Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.Br[CH2:23][CH2:24][CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[C:27]1([CH2:26][CH2:25][CH2:24][CH2:23][N:1]2[CH2:2][CH2:3][C:4]3([O:11][C:10]4[C:12]5[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=4[S:8][CH2:7]3)=[CH:16][CH:15]=[CH:14][CH:13]=5)[CH2:5][CH2:6]2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: BrCCCCc1ccccc1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(CCCCc3ccccc3)CC1)O2

Procedure:
Compound 149 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione and (4-bromobutyl)benzene and conditions outlined in procedure V. M.p.=145-147° C.; 400 MHz 1H NMR (DMSO-d6) δ: 7.93-7.88 (m, 1H), 7.84-7.73 (m, 2H), 7.62-7.52 (m, 1H), 7.35-7.1 (m, 5H), 3.06 (s, 2H), 2.76-2.64 (m, 2H), 2.62-2.54 (m, 2H), 2.4-2.2 (m, 4H), 2.04-1.9 (m, 2H), 1.87-1.7 (m, 2H), 1.68-1.4 (m, 4H); LCMS: 434 [M+H].
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[CH2:13][C:12]([CH3:15])([CH3:14])[NH:11][C:10]([CH3:17])([CH3:16])[CH2:9]2)[CH2:4][CH2:3]1.[C:18](O)(=[O:20])[CH3:19]>C1(C)C(C)=CC=CC=1>[C:18]([O:1][CH:2]1[CH2:7][CH2:6][CH:5]([CH:8]2[CH2:9][C:10]([CH3:17])([CH3:16])[NH:11][C:12]([CH3:15])([CH3:14])[CH2:13]2)[CH2:4][CH2:3]1)(=[O:20])[CH3:19]
Reactant: CC(=O)O
Reactant: CC1(C)CC(C2CCC(O)CC2)CC(C)(C)N1
Solvent: Cc1ccccc1C
Product: CC(=O)OC1CCC(C2CC(C)(C)NC(C)(C)C2)CC1

Procedure:
7 parts of 4-(4'-hydroxycyclohexyl)-2,2,6,6-tetramethylpiperidine were dissolved in xylene by warming 1.7 parts of acetic acid and 0.5 part of tetra-n-butyl-ortho-titanate were added and the solution allowed to stir and reflux for 48 hours. Water was continuously removed from the reaction. The xylene was removed under reduced pressure and the residue treated with 0.5 part carbon, 0.5 part sodium carbonate and water. The mixture was stirred and heated at reflux for 1 hour. The mixture was then filtered and the filtrate extracted with ether. The organic layer was dried over magnesium sulphate and evaporated under reduced pressure. The residue was distilled under reduced pressure to yield the desired product boiling at 114°-7°C/0.1mm and having the following elemental analysis:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1.[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH3:29][N:30]([CH3:35])[CH2:31][CH2:32][CH2:33][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[C:11]([C:13]([NH:15][C:16]3[S:17][CH:18]=[CH:19][N:20]=3)=[O:14])[N:12]=2)=[CH:4][CH:3]=1
Reactant: CN(C)CCCO
Reactant: COc1ccc(-c2[nH]c(-c3ccc(O)cc3)nc2C(=O)Nc2nccs2)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: COc1ccc(-c2[nH]c(-c3ccc(OCCCN(C)C)cc3)nc2C(=O)Nc2nccs2)cc1

Procedure:
2-(4-Hydroxyphenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)-imidazole-4-carboxamide, 3-dimethylaminopropanol, triphenyl-phosphine and diethyl azodicarboxylate are reacted and treated in the same manner as in Example 24 to give 2-(4-(3-dimethylamino-propyloxy)phenyl)-5-(4-methoxyphenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1>>[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:4](=[O:6])[C:3]4[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:2]=4[CH3:1])[CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: Cc1ccc(C)c(C(=O)O)c1
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: Cc1ccc(C)c(C(=O)N2CCN(c3ccc(C(=O)NCCC4CC4)nn3)CC2)c1

Procedure:
Following the procedure of Example 9, making variations only as required to use 2,5-dimethylbenzoic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-yl-pyridazine-3-carboxylic acid (2-cyclopropylethyl)amide, the title compound was obtained as a white solid (56% yield). 1H NMR (300 MHz, CDCl3) δ 8.05, 7.96, 7.16-7.11, 7.03-6.97, 4.12-3.67, 2.23, 2.22, 1.52, 0.82-0.69, 0.48-0.42, 0.11-0.05. MS (ES+) m/z 408.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH:21]4[CH2:26][CH2:25][N:24]([C:27]([O:29]C(C)(C)C)=O)[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].FC(F)(F)C(O)=O.[CH3:41][N:42](C)[C:43](Cl)=O>C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[N:19]=[C:18]([NH:20][CH:21]4[CH2:26][CH2:25][N:24]([C:27]([N:42]([CH3:43])[CH3:41])=[O:29])[CH2:23][CH2:22]4)[N:17]=[CH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Reactant: CN(C)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: CN(C)C(=O)N1CCC(Nc2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1

