Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:41]=[CH:40][C:6]([CH2:7][N:8]([CH2:31][C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.CCN(CC)CC.Cl[C:50]([O:52][CH3:53])=[O:51].O>C(Cl)Cl>[CH3:39][O:38][C:35]1[CH:34]=[CH:33][C:32]([CH2:31][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH:30][C:50](=[O:51])[O:52][CH3:53])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:37][CH:36]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(N)nc3)n2)cc1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COC(=O)Nc1ccc(Nc2ncc(Cl)cc2-c2nc(C)nc(N(Cc3ccc(OC)cc3)Cc3ccc(OC)cc3)n2)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 4.4 %

Procedure:
A solution of N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-yl)pyridine-2,5-diamine (Example 194, Step 2, 0.152 g, 0.266 mmol) and Et3N (0.111 mL, 0.799 mmol) in DCM (3 mL) was treated with methyl chloroformate (Aldrich) (0.025 mL, 0.319 mmol) and the mixture was stirred at rt for 2 days during which time solvent was lost due to evaporation. The residue was taken into the mixed solvent (1:1 DCM/THF, 5 mL) and Et3N (0.5 mL) and methyl chloroformate (0.1 mL) were added. The mixture was stirred at rt for 2 h. The resulting solid was collected and transferred to an Erlenmeyer flask using MeOH and DMSO. Water was added and the mixture was sonicated. The resulting orange solid was collected and this mixture was heated in TFA (2 mL) in the presence of trifluoromethanesulfonic acid (TCI) (0.2 mL) at rt for 30 min, then at 60° C. overnight. Solid sodium carbonate was added until effervescence subsided. Sodium bicarbonate was added slowly until no more effervescence was observed. The resulting solid was collected by filtration. The crude product was purified by preparative HPLC using Phenomenex, Gemni 5 micron C18 100×30mm column (1%-90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 15 min). The fractions containing product were collected and lyophilized to give an orange fluffy solid, which was taken into water and the resulting yellow precopitate was collected, washed with water and dried to give methyl 5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-ylcarbamate (0.0074 g, 7% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 11.84 (s, 1H); 10.10 (s, 1H); 8.74 (d, J=2.74 Hz, 1H); 8.64 (d, J=2.54 Hz, 1H); 8.37 (d, J=2.74 Hz, 1H); 8.19 (dd, J=9.00, 2.74 Hz, 1H); 7.98 (br. s., 1H); 7.82-7.90 (m, 1H); 7.80 (d, J=8.80 Hz, 1H); 3.68 (s, 3H); 2.45 (s, 3H). m/z (ESI, +ve ion) 386.9 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=C(C)C=[CH:4][N:3]=1.O.[NH2:10][NH2:11].Cl.[N+:13]([C:16]1OC(C=O)=[CH:18][CH:17]=1)([O-])=O>CO.O>[NH:10]([C:4]1[N:3]=[C:2]([NH2:7])[C:16]([CH3:13])=[CH:17][N:18]=1)[NH2:11]
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: NN
Reactant: Cc1ccnc(Cl)n1
Agent: Cl
Solvent: O
Solvent: CO
Product: Cc1cnc(NN)nc1N
Reaction time: 1 h

