Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.O.[NH2:9][C@@H:10]1[C:28](=[O:29])[N:12]2[C:13]([C:25]([OH:27])=[O:26])=[C:14]([CH2:17][S:18][C:19]3[N:23]([NH2:24])[N:22]=[N:21][N:20]=3)[CH2:15][S:16][C@H:11]12.[C:30]([NH:49][C:50]1[S:51][CH:52]=[C:53](/[C:55](=[N:68]/[O:69][CH3:70])/[C:56](ON2C3C=CC=CC=3N=N2)=[O:57])[N:54]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CC(N(C)C)=O>[C:30]([NH:49][C:50]1[S:51][CH:52]=[C:53](/[C:55](=[N:68]/[O:69][CH3:70])/[C:56]([NH:9][C@@H:10]2[C:28](=[O:29])[N:12]3[C:13]([C:25]([OH:27])=[O:26])=[C:14]([CH2:17][S:18][C:19]4[N:23]([NH2:24])[N:22]=[N:21][N:20]=4)[CH2:15][S:16][C@H:11]23)=[O:57])[N:54]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12
Reactant: CO/N=C(\C(=O)On1nnc2ccccc21)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Solvent: O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nnnn3N)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Yield: 57.6 %

Procedure:
To a solution of triethylamine (7.02 g, 69.4 mmol) and water (2.2 ml) in dimethylacetamide (72 ml) was added 7β-amino-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (11.5 g, 34.7 mmol) at room temperature and the mixture was stirred to dissolve it. The mixture was cooled to -6° to -3° C. and a solution of 1-benzotriazolyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetate (29.2 g, 52.1 mmol) in dimethylacetamide (120 ml) was added dropwise to the mixture and allowed to react at 5° C. for 17 hours. The reaction mixture was poured into ice-water (500 ml). The aqueous layer was washed with ethyl acetate (100 ml)--tetrahydrofuran (50 ml) and adjusted to pH 3 with 20% aqueous sulfuric acid. Precipitated material was extracted with ethyl acetate (200 ml)--tetrahydrofuran (100 ml). The organic layer was filtered to remove insoluble material, washed with water, dried over magnesium sulfate and evaporated under reduced pressure. The residue was treated with ether to give pale yellow substance of 7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-methoxyiminoacetamido]-3-[(1-amino-1H-tetrazol-5-yl)thiomethyl]-3-cephem-4-carboxylic acid (15.1 g, 57.7%), mp~175° C. (decomposition).
Reaction SMILES: O=[C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[N:10][NH:11][C:3]1=2.P(Cl)(Cl)([Cl:21])=O>>[Cl:21][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]2[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)=[N:10][NH:11][C:3]=12
Reactant: Cc1cc(=O)c2[nH]nc(-c3ccc(Cl)cc3)c2[nH]1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)c2[nH]nc(-c3ccc(Cl)cc3)c2n1

Procedure:
A mixture of 4,7-dihydro-7-oxo-5-methyl-3-(4-chlorophenyl)-1H-pyrazolo[4,3-b]pyridine (D15) (0.8 g) in phosphoryl chloride (20 ml) was heated under reflux under nitrogen for 20 mins and then evaporated to dryness in vacuo. The residue was basified with 10% sodium carbonate solution and extracted with ethyl acetate (3×200 ml). The organic fraction was washed with water, dried (Na2SO4), and evaporated to dryness in vacuo, and recrystallised from ethyl acetate to afford the title compound (0.4 g), m.p. 243°-245° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:19])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.C(=O)=O.[F:33][C:34]([F:40])([F:39])[S:35](Cl)(=[O:37])=[O:36]>CN(C)C1C=CN=CC=1.O.C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([O:19][S:35]([C:34]([F:40])([F:39])[F:33])(=[O:37])=[O:36])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc2c(O)ccnc2cc1OCc1ccccc1
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: CN(C)c1ccncc1
Agent: O=C=O
Solvent: O
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COc1cc2c(OS(=O)(=O)C(F)(F)F)ccnc2cc1OCc1ccccc1
Reaction time: 0.42 h
Yield: 83.5 %

