Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].C1C=CC=CC=1>O1CCCC1>[CH2:1]([NH:8][C:12](=[O:13])[C:11]1[CH:15]=[CH:16][CH:17]=[CH:18][C:10]=1[I:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: O=C(Cl)c1ccccc1I
Solvent: C1CCOC1
Solvent: c1ccccc1
Product: O=C(NCc1ccccc1)c1ccccc1I

Procedure:
A solution of 15 ml of benzylamine in 20 ml of tetrahydrofuran was reacted with a solution of 8.0 g of o-iodobenzoyl chloride in 20 ml of tetrahydrofuran in accordance with the procedure of Example 3. There was obtained by recrystallization from benzene 9.1 g of N-benzyl-o-iodobenzamide, m.p. 122°-123°, Rf 0.78.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[Cl:35][C:36]1[CH:37]=[C:38](B(O)O)[CH:39]=[C:40]([F:42])[CH:41]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:38]5[CH:39]=[C:40]([F:42])[CH:41]=[C:36]([Cl:35])[CH:37]=5)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: OB(O)c1cc(F)cc(Cl)c1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cc(F)cc(Cl)c5)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-chloro-5-fluorophenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([NH:8][C:9]([NH:11][CH2:12][C:13](=O)C2C=CC=CC=2)=[O:10])[CH:7]=1.S(=O)(=O)(O)O.[K+].[Br-]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH3:22])=[C:6]([N:8]2[CH:13]=[CH:12][NH:11][C:9]2=[O:10])[CH:7]=1
Reactant: COc1ccc(Cl)cc1NC(=O)NCC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Br-]
Agent: [K+]
Product: COc1ccc(Cl)cc1-n1cc[nH]c1=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
N-(5-Chloro-2-methoxyphenyl)-N'-(2-oxo-2-phenylethyl) urea (4 g, 12.7 mmol) was added to cold (0° C.) concentrated sulfuric acid and stirred for 3 h. The reaction mixture was poured into ice water (2 vol), and extracted with ethyl acetate, washed with saturated NaHCO3 solution and brine before drying over MgSO4. Recrystallization from diethylether/acetonitrile gave 1.35 g (36%).mp 133°-134° C.; IR(KBr, ν=cm-1) 2962, 1628, 1576, 1236, 1144, 1130; 1H NMR (300 MHz, CDCl3) δ3.90 (3H, s), 6.77 (1H, d, J=8.6 Hz), 6.91 (1H, dd, J=8.6 Hz, 2.5 Hz), 7.16 (1H, s), 7.22-7.27 (1H, m), 7.35-7.40 (2H, m), 7.51-7.55 (3H, m), 8.29 (1H, d, J=2.5 Hz); MS(DCl)m/z: 301(MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH2:9])=[CH:4][CH:3]=1.[F:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([N+:26]([O-:28])=[O:27])=[C:19](F)[CH:18]=1.C(N(CC)CC)C>CO>[Cl:1][C:2]1[CH:15]=[CH:14][C:5]([NH:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[NH:9][C:19]2[C:20]([N+:26]([O-:28])=[O:27])=[CH:21][C:22]([N+:23]([O-:25])=[O:24])=[C:17]([F:16])[CH:18]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccccc1Nc1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)cc1F
Solvent: CO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2ccccc2Nc2ccc(Cl)cc2)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The solid from step B was added to a solution of 1,3-difluoro-4,6-dinitrobenzene (46 g) in methanol (200 mL), then triethylamine (31.4 mL) was added, and stirred at rt for 4 h. The reaction mixture was filtered, and the cake was washed with methanol to give 80.6 g of red solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH:5]=1.[H-].[Na+].[CH3:22]I>CN(C)C=O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][N:11]([C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[CH3:22])[CH:5]=1
Reactant: COC(=O)c1cccc(CNC(=O)OC(C)(C)C)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(CN(C)C(=O)OC(C)(C)C)c1
Reaction time: 1 h
Yield: 57.4 %

