl:1][C:2]1[C:3]2[CH:14]=[CH:13][CH:12]=[CH:11][C:4]=2[S:5][C:6]=1[C:7]1[O:8][C:15](=[O:16])[NH:10][N:9]=1
Reactant: O=C(Cl)Cl
Reactant: NNC(=O)c1sc2ccccc2c1Cl
Product: O=c1[nH]nc(-c2sc3ccccc3c2Cl)o1

Procedure:
In the same way as above, 3-chlorobenzo(b)thiophene 2-carboxylic acid hydrazide was reacted with phosgene to give 3-chloro-2-(2-oxo-3H-1,3,4-oxadiazole-5-yl)-benzo(b)thiophene, mp. 218°-220°.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2.[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>C1COCC1>[CH:5]1[C:4]2[C:9](=[CH:10][C:11]3[C:16]([C:3]=2[CH2:2][N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:8]=[CH:7][CH:6]=1
Reactant: ClCc1c2ccccc2cc2ccccc12
Reactant: C1CNCCN1
Solvent: C1CCOC1
Product: c1ccc2c(CN3CCNCC3)c3ccccc3cc2c1

Procedure:
Synthesized according to General Procedure A: 9-(chloromethyl)anthracene (4{21}, 5 g, 18.7 mmol, 1 equiv.), piperazine (9.4 g, 109.0 mmol, 6 equiv.), THF (40.0 mL). Purification with flash column chromatography on silica gel (4:1 EtOAc:MeOH) afforded 5 {21} (4.75 g, 93%) as a white solid. 1H-NMR (500 MHz, CDCl3): δ 8.50 (dd, 2H, J=0.5, 9.0 Hz), 8.41 (s, 1H), 8.00 (td, 2H, J=1.0, 8.5 Hz), 7.52 (ddd, 2H, J=1.5, 6.5, 8.0 Hz), 7.47 (ddd, 2H, J=1.5, 6.5, 8.5 Hz), 4.42 (s, 2H), 2.81 (t, 4H, J=5.0 Hz), 2.59 (br s, 4H), 1.87 (br s, 1H). 13C-NMR (125 MHz, CDCl3): δ 131.4, 131.3, 129.6, 128.9, 127.3, 125.5, 125.1, 124.8, 54.8, 54.5, 46.1.
Reaction SMILES: [C:1](OC=O)(=[O:3])C.[CH2:7]([O:14][NH:15][CH2:16][C@@H:17]([CH2:21][CH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:18]([OH:20])=[O:19])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([O:14][N:15]([CH2:16][C@@H:17]([CH2:21][CH:22]1[CH2:23][CH2:24][CH2:25][CH2:26]1)[C:18]([OH:20])=[O:19])[CH:1]=[O:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)[C@@H](CNOCc1ccccc1)CC1CCCC1
Reactant: CC(=O)OC=O
Solvent: C1CCOC1
Product: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 94 %

Procedure:
Formic acetic anhydride (27.78 g, 0.32 mol) followed by TEA (52.7 mL, 0.38 mol) were added to a cooled (0° C.) solution of 2(R)-(benzyloxyamino-methyl)-3-cyclopentyl-propionic acid in THF (180 mL). The reaction mixture was stirred for 1 hour at 0° C. and then at room temperature for 1 hour before the solvent was removed in vacuo. The residue was purified by column chromatography (SiO2, 25-100% EtOAc in hexanes) to give the title compound as a colourless oil (36.10 g, 94%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[C:17]1(B(O)O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl.O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:12][CH:11]=2)=[C:2]([NH2:1])[CH:7]=1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: Cc1ccc(Sc2ccc(Oc3ccccc3)cc2)c(N)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 15.3 %