Procedure:
To a dry 2 L RBF containing 7-benzyloxy-6-methoxyquinolin-4-ol (75.3 g, 267 mmol) was added DCM (1 L), 4-dimethylaminopyridine (3.28 g, 26.8 mmol) and 2,6-lutidine (62 mL, 534 mmol). The mixture was cooled to −20° C. by controlled addition of dry ice to an acetone bath. Trifluoromethanesulfonyl chloride (37 mL, 350 mmol) was added dropwise to the cooled solution with magnetic stirring over 25 minutes. After addition was complete, the mixture was stirred in bath for 20 minutes, then at room temperature for 3 hours. LCMS indicated reaction completion. The reaction mixture was concentrated in vacuo and placed under high vacuum to remove residual 2,6-lutidine. To the resulting brown solids was added methanol (3.5 L). The resulting slurry was stirred with mechanical stirrer for 30 min before adding water (1.5 L). The solids were isolated by filtration, followed by a water wash. The resulting solid was dried under high vacuum overnight yielding trifluoromethanesulfonic acid 7-benzyloxy-6-methoxy-quinolin-4-yl ester as a light brown solid (92.2 g, 83.8%). 1H NMR (400 MHz, DMSO, d6): δ 8.82 (d, 1H), 7.67 (s, 1H), 7.59 (d, 1H), 7.54-7.52 (m, 2H), 7.46-7.42 (m, 2H), 7.39-7.36 (m, 1H), 7.23 (s, 1H), 5.35 (s, 2H), 3.97 (s, 3H). LC/MS: M+H=414.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([CH2:16]Cl)=[CH:12][CH:11]=3)[C:6]=2[CH:18]=1.[S].[CH2:20]([NH2:23])[CH2:21][NH2:22]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[NH:22][CH2:21][CH2:20][N:23]=4)=[CH:12][CH:11]=3)[C:6]=2[CH:18]=1
Reactant: ClCc1ccc(-c2nsc3ccc(Cl)cc23)cc1
Reactant: NCCN
Agent: [S]
Solvent: Cc1ccccc1
Product: Clc1ccc2snc(-c3ccc(C4=NCCN4)cc3)c2c1

Procedure:
44 g of 5-chloro-3-(4'-chloromethylphenyl)-1,2-benzisothiazole, 9.6 g of sulfur and 18 g of ethylenediamine in 500 ml of toluene are refluxed for 20 hours. The reaction mixture is filtered hot, the filtrate is cooled and the resulting crystals are filtered off. After recrystallization from toluene in the presence of active charcoal, 26 g of 5-chloro-3-[4-(imidazolin-2-yl)-phenyl]-1,2-benzisothiazole, melting at 195° C., are obtained. The yield corresponds to 55% of theory.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([OH:11])=[O:10])[CH2:5][CH2:4]1.Cl[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>[OH-].[Na+]>[C:13]([NH:1][CH2:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([OH:11])=[O:10])[CH2:7][CH2:8]1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NC[C@H]1CC[C@H](C(=O)O)CC1)OCc1ccccc1
Reaction time: 1 h

Procedure:
To a 0° C. solution of trans-4-aminomethyl-1-cyclohexane carboxylic acid (6.28 g, 0.04 mol) in 10% aqueous NaOH (16 mL) was added dropwise benzyl chloroformate (8.29 g, 0.049 mol) and 10% aqueous NaOH (20 mL). The cold bath was removed and the reaction mixture was stirred vigorously for one hour. The thick white paste was shaken with aqueous 1M HCl (100 mL) and the white solid was isolated by filtration, washed with H2O, and dried overnight in vacuo to give trans-4-(N-carbobenzyloxy)aminomethyl-1-cyclohexane carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C@@:11]3([CH2:15][CH2:14][N:13]([C:16]([O:18][C:19](C)(C)C)=[O:17])[CH2:12]3)[CH2:10][NH:9][C:5]2=[CH:6][C:7]=1[Cl:8].ClC([O:26][CH3:27])=O.Cl.[NH2:29][C:30]1[S:31][C:32]([F:35])=[CH:33][N:34]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C@@:11]3([CH2:15][CH2:14][N:13]([C:16]([O:18][CH3:19])=[O:17])[CH2:12]3)[CH2:10][N:9]([C:27](=[O:26])[NH:29][C:30]3[S:31][C:32]([F:35])=[CH:33][N:34]=3)[C:5]2=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)Cl
Reactant: Nc1ncc(F)s1
Reactant: CC(C)(C)OC(=O)N1CC[C@]2(CNc3cc(Cl)c(Cl)cc32)C1
Agent: Cl
Product: COC(=O)N1CC[C@@]2(C1)CN(C(=O)Nc1ncc(F)s1)c1cc(Cl)c(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Examples 1, 2, and 3, with the exceptions that (S)-t-butyl 5,6-dichlorospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was used instead of t-butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate, that methyl chloroformate was used instead of acetyl chloride, and that 2-amino-5-fluorothiazole hydrochloride was used instead of 2-amino-5-chlorothiazole hydrochloride.
Reaction SMILES: S(OC/C=C/C)(=O)(=O)C.[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]#[C:18][CH2:19]/[CH:20]=[CH:21]/[CH3:22]>>[Cl:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]/[CH3:22]
Reactant: C/C=C/CC#CCCCCCCCl
Agent: C/C=C/COS(C)(=O)=O
Product: C/C=C/C/C=C\CCCCCCCl
Reaction time: 1.5 h
Yield: 93 %

