Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(Cl)=O)C.[Cl:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1.C(N(CC)CC)C.[NH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CC(C)=O>[Cl:7][C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)=[O:14])=[CH:15][CH:16]=1
Reactant: NCCN1CCOCC1
Reactant: O=C(O)c1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: O=C(NCCN1CCOCC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5.3 Ml. of chloroformic acid ethyl ester are added dropwise to a solution of 8.6 g. of p-chlorobenzoic acid and 7.6 ml. of triethylamine in 150 ml. of acetone, with stirring and cooling with ice-water. After one hour at 0° C., a solution of 6.5 g. of N-(2-aminoethyl)-morpholine in 50 ml. of acetone is added dropwise to the mixture and the mixture is then stirred overnight at room temperature. Thereafter it is concentrated, allowed to stand for 2 hours in the refrigerator and filtered. The filtrate is evaporated to dryness and the residue is taken up in 250 ml. of water and 250 ml. of methylene chloride. The phases are separated and the methylene chloride extract is dried over sodium sulfate and evaporated. The residue is recrystallized from isopropanol and 7.8 g. of p-chloro-N-(2-morpholinoethyl)-benzamide are obtained, which is identical to the product obtained in Example 1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][C:34]=2[NH2:39])O1>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:39][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:33]=1[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[N:3]=1
Reactant: CC1(C)OB(c2ccncc2N)OC1(C)C
Reactant: COc1cc(Cl)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: COc1cc(-c2ccncc2N)nc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Yield: 13 %

Procedure:
Method 26 was followed using 4-chloro-N,N-di-BOC-6-methoxypyrimidin-2-amine (1.0 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyridin-3-amine (3.0 equiv.), Pd(dppf)Cl2-DCM (0.10 equiv.) in DME/2M Na2CO3 (0.07M) at 90° C. for 30 min. Purification via SiO2 column chromatography eluting with EtOAc and hexanes (1:1) afforded 4-(3-aminopyridin-4-yl)-6-methoxy-N,N-di-BOC-pyrimidin-2-amine in 13% yield). LCMS (m/z): 418.1 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[Cl:33])[C:9]1[C:10]2[CH2:19][N:18]([C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[CH2:17][CH2:16][C:11]=2[N:12]=[C:13](Cl)[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:34]1([CH2:39][C:40]([CH:42]2[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH2:43]2)=[O:41])[CH2:38][CH2:37][CH2:36][CH2:35]1>>[C:1]([O:5][C:6]([N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=1[Cl:33])[C:9]1[C:10]2[CH2:19][N:18]([C:20]([CH:22]3[CH2:23][CH2:24]3)=[O:21])[CH2:17][CH2:16][C:11]=2[N:12]=[C:13]([N:45]2[CH2:44][CH2:43][CH:42]([C:40](=[O:41])[CH2:39][N:34]3[CH2:38][CH2:37][CH2:36][CH2:35]3)[CH2:47][CH2:46]2)[N:14]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1Cl)c1nc(Cl)nc2c1CN(C(=O)C1CC1)CC2
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CN2CCCC2)CC1
Product: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1Cl)c1nc(N2CCC(C(=O)CN3CCCC3)CC2)nc2c1CN(C(=O)C1CC1)CC2

