Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].C(Cl)(Cl)Cl.[C:14](Cl)(=[O:16])[CH3:15]>C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(C)c(O)c1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
At 0° C., to a mixture of 2,5-dimethylphenol 20 g and chloroform 150 ml was added acetyl chloride 15 g and triethylamine 49 g. The resulting mixture was raised to room temperature and was stirred for four hours. Then, the reaction mixture was extracted with chloroform. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give acetic acid 2,5-dimethylphenyl ester 24 g.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]3[NH:14][C:13]4[CH2:15][CH2:16][N:17]([C:19]5[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=5)[CH2:18][C:12]=4[C:7]=3[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=[O:30].[Cs+].[Cs+].C[N+]([O-])(C)C.CS(C)=O>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[NH:14][C:13]([CH2:15][CH2:16][NH:17][C:19]4[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][CH:20]=4)=[C:12]([CH:18]=[O:30])[C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: CS(=O)(=O)c1ccc(N2CCc3[nH]c4c(cnc5cc(Cl)ccc54)c3C2)cc1
Reactant: O=C([O-])[O-]
Agent: C[N+](C)(C)[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: CS(=O)(=O)c1ccc(NCCc2[nH]c3c(cnc4cc(Cl)ccc43)c2C=O)cc1
Yield: 24.1 %

Procedure:
A mixture of 3.0 g (7.28 mmol) of the compound of step A, above, 4.74 g (14.6 mmol) of Cs2CO3, 1.62 g (14.6 mmol) of trimethylamine N-oxide and 24 ml of dimethyl sulfoxide is stirred at 120° C. for 4 days. The reaction mixture is cooled and diluted with 400 ml of water producing a brown precipitate which is collected by filtration. The crude product is dissolved in methanol, filtered and evaporated onto silica gel. The coated silica gel is then added to a column and eluted with 10% methanol in chloroform to yield 0.75 g (24%) of title compound as an off white solid.
Reaction SMILES: C[N:2]([CH3:20])/[CH:3]=[C:4](/[C:10](=[O:19])[C:11]1[CH:16]=[C:15]([I:17])[CH:14]=[CH:13][C:12]=1F)\[C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH3:21][N:22]1[CH2:27][CH2:26][CH:25]([CH:28](N)C)[CH2:24][CH2:23]1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[I:17][C:15]1[CH:16]=[C:11]2[C:12](=[CH:13][CH:14]=1)[N:2]([CH2:20][CH2:28][CH:25]1[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]1)[CH:3]=[C:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:10]2=[O:19]
Reactant: CCOC(=O)/C(=C\N(C)C)C(=O)c1cc(I)ccc1F
Reactant: CC(N)C1CCN(C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(CCC2CCN(C)CC2)c2ccc(I)cc2c1=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 90.1 %

Procedure:
To a solution of ethyl 3-(dimethylamino)-2-(2-fluoro-5-iodobenzoyl)acrylate (Intermediate 24, 1 g, 2.56 mmol) dissolved in THF (5.5 mL) was added 2-(1-methylpiperidin-4-yl-ethanamine (0.406 mL, 2.56 mmol). The reaction mixture was stirred at 60° C. for 2 h. Potassium carbonate was added (1.06 g, 7.67 mmol), and the reaction was stirred for 18 h and cooled down to room temperature. The reaction was quenched with 1 N HCl and partitioned between dichloromethane (10 mL) and water (20 mL). The aqueous layer was extracted with dichloromethane (2×10 mL), and the organics were dried over sodium sulfate and concentrated to give ethyl 6-iodo-1-(2-(1-methylpiperidin-4-yl)ethyl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as a light yellow solid (1.08 g, 90%).
Reaction SMILES: [CH2:1]([N:8]1[C:13](Cl)=[N:12][C:11]([O:15][CH3:16])=[N:10][S:9]1(=[O:18])=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C([N+:25]([O-])=O)=CC=C(O)C=1.N1C=CC=CC=1>C(Cl)Cl>[NH2:25][C:13]1[N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:9](=[O:18])(=[O:17])[N:10]=[C:11]([O:15][CH3:16])[N:12]=1
Reactant: COC1=NS(=O)(=O)N(Cc2ccccc2)C(Cl)=N1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC1=NS(=O)(=O)N(Cc2ccccc2)C(N)=N1

