Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OCC)=O)=O)C.[Cl:32][C:33]1[CH:34]=[C:35]([NH:40][C:41]([C:43]2[S:51][C:46]3=[N:47][CH2:48][CH2:49][CH2:50][N:45]3[C:44]=2[OH:52])=[O:42])[CH:36]=[C:37]([Cl:39])[CH:38]=1.[CH2:53]([O:55][C:56](=[O:59])[CH2:57]O)[CH3:54]>O1CCCC1>[Cl:39][C:37]1[CH:36]=[C:35]([NH:40][C:41]([C:43]2[S:51][C:46]3=[N:47][CH2:48][CH2:49][CH2:50][N:45]3[C:44]=2[O:52][CH2:57][C:56]([O:55][CH2:53][CH3:54])=[O:59])=[O:42])[CH:34]=[C:33]([Cl:32])[CH:38]=1
Reactant: O=C(Nc1cc(Cl)cc(Cl)c1)C1=C(O)N2CCCN=C2S1
Reactant: CCOC(=O)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)COC1=C(C(=O)Nc2cc(Cl)cc(Cl)c2)SC2=NCCCN21
Temperature: -78 °C
Reaction time: 1 h

Procedure:
In 40 ml of tetrahydrofuran was dissolved 916 mg of triphenylphosphin. To the solution was added 550 μl of azodicarboxylic acid diethylester under cooling with ice, followed by cooling to -78° C. To the reaction mixture was added 1.0 g of N-(3,5-dichlorophenyl)-6,7-dihydro-3-hydroxy-5H-thiazolo[3,2-a]pyrimidine-2-carboxamide obtained in Example 111 and 400 μl of hydroxyacetic acid ethylester, followed by raising the reaction temperature to room temperature by the degree. After stirring at room temperature for 1 hour, the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (silica gel:50 g) using chloroform and metanol (20:1 by volume) as an eluent to obtain 1.00 g of the titled compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[C:5]([NH2:21])=[C:4]([SH:22])[N:3]=1.[C:23](Cl)(=O)[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>>[CH2:24]([C:23]1[S:22][C:4]2[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([N:8]3[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]3)[C:5]=2[N:21]=1)[CH2:25][CH2:26][CH2:27][CH3:28]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc(S)c2N)CC1
Reactant: CCCCCC(=O)Cl
Product: CCCCCc1nc2c(N3CCNCC3)nc(N)nc2s1
Yield: 67 %

Procedure:
This compound was synthesized from tert-butyl 4-(2,5-diamino-6-mercaptopyrimidin-4-yl)piperazine-1-carboxylate using hexanoyl chloride, yielding the title compound in 67% yield.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[CH2:5][NH:4][C:3]1=[O:8].BrBr.[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(O)(=O)C>[OH:17][C:11]1[CH:16]=[CH:15][C:14]([CH:5]2[NH:4][C:3](=[O:8])[N:2]([CH3:1])[C:6]2=[O:7])=[CH:13][CH:12]=1
Reactant: Oc1ccccc1
Reactant: CN1C(=O)CNC1=O
Agent: BrBr
Solvent: CC(=O)O
Product: CN1C(=O)NC(c2ccc(O)cc2)C1=O
Temperature: 40 °C
Reaction time: 2 h
Yield: 50.9 %

Procedure:
4.56 g (40 mmol) of 3-methyl-hydantoin, 30 ml of acetic acid, and 2.0 ml (40 mmol) of bromine were mixed at room temperature. The reaction mixture was then vigorously stirred at a temperature of 40° C. for 2 hours. The reaction mixture was then allowed to cool to room temperature. To the reaction mixture was then added 5.7 g (60 mmol) of phenol. The reaction mixture was then allowed to undergo reaction at a temperature of 100° C. for 6 hours. The resulting precipitate was recovered by filtration, washed with water, and then dried to obtain 4.20 g (yield: 51%) of 5-(p-hydroxyphenyl)-3-methyl-hydantoin.
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[C:13]=3[C:12]([C:25]#[C:26][Si](CC)(CC)CC)=[CH:11]2)(=O)=O)C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CO.[OH-].[K+]>C1COCC1>[C:25]([C:12]1[C:13]2[C:18]([N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[N:17][CH:16]=[N:15][C:14]=2[NH:10][CH:11]=1)#[CH:26]
Reactant: CC[Si](C#Cc1cn(S(=O)(=O)c2ccccc2)c2ncnc(N3CCCCC3)c12)(CC)CC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1c[nH]c2ncnc(N3CCCCC3)c12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 79.5 %