Procedure:
Dissolve 3-(tert-butoxycarbonylamino-methyl)-benzoic acid methyl ester (2.80 g, 10.6 mmol) in dimethylformamide (60 mL). Add 60% sodium hydride dispersion in oil (0.52 g, 13 mmol). Stir for 1 hr. Add methyl iodide (0.81 mL, 13 mmol) and stir for additional 1 hr. Quench the reaction with water and concentrate. Partition the residue between ethyl acetate and water. Separate the organic layer and dry over sodium sulfate. Filter and concentrate. Purify the residue by chromatography (silica gel) eluting with 15-25% ethyl acetate/hexane to provide the title compound (1.70 g, 57%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[C:18]3[CH:17]=[N:16][CH:15]=[N:14][C:13]=3[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=2)=[O:9])[CH:5]=[N:6][CH:7]=1.[C:22]([C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](O)=[O:38])=[CH:32][CH:31]=1)(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:22]([C:30]1[CH:31]=[CH:32][C:33]([CH2:36][C:37]([NH:1][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([C:8]([C:10]3[C:18]4[CH:17]=[N:16][CH:15]=[N:14][C:13]=4[N:12]([CH:19]([CH3:21])[CH3:20])[CH:11]=3)=[O:9])[CH:3]=2)=[O:38])=[CH:34][CH:35]=1)(=[O:29])[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Reactant: O=C(O)Cc1ccc(C(=O)c2ccccc2)cc1
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)Cc3ccc(C(=O)c4ccccc4)cc3)c2)c2cncnc21

Procedure:
The title compound was prepared according to the method described for Example 34 starting from (5-aminopyridin-3-yl)(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 95) and 2-(4-benzoylphenyl)acetic acid (JOC, 1961, 1635) to afford the title compound in 94% yield, 34 mg. LCMS (system 3): Rt=3.12 min; m/z 504 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[C:12](O)(=[O:14])[CH3:13]>S(=O)(=O)(O)O.O>[C:12]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1)(=[O:14])[CH3:13]
Reactant: O=C(O)c1ccc(O)cc1F
Reactant: CC(=O)O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(=O)Oc1ccc(C(=O)O)c(F)c1
Temperature: 80 °C

Procedure:
4.3 Grams of 4-hydroxy-2-fluorobenzoic acid and 8.4 g of anhydrous acetic acid were placed in a two-necked flask and mixed, and five drops of sulfuric acid was added with cooling with water. After heat generation terminated, the mixture was heated at 80° C. for 30 minutes. Then, the reaction mixture was discharged into cold water, and a precipitated crystal was recovered by filtration.
Reaction SMILES: Cl.[CH2:2]([C@H:5]1[CH2:9][NH:8][CH2:7][C@@:6]1([N:22]=[N+:23]=[N-:24])[C:10]([O:12][CH2:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH:3]=[CH2:4].[C:25]([O:29][C:30]([N:32]1[CH:41]([C:42](O)=[O:43])[CH2:40][C:39]2[C:34](=[CH:35][C:36]([Cl:45])=[CH:37][CH:38]=2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CCN(CC)CC.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>C(Cl)Cl>[CH2:2]([C@H:5]1[CH2:9][N:8]([C:42]([CH:41]2[CH2:40][C:39]3[C:34](=[CH:35][C:36]([Cl:45])=[CH:37][CH:38]=3)[CH2:33][N:32]2[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])=[O:43])[CH2:7][C@@:6]1([N:22]=[N+:23]=[N-:24])[C:10]([O:12][CH2:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH:3]=[CH2:4]
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2CC1C(=O)O
Reactant: C=CC[C@H]1CNC[C@@]1(N=[N+]=[N-])C(=O)OCC(=O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@H]1CN(C(=O)C2Cc3ccc(Cl)cc3CN2C(=O)OC(C)(C)C)C[C@@]1(N=[N+]=[N-])C(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
A stirred mixture of racemic 2-oxo-2-phenylethyl (3R,4S)-4-allyl-3-azidopyrrolidine-3-carboxylate hydrochloride (228 mg, 0.650 mmol) and 2-(tert-butoxycarbonyl)-7-chloro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (258 mg, 0.826 mmol) in methylene chloride (6 mL) was treated with Et3N (0.272 mL, 1.95 mmol) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 321 mg, 0.845 mmol), and the resulting nearly homogeneous mixture was stirred at room temperature. After 1 h, the reaction was diluted with methylene chloride (20 mL), washed successively with water (20 mL), 1 N aqueous HCl (20 mL), saturated aqueous NaHCO3 (20 mL) and saturated aqueous sodium chloride (10 mL), dried over Na2SO4, and concentrated. Purification by silica gel chromatography (40 g column, 15-25% ethyl acetate in hexanes) gave tert-butyl 3-({(3R,4S)-4-allyl-3-azido-3-[(2-oxo-2-phenylethoxy)carbonyl]pyrrolidin-1-yl}carbonyl)-7-chloro-3,4-dihydroisoquinoline-2(1 H)-carboxylate (214 mg, 54%) as a pale amber film which was used without further purification. LC-MS ESI+ MS found for C31H34ClN5O6 m/z 608.2 (M+H), 630.3 (M+Na); ESI− MS m/z 606.3 (M−H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH2:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21]([C@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:22])[N:9]2[CH2:12][CH3:13])=[CH:5][CH:4]=1)#[N:2].Cl.[NH2:35][OH:36].C(=O)([O-])[O-].[Na+].[Na+].O>CO>[OH:36][N:35]=[N:2][CH2:1][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([CH2:14][CH2:15][C@@H:16]3[CH2:20][CH2:19][CH2:18][N:17]3[C:21]([C@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:22])[N:9]2[CH2:12][CH3:13])=[CH:5][CH:4]=1
Reactant: CCOC(=O)CN1CCC[C@@H]1C(=O)N1CCC[C@H]1CCc1cc2ccc(C#N)cc2n1CC
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCOC(=O)CN1CCC[C@@H]1C(=O)N1CCC[C@H]1CCc1cc2ccc(CN=NO)cc2n1CC
Yield: 5.2 %