Procedure:
6.8 g. crude 2-hydrazino-4-amino-5-methyl-pyrimidine (m.p. 174° - 175°C.), which was prepared by treating 8 g. 2-chloro-4-methyl-pyrimidine with 40 ml. hydrazine hydrate for 1.5 hours at 100°C., were dissolved in a mixture of 79'ml. water and 37 ml. 2N hydrochloric acid, a solution of 8.3 g. 5-nitro-furan-2-aldehyde in 116 ml. methanol then added thereto, the reaction mixture left to stand for 1 hour at ambient temperature and the precipitated crystals filtered off with suction, washed with 50% aqueous methanol and then with ether, there thus being obtained 12.7 g. of the crude hydrazone, which had a melting point of 264° - 268°C.
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH3:12])=[CH:7][CH:6]=1.CCCCC.C([Li])(C)(C)C.[C:23]([C:25]1[C:30]([O:31][Si](C)(C)C)=[CH:29][CH:28]=[CH:27][N:26]=1)#N.C([O:38]CC)C>>[CH2:11]([C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[C:6]([CH:7]=1)[C:23]([C:25]1[C:30]([OH:31])=[CH:29][CH:28]=[CH:27][N:26]=1)=[O:38])[CH3:12]
Reactant: CCc1ccc(OCOC)cc1
Reactant: CCOCC
Reactant: C[Si](C)(C)Oc1cccnc1C#N
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Product: CCc1ccc(O)c(C(=O)c2ncccc2O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-ethylphenol methoxymethyl ether (4.64 g) in diethyl ether (120 ml) was added dropwise, under argon atmosphere at -78° C., a 1.7M t-butyl lithium pentane solution (18 ml). The mixture was stirred for one hour, to which was then added dropwise 2-cyano-3-trimethylsilyloxypyridine (4.91 g), followed by removing the cooling bath. The reaction mixture was stirred for 3 hours while warming up to room temperature. To the reaction mixture was added methanol (10 ml) to quench the reaction, then the solvent was distilled off. To the residue were added acetone (200 ml), conc. sulfuric acid (4 ml) and water (40 ml), then the mixture was heated for 5 hours under reflux. The reaction mixture was cooled, neutralized with an aqueous solution of sodium hydroxide, and concentrated. The concentrate was subjected to extraction with chloroform, and the extract was dried (anhydrous magnesium sulfate), then the solvent was distilled off. The residue was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give 2-(5-ethyl-2-hydroxybenzoyl)-3-hydroxypyridine (4.40 g) (Compound A-17), whose physical propertphysical properties and spectrum data are shown in Table 1 and Table 4.
Reaction SMILES: [F:1][C:2]([C:5]1[N:6]=[CH:7][C:8]([C:11]([O:13]C)=[O:12])=[N:9][CH:10]=1)([F:4])[CH3:3].O.O.[OH-].[Li+]>O1CCOCC1>[F:1][C:2]([C:5]1[N:6]=[CH:7][C:8]([C:11]([OH:13])=[O:12])=[N:9][CH:10]=1)([F:4])[CH3:3]
Reactant: COC(=O)c1cnc(C(C)(F)F)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(F)(F)c1cnc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 19.7 %

Procedure:
Methyl 5-(1,1-difluoroethyl)pyrazine-2-carboxylate (0.65 g, approx. purity 85%) was dissolved in dioxan (2 mL) and water (2 mL) was added, followed by lithium hydroxide monohydrate (54 mg, portionwise). After stirring at RT for 90 mins, the mixture was concentrated to 2 mL and diethyl ether (20 mL) added. The mixture was then extracted with NaOH (1 N, aq., 20 mL), and the aqueous portions acidified with 6N HCl to pH 2. The aqueous portion was then extracted with EtOAc, dried over MgSO4 and evaporated to afford the title compound as a white solid (119 mg). 1H NMR (400 MHz, CDCl3) δ ppm 2.11 (t, J=18.8 Hz, 3H), 9.01 (d, J=1.3 Hz, 1H), 9.47 (d, J=1.3 Hz, 1H)
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:12][O:13][CH:14]([OH:18])[CH2:15][CH2:16][OH:17])[CH:3]=1.[NH2:19]C1C2C(Cl)=CN(COC(O)CCO)C=2N=CN=1>>[NH2:19][C:9]1[C:10]2[C:2]([Br:1])=[CH:3][N:4]([CH2:12][O:13][CH:14]([OH:18])[CH2:15][CH2:16][OH:17])[C:5]=2[N:6]=[CH:7][N:8]=1
Reactant: OCCC(O)OCn1cc(Br)c2c(Cl)ncnc21
Reactant: Nc1ncnc2c1c(Cl)cn2COC(O)CCO
Product: Nc1ncnc2c1c(Br)cn2COC(O)CCO

Procedure:
Compound 22b was prepared from 5-bromo4-chloro-7-[(1,3-dihydroxypropoxy)methyl]pyrrolo[2,3-d]pyrimidine by the method described for 22a to yield 0.27 g (20%). mp=170°-172° C. 1H NMR (DMSO-d6): δ3.15-3.50 (m, 5); 4.59 (t, 2, exchanges with D2O, OH); 5.57 (s, 2, C-1'), 6.80 (bs, 2, exchanges with D2O, NH2); 7.53 (s, 1, C-6); 8.11 (s, 1, C-2). Anal. Calcd. for C10H13N4O3Br. (C,H,N).
Reaction SMILES: [N:1]1([C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4])[CH3:2].[OH-].[Na+].Cl[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24]>O.CO>[CH3:2][N:1]1[C:12](=[O:13])[C:11]2[N:10]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])[CH:9]=[N:8][C:7]=2[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: OCCCCCCCCl
Reactant: Cn1c(=O)c2[nH]cnc2n(C)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1c(=O)c2c(ncn2CCCCCCCO)n(C)c1=O
Temperature: 70 °C
Yield: 21.4 %

