Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]=[C:6]2[CH:12]=[C:11]([C:13]([OH:15])=O)[S:10][C:7]2=[N:8][CH:9]=1)[CH3:2].S(Cl)([Cl:18])=O>>[CH2:1]([O:3][C:4]1[N:5]=[C:6]2[CH:12]=[C:11]([C:13]([Cl:18])=[O:15])[S:10][C:7]2=[N:8][CH:9]=1)[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOc1cnc2sc(C(=O)O)cc2n1
Product: CCOc1cnc2sc(C(=O)Cl)cc2n1
Yield: 100 %

Procedure:
A solution of 2-ethoxythieno[2,3-b]pyrazine-6-carboxylic acid (30 mg, 0.134 mmol) in thionyl chloride (1 mL) was stirred at 80° C. for 2 h. Evaporated to dryness and co-evaporated with toluene to give 2-ethoxythieno[2,3-b]pyrazine-6-carbonyl chloride (32 mg, 100%).
Reaction SMILES: ClC1C=CC([CH:8]2[NH:12][C:11]([C:13]3[CH:18]=[CH:17]C(OC)=CC=3OCC)=NC2CC)=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[N:37]([C:38]([N:40]3[CH2:45][CH2:44]N(C)[CH2:42][CH2:41]3)=[O:39])[C:36]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=3[O:55][CH2:56][CH3:57])=[N:35][CH:34]2[CH2:58][CH:59]2CCCC2)=[CH:29][CH:28]=1>>[Cl:26][C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[N:37]([C:38]([N:40]3[CH2:45][CH2:44][CH:8]([N:12]4[CH2:11][CH2:13][CH2:18][CH2:17]4)[CH2:42][CH2:41]3)=[O:39])[C:36]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=3[O:55][CH2:56][CH3:57])=[N:35][CH:34]2[CH2:58][CH3:59])=[CH:29][CH:28]=1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC2CCCC2)C(c2ccc(Cl)cc2)N1C(=O)N1CCN(C)CC1
Reactant: CCOc1cc(OC)ccc1C1=NC(CC)C(c2ccc(Cl)cc2)N1
Product: CCOc1cc(OC)ccc1C1=NC(CC)C(c2ccc(Cl)cc2)N1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
[5-(4-Chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-ethyl-4,5-dihydro-imidazol-1-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone was prepared from 5-(4-chloro-phenyl)-2-(2-ethoxy-4-methoxy-phenyl)-4-ethyl-4,5-dihydro-1H-imidazole (Example 20) in an analogous manner as described for the preparation of [5-(4-chloro-phenyl)-4-cyclopentylmethyl-2-(2-ethoxy-4-methoxy-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-methyl-piperazin-1-yl)-methanone (Example 24). HR-MS (ES, m/z) observed 539.2792, calculated for C30H40N4O3Cl [(M+H)+]539.2784.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Cl)=[CH:15][CH:14]=1>>[F:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:1][C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])=[CH:15][CH:14]=1
Reactant: COC(=O)c1cccc(O)c1
Reactant: Fc1ccc(CCl)cc1
Product: COC(=O)c1cccc(OCc2ccc(F)cc2)c1

Procedure:
Reaction of methyl 3-hydroxybenzoate with p-fluorobenzyl chloride as described in the preparation of Intermediate 1A gave the title ester as white prisms: mp 58-59° C. (hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 3.94 (3H, s, OCH3), 5.1 (2H, s, OCH2), 7.09-7.69 (8H, m, aromatics). Anal. Calcd for C15H13FO3: C, 69.22; H, 5.03. Found: C, 69.08; H, 4.97.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH3:14])=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[O:8][C:4]=2[CH:3]=1.[N+:17]([O-])([OH:19])=[O:18]>C(O)(=O)C>[CH2:12]([O:11][C:9]([C:7]1[O:8][C:4]2[C:3]([N+:17]([O-:19])=[O:18])=[C:2]([OH:1])[CH:16]=[CH:15][C:5]=2[C:6]=1[CH3:14])=[O:10])[CH3:13]
Reactant: CCOC(=O)c1oc2cc(O)ccc2c1C
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CCOC(=O)c1oc2c([N+](=O)[O-])c(O)ccc2c1C