Procedure:
The product from Example 6c (0.500 g, 1.91 mmol) was dissolved in CH2Cl2 along with phenyl boronic acid (0.701 g, 5.74 mmol), copper(II) acetate (0.659 g, 3.83 mmol), and triethylamine (0.387 g, 3.83 mmol). Stirred at room temperature for 48 h, at which time 2 more equivalents of each reagent was added. Stirred at room temperature for another 16 h at which time another 2 eq of each reagent was added. Stirred at room temperature for another 16 h. The reaction was diluted with water and extracted with ethyl acetate Dried over Na2SO4, filtered and concentrated under vacuum giving the crude product which was purified silica gel column chromatography eluting with 20% EtOAc/hexane (0.100 g, 15%). The product was reduced with SnCl2 following the procedure from Example 5I to give the title compound (90 mg, 98%).
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH:7]=1.[C:21]1(S(OC)(=O)=O)C=CC=CC=1>C(#N)C>[Br:1][C:2]1[C:3](=[O:20])[N:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:5]=[C:6]([CH:8]2[CH2:13][CH:12]=[CH:11][CH2:10][N:9]2[CH3:21])[CH:7]=1
Reactant: COS(=O)(=O)c1ccccc1
Reactant: O=c1c(Br)cc(-c2ccccn2)cn1-c1ccccc1
Solvent: CC#N
Product: CN1CC=CCC1c1cc(Br)c(=O)n(-c2ccccc2)c1
Temperature: 100 °C

Procedure:
99 mg of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one was dissolved in 10 ml of acetonitrile. 2 ml of methyl benzenesulfonate was added thereto, followed by stirring at 100° C. for 2 nights. After cooling to room temperature, the solvent was evaporated. The residue was dissolved in 10 ml of methanol, followed by cooled to 0° C. under stirring. Sodium borohydride was added 5 times at intervals of 5 hours, 1 g for each time, followed by further stirring at 0° C. overnight. Then the solvent was evaporated and a saturated aqueous solution of ammonium chloride was added to the residue, followed by extracting with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 107 mg of 3-bromo-5-(1-methyl-1,2,3,6-tetrahydropyridin-2-yl)-1-phenyl-1,2-dihydropyridin-2-one. The product was dissolved in 10 ml of dimethylformamide. 81 mg of 2-(2-cyanophenyl)-1,3,2-dioxaborinate, 142 mg of cesium carbonate and 7 mg of tetrakistriphenylphosphine palladium were added thereto, followed by stirring at 140° C. for 2 hours. After cooling to room temperature, water was added thereto, followed by extracting with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel chromatography (hexane/ethyl acetate system), to give 41 mg of the title compound.
Reaction SMILES: [C:1]([O:14][CH3:15])(=[O:13])[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[H-].[K+].[CH3:18]I>O1CCCC1>[CH3:18][CH:2]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1)[C:1]([O:14][CH3:15])=[O:13]
Reactant: CI
Reactant: COC(=O)Cc1ccc(C(=O)OC)cc1
Agent: [H-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C(C)C(=O)OC)cc1
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A solution of dimethyl homoterephthalate (7, R=H) (4.16 g, 20 mmole) in 15 ml of dry tetrahydrofuran was added dropwise over 15 minutes to a stirred mixture of potassium hydride (2.5 g of 35% oil suspension, 22 mmole) in 75 ml of dry tetrahydrofuran at 0° C. After 30 minutes a homogeneous yellow suspension had formed. Methyl iodide (2.79 g, 22 mmole) was then added over a 5 minute period and the resulting mixture stirred for 30 minutes. The mixture was quenched with 2 ml of 50% acetic acid, diluted with 500 ml of water and extracted with ether. The ether extract was washed with water, dried over magnesium sulfate and evaporated to leave an oil. The material was chromatographed on silica gel with elution by ether-hexane (1:9) to afford (71%) of a clear oil; m/e 222 (M+): NMR (CDCl3) 1.50 (3H, d, CH3), 3.65 (3H, s, OCH3), 3.93 (3H, s, OCH3 benzoate).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].[S:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[S:15](Cl)(=[O:17])=[O:16]>C(Cl)Cl>[OH:8][CH2:7][C@H:5]([NH:6][S:15]([C:11]1[S:10][CH:14]=[CH:13][CH:12]=1)(=[O:17])=[O:16])[C:4]([O:3][CH3:2])=[O:9]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: COC(=O)[C@@H](N)CO
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
A suspension of L-serine-methyl ester hydrochloride (3.0 g, 19.3 mmol) in CH2Cl2 (80 mL) was added with TEA (1.1 mol eq, 2.9 mL) and the mixture was stirred at r.t. for 10 minutes. Then 2-thiophen-sulphonyl chloride (1 mol eq, 3.52 g) and additional TEA (1.1 mol eq) were added and the solution hated at 60° C. overnight. The solvent was removed under reduced pressure, water was added to the residue (100 mL) and the aqueous phase extracted with EtOAc (3×40 mL). The recombined organic phases were dried over Na2SO4 and evaporated under reduced pressure to afford 5H as white solid (4.9 g, 95% yield). 1HNMR (DMSO, 200 MHz) δ 3.61 (s, 2H), 3.82 (t, 2H, J=6.3), 4.14 (m, 1H), 4.62 (t, 1H), 5.25 (t, 1H), 7.21 (m, 1H), 7.75 (dd, 1H, J=2.1), 7.96 (dd, 1H, J=1.9), 8.23 (d, 1H).
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([O:25]C(=O)C)=[C:8]2[C:16]([Cl:17])=[CH:15][N:14]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])C.[NH2:29][CH2:30][C:31]([OH:33])=[O:32].C[O-].[Na+].CO>>[Cl:17][C:16]1[C:8]2[C:9](=[C:10]([C:12]#[N:13])[N:11]=[C:6]([C:4]([NH:29][CH2:30][C:31]([OH:33])=[O:32])=[O:5])[C:7]=2[OH:25])[N:14]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:15]=1
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1nc(C#N)c2c(c(Cl)cn2-c2ccc(F)cc2)c1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Cl)cn(-c3ccc(F)cc3)c12