Procedure:
18 g of theophylline are added under stirring at room temperature to a solution of 4.1 g of sodium hydroxide in 50 ml of water and 50 ml of methanol. After stirring the mixture at 70° C. 15.8 g of 7-chloro-1-heptanol are added. The mixture is then maintained at 70° C. for 22 hours and then it is subjected to evaporation under reduced pressure until it is dry. The residue is dissolved in 150 ml of 1-N-sodium hydroxide and the mixture is extracted with methylene chloride. After washing out with water and drying over sodium sulfate the methylene chloride solution is concentrated under reduced pressure and the oily residue is several times recrystallized from diisopropyl ether. 6.3 g of 1,3-dimethyl-7-(7'-hydroxyheptyl)-xanthine are obtained (yield, referred to reacted theophylline, =79.3%).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:15][CH2:16][CH2:17][CH2:18]Br.Cl>CC(O)(C)C.C1C=CC=CC=1>[CH2:15]1[C:8]2([CH2:9][CH2:10][CH2:11][CH2:12][C:7]2=[O:13])[CH2:18][CH2:17][CH2:16]1
Reactant: O=C1CCCCC1
Reactant: BrCCCCBr
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: c1ccccc1
Product: O=C1CCCCC12CCCC2
Temperature: 120 °C

Procedure:
In a flask containing potassium tert-butoxide (45.7 g, 407.6 mmol) in t-BuOH (200 mL) and Benzene (150 mL) was added cyclohexanone (20.0 g, 203.8 mmol) and 1,4-dibromobutane (44.0 g, 203.8 mmol). The solution was heated at 120° C. for 6 hrs. The mixture was cooled to room temperature and neutralized with HCl (1N). The solution was extracted with ether, dried over Na2SO4, filtered and concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography (1% EtOAc/hexanes) to afford the title compound: GCMS ES+=153.1.
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH2:7][C:6]1=O)[CH2:2][CH2:3][CH3:4].CSC.B>O1CCCC1>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[NH:8][CH2:7][CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C(=O)CNc2ccc(C(=O)OC)cc21
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: CCCCN1CCNc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Yield: 45.8 %

Procedure:
To an ice-cold, stirred solution of methyl 4-butyl-3-oxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylate (840 mg) in tetrahydrofuran (32 mL) was added borane dimethylsulfide complex (3.2 mL, 2.0 M tetrahydrofuran) and the resulting mixture was refluxed for 24 h. The mixture was cooled to room temperature, quenched with methanol, and the solvent was removed under reduced pressure. Purification by flash column chromatography (silica, 1:1 ethyl acetate/hexanes) provided 364 mg of the title compound: 1H NMR (300 MHz, CDCl3) δ 7.27, 7.22, 6.41, 3.84, 3.47–3.45, 3.32–3.23, 1.60–1.58, 1.42–1.37, 0.99–0.94.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:13]=[N:14][N:15]([CH:17]([CH3:19])[CH3:18])[CH:16]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26](B(O)O)[CH:27]=2)[CH:22]=[N:21]1>C(=O)([O-])[O-].[Na+].[Na+].O1CCOCC1.C(Cl)Cl.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>[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([C:2]3[N:3]=[C:4]([NH:11][C:12]4[CH:13]=[N:14][N:15]([CH:17]([CH3:19])[CH3:18])[CH:16]=4)[C:5]4[N:6]([CH:8]=[CH:9][N:10]=4)[CH:7]=3)[CH:27]=2)[CH:22]=[N:21]1
Reactant: CC(C)n1cc(Nc2nc(Br)cn3ccnc23)cn1
Reactant: OB(O)c1ccc2cn[nH]c2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1cc(Nc2nc(-c3ccc4cn[nH]c4c3)cn3ccnc23)cn1
Temperature: 135 °C
Reaction time: 0.08 h
Yield: 39.1 %