Procedure:
A suspension of ethyl 6-hydroxy-3-methyl-benzofuran-2-carboxylate (220 mg, 1 mmole) in acetic acid (10 ml) was treated dropwise and with stirring with 0.2N nitric acid in acetic acid (5 ml). Solution occurred and then a yellow precipitate was formed. The solid was collected and washed with 50% aqueous acetic acid to give 98 mg of ethyl-6-hydroxy-7-nitro-3-methylbenzofuran-2-carboxylate, m.p. 186°-187.5° C.
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[CH2:8]([N:12]=[C:13]=[O:14])[CH2:9][CH2:10][CH3:11]>CO.O1CCCC1>[CH2:8]([NH:12][C:13](=[O:14])[N:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4])[CH2:9][CH2:10][CH3:11]
Reactant: OCCNCCO
Reactant: CCCCN=C=O
Solvent: C1CCOC1
Solvent: CO
Product: CCCCNC(=O)N(CCO)CCO
Reaction time: 1 h

Procedure:
To a solution of 106 g of diethanolamine in 700 mL of methanol was added a solution of 99 g of n-butylisocyanate in 40 mL of tetrahydrofuran over 1 hour, holding the temperature below 30° C. After the addition, the mixture was stirred for 1 hour and then the solvent was removed by vacuum distillation to give a white solid, N′-butyl-N,N-bis(2-hydroxyethyl)urea.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]2)[CH:7]=1.[F:20][C:21]([F:27])([F:26])[CH2:22][C:23](O)=[O:24]>>[F:20][C:21]([F:27])([F:26])[CH2:22][C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([F:19])=[C:6]([C@:8]2([CH3:18])[CH2:14][C:13]([CH3:16])([CH3:15])[O:12][CH2:11][C:10](=[S:17])[NH:9]2)[CH:7]=1)=[O:24]
Reactant: CC1(C)C[C@@](C)(c2cc(N)ccc2F)NC(=S)CO1
Reactant: O=C(O)CC(F)(F)F
Product: CC1(C)C[C@@](C)(c2cc(NC(=O)CC(F)(F)F)ccc2F)NC(=S)CO1
Yield: 54.8 %

Procedure:
The compound was prepared in an analogous manner as described for intermediate B14A from (S)-5-(5-amino-2-fluoro-phenyl)-5,7,7-trimethyl-[1,4]oxazepane-3-thione (intermediate A′7A) (94 mg, 0.33 mmol) and commercially available 3,3,3-trifluoropropionic acid [CAS-no 2516-99-6] (50 mg, 0.39 mmol). The compound was obtained as light yellow foam (71 mg, 46%). MS (ISP): m/z=393.1 [(M+H)+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([S:11][C:12](=[O:16])[N:13]([CH3:15])[CH3:14])=[C:4]([CH2:17]O)[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:38]([O:40][C:41](=[O:57])[CH2:42][C@@H:43]([N:47]1[C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=2[NH:49][C:48]1=[O:56])[CH2:44][CH2:45][CH3:46])[CH3:39].N#N.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:38]([O:40][C:41](=[O:57])[CH2:42][C@@H:43]([N:47]1[C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][C:50]=2[N:49]([CH2:17][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]=2[S:11][C:12](=[O:16])[N:13]([CH3:14])[CH3:15])[C:48]1=[O:56])[CH2:44][CH2:45][CH3:46])[CH3:39]
Reactant: CN(C)C(=O)Sc1c(CO)cc(Br)cc1[N+](=O)[O-]
Reactant: CCC[C@@H](CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: N#N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCC[C@@H](CC(=O)OCC)n1c(=O)n(Cc2cc(Br)cc([N+](=O)[O-])c2SC(=O)N(C)C)c2ccccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.8 %

Procedure:
Dimethyl-thiocarbamic acid S-(4-bromo-2-hydroxymethyl-6-nitro-phenyl) ester (250 mg, 0.74 mmol), triphenylphosphine (215 mg, 0.82 mmol) and (S)-3-(2-Oxo-2,3-dihydro-benzoimidazol-1-yl)-hexanoic acid ethyl ester (303 mg, 0.82 mmol,) are added to a flask with a N2 line. Dry THF (6 mL) is added and the reaction is cooled to 0° C. DIAD (1 ml of THF, 0.82 mmol) is added dropwise over the course of 5 minutes to the reaction and the reaction is warmed slowly to room temperature. The reaction is stirred for 1 hour then evaporated in vacuo and directly purified on silica gel with dichloromethane methanol as the eluent. Reaction is re-purified via-preparative LC/MS to give 166 mg (37%) of the desired compound. LCMS (ESMS): m/z 594.4 (M+H+).
Reaction SMILES: FC1C=CC([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=CC=1.NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.[F:61][C:62]1[CH:63]=[C:64](N=C=O)[CH:65]=[CH:66][CH:67]=1>>[F:61][C:62]1[CH:67]=[C:66]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)[CH:65]=[CH:64][CH:63]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Reactant: O=C=Nc1cccc(F)c1
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4cccc(F)c4)cc3)ccc2C1=O

