Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](O)([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(Cl)(=O)=O.C(N(CC)CC)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[N:16]=2)=[CH:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccc3ccccc3n2)CC1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(Cc2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-tert-Butoxycarbonyl-4-hydroxy-4-(2-quinolylmethyl)piperidine (5.95 g) was dissolved in anhydrous THF (50 ml), and methane sulfonylchloride (2.99 g) and triethylamine (7.3 ml) were added to the solution. The mixture was stirred at room temperature for two hours and concentrated under reduced pressure. Water and ethyl acetate were added to the mixture to thereby separate an organic phase, which was further washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The residue was dissolved in toluene (50 ml), and DBU (5.30 g) was added to the solution. The mixture was stirred at 60° C. for three hours and concentrated under reduced pressure. Water and ethyl acetate were added to the mixture to thereby separate an organic phase, which was further washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (developer: hexane-ethyl acetate (1:1)). The title compound was obtained through crystallization from hexane.
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:10]3[CH2:12][C:13]([NH:16][C:17](=[O:19])[CH3:18])=[CH:14][CH2:15][CH:9]3[C:8]([CH3:21])([CH3:20])[O:7][C:6]=2[CH:5]=[C:4]([C:22]([CH3:30])([CH3:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:3]=1>[Pd].C(O)C>[OH:1][C:2]1[C:11]2[CH:10]3[CH2:12][CH:13]([NH:16][C:17](=[O:19])[CH3:18])[CH2:14][CH2:15][CH:9]3[C:8]([CH3:20])([CH3:21])[O:7][C:6]=2[CH:5]=[C:4]([C:22]([CH3:29])([CH3:30])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH:3]=1
Reactant: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)C1CC=C(NC(C)=O)CC21
Agent: [Pd]
Solvent: CCO
Product: CCCCCCC(C)(C)c1cc(O)c2c(c1)OC(C)(C)C1CCC(NC(C)=O)CC21
Temperature: 50 °C
Reaction time: 12 h

Procedure:
A solution of 1.177 g. of dl-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-(acetamido)-6a,7,10,10a-tetrahydro-6H-dibenzo[b,d]pyran in 100 ml. of ten percent aqueous ethanol containing 0.5 g. of five percent palladium suspended on carbon was stirred at 50° C. for 12 hours under a hydrogen atmosphere at 50 psi. The reaction mixture then was cooled to room temperature and filtered. The filtrate was concentrated to dryness by evaporation under reduced pressure to provide 1.06 g. of dl-trans-1-hydroxy-3-(1,1-dimethylheptyl)-6,6-dimethyl-9-(acetamido)-6a,7,8,9,10,10a-hexahydro-6H-dibenzo[b,d]pyran. Nuclear magnetic resonance spectroscopy demonstrated the product thus formed to be indentical to that prepared in Example 5.
Reaction SMILES: CCN(CC)CC.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]2[O:29][C:26]([CH3:28])([CH3:27])[C:23]([CH3:25])([CH3:24])[O:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[CH3:27][C:26]1([CH3:28])[C:23]([CH3:24])([CH3:25])[O:22][B:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:11]([CH:8]3[CH2:10][CH2:9]3)=[O:12])=[CH:16][CH:17]=2)[O:29]1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: O=C(Cl)C1CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)OB(c2ccc(NC(=O)C3CC3)cc2)OC1(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.9 %