Procedure:
A mixture of impure 6-bromo-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (4) (195 mg), from above, and 1H-indazol-6-ylboronic acid (159 mg, 0.650 mmol) in 1 M aqueous sodium carbonate (1.3 mL) and 1,4-dioxane (3.5 mL) was sparged with nitrogen while stirring for 5 min. Tetrakis(triphenylphosphine)palladium(0) (69 mg, 0.060 mmol) was then added and the resulting mixture heated under microwave irradiation at 135° C. for 30 min. After this time, the reaction was diluted with methylene chloride (30 mL) and water (20 mL), and filtered through diatomaceous earth. The filtrate layers were separated and the aqueous phase was extracted with a mixture of 9:1 methylene chloride/methanol (100 mL). The combined organic layers were concentrated under reduced pressure and the resulting residue was purified by chromatography (silica, gradient, methylene chloride to 8:2 methylene chloride/methanol), then trituration with acetonitrile to afford 6-(1H-indazol-6-yl)-N-(1-isopropyl-1H-pyrazol-4-yl)imidazo[1,2-a]pyrazin-8-amine (5) (85 mg, 35%) as a yellow solid: mp >250° C.; 1H NMR (300 MHz, DMSO-d6) δ 13.23 (s, 1H), 9.95 (s, 1H), 8.59 (s, 1H), 8.24 (s, 1H), 8.18 (s, 1H), 8.10 (s, 1H), 8.00 (s, 1H), 7.97 (d, J=1.2 Hz, 1H), 7.85 (d, J=8.7 Hz, 1H), 7.75 (dd, J=8.7, 1.2 Hz, 1H), 7.62 (s, 1H), 4.52 (m, 1H), 1.47 (d, J=6.6 Hz, 6H); ESI MS m/z 359.4 [M+H]+; HPLC, 5.37 min, >99% (AUC).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH2:8]([CH:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12])[CH3:9].CC[O-].[Na+].I[CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:25][CH:24]=1>C(O)C>[CH2:8]([CH:10]([CH2:14][CH3:15])[C:11]([NH2:13])=[O:12])[CH3:9].[C:1]([O:7][CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:37])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:25][CH:24]=1)(=[O:6])[CH2:2][C:3]([O-:5])=[O:4]
Reactant: O=C(O)CC(=O)O
Reactant: CCCCCCCC(=O)c1ccc(CCI)cc1
Agent: CCC(CC)C(N)=O
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCCCCCCC(=O)c1ccc(CCOC(=O)CC(=O)[O-])cc1
Yield: 50.2 %

Procedure:
4′-(2-Iodoethyl)octanophenone (175 g) prepared in the step D-3 was dissolved in anhydrous tetrahydrofuran (700 ml) to obtain 4′-(2-iodoethyl)octanophenone solution. Diethyl acetamide malonate (320 g) and sodium ethylate (100 g) was dissolved in anhydrous ethanol (1050 ml), and the 4′-(2-iodoethyl)octanophenone (175 g) solution was added, and the solution was heated to reflux for 7 hours. Tetrahydrofuran was removed by distillation from the solution. The solution was poured into ice water to obtain a precipitate which was recrystallized from hexane-ethyl acetate (40:1) to obtain diethyl acetamide-2-(4-octanoyl phenyl)ethyl malonate (110 g) in the form of colorless crystal.
Reaction SMILES: FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:15]1[CH2:19][CH2:18][CH2:17][C@@H:16]1[CH2:20][O:21][C:22]1[C:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1.[F:33][C:34]([F:45])([F:44])[C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38](O)=[O:39].COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(O)=O)=NC=1>>[F:33][C:34]([F:44])([F:45])[C:35]1[CH:36]=[C:37]([CH:41]=[CH:42][CH:43]=1)[C:38]([N:15]1[CH2:19][CH2:18][CH2:17][C@@H:16]1[CH2:20][O:21][C:22]1[C:23]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[N:24][CH:25]=[CH:26][CH:27]=1)=[O:39]
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1ncccc1OC[C@H]1CCCN1
Agent: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 using (R)-ethyl 3-(pyrrolidin-2-ylmethoxy)picolinate bis(trifluoroacetic acid) salt (EXAMPLE 34 Step 1) and 3-trifluoromethylbenzoic acid instead of ammonium chloride and 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)methoxy)picolinic acid.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1.CCCCCC.C([Li])CCC.[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]=[O:28].O>C(OCC)C>[Br:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][CH:31]=1)[CH:27]([C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][CH:5]=[CH:4][N:3]=1)[OH:28]
Reactant: COCOc1cccnc1Br
Reactant: O=Cc1cccc(Br)c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: CCCCCC
Product: COCOc1cccnc1C(O)c1cccc(Br)c1
Reaction time: 1 h