Procedure:
Prepared in analogy to that of Example 1(e) from 4-acetoxy-3-chloro-7-cyano-1-(4-fluoro-phenyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, glycine and NaOMe/HOMe. The title compound, ESI MS (m/z): 389 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12](C=O)[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:18]([O:23][CH3:24])([O:21][CH3:22])OC>CO.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:24][O:23][CH:18]([O:21][CH3:22])[C@H:12]([CH:13]([CH3:15])[CH3:14])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: CC(C)[C@@H](C=O)NC(=O)OCc1ccccc1
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COC(OC)[C@@H](NC(=O)OCc1ccccc1)C(C)C
Reaction time: 16 h
Yield: 89.8 %

Procedure:
22.8 g (0.097 mol) of N-benzyloxycarbonyl-L-valinal were dissolved in 55 ml of dry methanol. The solution was treated with 10.8 g (0.102 mol) of trimethyl orthoformate and 0.3 g of toluene-4-sulphonic acid and the mixture was left to stand at room temperature for 16 hours. The solvents were removed by evaporation, the residue was dissolved in 150 ml of ethyl acetate and the solution was washed with 5% sodium bicarbonate solution and then with brine. After drying over magnesium sulphate and filtration, the solvent was removed by evaporation to yield 24.5 g (90%) of N-benzyloxycarbonyl-L-valinal dimethyl acetal as an oil; Rf-value [hexane/ethyl acetate (2:1)]: 0.69.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].CS(O[CH2:21][CH2:22][CH2:23][N:24]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:25][CH:26]([CH3:28])[CH3:27])(=O)=O>CC#N>[C:32]([O:31][C:29]([N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][CH2:21][O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])=[O:30])([CH3:34])([CH3:35])[CH3:33]
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Reactant: CC(C)CN(CCCOS(C)(=O)=O)C(=O)OC(C)(C)C
Solvent: CC#N
Product: COC(=O)c1cc(OCCCN(CC(C)C)C(=O)OC(C)(C)C)cc(C(=O)OC)c1
Reaction time: 16 h

