Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)(=[O:18])=[O:17])=[CH:12]OCC)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][N:27]=1>CC(N(C)C)=O>[Br:32][C:29]1[CH:30]=[CH:31][C:26]([NH:25][CH:12]=[C:11]([S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)(=[O:10])=[O:9])[S:16]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)(=[O:17])=[O:18])=[N:27][CH:28]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CCOC=C(S(=O)(=O)c1ccccc1)S(=O)(=O)c1cccc(Cl)c1
Solvent: CC(=O)N(C)C
Product: O=S(=O)(C(=CNc1ccc(Br)cn1)S(=O)(=O)c1cccc(Cl)c1)c1ccccc1
Yield: 60.1 %

Procedure:
A solution of 1-(3-chlorophenylsulphonyl)-2-ethoxy-1-phenylsulphonylethene (3.13 g) and 2-amino-5-bromopyridine (1.4 g) in dimethylacetamide (20 ml) was heated at reflux for 3.5 hours. The solution was cooled and poured onto ice (200 g), and the resulting pale yellow solid was filtered off and recrystallised from aqueous ehtaol (95% v/v), to give 2-(5-bromopyrid-2-ylamino)-1-(3-chloropheylsulphonyl)-1-phenylsulphonylethene (2.5 g), m.p. 170°-172° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[C:11]([C:13]([OH:15])=O)[NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:16][N:17](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CN>CN(C=O)C>[CH3:16][NH:17][C:13]([C:11]1[NH:10][C:7]2=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]2[CH:12]=1)=[O:15]
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])cnc2[nH]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc2cc([N+](=O)[O-])cnc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
5-nitro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (1.3 g, 6.5 mmoles), HATU (1.2 eq) and DIEA (5 eq) were dissolved in dry DMF under argon. After stirring at RT for 15 minutes, methylamine hydrochloride (3 eq) was added and the mixture was allowed to stir at RT overnight. The mixture was concentrated and washed by a saturated solution of sodium carbonate. The precipitate was filtered off, washed with water and diethyl ether to obtain a brownish solid (1.1 g, 5 mmoles). Yield=77%. ESI-MS: m/z 221 ([M+H]+). HPLC purity: 98%.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26]O[CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.N1CCCC1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Solvent: C1CCNC1
Product: CC(C)(C)c1nc(N2CCCC2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and pyrrolidine and isolated as white solid (12.4 mg, 71%). MS(m/e): 371.4 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([OH:9])[CH:3]=1.[C:10](O)(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.B(O)(O)O.O>C1(C)C(C)=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:8]=[CH:7][C:5]2[N:6]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1O
Reactant: O=C(O)c1ccccc1
Agent: OB(O)O
Solvent: Cc1ccccc1C
Solvent: ClCCl
Solvent: O
Product: Brc1ccc2nc(-c3ccccc3)oc2c1

Procedure:
38.65 g (205.56 mmol) 4-bromo-2-hydroxy-aniline are boiled together with 25.10 g (205.56 mmol) benzoic acid and 12.75 g (205.56 mmol) boric acid in 500 ml of xylene for 6 days using the water separator. The solv. is eliminated in vacuo and the residue is taken up in DCM. The mixture is extracted 1× each with 1N sodium hydroxide solution, water, 2N hydrochloric acid and again with water. The org. phase is concentrated i. V. by rotary evaporation and the residue is separated through silica gel (eluant cyclohexane/EA).
Reaction SMILES: [CH2:1]([OH:13])[C@H:2]([OH:12])[C@@H:3]([OH:11])[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6].OCC([C@H]([C@@H]([C@H](CO)O)O)O)=O.[N+]([O-])(O)=O>>[CH2:1]([OH:13])[C:2]([C@@H:3]([OH:11])[C@H:4]([OH:10])[C:5]([C:7]([OH:9])=[O:8])=[O:6])=[O:12]
Reactant: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Solvent: O=[N+]([O-])O
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)C(=O)CO