Procedure:
To a solution of 2-bromo-3-methoxymethoxypyridine (9.11 g) in diethyl ether (200 mL) was added, at -78° C., a 1.6M n-butyl lithium hexane solution (29 mL). The mixture was stirred for one hour at the same temperature, to which was further added a solution of 3-bromobenzaldehyde (6.0 mL) in diethyl ether (5 mL), and the mixture was stirred for one hour at the same temperature. The reaction mixture was poured into water, which was subjected to extraction with ethyl acetate. The extract was washed with a saturated aqueous saline solution, which was then dried (sodium sulfate) and concentrated. The concentrate was purified by means of a silica gel column (ethyl acetate--hexane) to afford 2-(3-bromo-α-hydroxybenzyl)-3-methoxymethoxypyridine (10.89 g) (compound A-1). Physical properties and spectrum data of the product are shown in Table 1 and Table 2. In substantially the same manner as above, compounds A-2 to A-4, and A-6 to A-7 shown in Table 1 were produced.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH:14]2[CH2:15][CH2:16][CH:9]1[CH2:10][NH:11][C:12](=[O:17])[CH2:13]2)=[O:7])(C)(C)C.Br[C:19]1[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[N:23][CH:24]=1>>[N+:25]([C:22]1[N:23]=[CH:24][C:19]([N:11]2[C:12](=[O:17])[CH2:13][CH:14]3[N:8]([C:6]([OH:5])=[O:7])[CH:9]([CH2:16][CH2:15]3)[CH2:10]2)=[CH:20][CH:21]=1)([O-:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)NC2
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Product: O=C1CC2CCC(CN1c1ccc([N+](=O)[O-])nc1)N2C(=O)O
Yield: 58 %

Procedure:
Following general N—C coupling procedure 1, 4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester, 1.86 g (7.72 mmoles) was combined with 5-Bromo-2-nitro-pyridine, 1.51 g (7.42 mmoles), which after recrystallized from CH2Cl2-Heptanes gave 3-(6-Nitro-pyridin-3-yl)-4-oxo-3,9-diaza bicyclo[4.2.1]nonane-9-carboxylic acid tea-butyl ester, (1.59 g) in 58% yield. TLC Rf ˜0.45 (75% Ethyl acetate-Heptane)
Reaction SMILES: [OH-:1].[K+].[OH:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2([C:25]3[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=3)[CH2:15][CH2:14][CH:13]([C@H:16]3[CH2:21][CH2:20][C@H:19]([CH2:22][CH2:23][CH3:24])[CH2:18][CH2:17]3)[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl[C:33]1[CH:38]=[CH:37][C:36]([N+:39]([O-:41])=[O:40])=[CH:35][CH:34]=1>CS(C)=O>[N+:39]([C:36]1[CH:37]=[CH:38][C:33]([O:3][C:4]2[CH:5]=[CH:6][C:7]([C:10]3([C:25]4[CH:26]=[CH:27][C:28]([O:31][C:33]5[CH:38]=[CH:37][C:36]([N+:39]([O-:40])=[O:1])=[CH:35][CH:34]=5)=[CH:29][CH:30]=4)[CH2:15][CH2:14][CH:13]([C@H:16]4[CH2:17][CH2:18][C@H:19]([CH2:22][CH2:23][CH3:24])[CH2:20][CH2:21]4)[CH2:12][CH2:11]3)=[CH:8][CH:9]=2)=[CH:34][CH:35]=1)([O-:41])=[O:40]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CCC[C@H]1CC[C@H](C2CCC(c3ccc(O)cc3)(c3ccc(O)cc3)CC2)CC1
Agent: [K+]
Solvent: CS(C)=O
Product: CCC[C@H]1CC[C@H](C2CCC(c3ccc(Oc4ccc([N+](=O)[O-])cc4)cc3)(c3ccc(Oc4ccc([N+](=O)[O-])cc4)cc3)CC2)CC1
Temperature: 65 °C
Reaction time: 5 h

