Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1(C)[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][NH:14]1.C([O-])([O-])=O.[K+].[K+].CCOCC>CCO>[CH3:19][C:16]1[CH:17]=[CH:18][C:13]2[N:14]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=3)[N:12]=2)[CH:15]=1
Reactant: Cc1ccc(C(=O)CBr)cc1
Reactant: CC1=CNC(C)(N)C=C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOCC
Product: Cc1ccc(-c2cn3cc(C)ccc3n2)cc1
Temperature: 93 °C
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
A mixture of 2-bromo-4′-methylacetophenone (90% pure, 10.21 g, 43.11 mmol), 2-amino-5-methyl picoline (4.66 g, 43.11 mmol) and K2CO3 (6.6 g, 47.75 mmol) in absolute EtOH (70 ml) was heated at 93° C. overnight. After cooled to 40° C., ether (100 mL) was added. The mixture was stirred for 30 minutes and cooled by ice-water bath. After removal of solvent through filtration, the solid was stirred with water (50 ml) for 30 minutes and filtered, rinsed with water and dried under vacuum at 80° C. for 2 hr to give 6.33 g of white solid (66.1% yield). m/e+ 223.4 for C15H15N2 (M+H)+; 1H-NMR (400 MHz, CDCl3, δ) 7.84 (m, 3H), 7.71 (d, J=9.531 Hz, 1), 7.51 (d, J=9.165 Hz, 1H), 7.24 (m, 2H), 7.00 (m, 1), 2.38 (s, 3H), 2.29 (d, J=6.23 Hz, 3H) ppm. 13C-NMR (100 MHz, CDCl3 δ) 145.065, 144.444, 137.991, 130.696, 130.635, 129.642, 129.483, 128.391, 128.262, 126.018, 123.652, 122.476, 116.486, 107.857, 21.520, 18.259 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[CH:14](O)[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>C(Cl)Cl>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][O:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][C:13]=2[CH:14]([Cl:24])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCCCC(O)c1ccncc1OCc1ccc(Cl)cc1
Solvent: ClCCl
Product: CCCCC(Cl)c1ccncc1OCc1ccc(Cl)cc1

Procedure:
Starting from 3-chloro-4-pyridine carbonitrile, by reaction with 4-chlorobenzyl alcohol in the presence of sodium hydride in dimethylformamide, 3-(4-chlorobenzyloxy)-4-pyridine carbonitrile is obtained, which is reacted with butyllithium in diethyl ether to 3-(4-chlorobenzyloxy)-4-valeryl pyridine. The keto group of this 4-valeryl derivative is reduced with sodium boron hydride to the hydroxyl group; 1-[3-(4-chlorobenzyloxy)-4-pyridyl]-1-pentanol is obtained. The hydroxyl group of the pentanol derivative is exchanged with thionyl chloride in methylene chloride for a chlorine group, 3-(4-chlorobenzyloxy)-4-(1-chloropentyl)-pyridine is obtained. By subsequent reaction with imidazole in the presence of sodium hydride (analogously to example 13), the 3-(4-chlorobenzyloxy)-4-[1-(1-imidazolyl)-pentyl]-pyridine is obtained.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[N+](=[CH2:15])=[N-]>O1CCCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:15])=[O:11])[CH:8]=2)[CH:3]=[CH:2]1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Solvent: C1CCOC1
Product: COC(=O)c1ccc2cc[nH]c2c1
Temperature: 25 °C
Yield: 98 %

Procedure:
To a solution of indole-6-carboxylic acid (2.0 g, 12.4 mmol), prepared as described in step 1, in tetrahydrofuran (20 mL) at 0° C. was added excess diazomethane (0.30M solution in ether). After 10 min the solution was warmed to room temperature and nitrogen was bubbled through the solution for 30 min. The solution was concentrated in vacuo and the residue purified by flash chromatography (SiO2, 85:15 hexane:ethyl acetate) to afford methyl indole-6-carboxylate (2.1 g, 98 %) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[CH:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1)C(O)=O.C(N(CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:35])C=CC=CC=1.O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:35])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19][CH3:20])=[CH:15][CH:14]=1
Reactant: CSc1ccc(C=C(C(=O)O)c2ccccc2F)cc1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: O
Product: CSc1ccc(CC(=O)c2ccccc2F)cc1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 64.7 %

