Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([O:23][CH3:24])=[O:22])=[O:15])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[F:25].[CH3:26][C:27]1[CH:39]=[CH:38][C:30]2[N:31]=[C:32](S(C)(=O)=O)[O:33][C:29]=2[CH:28]=1>ClC(Cl)C>[F:25][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([C@@H:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[C:21]([O:23][CH3:24])=[O:22])=[O:15])=[CH:12][CH:13]=2)[CH:6]=[CH:7][C:2]=1[NH:1][C:32]1[O:33][C:29]2[CH:28]=[C:27]([CH3:26])[CH:39]=[CH:38][C:30]=2[N:31]=1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(N)c(F)c2)cc1
Reactant: Cc1ccc2nc(S(C)(=O)=O)oc2c1
Solvent: CC(Cl)Cl
Product: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(C)cc4o3)c(F)c2)cc1
Temperature: 85 °C
Yield: 42.7 %

Procedure:
To a solution of methyl (1R,2R)-2-[(4′-amino-3′-fluoro-1,1′-biphenyl-4-yl)carbonyl]-cyclopentanecarboxylate (800 mg, 2.34 mmol, 78% ee) in dichloroethane (15 mL), 6-methyl-2-(methylsulfonyl)-1,3-benzoxazole (891 mg, 4.22 mmol) was added, and the mixture was heated at 85° C. overnight. The solvent was removed by rotary evaporation, and the residue was purified by using a Biotage QuadUV flash chromatography system (eluant: 80:20 hexane/EtOAc) to give methyl (1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)-cyclopentanecarboxylate (472 mg). This ester intermediate was redissolved in 1:1 dioxane/THF 20 mL), a solution of 1 N aqueous NaOH (7.02 mL, 7.02 mol) was added, and the mixture was heated at 50° C. overnight. The solvent was removed by rotary evaporation, and water (20 mL) and EtOAc (40 mL) were added to the residue. The aqueous layer was separated, acidified to pH 5 by the addition of 1 N aqueous HCl, and then extracted with EtOAc (2×60 mL). The combined organic phases were washed with saturated NaCl and dried (Na2SO4). The solvent was removed by rotary evaporation and the residue was redissolved in DMF (10 mL) and methanol (20 mL). The crude product was purified by preparative reverse-phase HPLC (water/acetonitrile gradient, containing 0.1% TFA) to afford (1R,2R)-2-({3′-fluoro-4′-[(6-methyl-1,3-benzoxazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylic acid as an off-white solid (161 mg, 15% yield, 80% ee). 1H NMR (300 MHz, DMSO-d6) δ 8.40 (m, 1 H), 8.00–7.60 (m, 6 H), 7.30 (d, 2 H), 7.00 (d, 2 H), 4.05 (m, 1 H), 3.20 (m, 1 H), 2.40 (s, 3 H), 2.20 (m, 1 H), 1.95 (m, 1 H), 1.80–1.60 (m, 4 H); LC-MS ret. time 3.57 min, m/z 459.3 (MH+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:11])[C@H:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH2:6].Cl[C:13]([O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1)=[O:14].CN1CCOCC1>ClCCl>[CH3:8][C:7]([CH3:10])([CH3:9])[C@H:5]([NH:6][C:13]([O:15][C:16]1[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=1)=[O:14])[C:4]([O:3][CH3:2])=[O:11]
Reactant: COC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)Oc1ccc([N+](=O)[O-])cc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 64 h
Yield: 109.8 %