Procedure:
A solution of 2-benzyl-3-chloro-5-methoxy-2H-1,2,4,6-thiatriazine-1,1-dioxide (3.8 g) in methylene chloride (10 ml) is added dropwise to a stirred mixture of p-nitrophenol (1.7 g) and pyridine (2.4 g) in methylene chloride (20 ml). The reaction mixture is heated to reflux for 3 hours, cooled, washed with 3N aqueous HCl and saturated aqueous Na2CO3. The methylene chloride layer is dried over MgSO4, filtered and evaporated in vacuo yielding the desired product as an oil.
Reaction SMILES: [H][H].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1.[C-:12]#[N:13].[Na+].S(=O)(O)[O-].[Na+]>>[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]([OH:9])[C:12]#[N:13])=[CH:6][CH:5]=1
Reactant: [H][H]
Reactant: [C-]#N
Reactant: O=Cc1ccc(O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Product: N#CC(O)c1ccc(O)cc1

Procedure:
The afore-mentioned process can not advantageously be employed to prepare cyanobisphenols wherein R1 is hydrogen. When R1 and all R2 are hydrogen, the following procedure is effective to prepare the cyanobisphenol. 4-Hydroxybenzaldehyde is reacted with sodium cyanide in the presence of sodium bisulfite to yield 4-hydroxymandelonitrile, a cyanohydrin which has the following formula. ##STR13## The reaction and conditions are described in Landenberg et al., "Synthesis of 3-Hydroxy-2(3)-Benzofuranone and of 4-Hydroxymandelic Acid", 58 J. Amer Chem Soc. 1292 (1936) and in Taylor, et al, "a-N,N-Dimethylaminophenylacetonitrile", 5 Organic Synthesis 437 (1962). 4-Hydroxymandelonitrile is then reacted with excess phenol in the presence of sulfuric acid at a temperature of about 55° C. to 60° C. to yield bis-(4-hydroxyphenyl)acetonitrile: ##STR14## A description of the reaction and its conditions is found in Schraufstatter, "Darstellung und Reaktionen von 4,4'-Dihydroxydiphenylacetonitril", 295 Arch. Pharm. 269 (1962).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][O:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][O:9]2)=[CH:4][CH:3]=1.[C:19]([O-:22])([O-])=O.[K+].[K+].[CH2:25](I)[CH2:26][CH2:27][CH2:28][CH2:29]C>CN(C=O)C>[CH2:19]([O:22][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][O:12][C@H:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:10][O:9]2)=[CH:4][CH:3]=1)[CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCI
Reactant: O=C([O-])[O-]
Reactant: CCCCC[C@@H]1CO[C@@H](c2ccc(N)cc2)CO1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc([C@H]2CO[C@H](CCCCC)CO2)cc1
Reaction time: 16 h

Procedure:
A mixture of 25 g. trans-2-p-hydroxyphenyl-5-pentyl-1,4-dioxane (obtainable by nitration of trans-2-phenyl-5-pentyl-1,4-dioxane, hydrogenation of the trans-2-p-nitrophenyl-5-pentyl-1,4-dioxane obtained to give trans-2-p-aminophenyl-5-pentyl-1,4-dioxane, diazotisation and hydrolysis), 6.9 g. K2CO3, 25 g. K2CO3, 25 g. hexyl iodide and 250 ml. DMF is heated, while stirring, for 16 hours at 80°, then cooled and up as usual. One obtains trans-2-p-hexoxyphenyl-5-pentyl-1,4-dioxane.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]([OH:32])=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[CH:33]([NH:35][NH2:36])=[O:34].CCOC(C)=O>C1COCC1.[Cl-].[Na+].O>[CH2:13]([O:20][N:21]1[C:27](=[O:28])[N:26]2[CH2:29][C@H:22]1[CH2:23][CH2:24][C@H:25]2[C:30]([NH:36][NH:35][CH:33]=[O:34])=[O:32])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: NNC=O
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=CNNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 190.9 %