Procedure:
The compound of example 228 was prepared analogous to compound of example 224 by reaction of compound of example 223 with 3-fluoro phenyl isocyanate. The compound of example 228 was used directly without isolation for the preparation of compound of example 229.
Reaction SMILES: CC(C)=CC[C@H](C(C)=C)CO.C[C@@H](CC)C(O)=O.[CH3:19][C@@H:20]([CH2:34][CH3:35])[C:21]([O:23][CH2:24][C@@H:25]1[CH2:28][C:27](=[C:29]([CH3:31])[CH3:30])[C:26]1([CH3:33])[CH3:32])=[O:22]>CO>[CH3:19][C@@H:20]([CH2:34][CH3:35])[C:21]([O:23][CH2:24][C@@H:25]([C:26]([CH3:33])=[CH2:32])[CH2:28][CH:27]=[C:29]([CH3:30])[CH3:31])=[O:22]
Reactant: CC[C@H](C)C(=O)OC[C@@H]1CC(=C(C)C)C1(C)C
Agent: C=C(C)[C@H](CO)CC=C(C)C
Agent: CC[C@H](C)C(=O)O
Solvent: CO
Product: C=C(C)[C@@H](CC=C(C)C)COC(=O)[C@@H](C)CC
Yield: 75 %

Procedure:
Esterification of (R)-(−)-lavandulol {(86% ee, [α]24D−9.6 (c 0.1, MeOH), prepared according to the method described by Cardillo et al. (Cardillo, G., et al., J. Org. Chem., 53: 2354-2356 (1988))} with (S)-(+)-2-methylbutanoic acid using the same procedures as compound 2a gave 75 mg (75% yield) of 1a as clear oil. Optical purity: 99% ee; [α]24D+5.0 (c 0.1, MeOH); 1H NMR (C6D6): δ 0.83 (3H, t, J=7.29 Hz), 1.08 (3H, d, J=7.0 Hz), 1.35 (1H, m), 1.50 (3H, s), 1.59 (3H, t, J=0.80 Hz), 1.61 (3H, d, J=1.13 Hz), 1.68 (1H, m), 2.06 (2H, m), 2.28 (1H, sextet, 6.85 Hz), 2.42 (1H, quintet, 7.00 Hz), 4.12 (2H, m), 4.79 (1H, m), 4.83 (1H, quintet, J=1.51 Hz), 5.11 (1H, t, quintet, J=7.19, 1.52 Hz); 13C NMR (C6D6): δ 175.88, 146.31, 132.70, 122.00, 112.50, 66.68, 45.41, 41.22, 29.13, 26.00, 25.80, 20.00, 17.80, 16.50, 11.52; EI-MS m/z (%): 238 [M]+ (1), 169 (2), 156 (3), 136 (15), 121 (39), 107 (11), 93 (100), 85 (23), 80 (25), 69 (75), 57 (59), 41 (40); HREIMS: obsd. 238.1934, calcd. for C15H16O2 (M+): 238.1933.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1.[H-].[Na+].I[CH3:25]>C1COCC1>[CH3:25][O:1][CH2:2][CH2:3][CH:4]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:20])[CH3:19])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[CH:6]=1
Reactant: CC(C)(C)OC(=O)NC(CCO)c1cccc([N+](=O)[O-])c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCC(NC(=O)OC(C)(C)C)c1cccc([N+](=O)[O-])c1
Reaction time: 0.33 h
Yield: 71.6 %