Procedure:
A solution of L-tert-leucine methyl ester hydrochloride (0.300 g, 1.65 mmol) in dichloromethane (4 mL) at 0° C. was treated with 4-nitrophenyl chloroformate (0.366, 1.82 mmol) and N-methyl morpholine (0.380 mL, 3.46 mmol), and the mixture was stirred at 25° C. for 64 hours. The reaction was partitioned between dichloromethane and saturated NaHCO3, and the organic phase was washed with brine and dried over MgSO4, filtered and concentrated to give the title compound (0.562 g, quantitative), which was used without further purification.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[I:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH2:14])=[CH:11][CH:10]=1>C(O)(=O)C>[I:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][NH:14][C:5](=[O:7])[CH3:6])=[CH:11][CH:10]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCc1ccc(I)cc1
Solvent: CC(=O)O
Product: CC(=O)NCc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.34 mL (3.5 mmol) acetic anhydride are added to 750 mg (3.22 mmol) 4-iodo-benzylamine in 15 ml acetic acid and the mixture is stirred at rt for 4 h. After that time, the solvent is evaporated and the residue partitionated between TBME and water. The organic layer is separated, washed with water (1×) and saturated NaHCO3 solution (2×). The organic layer is dried over sodium sulphate and the solvent is evaporated to yield the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:10][C@H:9]1[C:20](O)=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].CSC>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][C@H:9]1[CH2:20][OH:21])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1C(=O)O
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1C[C@@H](Oc2ccccc2)C[C@H]1CO
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 124.3 %

Procedure:
To a stirred solution of (2S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylcarboxylic acid (2.39 g, 7.76 mmol) in THF (50 ml) was added BH3.DMS (1.55 ml, 15.5 mmol) at 0° C. After 10 min. stirring at the same temperature, the mixture was allowed to room temperature and then heated at 50° C. for 2 h. After cooling to room temperature, the mixture was concentrated in vacuo and quenched by the addition of water at 0° C. The mixture was extracted with EtOAc. The combined extracts were washed with brine, dried over Na2SO4 and evaporated. The residue was chromatographed on silica gel [60 g, CHCl3/MeOH (50/1)] to give (2S,4S)-1-tert-butoxycarbonyl-4-phenoxy-2-pyrrolidinylmethanol (2.83 g, 100%) as a colorless oil. 1H-NMR (CDCl3) δ1.47 (s, 9H), 1.95 (br, 1H), 2.36 (m, 1H), 3.56-3.74 (m, 3H), 3.89-4.52 (m, 3H), 4.85 (br, 1H), 6.84 (dd, J=8.8, 1.2 Hz, 2H), 6.97 (t, J=7.2 Hz, 1H), 7.29 (t, 2H, J=7.8 Hz).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[Se:4][C:3]=1[C:13]#[N:14].C([OH:17])C>[OH-].[Na+]>[NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[Se:4][C:3]=1[C:13]([NH2:14])=[O:17]
Reactant: CCO
Reactant: N#Cc1[se]c(-c2ccccc2)cc1N
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1[se]c(-c2ccccc2)cc1N
Yield: 67 %

Procedure:
To a suspension of 3-amino-5-phenylselenophene-2-carbonitrile (4.0 g) in aqueous sodium hydroxide solution (120 mL, 10%) was added ethanol (50 mL) and the mixture refluxed for 45 min. The mixture was allowed to rt and the crystals separated were filtered off, washed with cold water and dried to give the product as golden yellow color solid (2.8 g, 67%), mp 184-186° C. 1H NMR (400 MHz, CDCl3): δ 7.50-7.53 (2H, m, Ar—H), 7.36-7.38 (3H, m, Ar—H), 7.04 (1H, s, H-4), 5.84 (2H, br s, —CONH2), 5.12 (2H, br s, —NH2).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8](=O)[S:7][C:6]=2[CH:11]=1.[C:12](=O)([O-])[O-].[K+].[K+].C(Br)C=C>CC(C)=O>[CH3:8][O:9][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:11][C:6]=1[S:7][CH3:12]
Reactant: O=c1oc2ccc(O)cc2s1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: CC(C)=O
Product: COc1ccc(O)cc1SC
Reaction time: 24 h
Yield: 93.8 %