Procedure:
2-Keto-L-Gulonic acid is an important intermediate in vitamin C manufacture. Condensation of L-sorbose with acetone in the presence of sulfuric acid followed by oxidation with permanganate and hydrolysis of the diisopropylidene derivative by boiling yields 2-keto-L-gulonic acid as described in Helv. Chim. Acta. 17, 311 (1934) and U.S. Pat. No. 2,301,811. The preparation of 2-keto-L-gulonic acid by careful oxidation of L-sorbose with nitric acid is claimed in British Pat. No. 443,901 and Dutch Pat. No. 59,584. The selective reduction of 2,5-diketogluconic acid to yield a mixture of 2-ketogluconic acid and 2-ketogulonic acid with subsequent hydrolysis of the 2-ketogulonic acid to afford ascorbic acid is described in co-pending application, Ser. No. 843,946, filed Oct. 20, 1977.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][C@@H:19]([C:28]1[CH:29]=[CH:30][C:31]([Cl:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[O:20][Si](CC)(CC)CC.Cl.O1CCOCC1>O1CCCC1>[ClH:39].[CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][C:2]=1[O:14][CH2:15][CH2:16][NH:17][CH2:18][C@@H:19]([C:28]1[CH:29]=[CH:30][C:31]([Cl:39])=[C:32]([NH:34][S:35]([CH3:38])(=[O:36])=[O:37])[CH:33]=1)[OH:20]
Reactant: CC[Si](CC)(CC)O[C@@H](CNCCOc1ccc2c(c1)[nH]c1ccccc12)c1ccc(Cl)c(NS(C)(=O)=O)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCCOc2ccc3c(c2)[nH]c2ccccc23)ccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Intermediate 108 (73.2 mg) was dissolved in anhydrous tetrahydrofuran (4.2 ml), whereto 4 N hydrogenchloride/1,4-dioxane (240 g 1) was added and the mixture was agitated at room temperature for 1 hour. The deposited precipitate was taken out and washed with tetrahydrofuran, whereupon it was dried under a reduced pressure at 40° C., whereby the above-identified compound was obtained (36.3 mg).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[C:14]3[N:15]=[C:16]([NH:18]C(=O)C)[S:17][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:5]=[C:4]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[N:3]=1.[CH2:32]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([OH:40])[CH2:35]1)[CH3:33].[C:41]([O-:44])(O)=[O:42].[Na+]>C(O)C>[CH2:32]([N:34]1[CH2:39][CH2:38][CH2:37][CH:36]([O:40][C:2]2[N:7]=[C:6]([O:8][C:9]3[C:14]4[N:15]=[C:16]([NH2:18])[S:17][C:13]=4[CH:12]=[CH:11][CH:10]=3)[CH:5]=[C:4]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=3)[N:3]=2)[CH2:35]1)[CH3:33].[C:41]([OH:44])([C:28]([F:31])([F:30])[F:29])=[O:42]
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4)nc(Cl)n3)cccc2s1
Reactant: O=C([O-])O
Reactant: CCN1CCCC(O)C1
Agent: [Na+]
Solvent: CCO
Product: CCN1CCCC(Oc2nc(Oc3cccc4sc(N)nc34)cc(-c3ccc(C(F)(F)F)cc3)n2)C1
Product: O=C(O)C(F)(F)F
Temperature: 140 °C

