Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][CH:3]([O:25][CH3:26])[C:4]1[NH:5][C:6]([CH:20]([O:23][CH3:24])[O:21][CH3:22])=[C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:8][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[CH3:26][O:25][CH:3]([O:2][CH3:1])[C:4]1[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:8][C:7]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:6]([CH:20]([O:23][CH3:24])[O:21][CH3:22])[N:5]=1
Reactant: CCOC(=O)C1=C(C(OC)OC)NC(C(OC)OC)=C(C(=O)OCC)C1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C(=O)OCC)c(C(OC)OC)nc1C(OC)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.7 %

Procedure:
To a solution of diethyl 2,6-bis[(dimethoxy)methyl]-1 ,4-dihydropyridine-3,5-dicarboxylate (3.40 g, 9.10 mmol) in toluene (200 ml) was added activated manganese dioxide (3.96 g, 45.5 mmol) and the resulting mixture was heated to reflux for 2 hours. At this time another 3.96 g (45.5 mmol) of activated manganese dioxide was added and reflux was continued an additional 2 hours. The reaction was allowed to cool to room temperature, filtered through celite, and concentrated to afford 3.10 g (92% yield) of diethyl 2,6-bis[(dimethoxy)methyl]-3,5-pyridine dicarboxylate as a colorless oil: 1H NMR (300 MHz, CDCl3) δ 8.29 (s, 1 H), 5.93 (s, 2H), 4.40 (q, J=7.2 Hz, 4 H), 3.48 (s, 12 H), 1.41 (t, J=7.2 Hz, 6 H). 13C NMR (75 MHz, CDCl3) dc 165.68 (s), 156.25 (s), 138.52 (d), 126.59 (d), 101.26 (d), 61.50 (t), 54.08 (q), 13.75 (q). MS (LR-CI) m/z 372 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[CH2:5][NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH2:18])=[S:17])=[CH:11][CH:10]=1.[CH3:22][S:23]([OH:26])(=[O:25])=[O:24].[CH3:27][S:28]([O:31][CH2:32][CH3:33])(=[O:30])=[O:29]>C(O)C>[CH3:22][S:23]([OH:26])(=[O:25])=[O:24].[CH3:27][S:28]([OH:31])(=[O:30])=[O:29].[CH2:32]([S:17][C:16](=[NH:18])[NH:15][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][CH2:7][NH:6][CH2:5][C:4]2[CH:19]=[CH:20][CH:21]=[C:2]([Cl:1])[CH:3]=2)=[CH:14][CH:13]=1)[CH3:33]
Reactant: CCOS(C)(=O)=O
Reactant: NC(=S)Nc1ccc(CCNCc2cccc(Cl)c2)cc1
Agent: CS(=O)(=O)O
Solvent: CCO
Product: CCSC(=N)Nc1ccc(CCNCc2cccc(Cl)c2)cc1
Reaction time: 2 h
Yield: 88.5 %

Procedure:
To a stirred mixture of the product of step (e) (272.5 mg, 0.852 mmol) and ethanol (2.6 ml) was added methanesulfonic acid (81.88 mg, 0.852 mmol). After stirring for a few minutes, ethyl methanesulfonate (211.6 mg, 1.70 mmol) was added. The reaction mixture was refluxed, with stirring, for 3 hours. Additional ethyl methanesulfonate (117 mg) was added and refluxing continued for 2 hours to complete the reaction. On cooling, the product crystallized to a thick mass. Ether was added and the product was isolated by filtration and then recrystallized from ethanol-ether to yield 407.3 mg of N-(4-(2-(3-chlorobenzylamino)ethyl)phenyl)carbamimidothioic acid ethyl ester dimethanesulfonate, m.p. 173°-5° C.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH3:8])[CH2:5][N:4]([CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([S:24]C#N)[CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:13])[CH2:3]1.SCC(C(CS)O)O>P([O-])(O)(O)=O.[K+]>[CH3:8][C@H:6]1[O:7][C@@H:2]([CH3:1])[CH2:3][N:4]([CH2:9][CH2:10][NH:11][C:12]([NH:14][C:15]2[S:16][C:17]3[CH:23]=[C:22]([SH:24])[CH:21]=[CH:20][C:18]=3[N:19]=2)=[O:13])[CH2:5]1
Reactant: C[C@@H]1CN(CCNC(=O)Nc2nc3ccc(SC#N)cc3s2)C[C@H](C)O1
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Agent: [K+]
Product: C[C@@H]1CN(CCNC(=O)Nc2nc3ccc(S)cc3s2)C[C@H](C)O1
Yield: 99.6 %