Procedure:
The synthetic procedure was about the same as in Example 1 excepting replacement of 271.5 g of (E)-2-butenyl chloride with 450 g (3 moles) of (E)-2-buten-1-ol mesylate which were added dropwise to the reaction mixture kept at 30° C. or below followed by further continued agitation of the reaction mixture at 30° C. for 1.5 hours to effect hydrolysis so that 216 g of 1-chloro-(E)-10-dodecen-7-yne were obtained in a purity of 94%. The yield was 35% of the theoretical value. Partial hydrogenation of this ene-yne compound in the same manner as in Example 1 gave 203 g of 1-chloro-(Z,E)-7,10-dodecadiene in a purity of 88%. The yield was 88% of the theoretical value.
Reaction SMILES: CO.C[O:4][C:5]([C:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[S:9][CH:8]=1)=[O:6].[OH-].[Li+].Cl>O.O1CCCC1>[S:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:7]([C:5]([OH:6])=[O:4])=[CH:8]1
Reactant: COC(=O)c1csc2ccccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1csc2ccccc12
Temperature: 25 °C
Reaction time: 15 h
Yield: 100.2 %

Procedure:
To a methanol (100 mL) solution of 1-benzothiophene-3-carboxylic acid methyl ester (20.6 g, 107 mmol), tetrahydrofuran (200 mL), water (100 mL) and lithium hydroxide (9.00 g, 214 mmol) were added at room temperature, and the mixture was stirred for 15 hours at room temperature. 1N-hydrochloric acid (214 mL, 214 mmol) was added to the reaction liquor, and then methanol was distilled off under reduced pressure. To the obtained aqueous layer, 1N-hydrochloric acid (50 mL, 50 mmol) was added, and the solids generated therefrom were collected by filtration, washed with water, and then dried for two days at 50° C. using a vacuum pump, to obtain the title compound (19.1 g, 100%) as a solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[O:7]1[CH:11]=[N:10][N:9]=[C:8]1[C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][CH2:26][C@@H:27]2[CH:32]=COC(=O)[O:28]2)[CH:20]=1.O>CN(C)C=O>[O:7]1[CH:11]=[N:10][N:9]=[C:8]1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:32][C@H:27]([OH:28])[CH2:26][CH2:25][C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:14][CH:13]=1
Reactant: O=C1OC=C[C@@H](CCc2cccnc2)O1
Reactant: Oc1ccc(-c2nnco2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: O[C@H](CCc1cccnc1)COc1ccc(-c2nnco2)cc1
Temperature: 90 °C
Yield: 18.3 %