Procedure:
A solution of 2-(2-fluorophenyl)-3-(4-methylthiophenyl)propenoic acid from Step 1 (7.86 g, 27.3 mmol) and triethylamine (2.80 g, 27.7 mmol) in 22 mL of anhydrous toluene was cooled to 0° C. and treated with diphenylphosphoryl azide (7.73 g, 28.1 mmol). The solution was stirred at 0° C. for 20 minutes and at room temperature for 3.50 hours. The reaction was poured into water, extracted with ether, dried over magnesium sulfate, and concentrated in vacuo to remove the ether. The remaining toluene solution was heated to reflux and a vigorous evolution of gas occurred. After 0.75 hours, 11 mL of tert-butyl alcohol was added to the reaction. After an additional twenty minutes, concentrated hydrochloric acid (5 mL) was added slowly and the reaction was heated at 90 ° C. overnight (14 hours). The solution was cooled to room temperature and diluted with ethyl acetate, washed with saturated aqueous NaHCO3, brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide a brown solid that was purified by crystallization from ether to afford 1-(2-fluorophenyl)-2-(4-methylthiophenyl)ethanone as a yellow solid (4.60 g, 65%): mp 58°-59.5° C. 1H NMR (CDCl3) 300 MHz 7.84 (m, 1H), 7.52 (m, 1H), 7.23-7.08 (m, 6H), 4.25 (d, J=2.6Hz, 2H), 2.46 (s, 3H). 19F NMR (CDCl3) -108.51 (m). Mass spectrum M+H+ =261.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].S(=O)(=O)(O)O.[CH2:10]([OH:13])[CH2:11]C>>[CH:11]1([NH:1][C:2]([NH2:4])=[O:3])[NH:4][C:2](=[O:3])[NH:1][C:10]1=[O:13]
Reactant: CCCO
Reactant: NC(N)=O
Agent: O=S(=O)(O)O
Product: NC(=O)NC1NC(=O)NC1=O
Temperature: 25 °C

Procedure:
A mixture of 26.4 g of glyoxylic acid propyl ester propyl hemiacetal (0.15 mol), 30.0 g of urea (0.5 mol), 600 g of propanol and 7.5 g of 8% strength propanolic sulfuric acid was heated under reflux for 4 hours. Thereafter, the reaction had ended and the reaction mixture was cooled to room temperature, whereupon a colorless precipitate separated out, which was filtered off, washed with methanol and dried in vacuo at 50° C. 13.6 g, that is to say 42% of theory, of crystalline allantoin acid propyl ester were obtained by this reaction.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1)[OH:4].O=[C:19]([CH3:33])[CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]([O:31][CH3:32])=[O:30])=[CH:24][CH:23]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:32][O:31][C:29]([CH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH:19]([NH:1][CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:6]=2)[OH:4])[CH3:33])=[CH:27][CH:26]=1)=[O:30]
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Reactant: NCC(O)c1cccc(Oc2ccccc2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)Cc1ccc(OCC(C)NCC(O)c2cccc(Oc3ccccc3)c2)cc1
Yield: 33.4 %

Procedure:
Following a procedure similar to that described in Example 6, but using 2 g of 2-amino-1-(3-phenoxyphenyl)ethanol (prepared as described in Preparation 15), 3.4 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 70 ml of benzene, 60 ml of absolute methanol and 3.7 g of sodium cyanoborohydride, 1.27 g of the title compound were obtained having an Rf=0.26 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: B([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8])(O)O.Br[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.O.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>[N:17]1[CH:18]=[CH:19][C:14]([C:4]2[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=2)[C:7]([OH:9])=[O:8])=[CH:15][CH:16]=1
Reactant: O=C(O)c1cccc(B(O)O)c1
Reactant: Brc1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: O=C(O)c1cccc(-c2ccncc2)c1
Yield: 83.7 %