Procedure:
Et3N (239 μL, 1.71 mmol) and cyclopropanecarbonyl chloride (114 μL, 1.26 mmol) were added to a solution of 4-aminophenylboronic acid pinacol ester (250 mg, 1.14 mmol) in DCM (5 mL) at 0° C. After stirring the mixture for 4 hours at room temperature, the mixture was concentrated. The residue was diluted with EtOAc and washed with 10% aqueous citric acid, sat. NaHCO3 and brine. The organic layer was dried over anhydrous Na2SO4, and concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=9:1→4:1) to afford desired product (291 mg, 88.9%) as white solid. 1HNMR (CDCl3) 400 MHz δ: 7.82-7.70 (m, 2H), 7.59-7.47 (m, 2H), 7.43 (br s, 1H), 1.54-1.44 (m, 1H), 1.33 (s, 12H), 1.09 (dt, J=7.4, 4.2 Hz, 2H), 0.85 (td, J=7.4, 4.2 Hz, 2H).
Reaction SMILES: [F:1][C@@H:2]1[C@H:8]([NH:9]C(=O)OC(C)(C)C)[CH2:7][CH2:6][C@@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[N+:23]([O-])=O)[O:4][CH2:3]1.[Si]([O:33][CH2:34][CH2:35][O:36][C:37]1[CH:42]=[C:41]([F:43])[C:40]([C:44]2[N:49]=[C:48]([C:50](O)=[O:51])[CH:47]=[CH:46][C:45]=2[F:53])=[C:39]([F:54])[CH:38]=1)(C(C)(C)C)(C)C>>[NH2:9][C@H:8]1[C@@H:2]([F:1])[CH2:3][O:4][C@H:5]([C:17]2[N:21]([CH3:22])[N:20]=[CH:19][C:18]=2[NH:23][C:50](=[O:51])[C:48]2[CH:47]=[CH:46][C:45]([F:53])=[C:44]([C:40]3[C:41]([F:43])=[CH:42][C:37]([O:36][CH2:35][CH2:34][OH:33])=[CH:38][C:39]=3[F:54])[N:49]=2)[CH2:6][CH2:7]1
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cc(F)c(-c2nc(C(=O)O)ccc2F)c(F)c1
Reactant: Cn1ncc([N+](=O)[O-])c1[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)[C@@H](F)CO1
Product: Cn1ncc(NC(=O)c2ccc(F)c(-c3c(F)cc(OCCO)cc3F)n2)c1[C@@H]1CC[C@@H](N)[C@@H](F)CO1
Yield: 62 %

Procedure:
Following the procedure for Example 111 starting from tert-butyl ((3R,4R,7S)-3-fluoro-7-(1-methyl-4-nitro-1H-pyrazol-5-yl)oxepan-4-yl)carbamate (Intermediate 24), and replacing 5-((tert-butoxycarbonyl)amino)-2-(2,6-difluorophenyl)thiazole-4-carboxylic acid with 6-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,6-difluorophenyl)-5-fluoropicolinic acid (see US2012/225062) gave 190 as a white solid (29 mg, 62%). 1H NMR (400 MHz, d6-DMSO) δ 10.59 (s, 1H), 8.40 (dd, J=8.6, 3.9 Hz, 1H), 8.27 (dd, J=8.6, 8.6 Hz, 1H), 8.10 (s, 1H), 7.15 (d, J=10.5 Hz, 2H), 5.09 (dd, J=8.4, 3.6 Hz, 1H), 4.86-4.83 (d, J=48 Hz, 1H), 4.28 (t, J=4.8 Hz, 2H), 4.12-3.92 (m, 2H), 3.92-3.86 (m, 5H), 3.70-3.38 (br s, 1H), 3.36-3.24 (m, 1H), 2.33-2.25 (m, 1H), 2.02-1.87 (m, 1H), 1.87-1.75 (m, 1H), 1.75-1.63 (m, 1H). Alkyl NH2 not observed. LCMS (ES+) m/z 524 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32](=[O:36])[CH2:33][C:34]#[N:35])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12.[CH:37]1([CH:40]=O)[CH2:39][CH2:38]1.N1CCCCC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:26]3[CH2:31][CH2:30][CH2:29][N:28]([C:32]([C:33](=[CH:40][CH:37]4[CH2:39][CH2:38]4)[C:34]#[N:35])=[O:36])[CH2:27]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][C:18]4[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:19]=4[F:25])=[CH:13][CH:12]=3)[C:3]=12
Reactant: O=CC1CC1
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3)c3c(N)ncnc32)C1
Solvent: CO
Solvent: C1CCNCC1
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4cccc(F)c4F)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 17 %