Procedure:
1,1′-Carbonyldiimidazole (5.8 g, 36.2 mmol) was added to a solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (5.0 g, 18.1 mmol) in dry THF (200 mL) at 0° C. The reaction mixture was stirred at rt for 3 hrs. Formohydrazide (5.4 g, 90.5 mmol) was added in one portion, and the reaction mixture was stirred for additional 3 hrs. The mixture was then diluted with brine and exacted with EtOAc (3×). The combined organic layer was washed with Saturated sodium chloride (2×), dried over Na2SO4, and concentrated to afford crude (2S,5R)-6-(benzyloxy)-N′-formyl-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbohydrazide (˜11 g), which was directly used in the next step. ESI-MS (EI+, m/z): 319.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:20]4[S:27][C:26]([C:28]5[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=5)=[CH:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1>>[NH:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:20]4[S:27][C:26]([C:28]5[CH:35]=[CH:34][C:31]([CH2:32][N:5]6[CH2:6][CH2:7][CH2:8][CH:4]6[CH2:3][O:2][CH3:1])=[CH:30][CH:29]=5)=[CH:25][C:21]=4[N:22]=[CH:23][N:24]=3)=[CH:15][CH:16]=2)[CH:11]=[CH:10]1
Reactant: COCC1CCCN1
Reactant: O=Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1
Product: COCC1CCCN1Cc1ccc(-c2cc3ncnc(Nc4ccc5[nH]ccc5c4)c3s2)cc1

Procedure:
The title compound was prepared from 2-methoxymethyl-pyrrolidine and 4-[4-(1H-indol-5-ylamino)-thieno[3,2-d]pyrimidin-6-yl]-benzaldehyde by a procedure analogous to example 17. M.P. 161-177° C.; LC-MS: 470 (MH+); HPLC RT: 4.55 minutes.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:36])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH:25]=O)=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH3:34])[CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:14]=1[CH3:35].[NH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[C:3]=1[CH2:10][NH:11][C:12](=[O:36])[C:13]1[CH:18]=[C:17]([C:19]2[CH:20]=[N:21][C:22]([CH2:25][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:23][CH:24]=2)[CH:16]=[C:15]([N:27]([CH3:34])[CH:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[C:14]=1[CH3:35]
Reactant: C1COCCN1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(C=O)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)nc3)cc(N(C)C3CCOCC3)c2C)c(=O)[nH]1
Temperature: 25 °C
Reaction time: 18 h
Yield: 70 %