Procedure:
To a solution of 3-boronobenzoic acid (1.5 g, 9 mmol) and 4-bromopyridine (1.5 g, 9.9 mmol) in acetonitrile (40 mL) and water (40 mL), potassium carbonate (5.5 g, 40 mmol), Bis(triphenylphosphine)palladium(II) chloride (400 mg, 0.37 mmol) was added. The mixture was stirred under reflux overnight. Then the hot suspension was filtered and concentrated to half of the original volume and washed with dichloromethane. The aquatic phase was adjusted to pH=3 with hydrochloric acid (1 M) and filtrated, washed with water. The residue was dried in vacuum to obtain 1.5 g 3-(pyridin-4-yl)benzoic acid. Yield: 83%. LC-MS (ESI) m/z: 200 (M+1)+.
Reaction SMILES: [NH2:1][C:2]1[C:3](=[N:16][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:4]([CH2:7][NH:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[N:5][N:6]=1.NCC1C(=NNC2C=CC=C(F)C=2)C(N)=NN=1.[Cl-].[NH4+]>C(OCC)(=O)C>[NH2:1][C:2]1[C:3](=[N:16][NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=2)[C:4]([CH2:7][NH:8][C:9]([CH:10]=[CH:11][C:12]([OH:14])=[O:13])=[O:15])=[N:5][N:6]=1
Reactant: NC1=NN=C(CNC(=O)CCC(=O)O)C1=NNc1cccc(F)c1
Agent: NCC1=NN=C(N)C1=NNc1cccc(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: NC1=NN=C(CNC(=O)C=CC(=O)O)C1=NNc1cccc(F)c1
Yield: 51 %

Procedure:
In a similar manner, N-{5-amino-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylmethyl}succinamic acid was prepared by reacting 5-aminomethyl-4-[(3-fluorophenyl)hydrazono]-4H-pyrazol-3-ylamine (60 mg, 0.25 mmole) with succinic anhydide (40 mg, 0.4 mmole). The reaction was worked up by the addition of aqueous ammonium chloride solution and ethyl acetate. The crude material was purified by preparative TLC (CH2Cl2:CH3OH:H2O:HOAc=210:21:1.6:0.8) to yield 45 mg (51%) of the title compound as a yellow powder. MS (m/z, ES−): 333 (M−1, 42%); 1H NMR (ppm, 300 MHz, DMSO-d6) δ 8.23 (br s, 1H), 7.35-7.63 (m, 3H), 6.83-7.20 (m, 3H), 4.42 (s, 2H), 2.33 (m, 4H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:11])([F:10])[C:5](OCC)=[O:6].[CH2:12]([O:14][CH:15]([O:20][CH2:21][CH3:22])[CH2:16][CH2:17][C:18]#[N:19])[CH3:13].O>O1CCCC1>[CH2:21]([O:20][CH:15]([O:14][CH2:12][CH3:13])[CH2:16][CH:17]([C:5](=[O:6])[C:4]([F:11])([F:10])[F:3])[C:18]#[N:19])[CH3:22]
Reactant: CCOC(CCC#N)OCC
Reactant: CCOC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(CC(C#N)C(=O)C(F)(F)F)OCC
Yield: 32.3 %