Procedure:
5-Hydroxy-1,3-benzoxathiol-2-one (2 g, 11.9 mmol) [prepared according to J. Org. Chem. 1990, 55, 27361] was dissolved in acetone (13 mL) and treated with potassium carbonate (3.29 g, 23.8 mmol) followed by allyl bromide (1.13 mL, 13.1 mmol). The mixture was then stirred under nitrogen atmosphere for 24 h. The reaction mixture was evaporated to dryness and the residue was partitioned between water and diethyl ether (50 mL each). The organic fraction was separated and the aqueous layer was re-extracted with diethyl ether (50 mL). The combined organic fractions were dried (MgSO4) and evaporated to a brown oil. Purification by flash chromatography [SiO2; pentane/EtOAc (95:5→90:10)] afforded the desired compound as a colourless oil (1.9 g, 77%); δH (CDCl3, 400 MHz) 4.50 (2H, d), 5.28 (1H, d), 5.38 (1H, d), 6.00 (1H, ddt), 6.83 (1H, dd), 6.91 (1H, d), 7.15 (1H, d).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:9]=[CH:8][C:6]([OH:7])=[CH:5][C:4]=1[OH:10].[C:11](Cl)(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:11]2[O:10][C:4]3[CH:5]=[C:6]([OH:7])[CH:8]=[CH:9][C:3]=3[N:2]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc(O)cc1O
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Product: Oc1ccc2nc(-c3ccccc3)oc2c1

Procedure:
0.005 mol of 4-aminoresorcinol hydrochloride were dissolved in 7.5 ml of benzoyl chloride, while heating, and the solution was then boiled under reflux for 7 hours. The excess benzoyl chloride was subsequently distilled off in vacuo, 10 ml of ethanol were added to the residue and the mixture was boiled up briefly and, after cooling, rendered alkaline with 10M NaOH solution. The alkaline solution was introduced into 200 ml of water and brought to pH 3 with concentrated hydrochloric acid, using a pH-meter. The crystal mass which precipitated here was filtered off with suction and recrystallized from 15 ml of toluene. The dried product (250 mg) was uniform according to thin layer chromatography (silica gel plate, ethyl acetate/glacial acetic acid 24:1).
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[CH:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:9]=2[CH:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.[Br:49][C:50]1[CH:51]=[N:52][C:53](Cl)=[N:54][CH:55]=1.C(N(C(C)C)CC)(C)C.Cl>O1CCOCC1>[Br:49][C:50]1[CH:51]=[N:52][C:53]([N:33]2[CH2:34][CH2:35][CH:30]([C:10]3[C:9]([CH:36]([F:47])[C:37]4[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=4)=[C:8]([CH:5]4[CH2:6][CH2:7][C:2]([F:1])([F:48])[CH2:3][CH2:4]4)[C:17]4[CH:16]([O:18][CH2:19][C:20]5[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=5)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=4[N:11]=3)[CH2:31][CH2:32]2)=[N:54][CH:55]=1
Reactant: Clc1ncc(Br)cn1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCN(c5ncc(Br)cn5)CC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 86.1 %

Procedure:
To a solution of 4.80 g (7.11 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, in 16 ml of 1,4-dioxane, 1.40 g (7.24 mmol) of 5-bromo-2-chloropyrimidine and 1.6 ml (9.4 mmol) of diisopropylethylamine were added, and the reaction solution was stirred at 80° C. for 3 hours. After completion of the reaction, the reaction solution was poured into 40 ml of 0.5 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution, saturated sodium hydrogencarbonate aqueous solution and saturated sodium chloride aqueous solution in order and dried with anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. n-Heptane was added to the obtained residue and the precipitate was obtained by filtration to provide 5.09 g of the title compound as a white solid (yield: 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([C:9]2[C:17]([Cl:18])=[C:12]3[CH2:13][CH2:14][CH2:15][CH2:16][N:11]3[N:10]=2)=[CH:4][C:3]=1[OH:19].Cl[C:21]1[N:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC.CS(C)=O>[Cl:18][C:17]1[C:9]([C:5]2[CH:4]=[C:3]([O:19][C:21]3[N:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[C:2]([Cl:1])=[CH:7][C:6]=2[F:8])=[N:10][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=12
Reactant: Oc1cc(-c2nn3c(c2Cl)CCCC3)c(F)cc1Cl
Reactant: Clc1ncccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCC(C)=O
Product: Fc1cc(Cl)c(Oc2ncccn2)cc1-c1nn2c(c1Cl)CCCC2
Temperature: 25 °C
Yield: 74.6 %