Procedure:
A mixture of N-{4-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzo[d]thiazol-2-yl}-acetamide (70 mg, 0.15 mmol, Example 7(d)) and 1-ethyl-3-hydroxypiperidine (39 mg, 0.3 mmol, Aldrich) in ethanol (1 mL) was heated in a microwave synthesizer at 140° C. for 20 min. The reaction mixture was diluted with sat. aqueous solution of NaHCO3 (10 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with brine (20 mL), dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo and the residue was purified by preparative HPLC [gradient 20-80% MeCN (0.1% TFA)/H2O (0.1% TFA)] to give the title compound as a salt with TFA. MS (ESI, pos. ion) m/z: 516 (M+1).
Reaction SMILES: [CH:1]1([CH2:6][C:7](Cl)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C@H:10]1([NH:19][C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([NH2:30])[CH:26]=3)[N:21]=2)[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12][CH2:11]1>C(N(CC)CC)C>[CH:1]1([CH2:6][C:7]([NH:30][C:25]2[CH:26]=[C:27]3[C:22](=[CH:23][CH:24]=2)[N:21]=[C:20]([NH:19][C@H:10]2[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH2:12][CH2:11]2)[CH:29]=[CH:28]3)=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=C(Cl)CC1CCCC1
Solvent: CCN(CC)CC
Product: O=C(CC1CCCC1)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method 9 described in example 116 from cyclopentylacetyl chloride, triethylamine and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=386.7 (M+H+).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([NH:9][C:10]([NH2:12])=[O:11])[CH:6]=[CH:7][CH:8]=1.[C:15]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)#[N:16].[N:25]1([C:31](=[O:36])[CH2:32][C:33](=O)[CH3:34])[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>C1COCC1>[CH3:34][C:33]1[N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:14])[F:1])[CH:4]=2)[C:10](=[O:11])[NH:12][CH:21]([C:20]2[CH:23]=[CH:24][C:17]([C:15]#[N:16])=[CH:18][CH:19]=2)[C:32]=1[C:31]([N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1)=[O:36]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: NC(=O)Nc1cccc(C(F)(F)F)c1
Reactant: CC(=O)CC(=O)N1CCOCC1
Solvent: C1CCOC1
Product: CC1=C(C(=O)N2CCOCC2)C(c2ccc(C#N)cc2)NC(=O)N1c1cccc(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
150 mg (0.73 mmol) N-[3-(trifluoromethyl)phenyl]urea, 96 mg (0.73 mmol) 4-cyanobenzaldehyde, 63 mg (0.37 mmol) 4-(4-morpholinyl)-4-oxo-2-butanone and 220 mg polyphosphoric acid ethyl ester are suspended in 3 ml of THF. The mixture is stirred at reflux for 18 hours. After cooling down to room temperature, the solvent is removed in vacuo and the residue is purified by column chromatography on silica with dichloromethane/methanol as eluent.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1>CO.Cl.[Pt](=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][CH:7]=1
Reactant: COC(=O)C=C(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Product: COC(=O)CC(c1ccc(Cl)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of methyl 3,3-bis(4-chlorophenyl)propenoate (Step A, 3.0 g, 14 mmol) and platinum dioxide (0.30 g) in MeOH (20 mL) and 2 M aqueous hydrochloric acid (1 mL) was degassed and filled with hydrogen with a balloon. After stirring at room temperature for 2 h, the reaction mixture was filtered through CELITE diatomaceous earth, and the filtrate was concentrated to dryness. The residue was dissolved in 50 mL ether and was concentrated with 20 g silica gel. The material was loaded onto a silica gel column, which was eluted with 10% ether in hexane to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.29-7.22 (m, 4H), 4.50 (t, 1H), 3.56 (s, 3H), 3.07 (d, 2H). LC-MS: m/e 309 (M+H)+(4.1 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]=O)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:18][C:19]1([CH3:27])[CH2:24][CH2:23][C:22](=O)[CH2:21][C:20]1=[O:26].[NH2:28][C:29]1[NH:33][N:32]=[CH:31][CH:30]=1.[CH2:34]1[CH:36]([CH2:37][C:38]([NH2:40])=[O:39])[CH2:35]1>>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11](/[CH:14]=[CH:15]/[CH:16]3[C:21]4[C:20](=[O:26])[C:19]([CH3:27])([CH3:18])[CH2:24][CH2:23][C:22]=4[NH:28][C:29]4[NH:33][N:32]=[CH:31][C:30]3=4)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:35]1[CH:36]([CH2:37][C:38]([NH2:40])=[O:39])[CH2:34]1
Reactant: Nc1ccn[nH]1
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: O=C/C=C/c1ccc(-c2cccc(F)c2)cn1
Agent: NC(=O)CC1CC1
Product: CC1(C)CCC2=C(C1=O)C(/C=C/c1ccc(-c3cccc(F)c3)cn1)c1cn[nH]c1N2