Procedure:
To a 40°-45° C. stirring suspension of hexanewashed sodium hydride (5.5 g of a 60% dispersion, 0.14 mol) in 200 mL of dried tetrahydrofuran is added dropwise a solution of ethyl trifluoroacetate (15 g, 0.11 mol) and 3-cyanopropionaldehyde diethyl acetal (17 g, 0.11 mol) in 100 mL of dry tetrahydrofuran. The previously gray suspension slowly turns light brown in color. The reaction mixture is stirred at 50°-55° C. overnight before being quenched by slow addition of 2-propanol (15 mL). Rotary evaporation of the volatiles yields a dark oil, to which is added 150 mL of pH 7 water. Unreacted starting materials are conveniently removed by washing the aqueous layer with diethyl ether (3×30 mL). The basic aqueous phase is then acidified with 12 N hydrochloric acid and extracted with ethyl acetate (2×100 mL). The combined organic layers are washed once with saturated sodium bicarbonate (40 mL) and once with brine (15 mL) before being dried over magnesium sulfate. Rotary evaporation yields a reddish oil which is flash chromatographed over silica gel using 4:1 hexane-ethyl acetate as eluent to provide the desired product (9 g, 32%) as a yellow oil.
Reaction SMILES: [CH2:1](Br)[CH:2]=[CH2:3].C1CCN2C(=NCCC2)CC1.[CH2:16]([NH:18][C:19](=[O:21])[O-:20])[CH3:17].[OH:22][C:23]1[C:24]([I:37])=[CH:25][C:26]2[CH:27]([CH2:35]C)[CH:28]3[CH2:32][NH:31][CH2:30][CH:29]3[C:33]=2[CH:34]=1>C(Cl)Cl.O>[CH2:16]([NH:18][C:19](=[O:20])[O-:21])[CH3:17].[CH2:1]([O:22][C:23]1[C:24]([I:37])=[CH:25][C:26]2[CH:27]([CH3:35])[CH:28]3[CH2:32][NH:31][CH2:30][CH:29]3[C:33]=2[CH:34]=1)[CH:2]=[CH2:3]
Reactant: CCC1c2cc(I)c(O)cc2C2CNCC12
Reactant: C=CCBr
Agent: CCNC(=O)[O-]
Solvent: ClCCl
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: C=CCOc1cc2c(cc1I)C(C)C1CNCC21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Allyl bromide (52 μL, 0.6 mmol) and DBU (65 μL, 0.6 mmol) were added to a solution of N-ethylcarbamate-5-hydroxy-6-iodo-8-ethyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole (116 mg, 0.3 mmol) in CH2Cl2 (3 mL), and stirred 2 hours at room temperature. The reaction solution was diluted with H2O and filtered through an Extrelut column. The column was washed with CH2Cl2 and the filtrate was concentrated. The crude product was purified via silica plug eluting with Hexanes/EtOAc (3/1, v/v) to afford 50 mg (39%—two steps) of the subtitle compound. MS calculated for C18H22INO3+H: 428, observed: 428.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH2:14])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])([O-:3])=[O:2].[CH:15](=O)[CH2:16][CH3:17].C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[N+:1]([C:4]1[CH:5]=[C:6]([NH:14][CH2:15][CH2:16][CH3:17])[C:7](=[CH:12][CH:13]=1)[C:8]([O:10][CH3:11])=[O:9])([O-:3])=[O:2]
Reactant: CCC=O
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCNc1cc([N+](=O)[O-])ccc1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 19.8 %

Procedure:
To a stirred suspension of methyl 4-nitroanthranilate (prepared from 4-nitroanthranilic acid, 14.2 g) in methanol (600 ml) was added propionaldehyde (5.04 g) followed by glacial acetic acid (7.2 ml). Sodium cyanoborohydride (4.56 g) was added and the reaction mixture stirred at room temperature for 16 hours. Further propionaldehyde (5.04 g) and sodium cyanoborohydride (4.56 g) were added and the mixture stirred for a further 24 hours. The solvent was evaporated and the residue partitioned between ethyl acetate and 10% potassium carbonate solution. The organic layer was separated and the aqueous re-extracted with ethyl acetate (2×100 ml). The combined organics were washed with saturated sodium chloride solution then dried (sodium sulphate) and evaporated to give the crude product, which was purified by column chromatography on silica using 10% diethyl ether/petroleum ether (60-80) to afford the required product (3.42 g, 20%). 1H NMR (250 MHz, DMSO-d6) δ0.98 (3H, t), 1.66 (2H, sextet), 3.26 (2H, dq), 3.86 (3H, s), 7.33 (1H, dd), 7.46 (1H, d), 7.88 (1H, t), 8.04 (1H, d).
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[C:13](=[O:22])[C:14]([CH3:21])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:15].[N+:23]([O-])([OH:25])=[O:24]>>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([N+:23]([O-:25])=[O:24])=[CH:9][C:8]=1[C:13](=[O:22])[C:14]([CH3:21])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH3:15]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)C(C)(C)C(=O)c1ccccc1Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)C(C)(C)C(=O)c1cc([N+](=O)[O-])ccc1Cl
Reaction time: 0.08 h
Yield: 82.9 %