Procedure:
480 mg of ethyl 2-[(R)-2-[[(S)-2-[2-(6-cyano-1-ethylindol-2-yl)ethyl]pyrrolidinyl]carbonyl]pyrrolidinyl]acetate obtained in Example 60-a) was dissolved in methanol. 304 mg of hydroxylamine hydrochloride and 695 mg of sodium carbonate were added and the reaction solution was refluxed overnight with stirring. After water was added, the reaction solution was extracted two times with dichloromethane. The extract was dried over MgSO4 and distilled under reduced pressure. The residue was purified with silica gel column chromatography [eluent: dichloromethane/methanol(20:1)] to obtain 27 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:29]=[CH:28][C:16]([O:17][CH:18]([CH3:27])[C:19](=O)[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH2:30]([NH2:32])[CH3:31]>>[Cl:1][C:2]1[C:3]([O:12][C:13]2[CH:29]=[CH:28][C:16]([O:17][CH:18]([CH3:27])[C:19]([NH:32][CH2:30][CH3:31])=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:15][CH:14]=2)=[N:4][CH:5]=[C:6]([C:8]([F:9])([F:11])[F:10])[CH:7]=1
Reactant: CCOC(=O)CC(=O)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1
Reactant: CCN
Product: CCNC(=CC(=O)OCC)C(C)Oc1ccc(Oc2ncc(C(F)(F)F)cc2Cl)cc1