Procedure:
The 1-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl}-3-(6-sulphanyl-1,3-benzothiazol-2-yl)urea was prepared according to the method described in Example 1b, but using 640 mg of 2-[({2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl}carbamoyl)amino]-1,3-benzothiazol-6-yl thiocyanate, 7 mg of potassium dihydrogen phosphate and 729 mg of DL-dithiothreitol. 597 mg of 1-{2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl}-3-(6-sulphanyl-1,3-benzothiazol-2-yl)urea are thus obtained in the form of a white solid, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH2:27][CH2:26][CH2:25][S:24]3(=[O:29])=[O:28])=[CH:19][C:18]=2[OH:30])=[O:16])[CH2:11][CH2:10]1.[C:31]([O:35][C:36](=[O:42])[NH:37][CH2:38][CH2:39][CH2:40]Br)([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Cs+].[Cs+].CC(=O)CC>O>[C:31]([O:35][C:36](=[O:42])[NH:37][CH2:38][CH2:39][CH2:40][O:30][C:18]1[CH:19]=[C:20]([N:23]2[CH2:27][CH2:26][CH2:25][S:24]2(=[O:29])=[O:28])[CH:21]=[CH:22][C:17]=1[C:15]([N:12]1[CH2:11][CH2:10][N:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[CH2:14][CH2:13]1)=[O:16])([CH3:34])([CH3:33])[CH3:32]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3O)CC2)c(C)c1
Reactant: CC(C)(C)OC(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCC(C)=O
Solvent: O
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3OCCCNC(=O)OC(C)(C)C)CC2)c(C)c1
Yield: 67.1 %

Procedure:
To a mixture of [4-(2,4-dimethylphenyl)piperazin-1-yl][4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-hydroxyphenyl]methanone (241 mg) described in Example 124, (3-bromopropyl)carbamic acid tert-butyl ester (200 mg) and cesium carbonate (548 mg) was added 2-butanone (4 mL), and the mixture was stirred with heating under reflux for 4 hr. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the solvent was evaporated. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give (3-{2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenoxy}propyl)carbamic acid tert-butyl ester (221 mg). The obtained (3-{2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenoxy}propyl)carbamic acid tert-butyl ester (221 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.46 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, the mixture was neutralized with sodium hydrogen carbonate and extracted with chloroform, and the solvent was evaporated. The obtained residue was purified by NH-coated silica gel column chromatography (ethyl acetate:methanol) to give the title compound (74 mg).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:38])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:19]=1)(C)(C)C.Cl>O1CCOCC1>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=[O:38])/[CH:16]=[CH:17]/[C:18]1[CH:22]=[CH:21][N:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=3)=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3cccnc3)cc2)c1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccccc1NC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3cccnc3)cc2)c1

Procedure:
The compound is prepared by treatment of (2-{(E)-3-[1-(4-pyridin-3-yl-benzenesulfonyl)-1H-pyrrol-3-yl]-allanoylamino}-phenyl)-carbamic acid tert-butyl ester (compound A20) in dioxane with HCl. After the reaction is finished, the product precipitates from the reaction mixture.
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[CH2:12][CH2:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:16])=[O:15]>>[C:17]1([S:14]([CH2:13][CH2:12][CH2:1][C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(CCCl)c1ccccc1
Reactant: Cc1ncccc1C(=O)O
Product: O=C(O)c1cccnc1CCCS(=O)(=O)c1ccccc1
Yield: 16 %