Procedure:
Prepared from 4-[(3-chloro-4-fluorophenyl)amino]-6-[1-tertbutyloxycarbonyl-4-piperidinylamino]pyrimido[5,4-d]pyrimidine by reaction with trifluoroacetic acid and subsequent reaction with dimethylcarbamoyl chloride and triethylamine. Melting point: 187°-188° C.; Rf : 0.59 (alumina; petroleum ether/ethyl acetate/methanol=10:10:2)
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][C@H:29]1[CH2:33][OH:34].C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([N:28]4[CH2:32][CH2:31][CH2:30][C@H:29]4[CH2:33][OH:34])[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: OC[C@@H]1CCCN1
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)N4CCC[C@H]4CO)cc3)cc12

Procedure:
((2S)-1-(1-(4-(2-(5-Amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethyl)pyrrolidin-2-yl)methanol was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and (S)-pyrrolidin-2-ylmethanol (commercially available) following the procedures described for Example 182, 1H NMR (Acetone-d6) TFA Salt: δ 8.83 (s, 1H), 8.80 (s, 1H), 8.43 (d, 1H), 7.36-7.53 (m, 6H), 4.68 (m, 1H), 3.69 (m, 2H), 3.19-3.21 (m, 4H), 2.55 (m, 4H), 1.75-1.78 (m, 6H), 1.74 (d, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:19]=[CH:18][C:9]2[O:10][C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[C:8]=2[CH:7]=1)=[O:4].[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[N:20]1([CH2:2][C:3]([NH:5][C:6]2[CH:19]=[CH:18][C:9]3[O:10][C:11]4[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=4[C:8]=3[CH:7]=2)=[O:4])[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1
Reactant: O=C(CCl)Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C(CN1CCOCC1)Nc1ccc2oc3c(c2c1)CCCCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
A mixture of 2-chloro-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.13 g, 0.45 mmol), morpholine (0.049 mL, 0.56 mmol), and cesium carbonate (0.29 g, 0.90 mmol) in acetonitrile (5 mL) was stirred overnight at room temperature. The reaction mixture was concentrated and the crude material was purified using reverse-phase HPLC to provide 2-morpholin-4-yl-N-7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-ylacetamide (0.085 g). MS (ESI) m/z 329 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:9][CH2:8][C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[N:7][CH:6]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(Cl)nc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ncc(CBr)cn1
Yield: 38 %

Procedure:
In 30 ml of carbon tetrachloride, 1.04 g (8.13 mmol) of 2-chloro-5-methylpyrimidine was dissolved. To this solution, 1.73 g (9.75 mmol) of N-bromosuccinimide and 20 mg of benzoyl peroxide were added, followed by heating under reflux for 6 hours. After completion of the reaction, the reaction liquid was returned to room temperature, and concentrated under reduced pressure. Then, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1). Thus, 641 mg of 5-bromomethyl-2-chloropyrimidine was obtained (Percentage Yield: 380).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2].[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: C1CCNC1
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Product: O=C(c1ccccc1)c1ccc(N2CCCC2)c([N+](=O)[O-])c1
Yield: 95 %

Procedure:
3Nitro-4-chloro-benzophenone is reacted with pyrrolidine as described in Examples 7 or 8 obtain 3-nitro-4-pyrrolidino-benzophenone with a yield of 95 %. The crystalline product melts at 89.5° - 90.5° C.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[CH2:4][NH:5][CH3:6].[Cl:9][C:10]1[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=1[O:12][CH:13]([C:15]1[S:19][C:18]([N:20]=[C:21]=[O:22])=[N:17][N:16]=1)[CH3:14]>C1C=CC=CC=1>[Cl:9][C:10]1[CH:26]=[CH:25][CH:24]=[CH:23][C:11]=1[O:12][CH:13]([C:15]1[S:19][C:18]([NH:20][C:21](=[O:22])[N:5]([CH3:6])[CH2:4][CH:3]([O:7][CH3:8])[O:2][CH3:1])=[N:17][N:16]=1)[CH3:14]
Reactant: CC(Oc1ccccc1Cl)c1nnc(N=C=O)s1
Reactant: CNCC(OC)OC
Solvent: c1ccccc1
Product: COC(CN(C)C(=O)Nc1nnc(C(C)Oc2ccccc2Cl)s1)OC
Yield: 72.7 %

