Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:44][C:4]2=[CH:5][C:6]3[C:19]4[N:18](C)[CH:17]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C:16]5[C:11](=[CH:12][CH:13]=[C:14]([O:41][CH3:42])[C:15]=5[O:33][CH2:34][C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=5)[C:10]=4[CH:9]=[CH:8][C:7]=3[CH:43]=[C:3]2[O:2]1>C1(C)C=CC=CC=1.CO.C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]1[O:44][C:4]2=[CH:5][C:6]3[C:19]4[C:10](=[C:11]5[C:16](=[C:17]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][Si:26]([C:29]([CH3:31])([CH3:30])[CH3:32])([CH3:28])[CH3:27])[N:18]=4)[C:15]([O:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[C:14]([O:41][CH3:42])[CH:13]=[CH:12]5)[CH:9]=[CH:8][C:7]=3[CH:43]=[C:3]2[O:2]1
Reactant: COc1ccc2c(c1OCc1ccccc1)C(CCCCO[Si](C)(C)C(C)(C)C)N(C)c1c-2ccc2cc3c(cc12)OCO3
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1ccc2c(c(CCCCO[Si](C)(C)C(C)(C)C)nc3c4cc5c(cc4ccc23)OCO5)c1OCc1ccccc1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
After 2,3-(methylenedioxy)-5-methyl-6-[4-(t-butyldimethylsiloxy)butyl]-7-benzyloxy-8-methoxy-5,6-dihydrobenzo[c]phenanthridine (300 mg, 0.49 mmol) was dissolved in toluene (8 mL), activated manganese dioxide (1.5 g) was added to the solution. The mixture was heated to reflux for an hour. After cooling to room temperature, the reaction mixture was diluted with a 10% methanol-methylene chloride solution (12 mL) followed by filtration. The filtrate was concentrated in vacuo. The resulting residue was purified by silica gel column chromatography (eluted with methylene chloride) to provide 2,3-(methylenedioxy)-6-[4-(t-butyldimethylsiloxy)butyl]-7-benzyloxy-8-methoxy-benzo[c]phenanthridine (205 mg, yield 70%) as light brown crystals.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[CH2:8](N(CC)CC)C.C[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O>CN(C)C(=O)C>[CH3:8][C:19]1[CH2:18][CH:17]2[CH:6]([CH:20]=1)[C:5](=[O:7])[CH2:16]2
Reactant: CCN(CC)CC
Reactant: CCCCCC
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC1=CC2C(=O)CC2C1
Temperature: 117.5 °C
Reaction time: 6 h
Yield: 54 %

Procedure:
(2E)-4-Methylhepta-2,6-dienoic acid (67.74 g) obtained by the method described above was dissolved in N,N-dimethylacetamide (210 mL) under a nitrogen atmosphere. To the solution, acetic anhydride (91 mL, 0.96 mol) and triethylamine (67 mL, 0.48 mol) were added. The reaction mixture was warmed and stirred at 115 to 120° C. for 6 hours. The reaction mixture was cooled to room temperature, and n-hexane (360 mL) and water (540 mL) were added thereto to separate an organic layer. The aqueous layer was subjected to two extractions with hexane (each with 180 mL), and all the organic layers were combined and then washed with a 5% aqueous sodium bicarbonate solution (90 mL) and water (90 mL) in this order. The obtained organic layer was concentrated under reduced pressure, and the residue was distilled (74-76° C., approximately 25 mmHg) to obtain the title compound (39.09 g, colorless oil substance) (overall yield from 1,1-bis(allyloxy)propane: 54%).