Procedure:
The title compound is prepared according to procedure A from 50 mg of (E)-3-[5-(3-fluorophenyl)pyridin-2-yl]propenal, 31 mg of 4,4-dimethylcyclohexane-1,3-dione and 40 mg of 5-amino-1H-pyrazole-3-cyclopropylmethylcarboxamide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][C:10]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:13]([CH2:22][CH2:23][OH:24])=[N:12][C:11]=2[CH:25]([CH3:27])[CH3:26])[CH:5]=[C:6]([Cl:8])[CH:7]=1.ClC(Cl)(Cl)[C:30]([N:32]=C=O)=[O:31].O.C(N(CC)CC)C>O1CCCC1>[C:30]([O:24][CH2:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)[C:10]([S:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:11]([CH:25]([CH3:27])[CH3:26])[N:12]=1)(=[O:31])[NH2:32]
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Reactant: CC(C)c1nc(CCO)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)c1nc(CCOC(N)=O)n(Cc2ccncc2)c1Sc1cc(Cl)cc(Cl)c1
Temperature: -20 °C
Reaction time: 0.05 h
Yield: 83.3 %

Procedure:
In 10 ml of dry tetrahydrofuran was dissolved 1.0 g (2.4 mmol) of the alcohol compound (123b), and the mixture was cooled to -20° C., followed by addition of 540 mg (2.9 mmol) of trichloroacetylisocyanate. After 3 minutes, the mixture was warmed to 0° C. and stirred for 10 minutes. There were added 4 ml of water and 2 ml of triethylamine, and the mixture was warmed at 50° C. for 2 hours. The mixture was diluted with ice-water, extracted with ethyl acetate, the extract was washed with water, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (10% methanol/ethyl acetate), and recrystallized from ethyl acetate to give 930 mg of Compound I-138 as crystals (yield 85%). mp 189-191° C.
Reaction SMILES: [CH2:1]([N:18]1[C:27](=[O:28])[C:26]2[N:25]([CH3:29])[CH:24]=[N:23][C:22]=2[N:21]([CH3:30])[C:19]1=[O:20])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17].C[N+]1([O-])CC[O:35]CC1.[OH2:39].S([O-])([O-])=O.[Na+].[Na+]>CC(C)=O.O.O1CCCC1>[OH:39][CH:16]([CH2:17][OH:35])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][N:18]1[C:27](=[O:28])[C:26]2[N:25]([CH3:29])[CH:24]=[N:23][C:22]=2[N:21]([CH3:30])[C:19]1=[O:20]
Reactant: O
Reactant: C=CCCCCCCCCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Reactant: C[N+]1([O-])CCOCC1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: Cn1cnc2c1c(=O)n(CCCCCCCCCCCCCCCC(O)CO)c(=O)n2C
Reaction time: 1 h
Yield: 81 %

Procedure:
A solution of 1-(16-Heptadecenyl)-3,7-dimethylxanthine (1.50 g, 3.60 mmol), 4-methylmorpholine-N-oxide (1.83 mL, 60% wt in water, 10.6 mmol) and potassium osmate dihydrate (16 mg, 0.04 mmol) in acetone/water/ tetrahydrofuran (10:7:5, 110 mL) was stirred for 60 hours. Water (100 mL) and sodium sulfite (1 g) were added and the reaction mixture stirred for 1 hour. The reaction mixture was extracted with dichloromethane (2×100 mL) and the organic phase dried using magnesium sulfate and the solvent evaporated to afford a cream solid. Recrystallization from hot ethyl acetate yields 1.31 g (81% yield) of 1-(16,17-dihydroxyheptadecyl)-3,7-dimethylxanthine (inventive compound no. 3514).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][C:3]2[CH:7]=[C:8]([N:11]([CH:21]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22]3)[CH2:12][CH2:13][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][N:15]3[CH3:20])[CH:9]=[CH:10][C:2]1=2.[CH3:30][I:31]>ClCCCl>[I-:31].[CH3:20][N+:15]1([CH3:30])[CH2:16][CH2:17][CH2:18][CH2:19][CH:14]1[CH2:13][CH2:12][N:11]([C:8]1[CH:9]=[CH:10][C:2]2[O:1][CH2:6][CH2:5][O:4][C:3]=2[CH:7]=1)[CH:21]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22]1
Reactant: CI
Reactant: CN1CCCCC1CCN(c1ccc2c(c1)OCCO2)C1Cc2ccccc2C1
Solvent: ClCCCl
Product: C[N+]1(C)CCCCC1CCN(c1ccc2c(c1)OCCO2)C1Cc2ccccc2C1
Product: [I-]
Temperature: 25 °C
Reaction time: 40 h