Procedure:
In the same way as Example 92 mentioned later, 4-(N-tert-butoxycarbonyl-2-chloro-4-fluorobenzylamino)-6-cyclopropylcarbonyl-2-[4-(2-pyrrolidin-1-ylacetyl)piperidino]-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine was prepared from 4-(N-tert-butoxycarbonyl-2-chloro-4-fluorobenzylamino)-2-chloro-6-cyclopropylcarbonyl-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine prepared according to Process Step 1 and tert-butyl 4-(2-pyrrolidin-1-ylacetyl)piperidinecarboxylate prepared according to Reference Example 12.
Reaction SMILES: [ClH:1].CO[C:4](=[NH:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1.N([C:24]1[C:37]([NH:38]C2C=CC=CC=2)=[CH:36][CH:35]=[CH:34][C:25]=1[C:26]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27])C1C=CC=CC=1>CO.C(OCC)C>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][C:9]=1[O:12][CH3:13])[CH2:5][C:4]1[NH:16][C:36]2[CH:35]=[CH:34][C:25]([C:26]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:27])=[CH:24][C:37]=2[N:38]=1.[ClH:1]
Reactant: O=C(c1ccccc1)c1cccc(Nc2ccccc2)c1Nc1ccccc1
Reactant: COC(=N)Cc1ccc(OC)c(OC)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: COc1ccc(Cc2nc3cc(C(=O)c4ccccc4)ccc3[nH]2)cc1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of methyl-(3,4dimethoxyphenyl)-acetimidate hydrochloride (2.5 g; 10 mmol) and 2,3-diamiinobenzophenone (2.1 g; 10 mmol) in methanol (70 mL) was stirred at ambient temperature for 72 hours. The reaction mixture was concentrated to dryness, and H2O was added. The solid (2.3 g) was subjected to flash chromatography on silica gel (CH2Cl2/MeOH; 9:1) to afford a gummy material. This was dissolved in diethyl ether, and Ether-HCl was added to obtain the title compound as a buff solid, hydrochloride, penta-hydrate (250 mg), m.p. 172-175° C. Anal. Calcd. for C23H20N2O3HCl.5H2O: C, 66.97; H, 5.23; N, 6.79. Found: C, 67.11, H, 4.84; N, 6.77. Mass Spectrum: (EI; M+) m/z 372. 1H-NMR (D)MSO-d6; 400 MHz) δ8.0 (s, 1H) 7.84-7.9 (m, 2H), 7.68-7.77 (m, 3H), 7.55-7.61 (m, 2H), 7.2 (s, 1H), 6.93-7.01 (m, 2H), 4.42 (s, 2H), 3.79 (s, 3H), 3.77 ppm (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]([F:24])([F:23])[F:22])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([CH2:18]Cl)=[CH:14][N:13]=3)[C:6]=2[CH:20]=1.[C-:25]#[N:26].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([C:21]([F:24])([F:23])[F:22])=[CH:4][C:5]2[N:9]=[C:8]([CH2:10][CH3:11])[N:7]([C:12]3[N:13]=[CH:14][C:15]([CH2:18][C:25]#[N:26])=[CH:16][CH:17]=3)[C:6]=2[CH:20]=1
Reactant: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CCl)cn1
Reactant: [C-]#N
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2cc(C(F)(F)F)c(Cl)cc2n1-c1ccc(CC#N)cn1
Reaction time: 2 h
Yield: 36.2 %

Procedure:
To a solution of 6-chloro-1-[5-(chloromethyl)-2-pyridinyl]-2-ethyl-5-(trifluoromethyl)-1H-benzimidazole (from step 5, 550 mg, 1.5 mmol) in DMF (5 ml) and water (1 ml) was added KCN (470 g, 7.2 mmol) at room temperature, and then the reaction mixture was stirred for 2 h. The mixture was diluted with water and extracted with ethyl acetate/toluene (4/1) solution (3×30 ml). The organic layer was washed with water, dried (MgSO4) and concentrated. This was purified by SiO2 column chromatography developing with hexane/ethyl acetate (1/) gave 198 mg (37%) of title compound as orange oil.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[N:15]3[C:16]4[C:21]([N:22]=[C:23]([NH:24][CH2:25][CH2:26][CH2:27][OH:28])[C:14]3=[N:13][CH:12]=2)=[CH:20][C:19]([C:29]([F:32])([F:31])[F:30])=[CH:18][CH:17]=4)[NH:8][N:7]=1)=O)C.[CH3:33][NH2:34]>C1COCC1>[OH:28][CH2:27][CH2:26][CH2:25][NH:24][C:23]1[C:14]2[N:15]([C:11]([C:9]3[NH:8][N:7]=[C:6]([C:4]([NH:34][CH3:33])=[O:3])[CH:10]=3)=[CH:12][N:13]=2)[C:16]2[C:21]([N:22]=1)=[CH:20][C:19]([C:29]([F:32])([F:31])[F:30])=[CH:18][CH:17]=2
Reactant: CCOC(=O)c1cc(-c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)[nH]n1
Reactant: CN
Solvent: C1CCOC1
Product: CNC(=O)c1cc(-c2cnc3c(NCCCO)nc4cc(C(F)(F)F)ccc4n23)[nH]n1
Yield: 35 %