Procedure:
Into a 10 mL sealed tube, was placed a solution of 3-[(3R)-3-[4-amino-3-[4-(2,3-difluorophenoxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidin-1-yl]-3-oxopropanenitrile (150 mg, 0.31 mmol, 1.00 equiv) in methanol (5 mL), cyclopropanecarbaldehyde (64 mg, 0.91 mmol, 3.0 equiv), and piperidine (78 mg). The resulting solution was stirred for 12 h at 25° C. and then concentrated under vacuum. The residue was diluted with 10 mL dichloromethane and the resulting mixture was washed with saturated aqueous ammonium chloride, water and brine and dried over anhydrous sodium sulfate and concentrated. The residue was loaded onto a silica gel column and elution with dichloromethane/methanol (20/1) gave 28.5 mg (17%) of the title compound as a white solid. LC-MS: (ES, m/z): 542 [M+H]+, H-NMR (300 MHz, CDCl3, ppm): δ 8.54 (s, 1H); δ7.68 (d, 2H); δ7.20 (d, 2H); δ7.16 (d, 2H); δ6.95 (m, 1H); δ6.55 (d, 1H); δ5.52 (s, 2H); δ6.98 (m, 1H); δ4.76 (m, 1H); δ4.34 (m, 1H); δ3.82 (m, 1H); δ3.23 (m, 1H); δ2.01˜δ2.42 (m, 4H); δ1.88 (m, 1H); δ0.85˜δ1.21 (m, 4H).
Reaction SMILES: CC1C=CC(S(O[C:12]2[C:13]3[CH2:23][CH2:22][CH2:21][C:20]4[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=4[C:14]=3[N:15]=[C:16]([NH2:18])[N:17]=2)(=O)=O)=CC=1.[N:28]1([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32][CH2:31][CH:30]2[CH2:34][NH:35][CH2:36][CH:29]12.C(N(CC)CC)C>C(#N)C>[NH2:18][C:16]1[N:17]=[C:12]([N:35]2[CH2:34][CH:30]3[CH:29]([N:28]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32][CH2:31]3)[CH2:36]2)[C:13]2[CH2:23][CH2:22][CH2:21][C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[C:14]=2[N:15]=1
Reactant: CC(C)(C)OC(=O)N1CCCC2CNCC21
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCc2ccccc2-3)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC2CN(c3nc(N)nc4c3CCCc3ccccc3-4)CC21

Procedure:
A solution of the product from Example 59C (76 mg, 0.2 mmol), t-butyl octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (CAS #159877-36-8) (59 mg, 0.22 mmol) and triethylamine (0.1 mL) in acetonitrile (1 mL) was heated in a microwave reactor at 160° C. for 1 hour. The mixture was concentrated and chromatographed on silica gel eluting with EtOAc:hexane (1:1) mixture to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([NH:18][NH2:19])[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1.[CH3:21][CH:22]([C:26](=O)[CH3:27])[C:23](=O)[CH3:24]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:17]=[C:16]([N:18]3[C:26]([CH3:27])=[C:22]([CH3:21])[C:23]([CH3:24])=[N:19]3)[N:15]=[C:14]3[C:10]=2[N:11]=[CH:12][N:13]3[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(=O)C(C)C(C)=O
Reactant: Cn1cnc2c(Nc3ccc(Cl)cc3)nc(NN)nc21
Product: Cc1nn(-c2nc(Nc3ccc(Cl)cc3)c3ncn(C)c3n2)c(C)c1C