Procedure:
In the same manner, ethyl 4-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]-3-oxopentanoate and ethylamine are reacted together to give ethyl 4-[4-(3-chloro-5-trifluoromethyl-2-pyridyloxy)phenoxy]-3-ethylamino-2-pentenoate.
Reaction SMILES: Cl[C:2]1[C:12]2[C:11]3[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:10]=3[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:8][CH2:7][C:6]=2[N:5]=[C:4]([CH3:24])[N:3]=1.[CH3:25][OH:26].C[O-].[Na+]>O1CCCC1>[Cl:17][C:15]1[CH:14]=[CH:13][C:11]2[C:12]3[C:2]([O:26][CH3:25])=[N:3][C:4]([CH3:24])=[N:5][C:6]=3[CH2:7][N:8]=[C:9]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:10]=2[CH:16]=1
Reactant: Cc1nc(Cl)c2c(n1)CN=C(c1ccccc1)c1cc(Cl)ccc1-2
Reactant: CO
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1nc(C)nc2c1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 1.0 g (2.8 mmol) of 1,9-dichloro-3-methyl-7-phenyl-5H-pyrimido[4,5-d][2]benzazepine and 1.0 mL of a 4.2 M methanol solution of sodium methoxide in 20 mL of a 1:1 mixture of methanol and tetrahydrofuran was stirred at room temperature for 1 hr. The solvent was removed at reduced pressure and the residue was triturated with water to give an off-white solid. Recrystallization from a mixture of ether and petroleum ether gave colorless prisms, mp 185°-187°.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH:8](P(=O)(OCC)OCC)[CH2:9][CH3:10])=[O:7])[CH3:4].COC(=O)/C=[CH:23]/[C:24]1[CH:29]=[CH:28][C:27]([CH2:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:26][CH:25]=1.C(O)(=O)C>O1CCCC1>[CH2:3]([O:5][C:6](=[O:7])/[C:8](/[CH2:9][CH3:10])=[CH:23]/[C:24]1[CH:25]=[CH:26][C:27]([CH2:30][C:31]2[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=2)=[CH:28][CH:29]=1)[CH3:4]
Reactant: CCOC(=O)C(CC)P(=O)(OCC)OCC
Reactant: COC(=O)/C=C/c1ccc(Cc2cccnc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)/C(=C/c1ccc(Cc2cccnc2)cc1)CC
Reaction time: 0.25 h
Yield: 113.6 %

Procedure:
To a suspension of 46 mg of sodium hydride(content 63%) in 3 ml of tetrahydrofuran was added dropwise 0.33 g of diethyl 1-ethoxycarbonylpropylphosphonate at room temperature, and the mixture was stirred at that temperature for 15 minutes. To it was added a solution of 206 mg of the aldehyde (prepared as described in Reference Example 1) in one ml, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was acidified with acetic acid, and concentrated under reduced pressure. To the residue was added a saturated aqueous solution of sodium bicarbonate, and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of cyclohexane and ethyl acetate (2:1) as eluent to give 273 mg of the title compound having the following physical characteristics:
Reaction SMILES: [C:1]12([NH2:11])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:12]([CH2:15][P:16](=[O:21])([O:19]C)[O:17]C)(O)=[O:13].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[C:1]12([NH:11][C:12]([CH2:15][P:16](=[O:17])([OH:21])[OH:19])=[O:13])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: COP(=O)(CC(=O)O)OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CP(=O)(O)O)NC12CC3CC(CC(C3)C1)C2

Procedure:
Adamantylamine (0.045 mole) and dimethyl (carboxymethyl)phosphonate (0.04 mole) were dissolved in 100 ml. of methylene chloride. As the solution was stirred, dicyclohexylcarbodiimide was added portionwise. The solution was stirred overnight, and the mixture filtered. The filtrate was concentrated to a solid. It was recrystallized from an appropriate solvent such as methanol. m.p. 190°-4° C.; yield, 32%
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](=S)[NH:7][C:6]=2[CH:17]=1.[NH2:18][CH2:19][C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1>C(OCCO)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([NH:18][CH2:19][C:20]3[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=3)=[N:7][C:6]=2[CH:17]=1
Reactant: Cc1ccc2c(c1)NC(=S)c1ccccc1N2
Reactant: NCc1cccnc1
Solvent: CCOCCO
Product: Cc1ccc2c(c1)N=C(NCc1cccnc1)c1ccccc1N2
Yield: 48.9 %