Procedure:
DMSO (300 ml) and KOH (38.0 g) were added to 1,1-bis(4-hydroxyphenyl)-4-(trans-4-n-propylcyclohexyl)cyclohexane (110.6 g) obtained in the first step, followed by dissolving these together on heating to 65° C., dropwise adding to the solution, a solution of p-chloronitrobenzene (97.8 g) in DMSO (500 ml) at 65° C., reacting the mixture, aging for 5 hours, cooling down to room temperature after completion of the reaction, extracting with dichloromethane, washing with lN-NaOH aqueous solution and further with saturated NaCl aqueous solution till the aqueous solution became neutral, drying over MgSO4, treating by alumina column, distilling off the resulting eluate and recrystallizing the resulting concentrate from a mixed solvent of toluene-acetone to obtain pale yellow crystals of 1,1-bis[4-(4-nitrophenoxy)phenyl]-4-(trans-4-n-propylcyclohexyl)cyclohexane (136.1 g).
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br)[CH:8]=[N:7][C:6]=2[N:5]([CH3:20])[C:3]1=[O:4].C([O-])(=[O:23])C.[K+].N1C(=O)C2NC=NC=2NC1=O.[I-].[K+]>C(OC(=O)C)(=O)C.C(O)(=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][OH:23])[CH:8]=[N:7][C:6]=2[N:5]([CH3:20])[C:3]1=[O:4]
Reactant: CC(=O)[O-]
Reactant: Cn1c(=O)c2c(ncn2CCCCCCBr)n(C)c1=O
Agent: O=c1[nH]c(=O)c2[nH]cnc2[nH]1
Agent: [I-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: Cn1c(=O)c2c(ncn2CCCCCCO)n(C)c1=O

Procedure:
1,3-dimethyl-7-(6-bromohexyl)-xanthine is refluxed overnight with a sixfold molar excess of potassium acetate with the addition of catalytic quantities, such as 2 mol percent, referred to the xanthine, of potassium iodide in a mixture of 5 ml of acetic anhydride and 200 ml of glacial acetic acid. The solvent is evaporated in vacuo. The residue is dissolved in water and the pH of the solution is adjusted to a value of 7 with 4N sodium hydroxide. The solution is then extracted with chloroform. The isolated 1,3-dimethyl-7-(acetoxyhexyl)-xanthine is subsequently hydrolysed to the corresponding hydroxyalkyl compound by boiling with 5% sulfuric acid.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.ClCl.[Cl:9][CH2:10][C:11](=[O:16])CC(Cl)=O.[CH3:17][S:18]C(O)C.N1C=CC=CC=1>C(Cl)Cl.O>[Cl:9][CH2:10][C:11](=[O:16])[CH2:3][C:4]([O:6][CH2:2][CH2:1][S:18][CH3:17])=[O:5]
Reactant: O=C(Cl)CC(=O)CCl
Reactant: C=C1CC(=O)O1
Reactant: CSC(C)O
Agent: ClCl
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CSCCOC(=O)CC(=O)CCl
Reaction time: 0.5 h

Procedure:
In 1.26 liters of methylene chloride was dissolved 420 g (5.0 moles) of diketene. The solution was cooled at -30° to -35° C. and 354 g (4.99 moles) of chlorine gas was bubbled into the solution for about an hour to prepare a 4-chloroacetoacetyl chloride solution. 244 ml of this solution (4-chloroacetoacetyl chloride: 109.2 g, 0.705 mole) was cooled to -30° to -40° C. and a solution of 50 g (0.543 mole) of methylthioethanol and 43 g (0.543 mole) of pyridine in 85 ml of methylene chloride was added dropwise at -20° to -30° C. over a period of about 30 minutes. After completion of addition, the reaction was allowed to proceed at -5° C. for 30 minutes. To the reaction mixture were added 500 ml of methylene chloride and 1 liter of water to extract the reaction product. The aqueous layer was further extracted with 500 ml of methylene chloride. The organic layers were combined, washed with 500 ml of water and concentrated to dryness under reduced pressure to give 114 g of methylthioethyl 4-chloroacetoacetate as an oil.