Reaction SMILES: Cl.[O:2]=[C:3]1[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][NH:4]1.[C:19]1(=O)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[C-:27]#[N:28].[K+]>O>[O:2]=[C:3]1[C:7]2([CH2:8][CH2:9][N:10]([C:19]3([C:27]#[N:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:11][CH2:12]2)[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:5][NH:4]1
Reactant: [C-]#N
Reactant: O=C1CCCCCC1
Reactant: O=C1NCN(c2ccccc2)C12CCNCC2
Agent: Cl
Agent: [K+]
Solvent: O
Product: N#CC1(N2CCC3(CC2)C(=O)NCN3c2ccccc2)CCCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 42.4 %

Procedure:
To a stirred mixture of 1-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane hydrochloride (578.8 mg, 2.16 mmol) and cycloheptanone (304 μl, 2.59 mmol) was added a solution of KCN (169 mg, 2.59 mmol) in water (1 ml) at room temperature. The reaction mixture was vigorously stirred at room temperature for 20 h. The precipitated white solid was collected by filtration, washed with water and hexane, and dried under vacuum at 50° C. for 1 h to afford 323 mg (42.4 %) of white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([N:10]([CH3:12])[CH3:11])[CH:7]=[CH:6][C:5]=1[Cl:13].Cl[CH2:16]Cl.C[O:19][S:20]([C:23]([F:26])([F:25])[F:24])(=[O:22])=[O:21]>C(OCC)C>[F:24][C:23]([F:26])([F:25])[S:20]([O-:22])(=[O:21])=[O:19].[Cl:13][C:5]1[CH:6]=[CH:7][C:8]([N+:10]([CH3:16])([CH3:11])[CH3:12])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:14]
Reactant: COC(=O)c1cc(N(C)C)ccc1Cl
Reactant: ClCCl
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: CCOCC
Product: COC(=O)c1cc([N+](C)(C)C)ccc1Cl
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 86 %

Procedure:
To a stirred solution of 4.49 g (21.0 mmol) 18a and 75 ml dichloromethane were added 34.5 g (21.0 mmol) methyltriflate (Aldrich) drop wisely. The reaction mixture was stirred for 2 days at room temperature. 17 g (10 mmol) methyltriflate (Aldrich) were added and the reaction mixture was stirred at 40° C. for 20 h. The reaction mixture was cooled to 20° C. and diethylether was added. The desired compound precipitates and the solvent was decanted and the solid was washed extensively (ten times) with large amounts of diethylether. The solid was dried by use of oil pump vacuum and purified by (C-18) RP-column chromatography (acetonitril/water-gradient 1:99 to 80:20). The desired compound 18b was obtained in 86% yield (6.78 g, 18.1 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([SH:9])[N:3]=1.[CH2:10](I)[CH2:11][CH2:12][CH2:13][CH3:14]>[OH-].[Na+].C(O)C>[CH2:10]([S:9][C:4]1[NH:3][C:2](=[O:1])[CH2:7][C:6](=[O:8])[N:5]=1)[CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: Oc1cc(O)nc(S)n1
Reactant: CCCCCI
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCSC1=NC(=O)CC(=O)N1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
To a solution of 4,6-dihydroxy-2-mercaptopyrimidine (14.4 g) in 2N sodium hydroxide solution (100 ml) was added pentyl iodide (15.6 ml) in ethanol (25 ml) and the resulting reaction mixture stirred at room temperature for four days. The ethanol was removed at reduced pressure and N,N-dimethylformamide (80 ml) and pentyl iodide (1.56 ml) added then the reaction mixture stirred for an additional 16 hours. The solution was made acidic by addition of 2N HCl solution and the aqueous layer decanted. The remaining gum was dissolved in methanol and evaporated