Procedure:
To concentrated sulfuric acid (15.0 ml) at 5° C. is added 2'-chloro-2-methyl-2-carboethoxypropiophenone (4.00 g, 0.01570 mol) followed by dropwise addition of concentrated nitric acid (90%, 0.740 ml, 0.0204 mol). After stirring 5 minutes, the mixture is poured onto ice and extracted with ethyl acetate. The organic layers are washed with saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a yellow oil (3.90 g, 83.0%) which is identified by NMR spectral analysis.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([CH:14]=[O:15])=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:16])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:18]1[CH2:23][CH2:22][CH:21]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=2)[CH2:20][CH2:19]1.CCN=C=NCCCN(C)C.Cl>CN(C)C=O.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[CH:1]1([C:5]2[C:13]([CH:14]=[O:15])=[CH:12][C:8]([C:9]([N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=4)[CH2:20][CH2:19]3)=[O:11])=[C:7]([CH3:16])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: Cc1cc(C2CCC2)c(C=O)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(C2CCC2)c(C=O)cc1C(=O)N1CCC(c2ccc(C#N)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
Into a round-bottom flask, was placed a solution of 4-cyclobutyl-5-formyl-2-methylbenzoic acid (compound 392.1, 490 mg, 1.57 mmol, 1.00 equiv, 70%) in N,N-dimethylformamide (8 mL). Compound 1.5 (500 mg, 1.57 mmol, 1.00 equiv), EDC.HCl (860 mg, 4.26 mmol, 2.00 equiv, 95%) and 4-dimethylaminopyridine (550 mg, 4.28 mmol, 2.00 equiv, 95%) were added to the reaction mixture. The resulting solution was stirred overnight at room temperature, and then diluted with 30 mL of ethyl acetate. The resulting mixture was washed with 4×30 mL of brine, then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified using silica gel column chromatography with ethyl acetate/petroleum ether (1:2) as eluent to yield 560 mg (74%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH2:14]([O:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([CH3:25])[C:23]=1Br)=[O:18])[CH3:15].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CC(N(C)C)=O>[CH2:14]([O:16][C:17]([C:19]1[CH:20]=[N:21][N:22]([CH3:25])[C:23]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:18])[CH3:15]
Reactant: Oc1ccccc1
Reactant: CCOC(=O)c1cnn(C)c1Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)c1cnn(C)c1Oc1ccccc1
Temperature: 140 °C
Reaction time: 0.17 h

Procedure:
Phenol (30.3 g; 322 mmol) is dissolved in DMA and K2CO3 (88.9 g; 643 mmol) is added portion wise. It is stirred for 10 minutes, then 5-Bromo-1-methyl-1H-pyrazole-4-carboxylic acid ethyl ester (50.0 g; 215 mmol) is dropped to the reaction mixture and heated up to 140° C. for 16 hours. A 10% citric acid solution is added and extracted with DCM. The organic layer is washed with sodium bicarbonate and brine, then dried and purified through column chromatography.
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)=[N:6][CH:5]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[Cl:21])[C:4]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].Cl.[NH:28]1[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=[O:35])[CH2:29]1>>[Cl:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[CH:5]1[N:6]=[C:7]([C:9]2[S:10][CH:11]=[CH:12][N:13]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH:30]([C:34]([OH:36])=[O:35])[CH2:29]2)=[C:4]1[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: O=C(O)C1CNCCO1
Reactant: CCOC(=O)C1=C(CBr)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(C(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Yield: 41.9 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.69 g, 1.5 mmol) was reacted with morpholine-2-carboxylic acid hydrochloride (0.3 g, 1.8 mmol) according to the procedure as described in Example 3 to give the title compound as a yellow solid (0.32 g, 42%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10](=[O:23])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([N+:20]([O-])=O)[CH:14]=2)=[CH:4][C:3]=1[N+:24]([O-])=O>CO.C(OCC)(=O)C.[Pd]>[NH2:20][C:15]1[CH:14]=[C:13]([CH2:12][CH2:11][C:10](=[O:23])[CH2:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([OH:1])=[C:3]([NH2:24])[CH:4]=2)[CH:18]=[CH:17][C:16]=1[OH:19]
Reactant: O=C(CCc1ccc(O)c([N+](=O)[O-])c1)CCc1ccc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1cc(CCC(=O)CCc2ccc(O)c(N)c2)ccc1O
Yield: 98 %