Procedure:
To a solution of 2-chloro-5-(3-chloro-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-2-yl)-4-fluorophenol (0.5 g) and 2-chloropyrimidine (0.25 g), in a mixed solvent of 2-butanone:dimethylsulfoxide (1:4) (50 ml) was added potassium carbonate (0.35 g) at room temperature. After addition, the mixture was heated at reflux for 12 hours under a nitrogen atmosphere. The mixture was allowed to cool to room temperature and partitioned between ethyl acetate and brine. The organic phase was washed with brine (×2) and dried over anhydrous sodium sulfate. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluent, ethyl acetate:hexane, 2:1) to give the desired compound (0.47 g).
Reaction SMILES: C(OP([CH2:9][C:10]1[N:11]=[C:12]([C:15]2[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=2[C:17]([O:19][CH3:20])=[O:18])[S:13][CH:14]=1)(OCC)=O)C.[H-].[Na+].[CH3:27][O:28][CH2:29][O:30][C:31]1[C:35]([CH:36]=O)=[CH:34][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:32]=1.O>O1CCCC1>[CH3:27][O:28][CH2:29][O:30][C:31]1[C:35](/[CH:36]=[CH:9]/[C:10]2[N:11]=[C:12]([C:15]3[CH:24]=[CH:23][CH:22]=[CH:21][C:16]=3[C:17]([O:19][CH3:20])=[O:18])[S:13][CH:14]=2)=[CH:34][N:33]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[N:32]=1
Reactant: CCOP(=O)(Cc1csc(-c2ccccc2C(=O)OC)n1)OCC
Reactant: COCOc1nn(-c2ccccc2)cc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1nn(-c2ccccc2)cc1/C=C/c1csc(-c2ccccc2C(=O)OC)n1
Reaction time: 0.5 h
Yield: 20.4 %

Procedure:
To a solution of methyl {4-[(diethoxyphosphoryl)methyl]-1,3-thiazol-2-yl}benzoate (4.7 g) in tetrahydrofuran (100 mL) was added sodium hydride (60% in oil, 1.1 g) at room temperature, and the mixture was stirred for 30 min. 3-(Methoxymethoxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (2.8 g) was added to the reaction mixture, and the mixture was heated under reflux for 3 hrs. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (30:70-60:40, v/v) to give methyl (4-{(E)-2-[3-(methoxymethoxy)-1-phenyl-1H-pyrazol-4-yl]ethenyl}-1,3-thiazol-2-yl)benzoate as pale-yellow crystals (1.1 g, yield 20%). Recrystallization from ethyl acetate-hexane gave pale-yellow prism crystals. melting point: 134-135° C.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[Br:49]C1C=C(C=CC=1)N>C(O)(=O)C>[Br:49][C:3]1[CH:2]=[C:1]([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1-c1cccc(Br)c1
Yield: 12 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (200 mg, 0.86 mmol), triethyl orthoformate (2 ml), 3-bromoaniline (280 mg, 1.63 mmol), and acetic acid (0.2 ml) were used to give 40 mg (0.10 mmol, 12% yield) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.[F:9][C:10]([F:21])([F:20])[O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Cl)=[CH:14][CH:13]=1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:16][C:15]2[CH:18]=[CH:19][C:12]([O:11][C:10]([F:9])([F:20])[F:21])=[CH:13][CH:14]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S)cc1
Reactant: FC(F)(F)Oc1ccc(CCl)cc1
Product: Cc1ccc(SCc2ccc(OC(F)(F)F)cc2)cc1
Yield: 80.1 %

Procedure:
The procedure of Example 87 is repeated using 11.8 g of p-thiocresol and 9.6 g of 4-(trifluoromethoxy)benzyl chloride. This affords 10.9 g of the desired product as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)CC)C.[CH3:23][O:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>CN(C=O)C>[Cl:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10]([NH:30][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([O:24][CH3:23])=[CH:26][CH:27]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: COc1ccc(CN)cc1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(CNc2c([N+](=O)[O-])c(Cl)nc3ccccc23)cc1
Yield: 93.4 %