to dryness then azeotroped with toluene (×2). The solid was triturated with ether, filtered and dried to give the subtitle compound as a white solid (11.9 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:13]3[C:14]([CH3:28])=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:33](Cl)(=[O:35])[CH3:34].O>ClCCl>[C:33]([C:8]1[CH:7]=[CH:6][C:5]([CH:9]2[C:13]3[C:14]([CH3:28])=[C:15]([NH:20][C:21](=[O:27])[CH2:22][C:23]([CH3:24])([CH3:25])[CH3:26])[C:16]([CH3:19])=[C:17]([CH3:18])[C:12]=3[O:11][CH2:10]2)=[CH:4][C:3]=1[O:2][CH3:1])(=[O:35])[CH3:34]
Reactant: CC(=O)Cl
Reactant: COc1cccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Product: COc1cc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)ccc1C(C)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 89 %

Procedure:
To a solution of N-(3-(3-methoxyphenyl)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (1.0 g, 2.62 mmol) obtained in Example 72 in dichloromethane (20 mL) was added at −50° C. under an argon atmosphere aluminum chloride (769 mg, 5.77 mmol) and the resulting mixture was stirred for 10 minutes. To the reaction solution was added dropwise at the same temperature acetyl chloride (0.62 mL, 8.65 mmol and the resulting mixture was warmed to room temperature. The reaction solution was added to water and the product was extracted with ethyl acetate. The combined organic layers were washed with an aqueous saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 993 mg (yield: 89%) of the title compound. Melting point: 131-133° C. (ethyl acetate-hexane).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][C:2]1=O.[CH2:12]([NH2:15])[CH2:13][CH3:14].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:12]([NH:15][CH:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)[CH2:13][CH3:14]
Reactant: CCCN
Reactant: O=C1CCc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCCNC1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 3,4-dihydro-1-H-naphthalen-2-one (5 g, 34 mmol) in 1,2-dichloroethane (250 mL), propyl amine (2.8 mL, 34 mmol) was added, followed by addition of sodium triacetoxyborohydride (22 g, 102 mmol). The reaction was stirred at ambient temperature under nitrogen for 24 hours, at which time it was concentrated in vacuo. The remaining solid was partitioned between 1 M sodium hydroxide and ethyl acetate. The ethyl acetate was washed with brine, dried over magnesium sulfate, and filtered. The filtrate was acidified with 1 M HCl in ether and 6.3 g of propyl-(1,2,3,4-tetrahydro-naphthalen-2-yl)-amine was collected as a pale pink precipitate.
Reaction SMILES: C1C2C(COC([NH:18][C@H:19]([C:23]([N:25]([CH3:42])[C@@H:26]([C@@H:38]([CH3:41])[CH2:39][CH3:40])[C@H:27]([O:36][CH3:37])[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:24])[CH:20]([CH3:22])[CH3:21])=O)C3C(=CC=CC=3)C=2C=CC=1.C(NCC)C>O1CCCC1.CC1CCCO1>[CH3:37][O:36][C@@H:27]([C@@H:26]([N:25]([CH3:42])[C:23](=[O:24])[C@H:19]([CH:20]([CH3:22])[CH3:21])[NH2:18])[C@@H:38]([CH3:41])[CH2:39][CH3:40])[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C
Solvent: CC1CCCO1
Solvent: CCNCC
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](N)C(C)C
Reaction time: 6 h

Procedure:
To a solution of #5 (26 g, 42 mmol, 1 eq.) in tetrahydrofuran (260 mL, 0.16 M) was added diethylamine (22 mL) over 30 minutes. The reaction was stirred for about 6 hours and the suspension was then filtered through Celite and washed with additional tetrahydrofuran (25 mL). The filtrate was concentrated in vacuo to provide a pale yellow oil, which was redissolved in 2-methyltetrahydrofuran (50 mL) and concentrated again to ensure complete removal of diethylamine. The crude oil of #6 (>15.25 g) was taken into the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:19])=[C:6]([C:8]2[C:9](=[O:18])[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[CH:13][CH:12]=3)[CH:7]=1.CCN(C(C)C)C(C)C.[F:29][C:30]([F:41])([F:40])[C:31]1[CH:32]=[C:33]([CH:37]=[CH:38][CH:39]=1)[C:34](Cl)=[O:35]>C1COCC1.CCOC(C)=O>[Cl:19][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:34](=[O:35])[C:33]2[CH:37]=[CH:38][CH:39]=[C:31]([C:30]([F:29])([F:40])[F:41])[CH:32]=2)=[CH:7][C:6]=1[C:8]1[C:9](=[O:18])[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][N:14]=[CH:13][CH:12]=2
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: Nc1ccc(Cl)c(-c2cc3cnccc3[nH]c2=O)c1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Cl)c(-c2cc3cnccc3[nH]c2=O)c1)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(5-amino-2-chloro-phenyl)-1H-[1,6]-naphthyridin-2-one (60 mg, 0.23 mmol) and DIPEA (82 μl, 0.46 mmol) in anhydrous THF (2.5 mL), is added a solution of 3-trifluoromethyl-benzoyl chloride (44 μl). This mixture is stirred for 30 minutes at room temperature, diluted with EtOAc (50 mL), washed with water (10 mL) and brine (10 mL), dried over MgSO4, concentrated and purified by preparative HPLC, to give N-[4-chloro-3-(2-oxo-1,2-dihydro-[1,6]naphthyridin-3-yl)-phenyl]-3-trifluoromethyl-benzamide (18.3 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][N:18]4[C:26](=[O:27])[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19]4=[O:28])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:34]1[CH:39]=[N:38][CH:37]=[CH:36][N:35]=1)CCC>>[N:35]1[CH:36]=[CH:37][N:38]=[CH:39][C:34]=1[C:2]1[CH:3]=[C:4]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([CH2:17][N:18]4[C:19](=[O:28])[C:20]5[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:26]4=[O:27])=[CH:16][C:11]=3[N:10]=[CH:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc2c(c1)ncn2-c1cccc(Br)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Product: O=C1c2ccccc2C(=O)N1Cc1ccc2c(c1)ncn2-c1cccc(-c2cnccn2)c1

Procedure:
This was prepared analogously from 2-[1-(3-bromo phenyl)-1H-benzimidazole-5-yl methyl]-isoindole-1,3-dione and 2-tri butylstannylpyrazine.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.N12CCN(CC1)CC2.[CH3:17][N:18]([CH3:22])[C:19](Cl)=[S:20].O>CN(C=O)C>[CH3:17][N:18]([CH3:22])[C:19](=[S:20])[O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: CN(C)C(=S)Cl
Reactant: Oc1ccc(I)cc1
Agent: C1CN2CCN1CC2
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C(=S)Oc1ccc(I)cc1
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 95.8 %

Procedure:
To a stirred solution of p-iodophenol (20.0 g, 90.9 mmol) in DMF (200 mL) was added 1,4-diazabicyclo[2,2,2]octane (20.4 g, 181.8 mmol) and dimethylthiocarbamoyl chloride (16.9 g, 136.4 mmol). The resulting solution was stirred for 3.5 hr at 75° C. After cooling, 300 mL of water was added. The solid was collected with suction and was dissolved in EtOAc. The EtOAc layer was washed with water, dried over Na2SO4, and evaporated under a reduced pressure. The crude solid was recrystallized from H2O to give the 26.75 g (96%) O-p-iodophenyl dimethylthiocarbamate as a pale a yellow crystalline powder. IR (KBr) 1479, 1207, 827 cm−1; 1H-NMR (400 MHz, CDCl3) δ 3.37 (s, 3H), 3.45 (s, 3H), 6.83 (d, J=8.8 Hz, 2H), 7.69 (d, J=8.3 Hz, 2H); MS (FAB) m/z 307 (M++1); Anal. Calcd for C9H10INOS: C, 35.19; H, 3.28; N, 4.56. Found: C, 35.17; H, 3.35; N, 4.44.