Procedure:
A solution of 5-[4-(3-Hydroxy-propylamino)-7-trifluoromethyl-imidazo[1,2-a]quinoxalin-1-yl]-1H-pyrazole-3-carboxylic acid ethyl ester (0.02 mmol; 7 mg), Methylamine (0.40 mmol; 40% wt in H2O; 0.1 mL), in THF (0.2 mL), under argon was stirred at 35° C. for 48 hr. Concentration, then purification by preparative TLC (dichloromethane/methanol) afforded the title compound as a white solid (3 mg; 0.007 mmol; 44%).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:4]([N:6]1[CH2:10][C@H:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=2)[CH2:8][C@H:7]1[C:19]([NH:21][C@H:22]([CH:28]([OH:35])[C:29]([NH:31][CH:32]1[CH2:34][CH2:33]1)=[O:30])[CH2:23][CH:24]1[CH2:27][CH2:26][CH2:25]1)=[O:20])=[O:5].C(N(CC)CC)C.[C:47]([N:51]=[C:52]=[O:53])([CH3:50])([CH3:49])[CH3:48]>ClCCl>[C:47]([NH:51][C:52](=[O:53])[NH:2][C@@H:3]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:4]([N:6]1[CH2:10][C@H:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=2)[CH2:8][C@H:7]1[C:19]([NH:21][C@H:22]([CH:28]([OH:35])[C:29]([NH:31][CH:32]1[CH2:33][CH2:34]1)=[O:30])[CH2:23][CH:24]1[CH2:27][CH2:26][CH2:25]1)=[O:20])=[O:5])([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)[C@H](N)C(=O)N1C[C@H](Oc2ccc(Cl)cn2)C[C@H]1C(=O)N[C@@H](CC1CCC1)C(O)C(=O)NC1CC1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)N[C@H](C(=O)N1C[C@H](Oc2ccc(Cl)cn2)C[C@H]1C(=O)N[C@@H](CC1CCC1)C(O)C(=O)NC1CC1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-(5-chloro-pyridin-2-yloxy)-N-((2S)-1-cyclobutyl-4-(cyclopropylamino)-3-hydroxy-4-oxobutan-2-yl)pyrrolidine-2-carboxamide HCl salt (45 mg, 0.077 mmol) in dichloromethane (3.0 mL) was added triethylamine (0.02 mL, 0.154 mmol). After 5 minutes at room temperature, tert-butylisocyanate (0.01 mL, 0.077 mmol) was added and the reaction mixture was stirred at room temperature. After 16 hours, the reaction mixture was diluted with dichloromethane and washed with 1N HCl, saturated sodium bicarbonate, and brine. The dichloromethane layer was then evaporated to dryness under reduced pressure to give (2S,4R)-1-((S)-2-(3-tert-butylureido)-3,3-dimethylbutanoyl)-4-(5-chloropyridin-2-yloxy)-N-((2S)-1-cyclobutyl-4-(cyclopropylamino)-3-hydroxy-4-oxobutan-2-yl)pyrrolidine-2-carboxamide.
Reaction SMILES: [H-].[Na+].[CH2:3]=[CH:4][CH2:5][CH:6]([OH:10])[CH2:7][CH:8]=[CH2:9].[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>C1COCC1>[Br:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:10][CH:6]([CH2:7][CH:8]=[CH2:9])[CH2:5][CH:4]=[CH2:3]
Reactant: C=CCC(O)CC=C
Reactant: BrCCCCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(CC=C)OCCCCCCCCCCBr
Reaction time: 13 h
Yield: 25.7 %

Procedure:
8.9 g of 60% sodium hydride was suspended in 100 ml of THF, and 25 g of 1,6-heptadien-4-ol dissolved in 50 ml of THF was dropped therein in an atmosphere of argon. 94 g of 1,10-dibromodecane dissolved in 50 ml of THF was further dropped therein, and reflux was carried out for 13 hours in an atmosphere of argon. After the generated precipitate was filtered off, the solvent was evaporated, and the residue was purified by silica gel column chromatography, to obtain 19 g of the compound (4). (Yield: 26%)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10](=[O:20])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[Cl:19])=[CH:6]OCC)[CH3:2].[F:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>C(O)(C)C>[CH2:1]([O:3][C:4](=[O:21])[C:5]([C:10](=[O:20])[C:11]1[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=1[Cl:19])=[CH:6][NH:27][C:26]1[CH:28]=[CH:29][C:23]([F:22])=[CH:24][CH:25]=1)[CH3:2]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1Cl
Reactant: Nc1ccc(F)cc1
Solvent: CC(C)O
Product: CCOC(=O)C(=CNc1ccc(F)cc1)C(=O)c1cc(F)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-(2-Chloro-4,5-difluorobenzoyl)-3-ethoxy-2-propenoic acid ethyl ester (material from preceding preparation) was mixed with isopropyl alcohol (250 ml) and cooled to 0°. 4-Fluoroaniline (9.33 g, 84.0 mmol) was added, and the reaction mixture was allowed to warm to room temperature and stir for 18 hours. The precipitate was filtered and washed with isopropyl ether, yielding the title product (11.0 g, 28.7 mmol). Additional product (10.2 g, 26.6 mmol, 73% overall yield for two steps) was obtained from the filtrate, which was concentrated in vacuo and subjected to column chromatography (eluting with chloroform), providing material was was further purified by recrystallization from ether/hexanes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:25]([O:27]CC)=O)[C:5]2[C:6](=O)[CH:7]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[CH:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][C:10]=2[CH:11]=1.O.[NH2:31][NH2:32]>CO>[Cl:1][C:2]1[CH:11]=[C:10]2[NH:9][CH:8]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:7]([C:18]3[N:19]([CH3:23])[CH:20]=[CH:21][N:22]=3)[C:6]3=[N:31][NH:32][C:25](=[O:27])[C:4]([CH:3]=1)=[C:5]23
Reactant: NN
Reactant: CCOC(=O)c1cc(Cl)cc2c1C(=O)C(c1nccn1C)C(c1ccccc1)N2
Solvent: CO
Solvent: O
Product: Cn1ccnc1C1c2n[nH]c(=O)c3cc(Cl)cc(c23)NC1c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 14 %