Procedure:
To a solution of tert-butyl [3-hydroxy-1-(3-nitrophenyl)propyl]carbamate (2 g; 6.75 mmol; 1.00 eq.) in anhydrous THF (10 mL) was added NaH (567 mg; 14.17 mmol; 2.10 eq.) at 0° C. The mixture was stirred for 20 minutes and iodomethane (1.53 g; 7.42 mmol; 1.10 eq.) was added. The mixture was stirred for 2 hours at 0° C. After work up, the crude product was purified by flash chromatography on silica gel (EtOAc:Hex=1:4) to provide 1.5 g of tert-butyl [3-methoxy-1-(3-nitrophenyl)propyl]carbamate.
Reaction SMILES: [Cl:1][S:2]([N:5]=C=O)(=[O:4])=[O:3].[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:16]([NH2:26])=[N:17][NH:18][C:19]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:11][CH:10]=1.[S:27](Cl)(=[O:30])(=[O:29])[NH2:28].C(N(CC)CC)C.[OH-].[NH4+]>C1C=CC=CC=1.C(#N)C.O>[S:2]([Cl:1])(=[O:4])(=[O:3])[NH2:5].[F:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[C:16]([NH:26][S:27]([NH2:28])(=[O:30])=[O:29])=[N:17][NH:18][C:19]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:13][CH:14]=1
Reactant: Nc1n[nH]c(-c2ccncc2)c1-c1ccc(F)cc1
Reactant: O=C=NS(=O)(=O)Cl
Agent: NS(=O)(=O)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: NS(=O)(=O)Nc1n[nH]c(-c2ccncc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Sulfamyl chloride was synthesized from chlorosulfonyl isocyanate according to the procedure described by R. Graf in Chemische Berichte, p. 509 (1959), which is incorporated herein by reference. A solution of 4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-amine prepared as set forth in Example 2 (200 mg, 0.77 mmol), sulfamyl chloride (100 mg, 0.8 mmol) and triethylamine (200 mg, 2 mmol) in benzene (5 ml) and acetonitrile (5 ml) was stirred at room temperature for 2 hours. The reaction was stripped in vacuo and residue was treated with water and basified to pH 7 with ammonium hydroxide. The resultant precipitate was purified by chromatography on silica gel using mixtures of ethyl acetate and methanol as eluents. The purified [4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-pyrazol-3-yl]sulfamide thus obtained had m.p. 201-202° C.
Reaction SMILES: [F:1][C:2]1([F:13])[CH2:4][CH:3]1[C:5]1[CH:10]=[CH:9][C:8]([O:11]C)=[CH:7][CH:6]=1.B(Br)(Br)Br>>[F:1][C:2]1([F:13])[CH2:4][CH:3]1[C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1
Reactant: COc1ccc(C2CC2(F)F)cc1
Agent: BrB(Br)Br
Product: Oc1ccc(C2CC2(F)F)cc1

Procedure:
p-(2,2-Difluorocyclopropyl)phenol was prepared from 120 g. of p-(2,2-difluorocyclopropyl)anisole and 81 g. of boron tribromide according to the procedure described above in Example 1, part (c), affording 72 g. of oil used directly in the following reaction.
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]=[C:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH-].[Na+]>C(O)(=O)C.[Zn]>[C:13]1(=[CH:12][C:11]2[CH:2]=[N:3][C:4]3[C:9]([CH:10]=2)=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: Clc1nc2ccccc2cc1C=C1CCCC1
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Product: C(=C1CCCC1)c1cnc2ccccc2c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99 %

Procedure:
A solution of 2-chloro-3-cyclopentylidenemethylquinoline (7.6 g, 31.3 mmol) in glacial acetic acid (80 ml) at 60° C. was treated with zinc powder (4.0 g, 62.6 mmol). After stirring at 60° C. for 3 hours, the reaction mixture was cooled and then treated dropwise with 2 M sodium hydroxide solution (330 ml); the temperature being kept below 20° C. throughout. The resulting mixture was then extracted with ethyl acetate (2×250 ml). The combined organic extracts were dried over sodium sulphate then concentrated in vacuo to give a crude red oil (8 g) which was extracted with hot pentane (2×200 ml). Concentration of the combined extracts in vacuo (20° C.; 14 nmmHg) afforded 3-cyclopentylidenemethylquinoline (4 g, 31 mmol) which was used without further purification;
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[N:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[CH:26]=O>>[N:20]1[CH:25]=[CH:24][N:23]=[CH:22][C:21]=1[CH2:26][N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5]1
Reactant: O=Cc1cnccn1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: FC(F)(F)c1nnc2ccc(N3CCN(Cc4cnccn4)CC3)nn12