Procedure:
Methylaminoacetaldehyde dimethylacetal (4.2 grams, 0.035 mole) was slowly added at ambient temperature to a 30 milliliter benzene solution containing 9.9 grams (0.035 mole) of the 5-[1-(2-chlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl isocyanate dimer (prepared above). The resulting solution was refluxed for 20 minutes, cooled and topped on a roto-vac at 70° C. to 13.4 grams of an orange oil which partially crystallized upon standing. The entire sample was recrystallized from a minimum amount of ethylacetate/hexane solution. The crystals were filtered off and dried in a vacuum oven at 80° C. to give 10.2 grams of white crystals of 3-[5-(2-chlorophenoxy)ethyl]-1,3,4-thiadiazol-2-yl]-1-methyl-1-1(2,2-dimethoxyethyl)urea. (Melting point 101°-104° C.).
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C:13]([CH3:37])([CH3:36])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([NH:31][CH2:32][C:33](=[O:35])[CH3:34])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:40][Mg]Br.Cl>O1CCCC1.C(OCC)C>[F:39][C:2]([F:1])([F:38])[C:3]1[CH:4]=[C:5]([C:13]([CH3:36])([CH3:37])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([NH:31][CH2:32][C:33]([OH:35])([CH3:40])[CH3:34])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: CC(=O)CNc1cc(-c2ccccc2Cl)c(N(C)C(=O)C(C)(C)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cn1
Reactant: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: CN(C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnc(NCC(C)(C)O)cc1-c1ccccc1Cl
Temperature: 65 °C
Reaction time: 3 h
Yield: 50 %

Procedure:
To a solution of 100 mg (0.175 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[4-(2-chloro-phenyl)-6-(2-oxo-propylamino)-pyridin-3-yl]-N-methyl-isobutyramide in 1 ml tetrahydrofuran was added a 3 N solution of methylmagnesium bromide in diethyl ether at room temperature. The reaction mixture was stirred at room temperature for 1 h and at 65° C. for 3 h. After cooling to room temperature few drops of a 1 N aqueous solution of hydrochloric acid were added to the reaction mixture, followed by extraction with dichloromethane and washing with saturated sodium carbonate solution. The combined organic layers were dried over sodium sulfate, concentrated in vacuo and purified by flash chromatography to give 51 mg (50%) of the title compound as a white foam.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([C:7]([NH:9][NH:10][C:11](=[O:28])[C@H:12]([NH:16][C:17]2[C:25]3[CH:24]=[CH:23][S:22][C:21]=3[C:20]([C:26]#[N:27])=[CH:19][CH:18]=2)[C@@H:13]([OH:15])[CH3:14])=[O:8])=[CH:5][CH:4]=1)#[N:2].N1C=CN=C1.[CH3:36][C:37]([Si:40](Cl)([CH3:42])[CH3:41])([CH3:39])[CH3:38]>CN(C=O)C>[Si:40]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:16][C:17]1[C:25]2[CH:24]=[CH:23][S:22][C:21]=2[C:20]([C:26]#[N:27])=[CH:19][CH:18]=1)[C:11]([NH:10][NH:9][C:7](=[O:8])[C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:30][CH:29]=1)=[O:28])([C:37]([CH3:39])([CH3:38])[CH3:36])([CH3:42])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@H](O)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccc(C#N)cc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: C[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](Nc1ccc(C#N)c2sccc12)C(=O)NNC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.7 %

Procedure:
To a solution of 4-cyano-N′-((2R,3S)-2-(7-cyanobenzo[b]thiophen-4-ylamino)-3-hydroxybutanoyl)benzohydrazide (320 mg, 0.76 mmol) in DMF (10 mL) was added imidazole (208 mg, 3.06 mmol) and TBSCl (230 mg, 1.53 mmol) at 0° C. After addition, the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched by adding ice-water and extracted with EtOAc. The EtOAc extracts were washed with water, brine and dried over Na2SO4. Removal of the solvent gave a residue, which was purified by SiO2 column to afford N′-((2R,3S)-3-(tert-butyldimethylsilyloxy)-2-(7-cyanobenzo[b]thiophen-4-ylamino)butanoyl)-4-cyanobenzohydrazide (380 mg, 93%). NMR (400 MHz, CDCl3, δ in ppm) 9.28 (b, 1H), 8.63 (b, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.2 Hz, 1H), 7.42 (d, J=5.6 Hz, 1H), 7.23 (d, J=5.6 Hz, 1H), 6.35 (d, 8.2 Hz, 1H), 5.59 (d, J=5.9 Hz, 1H), 4.44 (m, 1H), 4.01 (m, 1H), 1.14 (d, J=6.3 Hz, 3H), 0.83 (s, 9H), 0.03 (s, 3H), 0.00 (s, 3H).
Reaction SMILES: [C:1]1([CH3:8])[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:9]([OH:13])(=[O:12])[CH2:10][OH:11].Cl>[OH-].[Na+]>[OH:7][C:6]1[CH:5]=[CH:4][C:3]([CH:10]([OH:11])[C:9]([OH:13])=[O:12])=[CH:2][C:1]=1[CH3:8]
Reactant: O=C(O)CO
Reactant: Cc1ccccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C(O)C(=O)O)ccc1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 137.7 %