Procedure:
To a stirred solution of N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(6-formylpyridin-3-yl)-2-methyl-3-(methyl(tetrahydro-2H-pyran-4-yl)amino)benzamide (1 equiv.) and morpholine (5 equiv.) in methanol (10 mL), acetic acid (2 equiv.) was added and reaction stirred at room temperature for 18 h. Then sodium cyanoborohydride (2.5 equiv.) was added at 0° C. and reaction stirred overnight at room temperature. On completion, solvent was removed under reduced pressure and crude material was purified by column chromatography to afford the title compound (0.08 g, 70%). LCMS: 560.30 (M+1)+; HPLC: 99.22% (@ 254 nm) (Rt; 3.944; Method: Column: YMC ODS-A 150 mm×4.6 mm×5μ; Mobile Phase: A; 0.05% TFA in water/B; 0.05% TFA in acetonitrile; Inj. Vol: 10 μL, Col. Temp.: 30° C.; Flow rate: 1.4 mL/min.; Gradient: 5% B to 95% B in 8 min, Hold for 1.5 min, 9.51-12 min 5% B); 1H NMR (DMSO-d6, 400 MHz) δ 11.45 (s, 1H), 8.76 (s, 1H), 8.17 (t, 1H), 8.02 (d, 1H, J=7.6 Hz), 7.50 (d, 1H, J=8 Hz), 7.41 (s, 1H), 7.23 (s, 1H), 5.85 (s, 1H), 4.28 (d, 2H, J=4.8 Hz), 3.85 (d, 2H, J=11.2 Hz), 3.61 (s, 3H), 3.59-3.60 (m, 3H), 3.24-3.29 (m, 2H), 3.02-3.05 (m, 1H), 2.64 (s, 3H), 2.42 (bs, 4H), 2.24 (s, 3H), 2.20 (s, 3H), 2.10 (s, 3H), 1.61 (bs, 4H).
Reaction SMILES: [CH2:1]([C:3]1([C:18]2[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=2)[CH:8]2[CH:4]1[CH2:5][N:6]([CH2:9][CH2:10][CH2:11][C:12]1C=CC=[CH:14][CH:13]=1)[CH2:7]2)[CH3:2].[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26]>N1C=CC=CC=1>[CH2:1]([C:3]1([C:18]2[CH:19]=[C:20]([NH:24][S:27]([CH2:25][CH3:26])(=[O:29])=[O:28])[CH:21]=[CH:22][CH:23]=2)[CH:8]2[CH:4]1[CH2:5][N:6]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[CH2:7]2)[CH3:2]
Reactant: CCC1(c2cccc(N)c2)C2CN(CCCc3ccccc3)CC21
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCCCCCN1CC2C(C1)C2(CC)c1cccc(NS(=O)(=O)CC)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 25.4 %

Procedure:
To a solution of 3-[6-ethyl-3-(3-phenylpropyl)-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation 20, 500 mg, 1.56 mmol) in pyridine (5 ml), at 0° C. under nitrogen was added dropwise over 5 minutes ethanesulfonylchloride (0.25 ml, 0.34 g, 2.6 mmol). The mixture was allowed to warm to room temperature and was stirred for 18 hours. The mixture was concentrated in vacuo and the residue was purified by silica (25 g) column chromatography eluting with 50:50:1 ethyl acetate:hexane:ammonia solution (0.880). Product-containing fractions were combined and concentrated in vacuo to give the title compound as a pale yellow oil (150 mg, 31%).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:23]=[CH:22][C:21](Cl)=[N:20][C:8]=3[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N+:10]([O-:12])[CH2:11][C:5]2=[N:4][NH:3]1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1.O.C(O)(=O)C>C(Cl)(Cl)Cl>[O:1]=[C:2]1[N:6]2[C:7]3[CH:23]=[CH:22][C:21]([N:25]4[CH2:29][CH2:28][CH2:27][CH2:26]4)=[N:20][C:8]=3[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[Cl:19])=[N+:10]([O-:12])[CH2:11][C:5]2=[N:4][NH:3]1
Reactant: C1CCNC1
Reactant: O=c1[nH]nc2n1-c1ccc(Cl)nc1C(c1ccccc1Cl)=[N+]([O-])C2
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(=O)O
Product: O=c1[nH]nc2n1-c1ccc(N3CCCC3)nc1C(c1ccccc1Cl)=[N+]([O-])C2
Reaction time: 1 h