Procedure:
To a solution of ethyl 7-chloro-3-(1-methyl-1H-imidazol-2-yl)-4-oxo-2-phenyl-1,2,3,4-tetrahydroquinoline-5-carboxylate (429 mg, 1.05 mmol) in methanol (15 mL) was added hydrazine monohydrate (2 mL). The mixture was stirred at 25° C. for 5 hr. The resulting mixture was concentrated under reduced pressure to a volume of 10 ml and then filtered, giving 58 mg of solid (yield 14%). LC-MS (ESI) m/z: 378 (M+1)+; 379 (M+2)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 3.42 (s, 3H), 4.69 (d, J=10.0 Hz, 1H), 4.98 (d, J=10.4 Hz, 1H), 5.76 (s, 1H), 6.73 (s, 1H), 6.89 (s, 1H), 7.14 (s, 1H), 7.27 (dd, 4H), 7.38 (d, J=6.4 Hz, 2H), 7.62 (s, 1H), 12.36 (s, 1H).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCCC1=O.[CH3:18][C:19]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:20]=1[C:21](Cl)=[O:22]>O>[CH3:18][C:19]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:20]=1[C:21]([NH:10][NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:22]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: NNC(=O)c1ccccc1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1cc(C)c(C(=O)NNC(=O)c2ccccc2)c(C)c1
Reaction time: 24 h
Yield: 65 %

Procedure:
First, 16.7 g (123.3 mmol) of benzoylhydrazine and 100 mL of N-methyl-2-pyrrolidinone (NMP) were put into a 300-mL three-neck flask and stiffed under nitrogen flow while being cooled with ice. To this mixed solution, a mixed solution of 25.0 g (137.3 mmol) of 2,4,6-trimethylbenzoyl chloride and 20 mL of NMP was slowly added dropwise, and the mixture was stiffed at room temperature for 24 hours. After reaction for the predetermined time, this reacted solution was slowly added to 500 mL of water, so that a white solid was precipitated. The precipitated solid was washed by repeating twice ultrasonic cleaning in which water and then 1M hydrochloric acid were used. Then, ultrasonic cleaning using hexane was performed, so that 22.7 g of a white solid of 1-(2,4,6-trimethylbenzoyl)-2-benzoylhydrazine was obtained in a yield of 65%. A synthesis scheme of Step 1 is shown in (e-1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([SH:28])[CH:25]=[CH:26][CH:27]=1>>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([S:28][C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:21][CH3:20])[CH:23]=2)=[N:3][C:4]=1[C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14]
Reactant: O=C(O)CNC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: COc1cccc(S)c1
Product: COc1cccc(Sc2nc(C(=O)NCC(=O)O)c(O)c3ccccc23)c1