Procedure:
To a stirred solution of the product from Method S (194 mg/0.40 mmol) dissolved in 2.0 mL of dry THF was added dropwise 0.4 mL (0.4 mmol) of a 1 M solution of tetrabutylammonium fluoride in THF. The resulting mixture stirred at room temperature for 10 minutes, then was transferred to a methanol solution (3.0 mL) containing 1 gram of KOH, the new mixture stirred at room temperature for 15 minutes and concentrated in vacuo. The residue was partitioned between water and ethyl acetate, the ethyl acetate layer washed with water and brine, dried over MgSO4 and concentrated to dryness in vacuo. The crude product was purified by silica-gel chromatography (2:1 ethyl acetate/hexanes) affording 72 mg (64%) of the title compound as a white crystalline solid. Mp 179-181° C. 1H NMR (400 MHz) (CDCl3) d: 1.72 (br s, 6H), 3.20 (s, 1H), 3.82-3.83 (m, 4H), 7.47 (s, 1H), 8.35 (s, 1H). LRMS: 227 (M+1).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].C(N(CC)CC)C.C[Si](Cl)(C)C.[C:20](Cl)(=[O:24])[CH2:21][CH2:22][CH3:23].[OH-].[Na+]>ClCCl.O>[C:20]([NH:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4])(=[O:24])[CH2:21][CH2:22][CH3:23]
Reactant: CCCC(=O)Cl
Reactant: CCC(N)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCC(=O)NC(CC)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
25.78 g of 2-aminobutyric acid (250 mmol) and 55.66 g (550 mmol) of triethylamine are dissolved in 250 ml of dichloromethane, and the solution is cooled to 0° C. 59.75 g (550 mmol) of trimethylsilyl chloride are added dropwise, and the solution is stirred at room temperature for 1 hour and at 40° C. for one hour. After cooling to −10° C., 26.64 g (250 mmol) of butyryl chloride are added dropwise, and the resulting mixture is stirred at −10° C. for 2 hours and at room temperature for one hour. With ice-cooling, 125 ml of water are added dropwise, and the reaction mixture is stirred at room temperature for 15 minutes. Aqueous sodium hydroxide solution is added to the organic phase, and the organic solvent is removed under reduced pressure. The residue is acidified and the precipitated solid is triturated once with water and twice with petroleum ether and dried under reduced pressure at 45° C. 29.1 g (67%) of a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]([CH3:24])[N:18]=[CH:17]4)(O)[CH3:12])=[CH:9][N:10]=2)[N:7]=1.[I-].O[PH2]=O>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][C:22]=3[F:23])[N:19]([CH3:24])[N:18]=[CH:17]4)[CH3:12])=[CH:9][N:10]=2)[N:7]=1
Reactant: Cn1ncc2cc(C(C)(O)c3cnc4ccc(Cl)nn34)c(F)cc21
Agent: O=[PH2]O
Agent: [I-]
Solvent: CC(=O)O
Product: CC(c1cc2cnn(C)c2cc1F)c1cnc2ccc(Cl)nn12

Procedure:
(rac)-1-(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-1-(6-fluoro-1-methyl-1H-indazol-5-yl)-ethanol ((i), 21.4 g, 61.9 mmol) was dissolved in acetic acid (310 mL) and introduced in 20 microwave reactor-vials. Iodide (2.36 g×20, 186 mmol), followed by H3PO2 50% (2.56 mL×20, 464 mmol) were then added into each vial. Then they were submitted to microwave irradiations 10 min at 150° C. The combined RMs were concentrated in vacuo and the residue was diluted with water, basified by a 4 M NaOH solution and extracted twice with EtOAc. The organics were joined and washed with brine, dried over Na2SO4 and the solvent was removed. The residue was triturated with diisopropyl ether. The precipitate formed was filtered off to give a beige solid (tR 4.08 min (conditions 1), tR 14.39/16.40 min (conditions 2), MH+=330, 1H-NMR in DMSO-d6: 8.19 (d, 1H); 7.92 (s, 1H); 7.80 (s, 1H); 7.55 (d, 1H); 7.42 (d, 1H); 7.28 (d, 1H); 4.84 (m, 1H); 3.96 (s, 3H); 1.71 (d, 3H)).
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[Mg].[P:11](Cl)(Cl)(Cl)=[O:12].Cl>C1(C)C(C)=CC=CC=1.O.C(OCC)C>[CH2:1]([P:11](=[O:12])([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCCCl
Agent: Cl
Agent: [Mg]
Solvent: O
Solvent: Cc1ccccc1C
Solvent: CCOCC
Product: CCCCCCCCP(=O)(CCCCCCCC)CCCCCCCC
Reaction time: 1 h

