Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[C:10]2[C:9]3[O:11][C@@:12]45[CH2:22][CH2:21][C@H:20]([OH:23])[C:19]([CH3:25])([CH3:24])[C@@H:18]4[CH2:17][CH2:16][C@H:15]([CH3:26])[C@@:13]5([CH3:27])[CH2:14][C:8]=3[C:7]([OH:28])=[CH:6][C:5]=2[C:4](=[O:29])[NH:3]1.[C:30]1(C)[CH:35]=CC(S([O-])(=O)=O)=C[CH:31]=1.[NH+]1C=CC=CC=1.C(OCC)(=O)C>C(O)CC>[OH:28][C:7]1[C:8]2[CH2:14][C@:13]3([CH3:27])[C@@H:15]([CH3:26])[CH2:16][CH2:17][C@H:18]4[C:19]([CH3:25])([CH3:24])[C@@H:20]([OH:23])[CH2:21][CH2:22][C@@:12]34[O:11][C:9]=2[C:10]2[CH:2]([O:1][CH2:31][CH2:30][CH3:35])[NH:3][C:4](=[O:29])[C:5]=2[CH:6]=1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: C[C@H]1CC[C@H]2C(C)(C)[C@@H](O)CC[C@]23Oc2c(c(O)cc4c2C(O)NC4=O)C[C@]13C
Agent: c1cc[nH+]cc1
Solvent: CCCO
Solvent: CCOC(C)=O
Product: CCCOC1NC(=O)c2cc(O)c3c(c21)O[C@@]12CC[C@H](O)C(C)(C)[C@@H]1CC[C@H](C)[C@@]2(C)C3
Temperature: 25 °C
Reaction time: 1 h
Yield: 207.7 %

Procedure:
To a solution of Compound (30a) (33 mg, 0.08 mmol) in 3.0 ml of 1-propanol was added 6 mg of pyridinium p-toluenesulfonate, and the mixture stirred at room temperature for one hour. To the reaction was added 20 ml of ethyl acetate. The mixture was washed with saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was purified by a column chromatography (Merck, Lobar column, size A; ethyl acetate), and by crystallization from ethyl acetate to give 22 mg (60%) of Compound (30c).
Reaction SMILES: [O:1]1[C:9]2[C:4](=[N:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:10].[Br:11]Br.O>CN(C)C=O>[Br:11][C:7]1[CH:8]=[C:9]2[O:1][C:2](=[O:10])[NH:3][C:4]2=[N:5][CH:6]=1
Reactant: O=c1[nH]c2ncccc2o1
Reactant: BrBr
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2ncc(Br)cc2o1
Temperature: 25 °C

Procedure:
After dissolving oxazolo[4,5-b]pyridin-2(3H)-one (5 g, 23.25 mmol) in N,N-dimethylformamide (100 ml), bromine (1.28 ml, 25.58 mmol) is slowly added. Stirring is maintained at room temperature for 2 hours. Water (50 ml) is then added to the reaction mixture; the title product is isolated after having been filtered, rinsed with a little water and dried in vacuo. The yield obtained is 90%. ##STR22##
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])=[CH:6][CH:5]=1.Br[CH:17]([CH2:22][CH:23]([CH3:25])[CH3:24])[C:18]([O:20][CH3:21])=[O:19].Cl>C1COCC1.C(OCC)C.C(OCC)(=O)C>[CH3:24][CH:23]([CH3:25])[CH2:22][CH:17]([O:15][CH:10]([C:7]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1)[C:11]([F:14])([F:13])[F:12])[C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)C(Br)CC(C)C
Reactant: OC(c1ccc(Br)cc1)C(F)(F)F
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(CC(C)C)OC(c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Sodium hydride (60% W, 2.16 mmol, 87 mg) was suspended in dry THF and cooled to 0° C. A solution of 1-(4-bromophenyl)-2,2,2-trifluoroethanol from example 69 step 2 was added slowly and stirred at 0° C. over 0.75 h. A solution of methyl 2-bromo-4-methylpentanoate from example 69 step 1 was added and the mixture was allowed to warmed to r.t. and stirred overnight. The reaction was treated with 0.1 N aqueous hydrochloric acid, diluted with diethyl ether and ethyl acetate. The phases are separated and the organic layer was washed with 0.1N aqueous hydrochloric acid then brine and dried over magnesium sulfate. The volatiles were removed unde reduced pressure to yield methyl 4-methyl-2-(2,2,2-trifluoro-1-phenylethoxy)pentanoate that was used without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([I:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:19]=[C:18]2[C:13]([CH:14]=[CH:15][CH:16]=[N:17]2)=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[I:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:19]=[C:18]3[C:13]([CH:14]=[CH:15][CH:16]=[N:17]3)=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Nc1ccc2cccnc2c1
Reactant: Ic1cc(I)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Ic1cc(Nc2ccc3cccnc3c2)ncn1