Procedure:
The method described in Part A of Example 1 was used to treat 2,4-dichloro-3-nitroquinoline (10.0 g, 40.8 mmol) in DMF (100 mL) with triethylamine (8.53 mL, 61.2 mmol) and 4-methoxybenzylamine (4.85 mL, 40.8 mmol). After the precipitate was isolated by filtration, it was dried for three hours in a vacuum oven at 60° C. to provide 13.1 g of 2-chloro-N-(4-methoxybenzyl)-3-nitroquinolin-4-amine as a brown solid.
Reaction SMILES: C([O-])([O-])=O.[Cs+].[Cs+].[Br:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=1[OH:17].I[CH:19]([CH3:21])[CH3:20].CCOC(C)=O>CN(C=O)C>[Br:7][C:8]1[C:9]([O:17][CH:19]([CH3:21])[CH3:20])=[CH:10][CH:11]=[CH:12][C:13]=1[N+:14]([O-:16])=[O:15]
Reactant: CC(C)I
Reactant: O=[N+]([O-])c1cccc(O)c1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cccc([N+](=O)[O-])c1Br
Temperature: 0 °C
Reaction time: 17 h
Yield: 97.2 %

Procedure:
Cs2CO3 was added in 3 portions over 15 min to a stirred solution of 2-bromo-3 nitrophenol (3.00 g, 13.8 mmol) and 2-iodopropane (4.79 g, 27.6 mmol) in 50 ml anhydrous DMF cooled to 0° C. under N2. The reaction was allowed to warm to ambient temperature (2 h) and stirred overnight (17 h). EtOAc (250 ml) was added, the reaction mixture washed with water (2×250 ml) and brine (250 ml), dried (Na2SO4) and concentrated in vacuo to an orange oil (3.78 g). Purification by column chromatography (EtOAc/hexane, 5:95) afforded 3.49 g (97%) of 2-bromo-3-isopropoxynitrobenzene as a yellow oil. TLC (EtOAc/hexane 20:80)Rf =0.12; HPLC (Tr =16.1); 1H-NMR (CDCl3) d 1.35 (d, J=6 Hz, 6H), δ 4.56 (m, J=6 Hz, 1H), δ 6.95 (dd, J=8 Hz, J=3 Hz, 1H), δ 7.34 (d, J=3 Hz, 1H), δ 7.57 (d, J=8 Hz, 1H): MS m/z (relative intensity) 260 (MH+, 100), 262 (MH+ +2, 72).
Reaction SMILES: C[N:2](/[CH:4]=[C:5](/[C:8](=O)[CH3:9])\[C:6]#N)C.C(O)C.CC(O)C.[CH3:18][N:19]1[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH2:27][NH:28][C:29]([NH2:31])=[NH:30])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>>[CH3:9][C:8]1[C:5]([C:4]#[N:2])=[CH:6][N:31]=[C:29]([NH:28][CH2:27][CH2:26][CH2:25][CH:22]2[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]2)[N:30]=1
Reactant: CC(=O)/C(C#N)=C/N(C)C
Reactant: CN1CCC(CCCNC(=N)N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCO
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1C#N
Temperature: 72.5 °C
Reaction time: 1 h

Procedure:
In a 100 L glass-lined reactor, a solution of (E)-2-[(dimethylamino)methylene]-3-oxobutanenitrile in ethanol/2-propanol (4.48 kg, 32.43 mol in 8.81 kg of ethanol/2-propanol) was added at 20-25° C. to a stirring solution of N-[3-(N-methyl-4-piperidinyl)-1-propyl]guanidine in ethanol/2-propanol (5.41 kg, 27.28 mol in 28.35 kg of ethanol/2-propanol). The resultant mixture was heated for 1.5 h at reflux, followed by an additional charge of (E)-2-[(dimethylamino)methylene]-3-oxobutanenitrile in ethanol/2-propanol (2.02 kg, 14.57 mol in 3.96 kg of ethanol/2-propanol). The resultant mixture was stirred and cooled to 70-75° C. and then potassium carbonate (7.50 kg, 54.26 mol) was added. The resultant mixture was heated to reflux until the reaction was deemed complete by HPLC. When the reaction was deemed complete, about 35-40 L of solvent was removed via atmospheric distillation. The heating was discontinued and purified water (80.00 kg) was added to the resultant suspension, which was then cooled to 20-25° C. and stirred for about 1 h. The resultant suspension was then further cooled to 0-5° C. and aged for 30 min. The solid was filtered, washed with purified water (40.00 kg) and dried at 75-80° C. under vacuum to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([NH:12]C(=O)C)[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].S(=O)(=O)(O)O.O>C(O)C>[CH3:1][C:2]1[C:3]([N+:16]([O-:18])=[O:17])=[C:4]([NH2:12])[C:5]([CH3:11])=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CC(=O)Nc1c(C)cc([N+](=O)[O-])c(C)c1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: O
Product: Cc1cc([N+](=O)[O-])c(C)c([N+](=O)[O-])c1N
Yield: 85.8 %