Procedure:
Was prepared according to Example 9 from (4-chloro-phenyl)-(2-hydrazino-9-methyl-9H-purin-6-yl)-amine and 3-methyl-2,4-pentanedione.
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[N:7][C:8]([N:11]2[CH2:36][CH2:35][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[O:23][C:24]([CH2:27][N:28]6[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]6)=[CH:25][CH:26]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:9][CH:10]=1)=[O:4].C(Cl)Cl.[NH2:40][OH:41].[OH-].[Na+]>CO.O>[OH:41][NH:40][C:3]([C:5]1[CH:10]=[N:9][C:8]([N:11]2[CH2:36][CH2:35][C:14]3[NH:15][C:16]4[CH:17]=[CH:18][C:19]([C:22]5[O:23][C:24]([CH2:27][N:28]6[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]6)=[CH:25][CH:26]=5)=[CH:20][C:21]=4[C:13]=3[CH2:12]2)=[N:7][CH:6]=1)=[O:4]
Reactant: NO
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(-c5ccc(CN6CCN(C)CC6)o5)cc4c3C2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CN1CCN(Cc2ccc(-c3ccc4[nH]c5c(c4c3)CN(c3ncc(C(=O)NO)cn3)CC5)o2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of methyl-2-{8-[5-((4-methylpiperazin-1-yl)methyl)-2-furyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (0.1 g) in methanol:DCM (5:2 mL) was added 50% aqueous hydroxylamine solution (2 mL) and to the mixture was added solution of NaOH (0.8 g) in water (0.5 mL). The reaction mixture was stirred at room temperature for 1 hr and the progress of the reaction was monitored by TLC and upon completion of the reaction the solvent was removed under reduced pressure. The pH of the mixture was adjusted to 7.5 using 1N HCl and the obtained solid was filtered and washed with water followed by diethyl ether and dried under vacuum to give Example 108 (0.08, 64.87%). HPLC: (Rt=11.58); m/e=488 (M+1).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:17]=[C:18]([O:20][CH3:21])[CH:19]=1)[C:8]([NH:10][CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:9])#[N:2].[C:22]([O:26][C:27](N1CCC(NC(=O)C2C=C(OC)C=C(O)C=2)CC1)=[O:28])([CH3:25])([CH3:24])[CH3:23].BrCC#N.C(=O)([O-])[O-].[K+].[K+]>CC#N>[C:22]([O:26][C:27]([N:14]1[CH2:13][CH2:12][CH:11]([NH:10][C:8](=[O:9])[C:7]2[CH:17]=[C:18]([O:20][CH3:21])[CH:19]=[C:5]([O:4][CH2:3][C:1]#[N:2])[CH:6]=2)[CH2:16][CH2:15]1)=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: COc1cc(OCC#N)cc(C(=O)NC2CCNCC2)c1
Reactant: COc1cc(O)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: N#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(OCC#N)cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)c1

Procedure:
In analogy to the procedure described in example 50k), 3-cyanomethoxy-5-methoxy-N-piperidin-4-yl-benzamide [prepared by i) reaction of 4-(3-hydroxy-5-methoxy-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester (example 168a) with bromo-acetonitrile in MeCN at rt in the presence of anhydrous potassium carbonate to give 4-(3-cyanomethoxy-5-methoxy-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester; ii) Boc cleavage using trifluoro acetic acid (90%) in MeCl2 at rt in analogy to the procedure described in example 50i)] was reacted with 3,5-diethoxy-4-fluoro-benzaldehyde (example 50 g), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as off-white solid. MS: 486.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[OH-].[K+].[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1>O>[F:16][C:17]1[CH:24]=[CH:23][C:20]([CH2:21][O:1][C:2]2[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[C:5](=[CH:9][CH:10]=2)[C:6]([OH:8])=[O:7])=[CH:19][CH:18]=1
Reactant: O=C(O)c1ccc(O)cc1C(=O)O
Reactant: Fc1ccc(CBr)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc(OCc2ccc(F)cc2)cc1C(=O)O
Temperature: 25 °C
Yield: 29.3 %