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)[N:12]([CH3:22])[C:13]=2[S:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:5][CH:4]=1)#[N:2].[N:29]([Sn](C)(C)C)=[N+:30]=[N-:31]>C1(C)C(C)=CC=CC=1>[Cl:21][C:18]1[CH:19]=[CH:20][C:15]([S:14][C:13]2[N:12]([CH3:22])[C:11]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=3)=[N:10][C:9]=2[C:6]2[CH:5]=[CH:4][C:3]([C:1]3[N:29]=[N:30][NH:31][N:2]=3)=[CH:8][CH:7]=2)=[CH:16][CH:17]=1
Reactant: Cn1c(-c2ccccn2)nc(-c2ccc(C#N)cc2)c1Sc1ccc(Cl)cc1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Solvent: Cc1ccccc1C
Product: Cn1c(-c2ccccn2)nc(-c2ccc(-c3nn[nH]n3)cc2)c1Sc1ccc(Cl)cc1

Procedure:
A solution of 2-{4-(4-cyanophenyl)-5-[(4-chlorophenyl)thio]-1-methyl-1H-imidazol-2-yl}pyridine (Example 23, 160 mg, 0.41 mmol) and azidotrimethyltin (420 mg, 2.0 mmol) in xylene (1.5 mL) was heated at 140° C. under nitrogen for 2 hrs. After cooling, the reaction mixture was filtered through a pad of Celite and silica, and the filtrate was concentrated to afford 2-{5-[(4-Chlorophenyl)thio]-1-methyl-4-[4-(2H-tetrazol-5-yl)phenyl]-1H-imidazol-2-yl}pyridine, which was used in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[CH:3]=1.[N+:19]([O-])([OH:21])=[O:20]>C(O)(=O)C>[OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:4](=[O:18])[C:3]=1[N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: O=c1cc(O)c2ccccc2n1-c1ccccc1
Solvent: CC(=O)O
Product: O=c1c([N+](=O)[O-])c(O)c2ccccc2n1-c1ccccc1

Procedure:
A solution of 4-hydroxy-1-phenyl carbostyril (2.20g.; 0.0093 mole) in glacial acetic acid (10 ml.) was treated rapidly with concentrated nitric acid (2.5 ml.+ d 1.42) and the mixture heated on a steam bath for 21/2 mins. The red solution deposited a dark yellow solid on cooling which, after dilution with ethanol, was filtered off and washed well with ethanol, m.p. (AcOH - EtOH) 167°-169°C. (Found: C, 64.13; H, 3.70; N, 9.85; C15H10N2O4 requires; C, 63.83; H, 3.57; N, 9.92%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]([N+:15]([O-:17])=[O:16])=[N:13][OH:14])[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:6]=2[CH:25]=1.[CH3:26]COCC>O1CCCC1.[N+](=C)=[N-]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([C:12]([N+:15]([O-:17])=[O:16])=[N:13][O:14][CH3:26])[CH2:9][N:8]=[C:7]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:6]=2[CH:25]=1
Reactant: O=[N+]([O-])C(=NO)C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Reactant: CCOCC
Agent: C=[N+]=[N-]
Solvent: C1CCOC1
Product: CON=C(C1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1)[N+](=O)[O-]

Procedure:
A solution of diazomethane in ether was added to a suspension of 6 g (0.0163 mole) of 7-chloro-5-(2-fluorophenyl)-N-hydroxy-α-nitro-3H-1,4-benzodiazepine-2-methanimine in 100 ml of tetrahydrofuran. After sitting at room temperature for 1 hr in excess diazomethane was destroyed by addition of glacial acetic acid. The solvent was evaporated under reduced pressure and the residue was passed over 100 g of silica gel using methylene chloride. Crystallization from ether/hexane gave light yellow crystals with mp 130°-133° C.