Procedure:
A solution of 44.5 g of octyl chloride in 300 cc of xylene was added dropwise to 12 g of degreased and dry magnesium immersed in a few cc of anhydrous diethyl ether, whilst heating until the reaction started. When the reaction had started, the octyl chloride was added in the cold. When all the octyl chloride solution had been added, stirring was continued for about 1 hour further. 13.8 g of phosphorus oxychloride were then added in the cold. The mixture was then heated to boiling under reflux for 2 hours 30 minutes. The solution was hydrolysed by the addition of 1 litre of water acidified with 100 cc of HCl. The organic phase was decanted, washed with distilled water and neutralised with sodium bicarbonate. After decanting, the organic phase was recovered and then steam-distilled or steam-stripped to remove the solvent without distilling the product. A white solid, trioctylphosphine oxide, was obtained.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1[S:7][C:6](N)=[N:5][CH:4]=1.[C:11]([Cu])#[N:12]>>[F:1][C:2]([F:10])([F:9])[C:3]1[S:7][C:6]([C:11]#[N:12])=[N:5][CH:4]=1
Reactant: N#C[Cu]
Reactant: Nc1ncc(C(F)(F)F)s1
Product: N#Cc1ncc(C(F)(F)F)s1
Yield: 46.8 %

Procedure:
5-(trifluoromethyl)thiazol-2-amine (2.52 g, 15 mmol) was reacted with CuCN (2.7 g, 30.2 mmol) according to the procedure as described in Example 61, Step A to give the title compound as oil (1.25 g, 47%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([O:10][CH3:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[N:6]=1)=[O:4].S(Cl)([Cl:22])(=O)=O>C(O)(=O)C>[CH3:1][O:2][C:3]([C:5]1[C:9]([Cl:22])=[C:8]([O:10][CH3:11])[N:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OC)n(-c2ccccc2F)n1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)c1nn(-c2ccccc2F)c(OC)c1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.6 %

Procedure:
300 mg (1.2 mmol) of 1-(2-fluoro-phenyl)-5-methoxy-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 3 ml of acetic acid. 162 mg (1.2 mmol) of sulfuryl chloride were added and the mixture stirred for 4 h at room temperature. The solvent was removed in vacuo and the residue subjected to acidic aqueous work-up. The obtained crude title compound (330 mg) was used in the hydrolysis step without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][C:9]=1[NH2:10])([O-])=O.[C:17]1(=O)[C:27]2=[C:28]3[C:23](=[CH:24][CH:25]=[CH:26]2)[CH:22]=[CH:21][CH:20]=[C:19]3[C:18]1=O>>[C:11]1([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[N:10]=[C:17]2[C:27]4[CH:26]=[CH:25][CH:24]=[C:23]5[C:28]=4[C:19]([C:18]2=[N:1]3)=[CH:20][CH:21]=[CH:22]5)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccc(-c2ccccc2)cc1[N+](=O)[O-]
Reactant: O=C1C(=O)c2cccc3cccc1c23
Product: c1ccc(-c2ccc3nc4c(nc3c2)-c2cccc3cccc-4c23)cc1
Yield: 80 %

Procedure:
When 0.05 mole each of 3-nitro-4-biphenylamine and acenaphthenequinone were reacted by the method of Example 1, 13.2 g. (80 percent yield) of 9-phenylacenaphtho[1,2-b]quinoxaline, mp = 208°-210° C. were obtained.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1.CO.[ClH:26]>CCOCC>[ClH:26].[ClH:26].[O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: O=c1[nH]c2ncccc2n1C1CCNCC1
Reaction time: 2 h