Procedure:
The title compound was prepared from [(1-chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid (U.S. Pat. No. 6,093,730) and 3-methoxybenzenethiol under conditions analogous to Example D-110. The final product was precipitated from a solution of ethyl acetate using hexanes; MS (−) m/z 385.12 (M−1)
Reaction SMILES: Br/[CH:2]=[C:3]1\[C:4]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:5]=2[CH2:6][CH2:7][C:8]2[C:13]\1=[CH:12][CH:11]=[CH:10][N:9]=2.CC1(C)C(C)(C)OB([C:27]2[CH:36]=[CH:35][C:30]3[NH:31][C:32](=[O:34])[NH:33][C:29]=3[CH:28]=2)O1>>[F:18][C:15]1[CH:16]=[CH:17][C:4]2/[C:3](=[CH:2]\[C:27]3[CH:36]=[CH:35][C:30]4[NH:31][C:32](=[O:34])[NH:33][C:29]=4[CH:28]=3)/[C:13]3[C:8]([CH2:7][CH2:6][C:5]=2[CH:14]=1)=[N:9][CH:10]=[CH:11][CH:12]=3
Reactant: Fc1ccc2c(c1)CCc1ncccc1/C2=C/Br
Reactant: CC1(C)OB(c2ccc3[nH]c(=O)[nH]c3c2)OC1(C)C
Product: O=c1[nH]c2ccc(/C=C3\c4ccc(F)cc4CCc4ncccc43)cc2[nH]1
Yield: 59.4 %

Procedure:
Following procedures essentially as desctribed in Example 219, beginning with (E)-5-bromomethylene-8-fluoro-10,11-dihydro-benzo[4,5]cyclohepta[1,2-b]pyridine (100 mg, 0.33 mmol) and 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,3-dihydro-benzoimidazol-2-one (111 mg, 0.43 mmol). After work-up, purify the crude product by flash chromatography (100% ethyl acetate to 10% ethanol/ethyl acetate) to provide 70 mg (60%) of purified product. LCMS (APCI-pos): 358.0 (M+H). LCMS (APCI-neg): 356.0 (M−H). Purity by LCMS (UV Area percent): 99%. 1HNMR (d6-DMSO, 400 MHz): δ10.56 (s, 1H), 10/46 (s, 1H), 8.38 (dd, 1H), 7.88 (dd, 1H), 7.28 (dd, 1H), 7.23 (dd, 1H), 6.96-6.90 (m, 2H), 6.89 (s, 1H), 6.73 (d, 1H), 6.68 (d, 1H), 6.52 (s, 1H), 3.5-3.3 (m, 2H), 3.1-2.9 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[C:4]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][C:7](=[O:13])[C:6](=[O:14])[NH:5]2.[OH-].[K+].[NH2:20]OS(O)(=O)=O>O>[NH2:20][N:8]1[C:9]2[C:4](=[C:3]([N+:15]([O-:17])=[O:16])[C:2]([Cl:1])=[C:11]([Cl:12])[CH:10]=2)[NH:5][C:6](=[O:14])[C:7]1=[O:13]
Reactant: O=c1[nH]c2cc(Cl)c(Cl)c([N+](=O)[O-])c2[nH]c1=O
Reactant: NOS(=O)(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Nn1c(=O)c(=O)[nH]c2c([N+](=O)[O-])c(Cl)c(Cl)cc21
Reaction time: 0.17 h
Yield: 81.1 %

Procedure:
The procedure of Shin, S. C. and Lee, Y. Y., Taehan Hwahakhoe Chi 27(5):382-4 (1983) was adapted. A red solution of 6,7-dichloro-5-nitro-1,4-dihydro-2,3-quinoxalinedione (100 mg, 0.36 mMol, Cheeseman, supra) and 3N KOH (2 mL) in distilled water (5 mL) at 65° C. was dropwise added to a colorless solution of NH2OSO3H (75 mg, 0.66 mMol, Aldrich) in distilled water (0.5 mL) with stirring. A yellow precipitate came out after 10 mins. The mixture was stirred at 65° C. for 1 h and allowed to stand at room temperature overnight, then the precipitate was collected by filtration at 50° C. and was washed with distilled water (2 ml), then dried at 50° C. overnight, affording 85 mg (80% ) of crude 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione, as a yellow amorphous solid (80% of desired 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione with 20% starting material by NMR). A 85 mg sample of crude 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione (free base Na+, 0.293 mMol) was dissolved into distilled water (10 mL) at 50° C., then was acidified with AcOH to pH=5. After removal of the insoluble material by filtration, the mixture was heated at 60°-70° C. until a clear solution was obtained, which was slowly cooled, whereupon a yellow precipitate came out. The precipitate was crystallized from hot EtOH and the yellow microcrystals were collected by filtration, washed with cold ethanol (2 mL), and dried in the air at 60° C. for 4 h, affording 31 mg (29%) of pure 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione. Mp was measured: the color of 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione changed to dark yellow at 275° C.; the decomposition of 1-amino-5-nitro-6,7-dichloro-1,4-dihydro-2,3-quinoxalinedione is obvious at 280° C. and it melted to a black liquid at 290°-1° C. IR (KBr, cm-1): 3442; 3315; 3231; 1747; 1723; 1680; 1632; 1547. NMR (1H, DMSO-d6): δ5.848 (s, 2H); 7.951 (s, 1H); 12.595 (s, 1H). HRMS: calcd for C8H4N4O4Cl2 (M+) m/z: 289.9623; found 289.9616.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1)=O.Cl.[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][O:19][NH2:20].N1C=CC=CC=1>C(O)C>[F:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[CH2:18][O:19][N:20]=[C:2]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([F:12])[CH:5]=1)[CH3:1]
Reactant: NOCc1cccc(F)c1
Reactant: COc1ccc(C(C)=O)cc1F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COc1ccc(C(C)=NOCc2cccc(F)c2)cc1F
Temperature: 25 °C
Yield: 90.1 %