Procedure:
Starting from 2.1 g (15.0 mmol) of 2-methyl-nicotinic acid and 4.6 g (22.5 mmol) of (2-chloroethyl)-phenylsulfone, 0.7 g (2.4 mmol, 16%) of 2-(3-(phenylsulfonyl)propyl)-nicotinic acid was obtained according to the process described in precursor VB006.
Reaction SMILES: [C@H:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:9][NH:10][C:11]([C:13]1[N:20]2[C:16]([S:17][CH:18]=[CH:19]2)=[N:15][C:14]=1[CH3:21])=[O:12].[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]([C:28](O)=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=1>>[C:22]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:23]([C:28]([N:3]2[CH2:4][C@H:5]3[C@H:1]([CH2:8][CH2:7][CH2:6]3)[C@H:2]2[CH2:9][NH:10][C:11]([C:13]2[N:20]3[C:16]([S:17][CH:18]=[CH:19]3)=[N:15][C:14]=2[CH3:21])=[O:12])=[O:29])=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)c1ccccc1-c1ccccc1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2CCC[C@@H]21
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2CCC[C@H]2CN1C(=O)c1ccccc1-c1ccccc1

Procedure:
prepared by reaction of 6-methyl-imidazo[2,1-b]thiazole-5-carboxylic acid-[(1S,2S,5R)-3-aza-bicyclo[3.3.0]oct-2-ylmethyl]-amide with commercially available biphenyl-2-carboxylic acid.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.CC(C)(C)C(=O)CN1C2C=CC=CC=2C(C2C=CC=CN=2)=NN(CC(O)=O)C1=O.[C:69]([O:73][C:74](=[O:84])[N:75](C1C=CC=C(N)C=1)[CH3:76])([CH3:72])([CH3:71])[CH3:70].C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[C:69]([O:73][C:74](=[O:84])[N:75]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:76])([CH3:72])([CH3:71])[CH3:70]
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(c2ccccn2)c2ccccc21
Agent: COC(=O)c1cccc(N)c1
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1, step e) except that [1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-5-pyridin-2-yl-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 5, step a) and (3-amino-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step c) were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. 1H NMR (CDCl3) 8.62 (1H, d), 8.10 (1H, d), 8.00 (1H, br s), 7.79 (1H, dt), 7.55 (1H, m), 7.29 (3H, m), 7.13 (1H, d), 7.01 (1H, t), 6.92 (1H, t), 6.48 (1H, dd), 6.30 (1H, dd), 4.68 (2H, br d), 4.45 (2H, br d), 2.80 (1H, br s), 2.78 (3H, s), 1.27 (9H, s). Found: C, 67.18; H, 6.28; N, 16.63%; C28H30N6O3 requires: C, 67.45; H, 6.06; N, 16.86%.
Reaction SMILES: [Si]([O:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:11]/[C:10]/1=[CH:34]\[C:35]1[O:39][CH:38]=[N:37][CH:36]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[O:39]1[C:35](/[CH:34]=[C:10]2\[CH2:11][N:12]([C:15]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:13][CH2:14][CH:9]\2[OH:8])=[CH:36][N:37]=[CH:38]1
Reactant: CC(C)(C)[Si](C)(C)OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1cnco1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1CCN(C(c2ccccc2)(c2ccccc2)c2ccccc2)C/C1=C\c1cnco1
Temperature: 25 °C
Reaction time: 22 h
Yield: 64.7 %