Procedure:
2-Oxo-1-(1-tert-butoxycarbonylpiperidin-4-yl)-2,3-dihydro-1H-imidazo[4,5-b]pyridine (1.03 g, 3.23 mmol) was dissolved ill methanol (25 mL) and a solution of 2 N hydrochloric acid in ether (8 mL) was added at room temperature. After 2 h, the volatiles were removed in vacuo, to give the title compound (0.92 g). MS 219 (M+1). 1H NMR (500 MHz, CD3OD) δ 8.01 (dd, J=6, 1 Hz, 1H), 7.83 (d, J=8 Hz, 1H), 7.28 (dd, J=8, 6 Hz, 1H), 4.60 (m, 1H), 3.59 (d, J=12 Hz, 2H), 3.21 (t, J=12 Hz, 2H), 2.70 (dq, J=13, 4 Hz, 2H), 2.12 (d, J=13 Hz, 2H).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:24](O)=[O:25])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].O[C:28]1([C:34](=[NH:36])[NH2:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH2:29]1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:24]3[O:25][N:36]=[C:34]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:35]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:18][CH2:19][CH:20]([OH:23])[CH2:21][CH2:22]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: N=C(N)C1(O)C=CC=CC1
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)cc1
Product: CCc1ccc(C2CC(c3nc(-c4ccccc4)no3)CN(C(=O)N3CCC(O)CC3)C2)cc1

Procedure:
80 mg (0.22 mmol) of 5-(4-ethylphenyl)-1-[(4-hydroxypiperidin-1-yl)carbonyl]piperidine-3-carboxylic acid (Example 59A) and 45 mg (0.33 mmol, 1.5 eq.) of 1-hydroxybenzene-carboximidamide were reacted according to the General Method 2. Yield: 76 mg (74% of theory)
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH2:11][O:12][CH2:13][CH3:14])[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]1=2.[CH3:23][C:24]([CH3:39])([C:28]([NH:30][CH2:31][C:32]([F:38])([F:37])[C:33]([F:36])([F:35])[F:34])=[O:29])[C:25](O)=[O:26]>>[CH2:13]([O:12][CH2:11][CH2:10][N:7]1[C:8](=[O:9])[C@@H:2]([NH:1][C:25](=[O:26])[C:24]([CH3:23])([CH3:39])[C:28]([NH:30][CH2:31][C:32]([F:37])([F:38])[C:33]([F:34])([F:35])[F:36])=[O:29])[C:3]2[CH:22]=[CH:21][CH:20]=[CH:19][C:4]=2[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]1=2)[CH3:14]
Reactant: CC(C)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Reactant: CCOCCN1C(=O)[C@@H](N)c2ccccc2-c2ccccc21
Product: CCOCCN1C(=O)[C@@H](NC(=O)C(C)(C)C(=O)NCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21

Procedure:
Using (S)-7-amino-5-(2-ethoxy-ethyl)-5H,7H-dibenzo[b,d]azepin-6-one and 2,2-dimethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid, the title compound was prepared in the same manner as example 1c (80%). White solid. MS: m/e=542(M+H+).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][NH:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)[CH:6]=[CH:5][CH:4]=1.[C:22]([O:26][CH2:27][CH3:28])(=[O:25])[CH:23]=[CH2:24].C(N(CC)C(C)C)(C)C>C(O)C>[CH2:27]([O:26][C:22](=[O:25])[CH2:23][CH2:24][N:12]1[CH2:13][CH2:14][N:9]([C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([C:2]([F:1])([F:20])[F:21])[N:8]=2)[CH2:10][CH:11]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:28]
Reactant: CCOC(=O)C1CN(c2cccc(C(F)(F)F)n2)CCN1
Reactant: C=CC(=O)OCC
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CCN1CCN(c2cccc(C(F)(F)F)n2)CC1C(=O)OCC
Temperature: 80 °C
Reaction time: 96 h