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with pyrazine-2-carbaldehyde was carried out according to General Synthetic Method 5. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-(pyrazin-2-ylmethyl)piperazin-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]([OH:9])=O)[CH:4]=[N:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.Cl.[NH2:23][CH2:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]2[C:26]=1[C:27](=[O:43])[N:28]([CH:35]1[CH2:40][CH2:39][C:38](=[O:41])[NH:37][C:36]1=[O:42])[C:29]2=[O:34].C(N(CC)CC)C>CN(C=O)C>[O:42]=[C:36]1[CH:35]([N:28]2[C:27](=[O:43])[C:26]3[C:30](=[CH:31][CH:32]=[CH:33][C:25]=3[CH2:24][NH:23][C:7]([C:5]3[CH:4]=[N:3][CH:2]=[N:1][CH:6]=3)=[O:9])[C:29]2=[O:34])[CH2:40][CH2:39][C:38](=[O:41])[NH:37]1
Reactant: O=C(O)c1cncnc1
Reactant: NCc1cccc2c1C(=O)N(C1CCC(=O)NC1=O)C2=O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1CCC(N2C(=O)c3cccc(CNC(=O)c4cncnc4)c3C2=O)C(=O)N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 49.6 %

Procedure:
A mixture of pyrimidine-5-carboxylic acid (0.25 g, 2.0 mmol) and CDI (0.39 g, 2.4 mmol) in DMF (25 mL) was stirred at ambient temperature under nitrogen for 2 hours. 4-Aminomethyl-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione hydrochloride (0.65 g, 2.0 mmol) and triethylamine (0.61 g, 6.0 mmol) were added, and the mixture was allowed to stir for 16 hours. The solvent was evaporated under vacuum, and the residue was chromatographed using a methylene chloride-methanol gradient, eluting with 95:5 methylene chloride-methanol, providing 0.39 g of the product in 50% yield: mp>260° C.; 1H NMR (DMSO-d6) δ 2.05-2.10 (m, 1H), 2.53-2.65 (m, 2H), 2.83-2.91 (m, 1H), 4.98 (d, J=5.7 Hz, 2H), 5.18 (dd, J=12.4 Hz, d=5.4 Hz, 1H), 7.84 (s, 3H), 9.24 (s, 2H), 9.35 (s, 1H), 9.52 (t, J=5.7 Hz, 1H), 11.16 (s, 1H); 13C NMR (DMSO-d6) δ 22.0, 30.9, 38.3, 48.9, 122.1, 127.3, 127.5, 131.6, 133.4, 134.9, 138.4, 156.0, 160.1, 163.5, 167.0, 167.5, 169.8, 172.8; Anal. calcd for C19H15N5O5.0.3H2O: C, 57.23; H, 3.94; N, 17.56. Found: C, 57.27; H, 3.71; N, 17.27.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2C1CCN(C)CC=1>CO.[Pd].CCCCCC>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: CN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Agent: [Pd]
Solvent: CCCCCC
Solvent: CO
Product: Nc1ccc2[nH]ccc2c1
Reaction time: 18 h

Procedure:
To a solution of 11.3 gm (50 mMol) 5-amino-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in 250 mL methanol were added 3.0 gm 5% palladium on carbon. The mixture was hydrogenated at room temperature under an initial hydrogen pressure of 60 p.s.i. for 18 hours. The reaction mixture was filtered and the filtrate concentrated under reduced pressure to give a dark gum which was slurried in hexane to give the title compound as a brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N+:13]([O-])([OH:15])=[O:14].[OH-].[NH4+]>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:11]([N+:13]([O-:15])=[O:14])=[CH:10][C:9]([CH3:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Cc1ccc(C)c2ncccc12
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: Cc1c([N+](=O)[O-])cc(C)c2ncccc12
Temperature: -15 °C
Reaction time: 0.17 h

Procedure:
5,8-dimethylquinoline (1.25 g), in a 250 mL round bottom flask is cooled to O° C. in an ice-NaCl bath under argon. Concentrated sulfuric acid (50 mL) is added slowly via addition funnel so that the internal temperature does not exceed 5° C. The solution is allowed to stir a few minutes then cooled to -15° C. in an ethylene glycol-dry ice bath. Nitric acid (1.7 mL, 69-71%) in sulfuric acid (50 mL) is added dropwise (via syringe) at such a rate that the reaction temperature does not exceed -3° C. After 10 minutes, the reaction is poured into a beaker of ice and basified slowly to pH 10 by the addition of ammonium hydroxide solution (28-30%). The product is extracted with ethyl acetate (3×500 mL). The organic layer is dried over MgSO4, filtered, and rotary evaporated to yield crude product (2.6 g) which is flash chromatographed on silica gel eluting with 15% ethyl acetate/hexane. Compound-containing fractions are combined and rotary evaporated to yield 5,8-dimethyl-6-nitroquinoline.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=[C:15](OC3C=CC=CC=3)[C:14]=2[N:13]=[C:12]1[CH2:29][CH2:30][CH3:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:36].[OH-].[K+]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=[C:15]([NH2:36])[C:14]=2[N:13]=[C:12]1[CH2:29][CH2:30][CH3:31])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCc1nc2c(Oc3ccccc3)nc(C)c(C)c2n1CCOCc1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: CCCc1nc2c(N)nc(C)c(C)c2n1CCOCc1ccccc1
Temperature: 156 °C
Yield: 29.9 %