Procedure:
To a solution of (E)-4-(t-butyldimethylsilyloxy)-3-[(1,3-oxazol-5-yl)methylidene]-1-(triphenylmethyl)piperidine (499 mg) in tetrahydrofuran (8 ml) was added tetrabutylammonium fluoride (483 mg) under ice-cooling, and the resulting mixture was stirred at room temperature for 22 hours. The reaction mixture was diluted with ethyl acetate and washed with water and saturated aqueous sodium chloride solution, and the organic layer was dried over anhydrous sodium sulfate. The solvent was removed in vacuo, and the residue was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (3:7) as the eluent to afford the title compound (254 mg, yield: 65%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([CH:14]=[O:15])[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-:24])=[O:23])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.O.[Mn]([O-])(=O)(=O)=[O:27].[K+]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([C:14]([OH:27])=[O:15])[C:11]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N+:22]([O-:24])=[O:23])=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: COc1cccc(-n2cc(C=O)c(-c3ccccc3[N+](=O)[O-])n2)c1
Agent: [K+]
Solvent: c1ccncc1
Solvent: O
Product: COc1cccc(-n2cc(C(=O)O)c(-c3ccccc3[N+](=O)[O-])n2)c1
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a mixture of 1-(3-methoxyphenyl)-3-(2-nitrophenyl)-1H-pyrazole-4-carbaldehyde (1.00 g), water (2 ml) and pyridine (2 ml) was added portionwise potassium permanganate (538 mg). After stirring for 1 hour, the precipitated manganese oxide was filtered off through Celite, the Celite layer was washed with 1N aqueous sodium hydroxide solution. The filtrate and washings were combined, washed with ethyl acetate. The aqueous layer was acidified with 6N hydrochloric acid, extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was solidified by adding hexane. The solid was collected by filtration and washed with hexane to obtain the target compound (676 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:8])[N:5]=[N:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[Cl:8][C:4]1[N:5]=[N:6][CH:7]=[C:2]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:3]=1
Reactant: C1COCCN1
Reactant: Clc1cc(Br)cnn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Clc1cc(N2CCOCC2)cnn1
Temperature: 110 °C

Procedure:
A mixture of 5-bromo-3-chloropyridazine (1.0 equiv.), morpholine (1 equiv.) and potassium carbonate (6 equiv.) in NMP (0.2 M) were heated to 110° C. for 4 hours in an oil bath. The reaction mixture was partitioned between EtOAc and water. The organic phase was dried over sodium sulfate, concentrated and purified by normal phase chromatography. The combined fractions were concentrated and dried under vacuo to give crude 4-(6-chloropyridazin-4-yl)morpholine and was used in the next step without further purification. LCMS (m/z) (M+H)=200.0, Rt=0.34 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([C:28]([F:31])([F:30])[F:29])[CH2:24][CH2:23]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[F:20][C:17]([F:18])([F:19])[C:14]1[CH:15]=[CH:16][C:11]([C:9]2[S:10][C:6]([CH2:4][OH:3])=[C:7]([CH2:21][N:22]3[CH2:27][CH2:26][CH:25]([C:28]([F:30])([F:29])[F:31])[CH2:24][CH2:23]3)[N:8]=2)=[CH:12][CH:13]=1
Reactant: CCOC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1sc(-c2ccc(C(F)(F)F)cc2)nc1CN1CCC(C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 81.4 %

Procedure:
To a solution of 220 g of 2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazole-5-carboxylic acid ethyl ester in 2.2 L of tetrahydrofuran at 0° C. was dropwise added 250 mL of a 2M solution of lithium aluminum hydride in tetrahydrofuran. The resulting mixture was stirred for 1 h allowing it to warm up to room temperature then slowly poured into 1 L of cold water and extracted twice with 1.5 L of ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was washed with 500 mL of hot diisopropyl ether then purified by column chromatography on silica gel (gradient of dichloromethane/ethanol from 100/0 to 90/10) to give 163 g of [2-(4-trifluoromethyl-phenyl)-4-(4-trifluoromethyl-piperidin-1-ylmethyl)-thiazol-5-yl]-methanol as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.[CH3:9][NH:10][C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1>>[CH3:9][N:10]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=1)[C:2]1[CH:7]=[C:6]([N:10]([CH3:9])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[N:5]=[CH:4][N:3]=1
Reactant: CNc1cccc(O)c1
Reactant: Clc1cc(Cl)ncn1
Product: CN(c1cccc(O)c1)c1cc(N(C)c2cccc(O)c2)ncn1
Yield: 43 %