Procedure:
Cesium carbonate (0.72 g) and 4-(1,3,4)-oxadiazol-2-yl-phenol (0.54 g) were added to a solution of (4R)-4-[2-(pyridin-3-yl)ethyl]-1,3-dioxin-2-one (1.20 g, Example 14a)) in dry dimethylformamide (75 ml) and heated at 90° C. for 14 hours. After cooling, the reaction mixture was poured into water (50 ml) and extracted three times with ethyl acetate. The combined organic phases were extracted twice with 2M hydrochloric acid. The combined aqueous extracts were basified by dropwise addition of 2M aqueous sodium hydroxide and the aqueous solution was then extracted three times with ethyl acetate. The organic extracts were combined and dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by normal phase HPLC eluting with 0 to 25% ethanol in dichloromethane to give the title compound as a solid (0.19 g).
Reaction SMILES: C[Si](C)(C)[C:3]1[C:4]([NH:9]C#C)=[N:5][CH:6]=[CH:7][CH:8]=1.[F-].[CH2:15]([N+](CCCC)(CCCC)CCCC)[CH2:16]CC.O>O1CCCC1>[C:15]([C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1)#[CH:16]
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: C#CNc1ncccc1[Si](C)(C)C
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1cccnc1N
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 3-trimethylsilanyl ethinyl-pyridin-2-ylamine described in Preparation Example 1-1-4 (28.1 g, 148 mmoL) in tetrahydrofuran (300 mL) was added tetrabutyl ammonium fluoride (1M tetrahydrofuran solution, 20 mL, 20 mmol), which was stirred at room temperature for 15 minutes. To the reaction solution was added water and extracted four times with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the solvent thereof was evaporated under a reduced pressure. The residue was purified by silica gel chromatography (heptane:ethyl acetate=1:1 then 1:2) to obtain the title compound (16.4 g).
Reaction SMILES: [NH2:1][C@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]1[NH:11][C:12]([C:14]1[NH:18][C:17]2[C:19]([Cl:23])=[C:20]([Cl:22])[S:21][C:16]=2[CH:15]=1)=[O:13].CCN(CC)CC.[CH3:31][N:32]1[CH2:37][CH2:36][N:35]([C:38](Cl)=[O:39])[CH2:34][CH2:33]1>C(Cl)Cl>[Cl:22][C:20]1[S:21][C:16]2[CH:15]=[C:14]([C:12]([NH:11][C@H:3]3[CH2:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[C@@H:2]3[NH:1][C:38]([N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[O:39])=[O:13])[NH:18][C:17]=2[C:19]=1[Cl:23]
Reactant: N[C@H]1c2ccccc2C[C@@H]1NC(=O)c1cc2sc(Cl)c(Cl)c2[nH]1
Reactant: CN1CCN(C(=O)Cl)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)N[C@H]2c3ccccc3C[C@@H]2NC(=O)c2cc3sc(Cl)c(Cl)c3[nH]2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 44.7 %

Procedure:
To a solution of N-[(1S,2S)-1-amino-2,3-dihydro-1H-inden-2-yl]-2,3-dichloro-4H-thieno[3,2-b]pyrrole-5-carboxamide (Method 9, 240 mg, 0.5 mmol) and Et3N (101 mg, 1.0 mmol) in DCM (4 mL) was added a solution of 4-methyl-1-piperazine carbonyl chloride (100 mg, 0.5 mmol) in DCM (1 mL). The reaction was stirred at ambient temperature for 2 hours, washed with saturated NaHCO3 (1 mL), water (1 mL), brine (1 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure to give the title compound (110 mg, 45%) as a foam. MS m/z (M−H)− 491.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[C:5]([C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=1)=O.Cl.[C:19]([O:23][NH2:24])([CH3:22])([CH3:21])[CH3:20]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])/[C:5](/[C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:24]\[O:23][C:19]([CH3:22])([CH3:21])[CH3:20].[Br:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])/[C:5](/[C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:24]/[O:23][C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(c1ccc(F)c(Br)c1)c1ncccc1O
Reactant: CC(C)(C)ON
Agent: Cl
Solvent: CC(=O)O
Product: CC(C)(C)O/N=C(/c1ccc(F)c(Br)c1)c1ncccc1O
Product: CC(C)(C)O/N=C(\c1ccc(F)c(Br)c1)c1ncccc1O
Temperature: 90 °C
Reaction time: 14 h

Procedure:
A mixture of 2-(3-bromo-4-fluorobenzoyl)-3-hydroxypyridine (2.96 g), O-t-butyl hydroxylamine hydrochloride (1.88 g) and acetic acid (50 mL) was stirred at 90° C. for 14 hours. The reaction mixture was concentrated in vacuo, which was subjected to addition with ethyl acetate and water. The ethyl acetate solution was washed with aqueous NaHCO3 and a saturated aqueous saline solution, successively, which was dried (magnesium sulfate), followed by distilling off the solvent under reduced pressure. The residue was subjected to purification by means of a silica gel column (ethyl acetate--hexane) to afford (E)-2-(3-bromo-α-t-butoxyimino-4-fluorobenzyl)-3-hydroxypyridine (1.10 g) and (Z)-2-(3-bromo-α-t-butoxyimino-4-fluorobenzyl)-3-hydroxypyridine (1.97 g) (compounds 17 and 16).
Reaction SMILES: [ClH:1].Cl.[N:3]1([C:8]2[C:14]([N:15]3[CH:19]=[CH:18][N:17]=[CH:16]3)=[CH:13][C:11]([NH2:12])=[C:10]([N+:20]([O-])=[O:21])[CH:9]=2)[CH:7]=[CH:6][N:5]=[CH:4]1.[C:23]([OH:26])(=[O:25])[CH3:24].C[OH:28]>[Pd]>[OH2:21].[OH2:25].[ClH:1].[ClH:1].[N:3]1([C:8]2[CH:9]=[C:10]3[C:11](=[CH:13][C:14]=2[N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)[NH:12][C:24](=[O:28])[C:23](=[O:26])[NH:20]3)[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: Nc1cc(-n2ccnc2)c(-n2ccnc2)cc1[N+](=O)[O-]
Reactant: CO
Reactant: CC(=O)O
Agent: [Pd]
Agent: Cl
Product: O
Product: O=c1[nH]c2cc(-n3ccnc3)c(-n3ccnc3)cc2[nH]c1=O