Procedure:
To a solution of Example 94A (10 g, 33.0 mmol) and ethyl acrylate (14.29 mL, 132 mmol) in dry ethanol (30 mL) was added N,N-diisopropylethylamine (2.85 mL, 16.49 mmol). The mixture was heated to 80° C. and stirred for 4 days. Excess ethyl acrylate and ethanol were removed under vacuum. The residue was purified on a silica gel column (hexane:ethyl acetate=1:3) and then purified again via HPLC (Gilson®, Xbridge™ 50×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/acetonitrile, UV=220 nm) to give the title compound. 1H NMR (300 MHz, methanol-d4) δ ppm 1.20 (t, 3H, J=7 Hz) 1.26 (t, 3H, J=7 Hz), 2.52 (td, 2H, J=7, 3 Hz), 2.56-2.65 (m, 1 H), 2.83-3.07 (m, 2 H), 3.17 (ddd, 1H, J=12, 9, 3 Hz), 3.37 (ddd, 1H, J=12, 9, 3 Hz), 3.47-3.61 (m, 2 H), 3.86-3.95 (m, 1 H), 4.06-4.18 (m, 4 H), 4.29 (dd, 1H, J=13, 3 Hz), 6.92-7.01 (m, 2 H), 7.62-7.70 (m, 1 H); MS (DCI) m/z 404 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:25])[NH:4][N:5]=[C:6]([N+:22]([O-:24])=[O:23])[C:7]=1[NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH3:21])[CH:11]=1.[CH:26](I)([CH3:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH:26]([N:4]1[C:3](=[O:25])[C:2]([Cl:1])=[C:7]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH2:19][CH2:20][CH3:21])[CH:11]=2)[C:6]([N+:22]([O-:24])=[O:23])=[N:5]1)([CH3:28])[CH3:27]
Reactant: CCCOc1cc(CNc2c([N+](=O)[O-])n[nH]c(=O)c2Cl)ccc1OC
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCOc1cc(CNc2c([N+](=O)[O-])nn(C(C)C)c(=O)c2Cl)ccc1OC
Reaction time: 1.5 h

Procedure:
A mixture comprising 500 mg of 4-chloro-5-(3-n-propoxy-4-methoxybenzylamino)-6-nitro-3(2H)pyridazinone (Compound No. 22) prepared in Example 2, 691 mg of isopropyl iodide, 562 mg of anhydrous potassium carbonate and 25 ml of methyl ethyl ketone, was refluxed under stirring for 1.5 hours. The solvent was distilled off under reduced pressure, and water was added to the residue thereby obtained. The mixture was extracted with diethyl ether. The extract was washed with a saturated sodium chloride aqueous solution and dried over sodium sulfate. Then, the solvent was distilled off. The residual oily substance thereby obtained was crystallized from a solvent mixture of diethyl ether-n-hexane, to obtain 435 mg of the above identified compound having a melting point of from 82.5° to 84° C. as yellow crystals.
Reaction SMILES: O.O.[Sn](Cl)Cl.[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[N+:21]([O-])=O)=[CH:10][CH:9]=1)#[N:7]>Cl.O.C(O)C>[NH2:21][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:15]=1[NH:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]#[N:7])=[CH:9][CH:10]=1
Reactant: N#Cc1ccc(Nc2ccncc2[N+](=O)[O-])cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(Nc2ccncc2N)cc1
Temperature: 0 °C
Yield: 88.6 %

Procedure:
According to a modification of the method of Pharm. Helv. Acta, 50, 188 (1975), tin(II) dichloride dihydrate (56.4 g, 250 mmol) was added to a suspension of 4-[N-(4-cyanophenyl)amino]-3-nitropyridine (see part (a)) (12.0 g, 50 mmol) in 2N aqueous hydrochloric acid (35 ml), water (150 ml) and ethanol (75 ml) and the resulting mixture was heated under reflux for 10 minutes under nitrogen. The mixture was cooled in ice, poured into ice-cold 2N aqueous sodium hydroxide (400 ml) and filtered The creamy-coloured solid was washed with 2N aqueous sodium hydroxide and water, and then dried in a vacuum desiccator to provide the title compound, (9.31 g), which gradually turns reddish brown on exposure to light and air.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.[C-]#N.[K+].[CH3:28][O:29][C:30]1[CH:37]=[CH:36]C(CO)=[CH:32][CH:31]=1>>[Cl:1][C:2]1[C:7]2[C:8](=[O:24])[N:9]3[CH2:23][CH2:22][CH2:21][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:18][CH2:19][C:20]3[CH:36]=[CH:37][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Reactant: COc1ccc(CO)cc1
Agent: [C-]#N
Agent: [K+]
Product: COc1ccc(COC(=O)c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)cc1
Reaction time: 84 h