Procedure:
This compound was obtained (yield 43%) based on the method described in Production Example 2B using 4,6-dichloropyrimidine instead of the 4,6-dichloro-2-ethylpyrimidine, and using 3-methylaminophenol instead of the 3-aminophenol.
Reaction SMILES: Cl.[NH2:2]C(OCC)=CC(OCC)=O.COC1C=CC(CN)=CC=1.[OH-].[K+].CC(=O)CC(=O)C.[CH3:32][O:33][C:34]1[CH:54]=[CH:53][C:37]([CH2:38][NH:39][C:40]2[N:50]=[C:49]([CH3:51])[CH:48]=[C:47]([CH3:52])[C:41]=2[C:42](OCC)=[O:43])=[CH:36][CH:35]=1>C(O)C>[CH3:32][O:33][C:34]1[CH:54]=[CH:53][C:37]([CH2:38][NH:39][C:40]2[N:50]=[C:49]([CH3:51])[CH:48]=[C:47]([CH3:52])[C:41]=2[C:42]([NH2:2])=[O:43])=[CH:36][CH:35]=1
Reactant: CCOC(=O)c1c(C)cc(C)nc1NCc1ccc(OC)cc1
Reactant: CCOC(=O)C=C(N)OCC
Agent: COc1ccc(CN)cc1
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CC(=O)CC(C)=O
Product: COc1ccc(CNc2nc(C)cc(C)c2C(N)=O)cc1
Temperature: 22 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
In a three-necked flask containing ethanol (6.12mL) is added ethyl 3-amino-3-ethoxyacrylate hydrochloride(3g, 15.3mmol). The solution is treated with 4-methoxybenzylamine(2mL, 15.3mmol) and the mixture is stirred at 22° C. for 1.5 h. The reaction mixture was heated to 80° C. for 3 h. The reaction is cooled to 22° C. and an ethanolic solution of potassium hydroxide (0.86 g, 15.3 mmol, 25.0 mL of ethanol) is added. Neat 2,4-pentanedione (1.57 mL, 15.3 mmol) is added to the solution dropwise over 15 minutes at room temperature. The reaction mixture is aged at room temperature for 24 hours. During the age the nicotinate precipitates out of the reaction as does KCl. The reaction mixture is concentrated in vacuo. The crude mixture is chromatographed on silica gel to afford a 70% yield of the product, ethyl 2-(4-methoxybenzylamino )-4,6-dimethylnicotinate, 27.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8](N)[C:9]=1[C:10](O)=O)([O-:3])=[O:2].[CH3:14][C:15]([CH3:21])=[C:16]1C=[CH:19][CH:18]=[CH:17]1.C(ON=O)(C)(C)C>C(COC)OC>[C:15](=[C:16]1[CH:10]2[C:9]3[C:8]([CH:17]1[CH:18]=[CH:19]2)=[CH:7][CH:6]=[CH:5][C:4]=3[N+:1]([O-:3])=[O:2])([CH3:21])[CH3:14]
Reactant: Nc1cccc([N+](=O)[O-])c1C(=O)O
Reactant: CC(C)=C1C=CC=C1
Agent: CC(C)(C)ON=O
Solvent: COCCOC
Product: CC(C)=C1C2C=CC1c1c2cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 26.5 %