Procedure:
A mixture of 4-hydroxyphthalic acid (5.0 g, 27 mmol), potassium hydroxide (5.4 g, 30 mmol) and 4-fluorobenzylbromide (5.7 g, 30 mmol) in water (13 mL) was heated under reflux for 5 h. After cooling to room temperature, the mixture was washed with ether. The aqueous phase was then acidified to pH 2 at 0° C. with concentrated HCl and then extracted with ethyl acetate. The organic extracts were then washed with water and dried over sodium sulfate. Filtration and evaporation gave a residue which was purified by chromatography (SiO2, CHCl3:Acetone:AcOH:90:9:1) to afford the title compound (2.3 g, 29%) as a colorless oil. MS: m/e=289.0 (M−H+).
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=C2C(=C3[C:30]=1C=CC=C3)C=CC1C=CC=CC2=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3].C1[C:48]2[CH:47]=[CH:46][C:45]3[C:36](=[CH:37]C=[C:39]4[C:44]=3[CH:43]=[CH:42][CH:41]=[CH:40]4)[C:35]=2[CH:34]=CC=1C=O.N[C:52](C)(CO)CO>CCO>[CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:30]=[CH:34][C:35]2[C:36]3[C:45](=[C:44]4[C:39](=[CH:52][CH:37]=3)[CH:40]=[CH:41][CH:42]=[CH:43]4)[CH:46]=[CH:47][C:48]=2[CH:14]=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3]
Reactant: CC(N)(CO)CO
Reactant: CC(CO)(COS(C)(=O)=O)NCc1cc2c3ccccc3ccc2c2ccccc12
Reactant: O=Cc1ccc2c(ccc3c4ccccc4ccc23)c1
Solvent: CCO
Product: CC(CO)(COS(C)(=O)=O)NCc1ccc2c(ccc3c4ccccc4ccc23)c1

Procedure:
Using the reductive amination procedure outlined in 1C, chrysene-2-carbaldehyde (20D) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-((2-chrysenylmethyl)amino)-2-methyl-1,3-propanediol methanesulfonate, mp 225°-227° (dec), (abs. EtOH), (C,H,N,S)
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[C:5]([Cl:12])[N:6]=[CH:7]2.[C:13](Cl)(Cl)=[O:14]>C1(C)C=CC=CC=1.C(N(CC)CC)C>[Cl:12][C:5]1[N:6]=[CH:7][C:8]2[C:3]([CH:4]=1)=[C:2]([N:1]=[C:13]=[O:14])[CH:11]=[CH:10][CH:9]=2
Reactant: Nc1cccc2cnc(Cl)cc12
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C=Nc1cccc2cnc(Cl)cc12

Procedure:
5-Amino-3-chloroisoquinoline (740 mg, 4.15 mmol) was suspended in toluene (20 mL) and treated with 20% w/v phosgene solution in toluene (9 mL) and triethylamine (5 mL). The mixture was refluxed overnight and was then concentrated in vacuo and used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:17]=[CH:18][CH:19]=1)[CH:7]=[CH:8][C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=O)([O-:3])=[O:2].[CH2:20]([O:22][C:23](=[O:28])[CH2:24][C:25](=[NH:27])[NH2:26])[CH3:21]>C(O)C>[CH2:20]([O:22][C:23]([C:24]1[CH:7]([C:6]2[CH:17]=[CH:18][CH:19]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:26][C:25]=1[NH2:27])=[O:28])[CH3:21]
Reactant: O=C(C=Cc1cccc([N+](=O)[O-])c1)c1ccccc1
Reactant: CCOC(=O)CC(=N)N
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(c2ccccc2)=CC1c1cccc([N+](=O)[O-])c1
Yield: 71 %

Procedure:
Upon boiling a solution of 25.3 g of 3-nitrobenzylideneacetophenone and 13.0 g of amidinoacetic acid ethyl ester in 250 ml of ethanol for 2 hours, 2-amino-6-phenyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid ethyl ester of melting point 171°-172°C (ethanol) is obtained. Yield: 71 percent of theory.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[O:20][C:19](=[O:22])[C:18]([C:23]([OH:25])=O)=[CH:17]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:50][O:51][C:52]1[CH:57]=[C:56]([O:58][CH3:59])[CH:55]=[CH:54][C:53]=1[C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([NH2:66])[CH:61]=1>CN(C=O)C>[CH3:50][O:51][C:52]1[CH:57]=[C:56]([O:58][CH3:59])[CH:55]=[CH:54][C:53]=1[C:60]1[CH:65]=[CH:64][CH:63]=[C:62]([NH:66][C:23]([C:18]2[C:19](=[O:22])[O:20][C:21]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][C:12]=3[O:11][CH3:10])=[O:25])[CH:61]=1
Reactant: COc1ccc(-c2cccc(N)c2)c(OC)c1
Reactant: COc1cccc2cc(C(=O)O)c(=O)oc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cccc(NC(=O)c3cc4cccc(OC)c4oc3=O)c2)c(OC)c1
Temperature: 25 °C
Yield: 85.6 %