Procedure:
This compound could be prepared from 4,6-diiodo-pyrimidine and 7-aminoquinoline in the presence of K2CO3 and DMF.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[CH3:24][CH:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26]>>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:22]=[CH:21][C:20]([NH:23][S:27]([CH:25]([CH3:26])[CH3:24])(=[O:29])=[O:28])=[CH:19][CH:18]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1
Reactant: CC(C)S(=O)(=O)Cl
Product: CC(C)S(=O)(=O)Nc1ccc(C=C2c3ccccc3CCc3ccccc32)cc1

Procedure:
Following procedures essentially as described in Example 90, 4-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-phenylamine (100 mg, 0.336 mmol) and 2-propanesulfonyl chloride (144 mg, 1.01 mmol) affords the title compound. MS (ES) 426 (M+Na), 402 (M−H); HPLC shows 93% purity.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([CH3:10])=[N:6][N:5]2[C:11]=1[C:12]1[S:13][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)=[CH:15][C:16]=1[CH3:17].[CH2:25]1C[O:28][CH2:27][CH2:26]1.[Li+].CC([N-]C(C)C)C.CON(C)C(=O)CC>CCOC(C)=O>[CH3:1][C:2]1[N:3]=[C:4]2[C:9]([C:27](=[O:28])[CH2:26][CH3:25])=[CH:8][C:7]([CH3:10])=[N:6][N:5]2[C:11]=1[C:12]1[S:13][C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[N:19]=2)=[CH:15][C:16]=1[CH3:17]
Reactant: C1CCOC1
Reactant: Cc1cccc(-c2cc(C)c(-c3c(C)nc4ccc(C)nn34)s2)n1
Agent: CC(C)[N-]C(C)C
Agent: CCC(=O)N(C)OC
Agent: [Li+]
Solvent: CCOC(C)=O
Product: CCC(=O)c1cc(C)nn2c(-c3sc(-c4cccc(C)n4)cc3C)c(C)nc12
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 25 %

Procedure:
To a −78° C. solution of 2,6-dimethyl-3-[3-methyl-5-(6-methyl-pyridin-2-yl)-thiophen-2-yl]-imidazo[1,2-b]pyridazine (0.34 g, 1.02 mmol) and THF (9 mL) is added 2.0 M LDA (0.61 mL, 1.22 mmol). After 3 minutes, N-methoxy-N-methyl-propionamide (Wolberg et. el. Chem. Eur. J., 2001, 7, 4562) (1.17 g, 1.42 mmol) is added and the solution stirred for 20 minutes, warmed to ambient temperature and stirred for 30 minutes. The solution is diluted with EtOAc (50 mL) washed with sat. NH4Cl (30 mL), dried over MgSO4, filtered and concentrated. The residue is purified by ISCO column chromatography (20%-30% EtOAc/hexane gradient) furnish the title compound (0.10 g, 0.26 mmol, 25%). 1H NMR (CDCl3), δ 1.28 (t, J=7.0 Hz, 3H), 2.13 (s, 3H), 2.54 (s, 3H), 2.58 (s, 6H), 3.59 (q, J=7.0 Hz, 2H), 7.03 (d, J=7.5 Hz, 1H), 7.33 (s, 1H), 7.47 (d, J=7.9 Hz, 1H), 7.55 (bs, 1H), 7.58 (dd, J=7.9, 7.5 Hz, 1H). LC/MS (m/z): calcd. for C22H22N4OS (M+H)+: 391.2; found: 391.2.
Reaction SMILES: [OH:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2.C1CCC(N=C=NC2CCCCC2)CC1.C1C2C(COC([NH:62][CH2:63][C:64](O)=[O:65])=O)C3C(=CC=CC=3)C=2C=CC=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[NH2:62][CH2:63][C:64]([O:1][C@@H:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@:3]1([CH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1)[C:11]1[CH2:12][C:13]2[C:18]([CH:19]=1)=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:65]
Reactant: O=C(O)c1ccc(C[C@@]2(C3=Cc4ccccc4C3)Cc3ccccc3[C@H]2O)cc1
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: NCC(=O)O[C@@H]1c2ccccc2C[C@@]1(Cc1ccc(C(=O)O)cc1)C1=Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 51.9 %