Procedure:
15 grams of 1-keto-6-(o-chlorophenyl)-8-chloro-1,2-dihydro-4H-s-triazolo-(4,3-a)-pyrido-(2,3-f)-(1,4)-diazepine-5-oxide in 50 ml. of pyrrolidine were boiled at reflux with stirring for 1 hour. Then it was poured into 600 ml. of water and neutralized with acetic acid. The precipitated material was shaken with chloroform, the chloroform layer washed with water, dried and evaporated to dryness. The residue was dissolved in methanol, acidified with ethanolic HCl solution and treated with ether up to the beginning of turbidity. The material crystallized out. It was filtered off with suction and washed with methanol-ether, and then recrystallized again from methanol-ether. Yield 4 grams; M.P. 200° C. (hydrochloride).
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:7]([Sn+:11]([CH2:16][CH2:17][CH2:18][CH3:19])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:8][CH2:9][CH3:10].[C:20]1([CH3:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[CH2:16]([Sn+:11]([CH2:7][CH2:8][CH2:9][CH3:10])[CH2:12][CH2:13][CH2:14][CH3:15])[CH2:17][CH2:18][CH3:19].[CH2:1]=[CH:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Cc1ccccc1
Agent: C=C(C)C(=O)[O-]
Agent: CCCC[Sn+](CCCC)CCCC
Product: C=Cc1ccccc1

Procedure:
S5 was synthesized by the general method described above. In this synthesis, equimolar quantities of tri-n-butyltin methacrylate (0.1 mole) and stryene (0.1 mole) were reacted with the azo initiator* in 85 ml of toluene for 96 hours. The resultant polymer was a transparent, orange tinted elastomer which could be cast as a film from the toluene solution. Analysis showed 20.90% Sn.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([NH2:15])=[CH:8][C:7]=1[CH3:16])[CH3:2].[F:18][C:19]([F:29])([F:28])[C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1.O>C(O)C>[CH2:1]([O:3][C:4](=[O:17])[NH:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([NH:15][CH2:24][C:23]2[CH:22]=[CH:21][C:20]([C:19]([F:18])([F:28])[F:29])=[CH:27][CH:26]=2)=[CH:8][C:7]=1[CH3:16])[CH3:2]
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Nc1c(C)cc(N)cc1[N+](=O)[O-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)Nc1c(C)cc(NCc2ccc(C(F)(F)F)cc2)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 75 %

Procedure:
(4-Amino-2-methyl-6-nitro-phenyl)-carbamic acid ethyl ester (0.50 g) and 4-trifluoromethyl-benzaldehyde (0.29 mL) were dissolved in ethanol (10 mL) and refluxed for 16 h. The reaction mixture was poured into water (75 mL) and the precipitate collected by filtration. Sodium cyanoborohydride (0.3 g) and acetic acid (0.5 mL) were added to the precipitate dispersed in methanol (10 mL) and stirred for 60 minutes. The reaction mixture was filtered, water (50 mL) was added and the organic solvent was removed in vacuo. The product was allowed to precipitate at 25° C. and collected by filtration and washed with water (100 mL) to furnish 0.47 g (75% yield) of the title compound as a yellow solid. LC-MS (m/z) 398 (MH+); tR=3.18, (UV, ELSD) 86%, 94%. 1H NMR (500 MHz, DMSO-d6): 1.20 (1,3H), 2.10 (s, 3H), 4.05 (m, 2H), 4.45 (m, 2H), 6.75 (m, 1H), 6.90 (m, 1H), 7.55 (m, 2H), 7.73 (m, 2H), 8.75 (s, 1H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([CH:11]=1)=[C:9]([CH2:12][CH3:13])[CH:8]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6]2=[O:19].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1>N1C=CC=CC=1>[CH2:12]([C:9]1[CH:8]=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:6](=[O:19])[N:5]2[C:10]=1[CH:11]=[C:2]([N:24]1[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]1)[CH:3]=[CH:4]2)[CH3:13]
Reactant: CN1CCNCC1
Reactant: CCOC(=O)c1cc(CC)c2cc(Cl)ccn2c1=O
Solvent: c1ccncc1
Product: CCOC(=O)c1cc(CC)c2cc(N3CCN(C)CC3)ccn2c1=O
Temperature: 85 °C
Yield: 99.9 %