Procedure:
To a stirred solution of compound 61 (0.25 g, 0.64 mmol) in DCE (3 mL) was added methyl iodide (0.15 mL, 2.55 mmol) and the mixture was stirred at rt for 40 hours in a sealed tube. The reaction mixture was concentrated and the crude material was purified by Combiflash® chromatography eluting with 6-7% methanol-DCM to provide a solid. The solid material was triturated with ether and filtered through a sintered funnel and dried under high vacuum to get the desired compound.
Reaction SMILES: C(O[CH2:9][C@@H:10]1[C@@H:13]([CH2:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][C:11]1=O)C1C=CC=CC=1.[Cl-].[Cl-].[CH2:26]([Al+2])C(C)C>C1(C)C=CC=CC=1>[CH2:16]([O:15][CH2:14][C:13]1[CH:10]=[CH:9][CH:26]=[CH:11][CH:12]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)C[Al+2]
Reactant: O=C1C[C@H](COCc2ccccc2)[C@H]1COCc1ccccc1
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: c1ccc(COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of (2S-trans)-2,3-bis[(benzyloxy)methyl]cyclobutanone (0.5 g., 1.61 mmole) in toluene (1 ml.) was added dropwise to a solution of isobutylaluminum dichloride (0.71M in hexane, 3.41 ml., 2.42 mmole) at -78° C. The mixture was allowed to warm slowly to room temperature over 2 hours. After stirring for 30 minutes at room temperature, the mixture was allowed to stand at 0° C. overnight. After dilution with ethyl acetate, the reaction mixture was quenched with 10% hydrochloric acid. The organic phase was washed with brine, dried (magnesium sulfate) and the solvent evaporated to give [1S-(1α,2β,3β)]-3-hydroxy-1,2-cyclobutanedimethanol, dibenzyl ether; TLC (50% ethyl acetate/hexane) Rf =0.53.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:16][C@H:17]1[CH2:22][NH:21][CH2:20][CH2:19][N:18]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].ClCCCl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[Cl:1][C:2]1[CH:9]=[C:8]([N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:3]=1[CH2:4][N:21]1[CH2:20][CH2:19][N:18]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C@@H:17]([CH3:16])[CH2:22]1
Reactant: O=Cc1ccc(N2CCOCC2)cc1Cl
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: C[C@H]1CN(Cc2ccc(N3CCOCC3)cc2Cl)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.7 %

Procedure:
A 100 mL round-bottom flask was charged with 2-chloro-4-(morpholin-4-yl)benzaldehyde (0.800 g, 3.54 mmol, 1.00 equiv), tert-butyl (2S)-2-methylpiperazine-1-carboxylate (0.783 g, 3.91 mmol, 1.10 equiv), 1,2-dichloroethane (20 mL). The mixture was stirred for 30 min at room temperature. Sodium triacetoxyborohydride (2.26 g, 10.7 mmol, 3.00 equiv) was added. The resulting solution was stirred overnight at room temperature, diluted with H2O (30 mL), extracted with dichloromethane (3×30 mL) and the organic layers were combined, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was chromatographed on a silica gel column with ethyl acetate/petroleum ether (25/75) to provide 1.20 g (74% yield) of tert-butyl (2S)-4-[[2-chloro-4-(morpholin-4-yl)phenyl]methyl]-2-methylpiperazine-1-carboxylate as a white solid. LCMS (ESI, m/z): 410 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:12]=[C:11]([O:13][CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:15])[CH:9]=2)[N:4]=1.[Br:16]N1C(=O)CCC1=O>C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.C(Cl)(Cl)(Cl)Cl>[Br:16][CH2:15][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([O:2][CH3:1])[N:12]=[C:11]2[O:13][CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1nc(OC)c2cc(C)ccc2n1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1nc(OC)c2cc(CBr)ccc2n1
Yield: 102.9 %