Procedure:
DIEA (0.013 mL, 0.072 mmol) was added to 8-methoxy-3-carboxy-coumarin (0.014 g, 0.065 mmol) and HATU (0.027 g, 0.072 mmol) in 0.36 mL of DMF with constant stirring at room temperature until a clear solution resulted. Subsequently, 2′,4′-dimethoxy-biphenyl-3-ylamine (0.015 g, 0.065 mmol) was added and allowed to react overnight when a solid precipitated out of solution. The resulting precipitate was filtered, dried under suction, and finally dried overnight in vacuo to give 0.024 g of product in 86% yield: LCMS (ESI) m/z 432 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][NH:11][C:12]3=[O:17])=[CH:4][CH:3]=1.[C:18]1([CH3:27])[CH:23]=[CH:22][CH:21]=[C:20]([N:24]=[C:25]=[S:26])[CH:19]=1.O>CN(C=O)C>[CH3:27][C:18]1[CH:19]=[C:20]([NH:24][C:25]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[CH:16]=[CH:15][CH:14]=[C:13]4[C:9]=3[CH2:10][NH:11][C:12]4=[O:17])=[CH:6][CH:7]=2)=[S:26])[CH:21]=[CH:22][CH:23]=1
Reactant: Cc1cccc(N=C=S)c1
Reactant: Nc1ccc(-c2cccc3c2CNC3=O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cccc(NC(=S)Nc2ccc(-c3cccc4c3CNC4=O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.8 %

Procedure:
A solution of Example 1D (0.1 g, 0.44 mmol) in DMF (3 mL) was treated with m-tolylisothiocyanate (0.06 mL, 0.45 mmol), stirred at room temperature overnight, then cooled to 0° C., treated with water, and extracted twice with ethyl acetate. The combined extracts were washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 3% methanol/dichloromethane to give 72 mg of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 2.30 (s, 3H); 4.53 (s, 2H); 6.96 (d, J=7.12 Hz, 1H); 7.23 (t, J=7.80 Hz, 1H); 7.29 (d, J=7.80 Hz, 2H); 7.57–7.69 (m, 7H); 8.68 (s, 1H); 9.84 (s, 1H); 9.88 (s, 1H); MS (ESI(−)) m/e 372 (M−H)−.
Reaction SMILES: [CH3:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4].[Li]CCCC.[C:13](OC)(=[O:18])[CH2:14][CH2:15][CH2:16][CH3:17]>C1COCC1>[O:18]=[C:13]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:1][P:2](=[O:7])([O:5][CH3:6])[O:3][CH3:4]
Reactant: CCCCC(=O)OC
Reactant: COP(C)(=O)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCC(=O)CP(=O)(OC)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.1 %