Reaction SMILES: S(O)(=O)(=[O:3])C.[N:6]1[CH:11]=[CH:10][CH:9]=[N:8][CH:7]=1.FC1C=CC([CH2:17][NH2:18])=CC=1>CCO>[N:6]1[CH:11]=[CH:10][CH:9]=[N:8][C:7]=1[C:17]([NH2:18])=[O:3]
Reactant: NCc1ccc(F)cc1
Reactant: CS(=O)(=O)O
Reactant: c1cncnc1
Solvent: CCO
Product: NC(=O)c1ncccn1
Reaction time: 1 h
Yield: 126.4 %

Procedure:
To a solution of seven-membered ring-pyrimidine mesylate 9 (6 g) in EtOH (80 mL) was added 4-fluorobenzylamine (5.060 g). The resulting solution was reflux for 8 h. (100% conversion by HPLC). The reaction mixture was concentrated to about 20 mL total volume, and 80 mL of EtOAc was added. To the resulting solution was added 20% brine (15 mL), 4 N HCl (15 mL), and water 10 mL). After a phase cut, the aqueous layer was back-extracted with EtOAc (25 mL). The combined organic layers were washed with 4 N HCl: 20% brine (1:1, 3×15 mL), brine (15 mL). The organic solution was concentrated to a total volume about 30 mL. Hexane-(70 mL) was slowly added to the solution over 1 h. The resulting slurry was aged at 0-5° C. for 1 h. The crystalline solid was filtered off, washed with hexane:EtOAc (4:1, 50 mL), dried under vacuum with nitrogen sweep to afford seven-membered ring-pyrimidine amide 10 (5.30 g, 86%, HPLC>97A %). 1H NMR (CDCl3, 400 MHz) δ: 11.85 (br s, 1H), 7.84 (br s, 0.5H), 7.68 (br s, 0.5H), 7.31 (m, 2H), 7.04 (m, 2H), 5.40-4.90 (m, 2H), 4.53 (m, 2H), 3.38 (m, 1H), 2.87 (s, 3H), 2.20-2.15 (m, 3H), 1.90-1.40 (m, 3H), 1.37 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]([CH3:14])[CH:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[C:19]1[C:27](O)=[O:28].C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC>CN(C=O)C.CN(C1C=CN=CC=1)C.O>[CH3:14][N:7]([CH2:6][C:5]1[CH:4]=[CH:3][C:2]([NH:1][C:27]([C:19]2[N:18]([CH3:17])[C:26]3[C:21]([CH:20]=2)=[CH:22][CH:23]=[CH:24][CH:25]=3)=[O:28])=[CH:16][CH:15]=1)[CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1
Reactant: Cn1c(C(=O)O)cc2ccccc21
Reactant: CN(Cc1ccc(N)cc1)C1CCOCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CN(Cc1ccc(NC(=O)c2cc3ccccc3n2C)cc1)C1CCOCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
EDIC (0.33 mmol, 0.07 g) was added in one portion to a mixture of (4-amino-benzyl)-methyl-(tetrahydro-pyran -4-yl)-amine Compound 1d (0.25 mmol, 0.06 g), 1-methyl-1H-indole-2-carboxylic acid Compound 12a (0.22 mmol, 0.04 g) and HOBt (0.22 mmol, 0.03 g) in DMF (5.0 mL) at 0° C. The resulting suspension was warmed to r.t. and then a crystal of DMAP and Et3N (0.65 mmol, 0.11 mL) was added and the reaction mixture was stirred overnight. The resulting orange-yellow suspension was poured in water and was extracted with EtOAc (25 mL). The organic layer was washed with water (2×20 mL) followed by 5% NaOH solution (10 mL) and brine. The organic layer was separated, dried over Na2SO4 and filtered. The solvent was removed in vacuo and the resulting residue was purified by preparative TLC (15:1 CH2Cl2/MeOH) to yield 1-methyl-1H-indole-2-carboxylic acid (4-{[methyl-(tetrahydro-pyran -4-yl)-amino]-methyl}-phenyl)-amide Compound 12b as a pale yellow solid (0.05 g, 60%). MS m/e 378 (M+H, 100%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH2:2]1.[OH-].[Na+].O.Cl[C:11]1[N:16]=[C:15]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[C:20]([Cl:26])[CH:19]=2)[N:14]=[C:13]([NH:27][CH:28]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[N:12]=1>O1CCOCC1>[Cl:26][C:20]1[CH:19]=[C:18]([NH:17][C:15]2[N:14]=[C:13]([NH:27][CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[N:12]=[C:11]([N:1]3[CH2:6][CH2:5][S:4][CH2:3][CH2:2]3)[N:16]=2)[CH:23]=[CH:22][C:21]=1[O:24][CH3:25]