Procedure:
1-[2-(Benzyloxy)ethyl]-6,7-dimethyl-4-phenoxy-2-propyl-1H-imidazo[4,5-c]pyridine (6.6 g, 15.8 mmol) and ammonium acetate (66 g) were combined in a dried glass pressure flask under nitrogen with stirring. The flask was sealed with a teflon screw cap and heated to 156° C. for 44 hours. The reaction was complete as determined by HPLC and LC/MS, and the resulting solution was cooled and basified to a pH of about 14 with 1 N potassium hydroxide. The basic solution was extracted with dichloromethane (5×), and the organic layers were combined, washed with 1 N potassium hydroxide (3×), water (1×) and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was triturated with ethyl acetate/diethyl ether, and the resulting solids were filtered off and dried. NMR analysis of the solids indicated impurities. The solids were recrystallized from isopropyl alcohol and dried. Impurities were found in the resulting solids (3.2982 g), which were then recrystallized from ethyl acetate/hexane and again dried. The resulting solids (2.4076 g), still with impurities, were dissolved in ethanol, and the resulting solution was treated with 1 M hydrochloric acid in diethyl ether (10 mL). The resulting hydrochloride salt was filtered off, dissolved in water, and the aqueous solution was basified with 1N potassium hydroxide to a pH of about 14. The resulting aqueous mixture was extracted with dichloromethane (5×), and the combined organic layers were washed with water (3×) and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting white solid was dried to provide 1.5999 g of 1-[2-(benzyloxy)ethyl]-6,7-dimethyl-2-propyl-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 99.5–100.0° C.
Reaction SMILES: C([O-])([O-])=O.O.O.[Cu:7].[Cu+2].[C:9]([OH:15])(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11]>O>[C:9]([O-:15])(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].[C:9]([O-:15])(=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11].[Cu+2:7]
Reactant: [Cu]
Reactant: CC(C)(C)C(=O)O
Agent: [Cu+2]
Agent: O=C([O-])[O-]
Solvent: O
Product: CC(C)(C)C(=O)[O-]
Yield: 44.4 %

Procedure:
To a suspension of 13.6 g of CuCO3.Cu(OH)2 in 50 ml of water is added, dropwise at rt, a solution of 18.6 g of pivalic acid in 100 ml of hot water, and the mixture is stirred until the evolution of gas has ceased. The reaction mixture is filtered by suction and the precipitate is washed four times with water. The precipitate is taken up in 300 ml of THF, the insoluble material is filtered off and the filtrate is concentrated under vacuum. 7.2 g of the expected product are obtained after drying under vacuum.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.CN([CH:9]=[C:10]1[C:15](=[O:16])[O:14][C:13]([CH3:18])([CH3:17])[O:12][C:11]1=[O:19])C>O1CCCC1>[CH:1]1([CH:9]=[C:10]2[C:11](=[O:19])[O:12][C:13]([CH3:17])([CH3:18])[O:14][C:15]2=[O:16])[CH2:3][CH2:2]1
Reactant: CN(C)C=C1C(=O)OC(C)(C)OC1=O
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: CC1(C)OC(=O)C(=CC2CC2)C(=O)O1
Reaction time: 1 h
Yield: 51 %

Procedure:
A 0.5 M solution (13 ml, 6.6 mmol) of cyclopropylmagnesiumbromide in tetrahydrofuran was added dropwise to a solution of 5-dimethylaminomethylene-2,2-dimethyl-1,3-dioxane-4,6-dione (1.0 g, 5.0 mmol) in tetrahydrofuran (12 ml) at 23° C. After stirring the mixture for 1 hr, the reaction solution was quenched with saturated aqueous ammonium chloride solution. The organic layer was separated and the water layer was extracted with dichloromethane. The combined organic layers were washed with water and brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (hexane/EtOAc 5:1) followed by crystallization from hexane to give 498 mg of the pure title product as a pale yellow powder. (yield: 51%)