Procedure:
To a solution of dimethyl methylphosphonate (3.25 mL, 30 mmol) in anhydrous THF (30 mL), cooled at −78° C. was added n-BuLi (1.6 M in hexane, 20.6 mL, 33 mmol). The mixture was stirred for 30 minutes at this temperature under nitrogen. Methyl valerate (2.0 mL, 15 mmol) was added dropwise for 10 minutes. The mixture was stirred for 2 hours at −78° C., gradually was warm to room temperature. The mixture was quenched with addition of 1N HCl to pH 4-5. The organic layer was separated, washed with brine and dried over MgSO4. The residue was purified through flash chromatography on silica gel (MeOH/DCM 2/98) to give the product (3.0 g) with colorless oil in 96% yield. 1H NMR (CDCl3) δ 0.848 (t, J=7.3 Hz, 3H), 1.28 (m, 2H), 1.52 (m, 2H), 2.57 (t, J=2.4 Hz, 2H) 3.074 (d, J=21 Hz, 2H), 3.760 (s, 3H), 3.762 (s, 3H).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:27]2([CH3:28])[C@H:12]([C@H:13]3[C@H:24]([CH2:25][CH2:26]2)[C@:22]2([CH3:23])[C:16]([CH2:17][C@H:18]([CH2:20][CH2:21]2)[OH:19])=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>N1C=CC=CC=1>[CH3:36][C:35]1[CH:37]=[CH:38][C:32]([S:29]([O:19][C@@H:18]2[CH2:17][C:16]3[C@@:22]([CH3:23])([C@@H:24]4[C@@H:13]([CH2:14][CH:15]=3)[C@@H:12]3[CH2:11][CH2:10][C@H:9]([C@@H:7]([CH2:6][CH2:5][CH2:4][CH:2]([CH3:1])[CH3:3])[CH3:8])[C@@:27]3([CH3:28])[CH2:26][CH2:25]4)[CH2:21][CH2:20]2)(=[O:31])=[O:30])=[CH:33][CH:34]=1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
50 g (0.129 mmol) of cholesterol are dissolved in 250 ml of pyridine and cooled to about 5° C. with ice/water. Under argon, 49 g (0.258 mol) of tosyl chloride are added in portions thereto. When the addition is complete, the mixture is stirred for a further 15 minutes with cooling. The ice-bath is then removed and the mixture is stirred for 2 days at room temperature to complete the reaction. The resulting fine suspension is poured onto 1.2 liters of ice-water and stirred for 30 minutes. The precipitate is filtered off with suction, washed thoroughly with H2O and dried under a high vacuum at 40°. The substance, which still contains a large mount of pyridine hydrochloride, is dissolved in CH2Cl2 and the organic phase is washed twice with water, once with 1N hydrochloric acid and again with water. After drying over Na2 SO4 and concentration in a rotary evaporator, the residue is recrystallized from CH2Cl2 /hexane, yielding cholesteryl tosylate; m.p. 130°-131°.
Reaction SMILES: S(=O)(=O)(O)O.C(OC[O:10][C:11]1[CH:12]=[C:13]([CH:22]=[CH:23][C:24]2[CH:25]=[C:26]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])[CH:27]=[CH:28][CH:29]=2)[CH:14]=[C:15]([O:17]COCC)[CH:16]=1)C>CO.C1COCC1>[OH:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][C:26]1[CH:25]=[C:24]([CH:23]=[CH:22][C:13]2[CH:12]=[C:11]([OH:10])[CH:16]=[C:15]([OH:17])[CH:14]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOCOc1cc(C=Cc2cccc(CCCCCO)c2)cc(OCOCC)c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CO
Product: OCCCCCc1cccc(C=Cc2cc(O)cc(O)c2)c1

Procedure:
In a manner similar to Example 1(j), by reacting 0.1 ml of concentrated sulphuric acid in 1 ml of methanol with 90 mg (0.2 mmol) of 5-{3-[2-(3,5-bis-ethoxymethoxyphenyl)vinyl]phenyl}pentan-1-ol in 1 ml of methanol and 1 ml of THF, after purification on a silica column (ethyl acetate 60-heptane 40), a white powder (m=33 mg; Y=55%) is obtained.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]([OH:11])=O)=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[CH:12]([NH2:14])=O>>[F:8][C:5]1[N:6]=[CH:7][C:2]2[N:1]=[CH:12][NH:14][C:9](=[O:11])[C:3]=2[CH:4]=1
Reactant: NC=O
Reactant: Nc1cnc(F)cc1C(=O)O
Product: O=c1[nH]cnc2cnc(F)cc12
Yield: 20 %

Procedure:
Reaction of 5-amino-2-fluoropyridine-4-carboxylic acid with formamide at 140° C. as above gave 6-fluoro-3H-pyrido[3,4-d]pyrimidin-4-one (~20%). 1H NMR (DMSO) δ 12.48 (1H, m), 8.74 (1H, s), 8.16 (1H, s), 7.63 (1H, d, J=3 Hz).