Procedure:
A solution of 8.2 g of 1,5-bis(4-hydroxy-3-nitrophenyl)pentan-3-one in 50 ml of methanol and 150 ml of ethyl acetate was placed in a Parr hydrogenator with 300 mg of 10% Pd/C. After 3 hours the solution was filtered and evaporated to dryness to give 6.7 g of product of m.p. 131°-133° C. Anal. calcd. for C17H20N20. Calcd C, 67.98; H, 6.71; N, 9.32. Found C, 66.91; H, 6.62; N, 8.64.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:8])=[N:4][CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:15](I)[CH3:16]>CN(C=O)C>[Br:1][C:2]1[C:3](=[O:8])[N:4]([CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1
Reactant: CCI
Reactant: Oc1ncccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCn1cccc(Br)c1=O
Temperature: 80 °C
Yield: 77.9 %

Procedure:
A mixture of 3-bromopyridin-2-ol (1.0 g, 5.75 mmol) in DMF (6 mL) was treated with cesium carbonate (1.87 g, 5.75 mmol) and ethyl iodide (1.38 mL, 17.2 mmol). The mixture was heated at 80° C. for 4 hours. The solvent was concentrated and the residue taken in EtOAc, washed with brine, dried (phase separator silicone treated filter paper), concentrated and purified on silica gel (1:2 hexane/ether) to provide 3-bromo-1-ethylpyridin-2(1H)-one (0.905 g, 78% yield) as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([F:11])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][NH:6]2.Cl.[CH3:13][O:14][C:15]1[C:19]([NH2:20])=[CH:18][N:17]([CH3:21])[N:16]=1.C(=O)(O)[O-].[Na+]>CCOC(C)=O>[F:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][NH:6]2)=[C:2]([NH:20][C:19]2[C:15]([O:14][CH3:13])=[N:16][N:17]([CH3:21])[CH:18]=2)[N:10]=1
Reactant: COc1nn(C)cc1N
Reactant: Fc1nc(Cl)c2nc[nH]c2n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COc1nn(C)cc1Nc1nc(F)nc2[nH]cnc12
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A suspension of 6-chloro-2-fluoro-9H-purine (88% potency, 5.90 kg, 30.20 mol, 1.00 eq), 3-methoxy-1-methyl-1H-pyrazol-4-amine hydrochloride (98% potency, 5.55 kg, 33.22 mol, 1.10 eq), and sodium bicarbonate (10.1 kg, 120.81 mol, 4.00 eq) in EtOAc (106 L) was stirred at 50° C. for 12 hr. The reaction mixture was then cooled to 20° C., granulated for 1 hr, filtered, and the solids were washed with EtOAc (18 L) and dried on the filter. The crude product was charged back into the reactor and suspended in water (106 L) and stirred at 35° C. for 2 hr. The resulting slurry was cooled to 20° C. and the desired product was isolated by filtration and the cake was washed with water (30 L) and then with EtOAc (30 L) and dried for 16 hr at 50° C. to give the title compound (6.26 kg, 23.8 mol, 79% yield) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.03 (br. s., 1 H) 9.21 (br. s., 1 H) 8.18 (br. s., 1 H) 7.74 (br. s., 1 H) 3.81 (br. s., 3 H) 3.71 (s, 3 H). m/z (APCI+) for C10H11FN7O 264.2 (M+H)+.
Reaction SMILES: [NH2:1][NH2:2].Cl[C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:7]=[CH:6][N:5]=1>N1C=CC=CC=1>[NH:1]([C:4]1[CH:9]=[C:8]([O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:7]=[CH:6][N:5]=1)[NH2:2]
Reactant: NN
Reactant: COCCOc1ccnc(Cl)c1
Solvent: c1ccncc1
Product: COCCOc1ccnc(NN)c1
Yield: 32.8 %

Procedure:
Hydrazine (10 mL, 318.6 mmol) was added to a solution of 2-chloro-4-(2-methoxyethoxy)pyridine (1.00 g, 5.330 mmol) in pyridine (25 mL), then heated to reflux. After 18 hours the reaction mixture was partitioned between H2O and DCM and the aqueous phase was extracted with DCM. The combined organic extracts were dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (40:1 DCM/MeOH followed by 20:1 DCM/MeOH) to provide 320 mg (33%) of desired product as a white solid.