Procedure:
32.4 g (0.30 mol) of o-cresol are dissolved in 150 ml of 2N sodium hydroxide solution under a nitrogen atmosphere. After cooling to +5° C., 4.8 g (0.12 mol) of sodium hydroxide and 13.3 ml (0.12 mol) of 50% aqueous glycolic acid are added, and the reaction mixture is stirred at room temperature for 4 hours. A further 0.12 mol of sodium hydroxide and glycolic acid (a total of 0.36 mol) is added twice after 4 hours each time. The reaction mixture is then stirred for another 12 hours, neutralised with concentrated hydrochloric acid and washed twice with 75 ml of petroleum ether. The aqueous phase is then acidified with concentrated hydrochloric acid and extracted several times with ether. The organic phases are combined, dried over magnesium sulfate and concentrated on a vacuum rotary evaporator, giving 30.1 g (55%) of 4-hydroxy-3-methylmandelic acid, melting point 115°-120° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=1.[CH2:20]([C:29](Cl)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1>C(Cl)Cl.N1C=CC=CC=1>[CH2:20]([C:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:1][CH2:2][CH2:3][O:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:18])[C:14]([CH3:16])([CH3:15])[CH3:17])=[CH:9][CH:8]=1)[C:21]1[CH:22]=[CH:23][C:24]([O:27][CH3:28])=[CH:25][CH:26]=1
Reactant: COc1ccc(CC(Cl)(c2ccccc2)c2ccccc2)cc1
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)NOCCO)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(CC(OCCONC(=O)c2ccc(C(=O)C(C)(C)C)cc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 2.8 grams (10.6 mmol) of N-(2-hydroxy-ethoxy)-4-pivaloylbenzamide in 5 ml of methylene chloride and 3 ml of pyridine at 0° C. are added 3.92 grams (12.7 mmol) of ρ-anisylchlorodiphenylmethane. The mixture is warmed to room temperature over two hours and then diluted with 40 ml of methylene chloride. This solution is washed with 50 ml of 10% sodium bicarbonate and 30 ml of brine, dried over magnesium sulfate and concentrated by evaporation. The residue is purified by column chromatography using 5:1 hexane/ethyl acetate as the eluent to obtain the protected product, N-(2-[ρ-anisyldiphenylmethyloxy]ethoxy)-4-pivaloylbenzamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([C:10]([O:12]C)=[O:11])[CH:4]=1.[OH-].[Na+]>O.CO>[CH3:1][O:2][C:3]1[N:8]=[C:7]([CH3:9])[N:6]=[C:5]([C:10]([OH:12])=[O:11])[CH:4]=1
Reactant: COC(=O)c1cc(OC)nc(C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1cc(C(=O)O)nc(C)n1
Yield: 43.4 %

Procedure:
62.6 g of methyl 6-methoxy-2-methylpyrimidine-4-carboxylate are added to a stirred solution of 14.4 g of sodium hydroxide in 100 ml of water and 350 ml of methanol and stirring is continued until hydrolysis is complete (TLC checking). 200 ml of methanol are added to the reaction mixture, and the sodium salt is filtered off with suction and then washed with methanol/diethyl ether (1:1) on the suction filter. The filter residue (59.3 g; melting point above 265° C.) dried in vacuo at 50° C. is introduced in portions into a solution of 24.5 g of acetyl chloride in 300 ml of methanol. The mixture is then stirred at room temperature for 1/2 h, the solid is filtered off with suction and the filter residue is then washed with abs. methanol. The filtrate is concentrated in vacuo on a rotary evaporator and the residue is dried at high vacuum. 25.1 g of 6-methoxy-2-methylpyrimidine-4-carboxylic acid of melting point 184°-188° C. (dec.) are obtained in this way.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[CH2:7][N:8]=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:24][CH2:25][CH:26]=[CH2:27].C1COCC1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>C(OCC)C>[C:16]1([C:9](=[N:8][CH:7]([CH2:27][CH2:26][CH:25]=[CH2:24])[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:22])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: C=CCCBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCCC(N=C(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.9 %