Procedure:
A solution of 3-fluoro-4-methoxyacetophenone (0.063 g, 0.377 mmol), O-(3-fluorobenzyl)hydroxylamine hydrochloride (0.100 g, 0.569 mmol) and pyridine (0.14 ml, 1.73 mmol) in ethanol (5 ml) was stirred at reflux under nitrogen for 4 h and cooled to room temperature. The solution was concentrated to a pale yellow oil which was diluted with water. The suspension was extracted with dichloromethane (×3). The combined organic phases were washed with water and brine, dried over magnesium sulphate, filtered and concentrated to a white solid. The crude product was purified by column chromatography (SiO2), eluting with 95:5 petrol/ethyl acetate, to give 3′-fluoro-4′-methoxyacetophenone-O-3-fluorobenzyloxime (CP9-126) as a white solid (0.099 g, 90%), m.p. 67°.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][C:11]=2[C:10]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[Na+].[Na+].[CH3:31][O:32][C:33](=[O:36])[CH2:34]Br>CC(C)=O>[CH3:31][O:32][C:33](=[O:36])[CH2:34][N:14]1[CH2:15][CH2:16][C:17]2[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:12][CH2:13]1
Reactant: Clc1ccc(-c2nn(Cc3ccccc3)c3c2CCNCC3)cc1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)CN1CCc2c(-c3ccc(Cl)cc3)nn(Cc3ccccc3)c2CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzyl-3-(4-chloro-phenyl)-1,4,5,6,7,8-hexahydro-1,2,6-triaza-azulene (Example 59, Step E; 1 mmol) in acetone (3 mL) was added Na2CO3 (2 mmol) and bromoacetic methyl ester (2 mmol). The mixture was stirred at RT for 1 h. After concentration and purification (SiO2, 2 M NH3 in MeOH/CH2Cl2), the title compound was obtained (60 mg). MS (ESI): exact mass calculated for C23H24ClN3O2, 409.16; found, m/z 410.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.44-7.42 (m, 2H), 7.31-7.29 (m, 2H), 7.25-7.23 (br m, 2H), 7.20-7.18 (br m, 1H), 7.02-6.99 (br m, 2H), 5.26 (s, 2H), 3.64 (s, 2H), 3.41 (s, 2H), 2.81-2.79 (br m, 4H), 2.75-2.73 (br m, 2H), 2.70-2.68 (br m, 2H).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][SH:4].F[C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14].C(N(CC)CC)C>O1CCCC1>[CH2:3]([S:4][C:6]1[CH:11]=[C:10]([F:12])[CH:9]=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14])[CH:2]=[CH2:1]
Reactant: C=CCS
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCSc1cc(F)ccc1[N+](=O)[O-]
Reaction time: 4 h
Yield: 63.5 %

Procedure:
A solution of 2.3 g (0.031 mole) of allylthiol in 25 ml of tetrahydrofuran was added to 5.0 g (0.031 mole) of 2,4-difluoronitrobenzene in 25 ml of tetrahydrofuran at -30° C. To this mixture was added dropwise 3.1 g (0.031 mole) of triethylamine. The temperature was allowed to rise to room temperature and stirring was continued for four hours. The tetrahydrofuran was evaporated under reduced pressure, and water and diethyl ether were added to the residue. The ether layer was separated and dried over anhydrous potassium carbonate. The ether was evaporated under reduced pressure, leaving a liquid residue. This residue was distilled at 105° C./1.2 mm of Hg, yielding 4.2 g of 2-allylthio-4-fluoronitrobenzene. The nmr spectrum was consistent with the proposed structure.