Procedure:
Dimethyl 5-hydroxyisophthalate (0.30 g, 1.44 mmol) cesium carbonate (0.95 g, 2.88 mmol) and CH3CN (25 mL) were stirred for 30 min. 3-((tert-Butoxycarbonyl)(isobutyl)amino)-propyl methanesulfonate (0.63 g, 2.02 mmol) was added and the reaction mixture was stirred for 16 h. The reaction mixture was concentrated under reduced pressure and partitioned between EtOAc (50 mL) and H2O (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product, which was used without further purification.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=[O:15])=[CH:6]1)[CH2:2][CH2:3][CH3:4].C([Li])CCC.Br[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[N:37]=[N:38][N:39]([C:41]([CH3:49])([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH3:42])[N:40]=2)=[CH:26][CH:25]=1.[OH-].[Na+]>C1COCC1.[Cl-].[Zn+2].[Cl-].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.C(OCC)(=O)C>[CH2:1]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]([OH:16])=[O:15])=[C:6]1[CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:36]2[N:37]=[N:38][N:39]([C:41]([CH3:49])([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH3:42])[N:40]=2)=[CH:28][CH:29]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(c1ccccc1)n1nnc(-c2ccccc2-c2ccc(CBr)cc2)n1
Reactant: CCCCn1cc(C(=O)O)c2ccccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCn1c(Cc2ccc(-c3ccccc3-c3nnn(C(C)(C)c4ccccc4)n3)cc2)c(C(=O)O)c2ccccc21
Temperature: 0 °C

Procedure:
A solution of 1-butyl-3-indolecarboxylic acid (20.0 g, 0.092 mol), preparedas Example 13, in 450 mL of THF was cooled to -40° C. under argon. n-Butyllithium (2.5M in hexane, 73.7 mL, 0.184 mol) was added at a rate such that the reaction temperature remained below -25° C. and then the mixture was allowed to warm to 0° C. The mixture was let stand for 30 minutes, cooled to -40° C. and then zinc chloride (1M in diethyl ether, 220 mL, 0.219 mol), tetrakis(triphenylphosphine)palladium(0) (2.03 g, 0.0018 mol) and 4-bromomethyl-2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl (38.01 g, 0.0878 mol), prepared as in Example 12, were sequencially added.The mixture was allowed to warm to room temperature and then 200 mL of ethyl acetate and 200 mL of 1N sodium hydroxide were added. The aqueous layer was separated and extracted with 50 mL of ethyl acetate. The combined ethyl acetate layers were washed with 200 mL of 1M hydrochloric acid and then brine and dried (sodium sulfate). The mixture was filtered and the solvent was removed. The residue was redissolved in 200 mL of ethyl acetate and 200 mL of methanol was slowly added to the solution giving a crystalline product which was isolated by filtration. The filtrate was concentrated and the residue was dissolved in 50 mL of ethyl acetate and proceeding similarly additional crystalline product was obtained. Drying and combining the products from each crystallization gave1-butyl-2-{2'-[2-(1-methyl-1-phenylethyl)-2H-tetrazol-5-yl]biphenyl-4-ylmethyl}-1H-indole-3-carboxylic acid (45.5 g, 0.08 mol), m.p. 146°-148° C.
Reaction SMILES: C([N:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][OH:17])[C:9](=[O:18])[N:8]([CH2:19][CH3:20])[C:7]=2[N:6]=[C:5]1[Cl:21])C=C.N1CCOCC1>C1COCC1.CS(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:21][C:5]1[NH:4][C:12]2[C:11](=[O:13])[N:10]([CH2:14][CH2:15][CH2:16][OH:17])[C:9](=[O:18])[N:8]([CH2:19][CH3:20])[C:7]=2[N:6]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(CCCO)c(=O)n2CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCn1c(=O)n(CCCO)c(=O)c2[nH]c(Cl)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.2 %