Procedure:
While under an atmosphere of argon, a solution of N-(diphenylmethylene)glycine tert-butyl ester (6.30 g, 21.33 mmol) and 4-bromo-butene (3.45 g, 25.56 mmol) in freshly distilled THF (50 mL) was cooled to −78° C. and treated with sodium bis(trimethylsilyl)amide (23.4 mL, 1.0 M in THF). Once the addition was complete, the reaction was warmed to room temperature and stirred for 16 h, cooled to 0° C., diluted with ethyl ether and washed successively with saturated aqueous NaHCO3 and saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. Rapid purification by MPLC (1-25% ethyl acetate in heptane over 8 CV) gave product tert-butyl 2-(diphenylmethyleneamino)hex-5-enoate as a colorless oil (7.00 g, 94%). Rf 0.50 (30% ethyl acetate in heptane).
Reaction SMILES: [F:1][C:2]1[CH:34]=[C:33]([N+:35]([O-])=O)[CH:32]=[CH:31][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[N:15]([CH3:30])[C:16]([C:19]([NH:21][CH2:22][CH2:23][N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[O:20])=[CH:17][N:18]=3)[S:13][C:6]=12.[Cl-].[NH4+]>CCO.O.[Fe]>[NH2:35][C:33]1[CH:32]=[CH:31][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[C:7]3[CH:11]=[C:12]([C:14]4[N:15]([CH3:30])[C:16]([C:19]([NH:21][CH2:22][CH2:23][N:24]5[CH2:29][CH2:28][O:27][CH2:26][CH2:25]5)=[O:20])=[CH:17][N:18]=4)[S:13][C:6]=23)=[C:2]([F:1])[CH:34]=1
Reactant: Cn1c(C(=O)NCCN2CCOCC2)cnc1-c1cc2nccc(Oc3ccc([N+](=O)[O-])cc3F)c2s1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cn1c(C(=O)NCCN2CCOCC2)cnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Yield: 76.6 %

Procedure:
The reaction mixture of the nitro compound 215 (180 mg, 0.342 mmol), iron powder (162 mmol), and ammonium chloride (15.7 mg, 0.294 mmol) in EtOH/water mixture (10 mL/5 mL) was heated to reflux for 1 hr. The reaction mixture was filtered while hot. The filtrate was concentrated to give title compound 216 (130 mg, 0.262 mmol, 77% yield) as a white solid. MS: 497.5 (MH)+.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[S:15][C:14]([NH:16][C:17]([C@H:19]4[C@@H:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:22][CH2:21][N:20]4C(OC(C)(C)C)=O)=[O:18])=[N:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1[C:10]2[C:5](=[CH:6][C:7]([C:11]3[S:15][C:14]([NH:16][C:17]([C@H:19]4[C@@H:23]([C:24]5[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=5)[CH2:22][CH2:21][NH:20]4)=[O:18])=[N:13][N:12]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@@H]1C(=O)Nc1nnc(-c2ccc3cnccc3c2)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1nnc(-c2ccc3cnccc3c2)s1)[C@@H]1NCC[C@@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 6.8 %

Procedure:
To a stirred mixture of (±)-cis-tert-butyl 2-((5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yl)carbamoyl)-3-phenylpyrrolidine-1-carboxylate (54 mg, 0.11 mmol) in DCM (3.0 mL) was added TFA (3.0 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated. The crude residue was purified by flash column chromatography (eluting with a gradient of DCM to DCM containing 5% of 10% MeOH in ammonia) to provide (±)-cis-N-(5-(isoquinolin-6-yl)-1,3,4-thiadiazol-2-yl)-3-phenylpyrrolidine-2-carboxamide as a white solid (3.0 mg, 7%). LCMS (M+H) 402.2 calc. for C22H20N5OS 402.1. 1H NMR (400 MHz, CDCl3): δ ppm 9.23 (s, 1H) 8.55 (d, J=4.89 Hz, 1H) 8.08-8.29 (m, 2H) 7.97 (d, J=7.63 Hz, 1H) 7.65 (d, J=5.48 Hz, 1H) 7.15-7.24 (m, 5H) 4.42-4.87 (m, 1H) 3.89 (d, J=5.48 Hz, 1H) 3.56-3.72 (m, 1H) 3.35-3.51 (m, 1H) 2.18-2.54 (m, 2H). 2H obscured.