Reactant: C1CSCCN1
Reactant: COc1ccc(Nc2nc(Cl)nc(NC3CCCCCC3)n2)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Nc2nc(NC3CCCCCC3)nc(N3CCSCC3)n2)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of thiomorpholine (97 mg, 0.942 mmol), sodium hydroxide (31.4 mg, 0.785 mmol) and water (0.5 mL) in 1,4-dioxane (15 mL) was heated to reflux for 3 hours with stirring under nitrogen atmosphere and then cooled to 25° C. followed by the addition of compound 133 (0.30 g, 0.785 mmol) at same temperature. The mixture was heated to reflux for 12 hours, concentrated under vacuum and diluted with water (20 mL). The mixture was then extracted with EtOAc (2×20 mL). The combined organic layers were washed with water (2×10 mL), dried over anhydrous Na2SO4 and concentrated under vacuum. The residue thus obtained was purified by column chromatography (10-20% EtOAc-Hexane) to afford the title compound E27 as a pale yellow solid (0.26 g, 74%). mp 78-80° C.; HPLC: Inertsil ODS 3V (250×4.6 mm) 5 microns [solvent A=0.01 M KH2PO4; solvent B=CH3CN], A:B=20:80; 220 nm, Rt 20.36 min, 97.15% purity; MS (CI): m/z 449 (M+H, 100).
Reaction SMILES: C[O-].[Na+].[N+:4](C)([O-:6])=[O:5].[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH:16][S:17]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:19])=[O:18])=[CH:11][CH:10]=1>CS(C)=O>[F:8][C:9]1[CH:10]=[CH:11][C:12]([CH:15]([N+:4]([O-:6])=[O:5])[CH2:16][S:17]([O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)(=[O:18])=[O:19])=[CH:13][CH:14]=1
Reactant: C[N+](=O)[O-]
Reactant: O=S(=O)(C=Cc1ccc(F)cc1)Oc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=[N+]([O-])C(CS(=O)(=O)Oc1ccccc1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
56.3 g of sodium methanolate were taken up in 1 l of DMSO and, at RT, 56.3 ml of nitromethane were added dropwise. The internal temperature rose to 40° C. during this. Then, at a temperature between 26° C. and 30° C., a solution of 145.0 g of phenyl 2-(4-fluorophenyl)ethenesulfonate in 1 l of DMSO was added dropwise. Stirring at RT for 1 hour was followed by leaving to stand at RT for 16 hours and then stirring at RT for a further 6 hours and 30 minutes. The reaction mixture was then poured into 8 kg of ice and extracted 5 times with 2 l of EA each time. After drying over Na2SO4, the solvent was removed in vacuo. Chromatography on silica gel with EA/HEP 1:5 afforded 77.35 g of a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[CH2:16][C:17]#N)=[CH:11][CH:10]=1.C([OH:26])CCCCC.OS(O)(=O)=O.[OH2:32]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]([CH3:19])[CH2:16][C:17]([OH:26])=[O:32])=[CH:11][CH:10]=1
Reactant: O
Reactant: CCCCCCO
Reactant: CC(CC#N)c1ccc(-c2ccc(F)cc2F)cc1
Agent: O=S(=O)(O)O
Product: CC(CC(=O)O)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
1 g. of 3-(2',4'-difluoro-4-biphenylyl)butyronitrile, 3 ml. of n-hexanol and 0.1 g. of concentrated H2SO4 are heated under reflux for 48 hours. 3 ml of water are added and the mixture is heated under reflux for 48 hours more and worked up in the customary manner to give 3-(2',4'-difluoro-4-biphenylyl)butyric acid, m.p. 109°-110°.