Procedure:
Ethyl 8-chloro-1-ethyl-4H-quinolizin-4-one-3-carboxylate (279 mg, 1.0 mmol), the product of Step 3 of Example 62, was dissolved in 5 mL of dry pyridine under a nitrogen atmosphere. To the resultant solution was added 2 mL (2.0 mmol) of N-methylpiperazine and the stirred reaction mixture was heated at 85° C. for 2.5 hours. The reaction mixture was allowed to cool to ambient temperature and then concentrated in vacuo in order to remove all of the pyridine. The residue was dissolved in 50 mL of methylene chloride and the methylene chloride solution was washed with 50 mL of 5% aqueous sodium bicarbonate solution. The aqueous layer was extracted with 3×50 mL of methylene chloride and the combined methylene chloride solutions were dried over anhydrous sodium sulfate, filtered and concentrated and dried in vacuo to afford 343 mg of the title compound, m.p. 94°-96° C.; MS DCI-NH3 : 344 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[Cl:35][C:36]1[N:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](Cl)=[O:39]>CN(C=O)C>[Cl:35][C:36]1[C:37]([C:38]([N:25]2[CH2:26][CH2:27][CH:22]([O:21][C:16]3[C:17]([N+:18]([O-:20])=[O:19])=[C:12]([NH:11][C:8]4[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=4)[N:13]=[CH:14][N:15]=3)[CH2:23][CH2:24]2)=[O:39])=[CH:41][CH:42]=[CH:43][N:44]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCN(C(=O)c4cccnc4Cl)CC3)c2[N+](=O)[O-])cc1

Procedure:
Compound A25 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (16 mg, 0.037 mmol), triethylamine (50 μl), 2-chloro-nicotinoyl chloride (10 mg, 0.046 mmol), DMF (1 mL), 1H NMR (CDCl3, 400 MHz) δ 1.91 (m, 1H), 2.00 (m, 1H), 2.14 (m, 2H), 3.08 (s, 3H), 3.36 (m, 1H), 3.65 (m, 2H), 4.13 (m, 1H), 4.31 (m, 1H), 5.72 (m, 1H), 7.36 (m, 1H), 7.69 (m, 1H), 7.87 (d, 2H), 7.97 (d, 2H), 8.41 (m, 1H), 8.47 (m, 1H), 10.20 (s, 1H). Exact mass calculated for C22H21ClN6O6S 532.09, found 533.3 (MH+).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:12][NH2:13])(=[O:11])=[O:10].[NH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([CH3:23])[N:17]=1.CO.ClCCl.CCOCC>ClCCl>[C:1]1([CH3:14])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O-:12])(=[O:11])=[O:10].[NH2:13][N+:19]1[C:20]([CH3:22])=[CH:21][C:16]([NH2:15])=[N:17][C:18]=1[CH3:23]
Reactant: Cc1cc(C)c(S(=O)(=O)ON)c(C)c1
Reactant: Cc1cc(N)nc(C)n1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CO
Product: Cc1cc(C)c(S(=O)(=O)[O-])c(C)c1
Product: Cc1cc(N)nc(C)[n+]1N
Reaction time: 2 h

Procedure:
O-(Mesitylenesulfonyl)hydroxylamine containing ca. 18% water (3.03 g, 2.56 g dry wt., ca. 11.9 mmole) was dissolved in dichloromethane (15 mL) and dried over Na2SO4 and filtered. This was added dropwise to a solution of 4-amino-2,6-dimethylpyrimidine (1 g, 8.12 mmole) in 1:6 methanol-dichloromethane (10.5 mL) in an ice bath with stirring for 2 hr. Ether (20 mL) was added and the mixture was stored at 4 C for 18 hr. The crude aminated product was filtered out and dried (2.65 g). This was dissolved in a minimum amount of methanol, filtered and reduced in volume to ca. 20 mL under reduced pressure. This was diluted with dichloromethane (15 mL) and ether (20 mL) was added, and the mixture was stirred at room temp. for 2 hr. Filtration, washing with 1:1 dichloromethane-ether and drying gave 0.73 g of a fraction, mp 262–264 C, consisting mainly of 1,6(or 4)-diamino-2,4(or 6)-dimethylpyrimidinium mesitylene-2-sulfonate. Storage of the filtrate resulted in deposition of more crystals, which were filtered out and washed with 1:1 dichloromethane-ether to give 1.39 g in two crops of a fraction, mp 194–196 C, consisting mainly of 1,4(or 6)-diamino-2,6(or 4)-dimethylpyrimidinium mesitylene-2-sulfonate. Isomer assignment is tentative.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[S:10][C:9]=2[CH:18]=1)=[O:4].[I-].[Li+]>N1C=CC=CC=1>[CH3:17][CH2:16][O:15][C:13]([C:11]1[S:10][C:9]2[CH:18]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=[CH:7][C:8]=2[CH:12]=1)=[O:14]
Reactant: CCOC(=O)c1cc2ccc(C(=O)OC)cc2s1
Agent: [I-]
Agent: [Li+]
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2ccc(C(=O)O)cc2s1
Temperature: 25 °C
Yield: 48.7 %