Procedure:
A mixture of N-(3,6-dimethyl-2,4-dinitro-phenyl)-acetamide (14.4 g, from above), concentrated sulfuric acid (15 mL), water (30 mL) and ethanol (150 mL) was heated at reflux for 24 hr. The precipitated product was filtered, washed with little ethanol and dried to afford 3,6-dimethyl-2.4-dinitro-phenylamine (10.3 g).
Reaction SMILES: [F:1][C:2]([F:22])([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=1)[C:3]1[NH:12][C:11](=O)[C:10]2[C:5](=[C:6]([F:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.CCN(C(C)C)C(C)C.P(Cl)(Cl)([Cl:34])=O>>[Cl:34][C:11]1[C:10]2[C:5](=[C:6]([F:14])[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:2]([F:22])([F:1])[C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][N:16]=2)[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1[nH]c(C(F)(F)c2ccc(F)cn2)nc2c(F)cccc12
Solvent: CCN(C(C)C)C(C)C
Product: Fc1ccc(C(F)(F)c2nc(Cl)c3cccc(F)c3n2)nc1
Temperature: 115 °C

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-fluoroquinazolin-4(3H)-one (309 mg, 1.0 mmol) were added DIEA (0.36 mL, 2.0 mmol) and phosphorous oxychloride (7.0 mL, 76 mmol, and the mixture was heated at 115° C. for 6 h. The mixture was allowed to cool to rt and then was concentrated under reduced pressure. Toluene was added and evaporated twice to remove residual phosphorous oxychloride. The residue was partitioned between EtOAc (20 mL) and cold saturated aq NaHCO3 (10 mL). The separated EtOAc layer was diluted with EtOAc (60 mL) and washed with saturated aq NaHCO3 (10 mL) and brine (2×10 mL), dried over MgSO4, filtered, and concentrated under reduced pressure to afford 4-chloro-2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-fluoroquinazoline as a brown viscous oil (222 mg).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].[CH2:16](Br)[CH2:17][C@H:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH3:19].O>CS(C)=O>[CH3:19][C@@H:18]([CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[CH2:17][CH2:16][N:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5]
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(C)=CCC[C@H](C)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)=CCC[C@H](C)CCn1c(=O)c2c(ncn2C)n(C)c1=O
Reaction time: 0.33 h
Yield: 78.5 %

Procedure:
This example illustrates a synthesis of 1-(3-(S)-methyl-7-methyl-6,7-oxidooctyl)-3,7-dimethylxanthine (inventive compound no. 1588S). Sodium hydride (95%) (631 mg, 25 mmol) was added to a solution of theobromine (4.14 g, 23 mmol) in dimethylsulfoxide (75 mL). After 20 minutes of stirring, (S)(-)Citronellyl bromide (5.0 g, 22.8 mmol) was added. After 16 hours of stirring at room temperature, the reaction mixture was poured into a separatory funnel containing 500 mL water and extracted with dichloromethane (3×100 mL). The organic portions were combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel using 30% petroleum ether/ethyl acetate eluant to yield 5.7 g (80% yield) 1-(3-(S)-methyl-7-methyloct-6-enyl)-3,7-dimethylxanthine (inventive compound no. 1596S) as an yellow oil.