Procedure:
A mixture of 1 g of 4,5-di-(1-imidazolyl)-2-nitroaniline dihydrochloride, 5 ml of acetic acid, 5 ml of methanol and 0.1 g of 10% palladium-on-carbon was subjected to hydrogenation reaction. The reaction mixture was filtered and the filtrate was washed with hydrochloric acid and concentrated under reduced pressure. The concentrate was dissolved in 350 mg oxalic acid-6 ml of 4N-hydrochloric acid and the solution was subjected to dry distillation overnight. The resulting crystals were recovered by filtration and recrystallized from 4N-hydrochloric acid to provide 170 mg of 6,7-di-(1-imidazolyl)quinoxaline-2,3-(1H,4H)-dione dihydrochloride dihydrate.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10](/[C:13](/[C:21](=[O:24])[CH:22]=[CH2:23])=[CH:14]\[CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[S:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH:30]=[O:31].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10](/[C:13](=[CH:14]\[CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)/[C:21](=[O:24])[CH2:22][CH2:23][C:30]([C:26]3[S:25][CH:29]=[CH:28][N:27]=3)=[O:31])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:2][CH2:3]1
Reactant: O=Cc1nccs1
Reactant: C=CC(=O)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(CCC(=O)c1nccs1)/C(=C/C1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Yield: 49 %

Procedure:
To a solution of (1E)-2-[4-(cyclopropylsulfonyl)phenyl]-1-(tetrahydro-2H-pyran-4-yl)penta-1,4-dien-3-one (425 mg) in ethanol (5 mL) were added 1,3-thiazole-2-carbaldehyde (130 μL), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (36.0 mg) and triethylamine (75 μL), and the mixture was stirred with heating under reflux for 4 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (278 mg, yield 49%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio). MS: 460 (MH+).
Reaction SMILES: [CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:26])[CH:24]=[O:25])[CH3:2].[BH4-].[Li+]>CO.CO.O.C1COCC1>[CH2:1]([C:3]1[C:11]([CH3:12])=[C:10]2[C:6](=[C:5]([O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[C:4]=1[CH2:21][CH:22]=[C:23]([CH3:26])[CH2:24][OH:25])[C:7](=[O:13])[O:8][CH2:9]2)[CH3:2]
Reactant: CCc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)C=O)C(=O)OC2
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCc1c(C)c2c(c(OCC[Si](C)(C)C)c1CC=C(C)CO)C(=O)OC2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 73.4 %