Procedure:
A solution containing 6-nitroanthranilic acid (3) (19.65 g, 0.108 mol) and commercially available 6,6-dimethylfulvene (4) (17.2 g, 0.162 mol) in dimethoxyethane (DME, 125 mL) was added dropwise over 50 min to a stirred, 70° C. solution of tert-butylnitrite (90%, 17.3 g, 0.151 mol) in DME (350 mL). The mixture was stirred for 1 h and was cooled to room temperature. The reaction mixture was evaporated to yield a crude thick black oil which was directly subjected to silica gel chromatography eluting with ethyl acetate in petroleum ether (0-5% gradient) to afford 10 g of the crude product as a yellow oil, which partially crystallized on standing. Recrystallization from heptane gave the title compound (6.5 g, 26.5%) as a pale yellow solid: 1H NMR (300 MHz, DMSO) δ 7.70 (d, 1H), 7.42 (d, 1H), 7.09-7.01 (m, 1H), 7.00-6.92 (m, 2H), 5.33 (bs, 1H), 4.45 (bs, 1H), 1.55 (s, 6H); EIMS m/z 227.
Reaction SMILES: [I:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[C:3]=1[C@@H:21]([CH2:23][C:24]([O:26]C)=[O:25])[CH3:22].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:17]([O:16][C:14]([N:11]1[CH2:10][CH2:9][N:8]([C:4]2[C:3]([C@H:21]([CH3:22])[CH2:23][C:24]([OH:26])=[O:25])=[C:2]([I:1])[N:7]=[CH:6][N:5]=2)[CH2:13][CH2:12]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)C[C@@H](C)c1c(I)ncnc1N1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](CC(=O)O)c1c(I)ncnc1N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 92.1 %

Procedure:
Into a solution of (R)-tert-butyl 4-(6-iodo-5-(4-methoxy-4-oxobutan-2-yl)pyrimidin-4-yl)piperazine-1-carboxylate (219 g, 0.447 mol) in tetrahydrofuran (657 mL) was added a solution of lithium hydroxide monohydrate (56.2 g, 1.34 mol) in 329 mL of water at 25° C. The mixture was stirred at 25° C. for 5 h. The bottom aqueous layer was discarded. The mixture was acidified with 1 N hydrochloric acid at 5° C. to give a final pH value of between about 1 to 2. The layers were separated. The top layer was then extracted with isopropyl acetate (440 mL×3), combined with the bottom layer, and washed with water (220 mL×2). The solvents was distilled off at reduced pressure below 50° C. The residual isopropyl acetate was azeotroped off with heptane under reduced pressure below 50° C. Product gradually precipitated out and was filtered to give an off-white to light yellow powder (196 g, 84% yield). 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 3.80-3.68 (m, 1H), 3.59-3.56 (m, 4H), 3.23-3.14 (m, 5H), 2.86 (dd, J=16.5, 5.4 Hz, 1H), 1.50 (d, J=7.2 Hz, 3H), 1.48 (s, 9H). HRMS calcd. For C17H26IN4O4 [M+H]+: 477.0993. found 477.0995.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:7]([O:9][C:10](=[O:11])[C:5]=12)=O)([O-:3])=[O:2].[NH2:15][C@H:16]([C:22]([OH:24])=[O:23])[CH2:17][CH2:18][C:19]([OH:21])=[O:20]>CN(C=O)C>[N+:1]([C:4]1[CH:14]=[CH:13][CH:12]=[C:6]2[C:5]=1[C:10](=[O:11])[N:15]([CH:16]([C:22]([OH:24])=[O:23])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])[C:7]2=[O:9])([O-:3])=[O:2]
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Solvent: CN(C)C=O
Product: O=C(O)CCC(C(=O)O)N1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Temperature: 85 °C
Yield: 60.3 %

Procedure:
A mixture of 3-nitrophthalic anhydride (1.5 g, 7.77 mmol) and L-glutamic acid (1.2 g, 7.77 mmol) in DMF (15 mL) is heated at 85° C. for 6 hours. The mixture is concentrated in vacuo and the residue is purified by chromatography (silica gel, CH2Cl2:CH3OH 95:5) to give 1-(4-nitro-1,3-dioxoisoindolin-2-yl)propane-1,3-dicarboxylic acid (1.51 g, 60%); 1H NMR (DMSO-d6) δ8.32 (d, J=7.9 Hz, 1H), 8.21 (d, J=7.3 Hz, 1H), 8.10 (t, J=7.8 Hz, 1H), 4.88-4.82 (dd, J=3.0 and 10.0 Hz, 1H), 2.35-2.20 (m, 4H).