Procedure:
A solution of 0.32 g (1.3 mmol) of 8-methyl-5,10-dihydro-dibenzo[b,e][1,4]diazepin-11-thione (Hunziker F., et al., Helv. Chim. Acta, 50:1588 (1967)) in 10 mL 2-ethoxyethanol was treated with 0.3 mL (2.9 mmol) of 3-(aminomethyl)pyridine and heated at reflux overnight. The solvent was removed under reduced pressure and the residue taken up in EtOAc and washed two times with H2O, then saturated NaHCO3 solution and saturated NaCl solution. Drying over MgSO4 and removal of the solvent under reduced pressure left the crude product. Recrystallization from EtOAc/hexane gave 0.2 g (50% yield) of the pure product as a light yellow solid, mp 186-187° C. The structure was confirmed by NMR and mass spectroscopy. (m+H)+ =315.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:52]1([N:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[NH:58][CH2:57][CH2:56]2)[CH2:54][CH2:53]1>CN(C=O)C>[CH:52]1([N:55]2[C:64]3[C:59](=[CH:60][CH:61]=[CH:62][CH:63]=3)[N:58]([C:7]([C:6]3[C:5]([O:4][C:3]4[CH:14]=[C:15]([Cl:18])[CH:16]=[CH:17][C:2]=4[Cl:1])=[N:13][CH:12]=[CH:11][CH:10]=3)=[O:9])[CH2:57][CH2:56]2)[CH2:54][CH2:53]1
Reactant: c1ccc2c(c1)NCCN2C1CC1
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1cccnc1Oc1cc(Cl)ccc1Cl)N1CCN(C2CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 34.5 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (70 mg, 0.25 mmol, 1.0 equiv; Example 31, Step 1) in anhydrous DMF (1.4 mL) was added N-ethyldiisopropylamine (96 mg, 126 μL, 0.74 mmol, 3.0 equiv; [CAS RN 7087-68-5]) and HATU (112 mg, 0.30 mmol, 1.2 equiv; [CAS RN 148893-10-1]) and the reaction mixture stirred at rt. After 15 min, 1-cyclopropyl-1,2,3,4-tetrahydro-quinoxaline (52 mg, 0.30 mmol, 1.2 equiv) was added and stirring at rt continued over night. Purification by preparative HPLC on reversed phase (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) eluting with a gradient of acetonitrile/water provided 38 mg (35%) of the title compound. MS (ISP): 440.1 [M+H]+.
Reaction SMILES: [C:1]1([CH:7]([N:9]2[C:13]([C:14]([OH:16])=[O:15])=[CH:12][N:11]=[CH:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:18]>CC(O)C>[Na+:18].[C:1]1([CH:7]([N:9]2[C:13]([C:14]([O-:16])=[O:15])=[CH:12][N:11]=[CH:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(c1ccccc1)n1cncc1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: CC(c1ccccc1)n1cncc1C(=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 17.7 parts of (-)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid, 3.28 parts of sodium hydroxide and 120 parts of 2-propanol is stirred and refluxed until the reaction mixture becomes homogenous and thereafter for 1 further hour. During reflux part of the product crystallizes out. The reaction mixture is allowed to cool to room temperature and the precipitated product is filtered off. The product is washed with 2-propanol and dried in vacuo, yielding (-)-1-(1-phenylethyl)-1H-imidazole-5-carboxylic acid sodium salt.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[NH:16][C:15](=[O:17])[C:14]2=[C:18]([CH3:26])[N:19]=[C:20]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[N:13]2[N:12]=1)[CH2:2][CH3:3].[N+:27]([O-])([OH:29])=[O:28]>FC(F)(F)C(O)=O>[N+:27]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:1][CH2:2][CH3:3])=[C:6]([C:11]2[NH:16][C:15](=[O:17])[C:14]3=[C:18]([CH3:26])[N:19]=[C:20]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)[N:13]3[N:12]=2)[CH:7]=1)([O-:29])=[O:28]
Reactant: O=[N+]([O-])O
Reactant: CCCOc1ccccc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCCOc1ccc([N+](=O)[O-])cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
Analogously to the procedure of example 41A, 10.0 g (28.4 mmol) of the compound from example 26A are nitrated in 160 ml of trifluoroacetic acid and 40 ml of 70% strength nitric acid. The product is purified by silica gel chromatography using toluene and ethyl acetate in a gradient system.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].[OH-].[Na+].[O:10]1[CH2:19][C:11]1([CH3:20])[CH2:12][CH2:13][C:14](OCC)=[O:15].C(O)C>O>[OH:7][N:6]1[CH2:19][C:11]([OH:10])([CH3:20])[CH2:12][CH2:13][C:14]1=[O:15]
Reactant: NO
Reactant: CCOC(=O)CCC1(C)CO1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(O)CCC(=O)N(O)C1
Reaction time: 17 h
Yield: 4.2 %