Procedure:
4-[6-Ethyl-7-methyl-3-oxo-4-(2-trimethylsilanyl-ethoxy)-1,3-dihydro-isobenzofuran-5-yl]-2-methyl-but-2-enal (77.6 mg, 0.207 mmol) was dissolved in MeOH (4 mL). A solution of CeCl3 (51.1 mg, 0.207 mmol) in MeOH/water (9/1, 0.66 mL) was added and the solution was cooled to 0° C. A solution of lithium borohydride in THF (2M, 0.105 mL) was added dropwise. After 15 minutes, the reaction was quenched with 1N HCl (0.5 mL). The MeOH was removed in vacuo and the crude material was partitioned between DCM and water. The aqueous layer was extracted with DCM and the combined organic layers were washed with sodium bicarbonate solution and dried over sodium sulfate. Filtration and evaporation of solvents yielded a crude oil, which was purified by silica gel chromatography to provide 57.2 mg (73%) of the desired product. 1H NMR (300 MHz, CDCl3): δ=0.04 (s, 9H), 1.15 (t, J=7.8 Hz, 3H), 1.26 (m, 2H), 1.86 (s, 3H), 2.19 (s, 3H), 2.72 (q, J=7.8 Hz, 2H), 3.52 (d, J=6.3 Hz, 2H), 3.99 (s, 2H), 4.34 (m, 2H), 5.14 (s, 2H), 5.32 (m, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][CH3:24])=[CH:19][CH:20]=3)[C:15](=[O:25])[N:14]2[CH3:26])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[O:27]=[C:28]1[NH:33][CH2:32][CH2:31][CH2:30][N:29]1[CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH2:23][CH3:24])=[CH:19][CH:20]=3)[C:15](=[O:25])[N:14]2[CH3:26])[CH2:10][CH2:11][N:37]2[CH2:38][CH2:39][CH:34]([N:29]3[CH2:30][CH2:31][CH2:32][NH:33][C:28]3=[O:27])[CH2:35][CH2:36]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CCOc1ccc2c(c1)C(=O)N(C)C2C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C1NCCCN1C1CCNCC1
Product: CCOc1ccc2c(c1)C(=O)N(C)C2C(CCN1CCC(N2CCCNC2=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 122.9 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(5-ethoxy-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.3 g) was coupled to 4-(2-oxoperhydropyrimidine-1-yl)piperidine (0.135 g) by a method similar to that described in Example 8. The reaction product was not purified by chromatography but converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.28 g); mp 190°-200° C.; MS: m/z=559(M+1); NMR(CDCl3): 1.33 (t,6, J=6.9), 1.71 (m,4), 2.20 (m,2), 2.5 (m,2), 2.74 (broad,1), 3.52 (m,3), 4.04 (m,2), 4.31 (m,1), 4.76 (m,2), 7.05 (m,5), 7.81 (d,1, J=8.41). Analysis for C29H36Cl2N4O3.2.0 HCl.0.5 H2O: Calculated: C, 54.30; H, 6.13, N, 8.73; Found: C, 54.02; H, 6.00; N, 8.47.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:11])([F:10])[F:9])[C:3]=1[NH2:12].C12CC3CC(CC(C3)C1N=[C:24]=[O:25])C2.ClC(OC(=O)OC(Cl)(Cl)Cl)(Cl)Cl.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]([F:9])([F:10])[F:11])[C:3]=1[N:12]=[C:24]=[O:25]
Reactant: O=C=NC1C2CC3CC(C2)CC1C3
Reactant: Cc1cccc(C(F)(F)F)c1N
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C(F)(F)F)c1N=C=O

Procedure:
This compound was made from 2-methyl-6-trifluoromethyl-phenylamine in analogy to Eur. J. Med. Chem. 28 (1), 1993, 37-45 by treatment with bis-(trichloromethyl)-carbonate (627 mg) and triethylamine (1.58 mL) in DCM (16 mL). (2-Methyl-6-trifluoromethylphenyl)isocyanate was obtained as a colorless solid (1.17 g). 1H-NMR (δ, CDCl3): 7.49 (d, J=7.8 Hz, 1H), 7.41 (d, J=7.5 Hz, 1H), 7.20 (t, J=7.8 Hz, 1H), 2.40 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:17][CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)=[CH:4][C:5]([NH:8][C:9]2[CH:14]=[N:13][C:12]([C:15]#[N:16])=[CH:11][N:10]=2)=[N:6][CH:7]=1.CO[CH:34]1[CH:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:37][CH:36](OC)O1>C(O)(=O)C>[C:15]([C:12]1[N:13]=[CH:14][C:9]([NH:8][C:5]2[CH:4]=[C:3]([NH:17][CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]3)[C:2]([N:1]3[CH:36]=[CH:37][C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:34]3)=[CH:7][N:6]=2)=[N:10][CH:11]=1)#[N:16]
Reactant: CCOC(=O)C1CC(OC)OC1OC
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2N)C1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccn(-c2cnc(Nc3cnc(C#N)cn3)cc2NCC2CCCN(C(=O)OC(C)(C)C)C2)c1
Temperature: 80 °C
Reaction time: 6.5 h

Procedure:
tert-Butyl 3-((5-amino-2-(5-cyanopyrazin-2-ylamino)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (163 mg, 0.384 mmol) (Synthesis 101-C) and ethyl 2,5-dimethoxy-tetrahydrofuran-3-carboxylate (196 mg, 0.96 mmol) were dissolved in acetic acid (4 mL) and the solution was stirred at 80° C. for 6.5 h. The reaction mixture was evaporated to dryness and the residue was used directly in the next step.