Procedure:
A mixture of benzo[b]thiophene-2,6-dicarboxylic acid 2-ethyl ester 6-methyl ester (3.9 g, 14.77 mmol) and Lithium iodide (10 g, 74.6 mmol) in anhydrous pyridine (30 ml, 9 vol) was stirred at reflux for 16 h. After cooling to r.t., the mixture was added (either as a melt or chipped out) to ice-cold 2N HCl (200 mL). The solid formed was isolated by filtration and washed with water (3×50 mL). The product was purified by recrystallisation from methanol to give the title compound (1.8 g, 49%). LCMS m/z 251 [M++H]+, 1H NMR (300 MHz, DMSO), δ: 1.35 (3H, t J=6.9 Hz, CH3), 4.38 (2H, q J=7.1 Hz, CH2), 7.99 (1H, d J=8.3 Hz, ArH), 8.12 (1H, d J=8.3 Hz, ArH), 8.27 (1H, s, ArH), 8.70 (1H, s, ArH).
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH2:9][C@H:8]([NH:12][C:13]2[S:14][C:15]3[CH:21]=[C:20]([OH:22])[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:7]1)(=[O:5])=[O:4])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[Cl:29][C:30]1[CH:35]=[C:34](F)[CH:33]=[CH:32][N:31]=1>CN1C(=O)CCC1.O.C(OCC)(=O)C>[Cl:29][C:30]1[CH:35]=[C:34]([O:22][C:20]2[CH:19]=[CH:18][C:16]3[N:17]=[C:13]([NH:12][C@H:8]4[CH2:9][CH2:10][CH2:11][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:7]4)[S:14][C:15]=3[CH:21]=2)[CH:33]=[CH:32][N:31]=1
Reactant: Fc1ccnc(Cl)c1
Reactant: CCS(=O)(=O)N1CCC[C@H](Nc2nc3ccc(O)cc3s2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: O
Product: CCS(=O)(=O)N1CCC[C@H](Nc2nc3ccc(Oc4ccnc(Cl)c4)cc3s2)C1
Temperature: 60 °C
Reaction time: 17 h

Procedure:
To a mixture of (S)-2-(1-(ethylsulfonyl)piperidin-3-ylamino)benzo[d]thiazol-6-ol (1.15 g, 3.37 mmol) and cesium carbonate (2.20 g, 6.74 mmole) in 12 ml of NMP was added 2-chloro-4-fluoropyridine (532 mg, 4.05 mmol). The reaction mixture was stirred at 60° C. for 17 hours. The reaction mixture was diluted with water (100 ml) and ethyl acetate (100 ml). The separated organic layer was washed with water (3×50 ml), saturated sodium bicarbonate solution (3×50 ml), water (50 ml), brine (100 ml) and dried over sodium sulfate. Concentration in vacuo and purification by flash chromatography over silica gel with ethyl acetate:hexane (1:1 to 3:1) provided the title compound. Yield: 671 mg. ES/MS m/z 453.0 (MH+), Rt=2.59 min.