Procedure:
A mixture of 2,4-dimethoxy-6-methylquinazoline (8.2 g), N-bromosuccinimide (7.9 g), benzoyl peroxide (0.19 g) and carbon tetrachloride (200 ml) was heated to reflux for 2 hours. The warm solution was filtered and the filtrate was evaporated to give 6-bromomethyl-2,4-dimethoxyquinazoline (11.7 g), m.p. 138°-143° C.
Reaction SMILES: OCCC[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].N1CCCC([CH2:27][CH2:28][OH:29])C1>>[OH:29][CH2:28][CH2:27][CH:8]1[CH2:9][CH2:10][CH2:5][N:6]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[CH2:7]1
Reactant: O=C(OCc1ccccc1)N1CCCCC1CCCO
Reactant: OCCC1CCCNC1
Product: O=C(OCc1ccccc1)N1CCCC(CCO)C1

Procedure:
Prepared similarly to Intermediate 9 from 2-(3-piperidinyl)ethanol (commercially available, for example from Tyger).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:20][CH2:21][OH:22])[C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.[S:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[S:30][CH+:29]1.N1C=CC=CC=1.C(N(CC)CC)C>ClCCl>[S:28]1[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=2[S:30][CH:29]1[O:22][CH2:21][CH2:20][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([O:12][CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OCc1ccccc1
Reactant: c1ccc2s[cH+]sc2c1
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N[C@@H](CCOC1Sc2ccccc2S1)C(=O)OCc1ccccc1
Reaction time: 8 h

Procedure:
(S)-Benzyl 2-(tert-butoxycarbonylamino)-4-hydroxybutanoate (5.76 g, 18.62 mmol) and 1,3-benzodithiol-2-ylium tetrafluoroborate (4.69 g, 19.55 mmol) were dissolved in dichloromethane (186 mL) and pyridine (4.42 g, 55.86 mmol) was added at room temperature. The mixture was stirred overnight. Upon completion of the reaction, it was quenched with triethylamine (11.5 g, 113.5 mmol) and diluted with dichloromethane. The organic layer was then washed with saturated NaHCO3 and brine. The organic layer was dried over MgSO4 and concentrated down in vacuo. The residue was then purified on normal phase column to obtain a clear oil. 7.6 g (88%).
Reaction SMILES: C(O[C:4](=[C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=2)[NH:13][C:12]1=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)C.[CH2:24]([O:26][C:27]([CH:29]1[CH2:34][CH2:33][N:32]([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]>CN(C=O)C>[CH2:24]([O:26][C:27]([CH:29]1[CH2:30][CH2:31][N:32]([CH2:35][C:36]2[CH:42]=[CH:41][C:39]([NH:40]/[C:4](=[C:11]3\[C:12](=[O:23])[NH:13][C:14]4[C:19]\3=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=4)/[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[CH:38][CH:37]=2)[CH2:33][CH2:34]1)=[O:28])[CH3:25]
Reactant: CCOC(=C1C(=O)Nc2ccc([N+](=O)[O-])cc21)c1ccccc1
Reactant: CCOC(=O)C1CCN(Cc2ccc(N)cc2)CC1
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCN(Cc2ccc(N/C(=C3\C(=O)Nc4ccc([N+](=O)[O-])cc43)c3ccccc3)cc2)CC1

Procedure:
Prepared analogously to Example 89 from 3-(1-ethoxy-1-phenyl-methylidene)-5-nitro-2-indolinone and 4-(4-ethoxycarbonyl-piperidinomethyl)-aniline in DMF.