Procedure:
To a mixture of 28.27 g (0.172 m) of hydroxylamine sulfate in 25 ml of water was added slowly a 25 ml aqueous solution of 13.80 g (0.344 m) of sodium hydroxide. To the resulting solution was added 5.45 g (0.034 m) of ethyl 4,5-epoxy-4-methylpentanoate with the aid of 2 ml of ethanol. The mixture was heated to reflux and stirred for 17 hours. The reaction mixture was cooled and concentrated under reduced pressure to yield a yellow moist solid. The solid was washed with methanol several times and the methanol solution was then concentrated. Triuration with acetone yielded 3.72 g (74.4% yield) of a nicely crystalline white solid. A second crop of 0.21 g of solid was obtained. The total yield was 78.5%; mp 98°-100° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH3:13])[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8].[CH3:15][N:16]([CH3:25])[C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1.Cl>CO>[OH:1][C:2]1[CH:3]=[C:4]([C:12](=[O:14])[CH:13]=[CH:21][C:20]2[CH:23]=[CH:24][C:17]([N:16]([CH3:25])[CH3:15])=[CH:18][CH:19]=2)[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[OH:8]
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CC(=O)c1cc(O)c(O)c([N+](=O)[O-])c1
Agent: Cl
Solvent: CO
Product: CN(C)c1ccc(C=CC(=O)c2cc(O)c(O)c([N+](=O)[O-])c2)cc1

Procedure:
A solution containing 0.5 g of the product obtained in Example 19 and 0.38 g of 4-dimethylaminobenzaldehyde in 5 ml of methanol was saturated with gaseous hydrogen chloride. The solution was refluxed for 1 h. After cooling the product was filtered and washed with methanol. Yield 0.26 g (70%), decomp. on heating.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:14]=1)[C:8]([O:10]C)=[O:9])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>CO.C1COCC1>[C:1]([C:5]1[CH:6]=[C:7]([CH:12]=[C:13]([O:15][CH2:16][CH2:17][O:18][CH3:19])[CH:14]=1)[C:8]([OH:10])=[O:9])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1cc(C(=O)OC)cc(C(C)(C)C)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COCCOc1cc(C(=O)O)cc(C(C)(C)C)c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 100.3 %

Procedure:
Methyl 3-tert-butyl-5-(2-methoxyethoxy)benzoate (O5.043; 2.0 g) was dissolved in methanol (30 ml) and THF (60 ml), and lithium hydroxide solution (30 ml, 1 M in water) was added. The mixture was heated to 40° C. and stirred for 3 h. Then the organic solvents were drawn off and the aqueous phase was adjusted to pH 3 with 1 N hydrochloric acid. The mixture was extracted with EA, dried, filtered and concentrated. 1.9 g of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Cl:9])=[C:4]([Cl:10])[C:3]=1[CH3:11].[C:12](O)(=[O:16])[C:13](O)=[O:14]>Cl>[Cl:10][C:4]1[C:3]([CH3:11])=[C:2]2[C:7](=[CH:6][C:5]=1[Cl:9])[NH:8][C:13](=[O:14])[C:12](=[O:16])[NH:1]2
Reactant: Cc1c(N)c(N)cc(Cl)c1Cl
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: Cc1c(Cl)c(Cl)cc2[nH]c(=O)c(=O)[nH]c12
Yield: 65.7 %

Procedure:
A mixture of 2,3-diamino-5,6-dichlorotoluene (21.6 g, 0.137 mol) and oxalic acid (18.45 g, 0.206 mol) in hydrochloric acid (4M, 900 mL) was heated at reflux for 6 hours, cooled and filtered. The dark brown solid was suspended in diethyl ether, filtered and washed with more ether to give 1,4-dihydro-6,7-dichloro-5-methyl-quinoxaline-2,3-dione (22.06 g, 66%). 1H NMR (300 MHz, DMSO) 2.40 (3H, s), 7.14 (1H, s), 11.37 (1H, s), 11.94 (1H, s).