Procedure:
To a solution of 7-allyl-8-chloro-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (3.8 g, 12.18 mmol) in THF (40 mL) and DMSO (10 mL) was added tetrakis(triphenylphosphine)palladium(0) (800 mg, 0.693 mmol) and morpholine (5.4 mL, 62.07 mmol). The reaction was degassed and refilled with nitrogen 3 times. The reaction was stirred at room temperature overnight. The mixture was poured into water (20 mL) and ethyl acetate (100 mL). The solid precipitate was collected, washed with ethyl acetate, and dried under vacuum to give 8-chloro-3-ethyl-1-(3-hydroxypropyl)-1H-purine-2,6(3H,7H)-dione (2.2 g, 66.4% yield) as grey solid. LCMS retention time 0.404 min; LCMS MH+ 273.
Reaction SMILES: [CH2:1]([CH:8]([C:12]([OH:14])=[O:13])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH3:19]O>>[CH2:1]([CH:8]([C:9]([O:11][CH3:19])=[O:10])[C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(Cc1ccccc1)C(=O)O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)C(Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
Benzyl malonic acid (19.4 g, 0.10 mol) was dissolved in 180 mL of MeOH. The mixture was cooled in an ice-bath and to it was added thionyl chloride dropwise over 30 min (7.3 mL, 0.10 mol). The mixture was stirred in the ice-bath for 30 min and then at RT for 30 min under N2. The solvent was removed, and the residue was dissolved in aqueous NaHCO3. The basic solution was extracted with EtOAc to remove the bis-ester which was discarded. The aqueous solution was then acidified with aqueous HCl to pH 5 and extracted with EtOAc. The EtOAc extract was washed with brine, dried over Na2SO4, and concentrated to give 7.2 g of 2-benzyl-3-methoxy-3-oxopropanoic acid (35%). MS 209.24 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:12](O)=[O:13])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[CH3:44][NH:45][NH2:46]>ClCCl>[CH3:1][O:2][C:3]1[CH:29]=[CH:28][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=2[O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:12]([N:45]([CH3:44])[NH2:46])=[O:13])=[CH:5][CH:4]=1
Reactant: CNN
Reactant: COc1ccc(COc2ccc(C(=O)O)cc2OCc2ccc(OC)cc2)cc1
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COc2ccc(C(=O)N(C)N)cc2OCc2ccc(OC)cc2)cc1
Temperature: -40 °C
Yield: 97.4 %

Procedure:
3,4-bis-(4-Methoxybenzyloxy)benzoic acid (0.792 g, 2.0 mmol) was dissolved in dichloromethane (20 ml) and treated with N,N-diisopropylethylamine (0.35 ml, 2.0 mmol). The solution was cooled to -40° C. and treated with methanesulphonyl chloride (0.15 ml, 2.0 mmol). The mixture was allowed to warm to room temperature for 10 minutes and then re-cooled to -40° C. and added to a solution of methylhydrazine (0.215 ml, 4 mmol) in dichloromethane (10 ml) at -40° C. The mixture was allowed to warm to room temperature for 1.5 h and then evaporated to dryness under reduced pressure. The residue was dissolved in ethyl acetate which was washed with water and brine. Evaporation of the solvent gave the title compound (0.823 g, 94%); δH (CDCl3) 3.08 (3H, s), 3.74 (6H, s), 4.25 (2H, brs), 5.03 (4H, s), and 6.70- 7.40 (11H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]([N+:13]([O-])=O)[C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2].[SH-].[Na+].CO>O>[NH2:13][C:9]1[CH:10]=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: [Na+]
Agent: [SH-]
Solvent: O
Solvent: CO
Product: Nc1cccc([N+](=O)[O-])c1C(=O)O

Procedure:
In one non-limiting reaction scheme, dinitrobenzoic acid may be reacted with about one to about five equivalents of an alkali hydrosulfide in a methanol:water mixture at reflux temperature for about 20 to about 40 minutes to produce an aminonitrobenzoic acid. As is described in the Example below, 2,6-dinitrobenzoic acid may be allowed to react with about three equivalents of sodium hydrosulfide in a methanol:water mixture at reflux temperature for about 30 minutes to produce 2-amino-6-nitrobenzoic acid. In some non-limiting embodiments, three equivalents of sodium hydrosulfide may be reacted with one equivalent of the sodium salt of 2,6-dinitrobenzoic acid in refluxing methanol/water followed by acidification.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:29]([O:36][CH2:37][CH2:38][CH2:39][CH2:40]Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:40][CH2:39][CH2:38][CH2:37][O:36][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: BrCCCCOCc1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCOCc2ccccc2)CC1
Yield: 23.4 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.1 g) as starting compound, potassium carbonate (1.5 g) and 4-benzyloxybutyl bromide (1.0 g) were reacted and treated in the same manner as in Example 168 to give 0.32 g of 4-amino-5-chloro-2-methoxy-N-((1-(4-benzyloxybutyl)piperidin-4-yl)methyl)benzamide.