Procedure:
A mixture of 3.45 g (10 mmol) of ethyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate, 100 mg (1.5 mmol) of potassium cyanide and 20 ml of 4-methoxybenzyl alcohol is stirred at 110° for 3.5 days, the resulting ethanol being removed in vacuo from time to time. The solvent is subsequently removed by distillation in a high vacuum, the residue is taken up in methylene chloride, the methylene chloride solution is washed three times with water, dried over magnesium sulphate and evaporated. The crude product is chromatographed on silica gel while eluting with ethyl acetate. By recrystallization from ethyl acetate there is obtained p-methoxybenzyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 185°-186°.
Reaction SMILES: Cl[CH:2]([C:4]1[N:13]([CH3:14])[C:12]2[C:11](=[O:15])[N:9]([CH3:10])[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[N:5]=1)[CH3:3].[Na].[CH3:19][C:20]1[N:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:21]=1[C:22]([OH:24])=[O:23]>CN(C)C=O>[CH3:19][C:20]1[N:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:21]=1[C:22]([O:24][CH:2]([C:4]1[N:13]([CH3:14])[C:12]2[C:11](=[O:15])[N:9]([CH3:10])[C:8](=[O:16])[N:7]([CH3:17])[C:6]=2[N:5]=1)[CH3:3])=[O:23]
Reactant: CC(Cl)c1nc2c(c(=O)n(C)c(=O)n2C)n1C
Reactant: Cc1ccnc(C)c1C(=O)O
Agent: [Na]
Solvent: CN(C)C=O
Product: Cc1ccnc(C)c1C(=O)OC(C)c1nc2c(c(=O)n(C)c(=O)n2C)n1C

Procedure:
1.54 g of 8-α-chloroethylcaffeine are dissolved in 15 ml of anhydrous dimethylformamide, and 1.75 g of the sodium salt of dry 2,4-dimethylnicotinic acid are then added.
Reaction SMILES: C([O-])=O.[NH4+].[N+:5]([C:8]1[C:13]([OH:14])=[CH:12][CH:11]=[C:10]([CH3:15])[N:9]=1)([O-])=O.[OH-].[K+].Cl.[C:19](=S)=[S:20]>CCO.[OH-].[OH-].[Pd+2]>[CH3:15][C:10]1[N:9]=[C:8]2[NH:5][C:19](=[S:20])[O:14][C:13]2=[CH:12][CH:11]=1
Reactant: Cc1ccc(O)c([N+](=O)[O-])n1
Reactant: S=C=S
Agent: [Pd+2]
Agent: Cl
Agent: O=C[O-]
Solvent: CCO
Product: Cc1ccc2oc(=S)[nH]c2n1
Temperature: 70 °C

Procedure:
Ammonium formate (1.64 g, 26 mmol) was added to a suspension of Pd(OH)2 on carbon (˜20% Pd, 0.73 g, 1.0 mmol) and 2-nitro-3-hydroxy-6-methylpyridine (2.0 g, 13 mmol) in EtOH (20 mL). The reaction mixture was heated to 70° C. for 1 h at which point the reaction mixture was allowed to cool to rt and was filtered through Celite®. The filtrate was concentrated under reduced pressure, yielding a thick orangish oil. The material was dissolved in EtOH (25 mL) and potassium hydroxide (0.875 g, 15.6 mmol) and carbon disulfide (15 mL) were added. The reaction mixture was heated to reflux overnight. Upon cooling to rt, the reaction mixture was acidified with 1 N HCl, and the resulting solid was collected by filtration. The solid was washed with water (2×) and air dried followed by drying in a 35° C. vacuum oven. LC-MS: RT=5.58 min, [M+H]+=167.0.
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]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[O:18]1[CH:22]=[CH:21][C:20]([C:23](O)=[O:24])=[CH:19]1>>[O:18]1[CH:22]=[CH:21][C:20]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:24])=[CH:19]1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(O)c1ccoc1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccoc4)cc23)CC1
Yield: 85.3 %

Procedure:
Beginning with 12.0 mg (0.05 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 17.0 mg (0.15 mMol) 3-furoic acid, 13.8 mg (85%) of the title compound were recovered.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=2)O)[CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:37]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Br:16])[N:11]=2)[Cl:37])[N:7]=1
Reactant: OC(c1cccc(Br)n1)c1cccc(Br)n1
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ClC(c1cccc(Br)n1)c1cccc(Br)n1
Reaction time: 8 h

Procedure:
To the solution of bis(6-bromopyridin-2-yl)methanol (1.07 g, 3.11 mmol) in CCl4 (15 mL) and CH2Cl2(15 mL) was added triphenylphophine (1.14 g, 4.36 mmol) and stirred overnight. The mixture was concentrated and the residue was purified by silica gel chromatography (5-10% EtOAc in hexane) to give 2-bromo-6-[(6-bromopyridin-2-yl)(chloro)methyl]pyridine. LRMS m/z (M+H) Calcd: 362.5, found: 362.8.