Procedure:
To a solution of 4-(((1S,2S)-1-hydroxy-2,3-dihydro-1H,1′H-[2,2′-biinden]-2-yl)methyl)benzoic acid (220 mg, 0.57 mmol), DCC (142 mg, 0.69 mmol) and DMAP (7 mg, 0.057 mmol) in ethyl acetate (10 mL), was added N-[(9H-fluoren-9-ylmethoxy)carbonyl]glycine (171 mg, 0.57 mmol) and then stirred at room temperature for 12 h. The solids were filtered, washed with ethyl acetate (25 ml) and the combined filtrate was washed with 1.5 N HCl (25 mL), water (25 mL), brine (10 mL), dried over anhydrous Na2SO4. The organic layer was evaporated under reduced pressure and the residue 1 (250 mg) was dissolved in dry THF (8 mL) and cooled to 0° C. Dimethylamine (8 mL, 20% in THF) was added drop wise at N2 atmosphere and the reaction mixture was slowly allowed to stir at room temperature for 1 h. The reaction mixture was evaporated under reduced pressure and the residue was purified by CombiFlash using 10% methanol in chloroform as an eluent to yield 130 mg (56%) of the title compound as an off white solid.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH:8](Cl)[CH:9]=[C:10]([Cl:12])[Cl:11])[CH2:3][C:4]([O:6]C)=[O:5].O.Cl>CO.[OH-].[Na+]>[CH3:1][C:2]1([CH3:14])[CH:8]([CH:9]=[C:10]([Cl:12])[Cl:11])[O:6][C:4](=[O:5])[CH2:3]1.[CH3:1][C:2]1([CH3:14])[CH:8]([CH:9]=[C:10]([Cl:12])[Cl:11])[CH:3]1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)CC(C)(C)C(Cl)C=C(Cl)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)C(C=C(Cl)Cl)C1C(=O)O
Product: CC1(C)CC(=O)OC1C=C(Cl)Cl
Reaction time: 0.5 h
Yield: 25 %
Yield: 53 %

Procedure:
In 80 parts of methanol was dissolved 12.0 parts of sodium hydroxide and, at the reflux temperature of methanol, 51.9 parts of methyl 3,3-dimethyl-4,6,6-trichloro-5-hexenoate was added dropwise to the above solution over a period of 30 minutes, followed by stirring the mixture at that temperature for 30 minutes. Then, about 50 parts of water was added and, after refluxing for about 30 minutes, the reaction mixture was allowed to cool and neutralized with concentrated hydrochloric acid. The methanol was distilled off under reduced pressure and the residue was extracted with diethyl ether. The ether layer was dried and the ether was distilled off, whereupon 42.2 parts of a mixture of 2,2-dimethyl-3-(2',2'-dichlorovinyl) cyclopropanecarboxylic acid and 3,3-dimethyl-4-(2',2'-dichloroviyl)-4-butanolide. This mixture was further distilled under reduced pressure to separate 10.4 parts of 3,3-dimethyl-4-(2',2'-dichlorovinyl)-4-butanolide (yield 25%; bp: 86°-91° C./0.2 mmHg) and 22.3 parts of 2,2-dimethyl-3-(2',2'-dichlorovinyl) cyclopropanecarboxylic acid (yield 53%; bp: 105°-108° C./0.2 mmHg). Then, 10.4 parts of the former product 3,3-dimethyl-4-(2',2'-dichlorovinyl)-4-butanolide was dissolved in 70 parts of methanol and, under cooling with ice, hydrogen chloride gas was bubbled into the solution for about 1.5 hours. Thereafter, the excess hydrogen chloride and methanol were distilled off under reduced pressure and the residue was further subjected to distillation under reduced pressure. By this procedure was obtained 12.1 parts of methyl 3,3-dimethyl-4,6,6-trichloro-5-hexenoate (yield 23% based on starting material).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15](OS(C(F)(F)F)(=O)=O)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[CH3:25][C:26]([OH:30])([C:28]#[CH:29])[CH3:27]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:29]#[C:28][C:26]([CH3:27])([OH:30])[CH3:25])=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: C#CC(C)(C)O
Reactant: O=S(=O)(Oc1ccc2c(-c3ccc(Br)cc3)nsc2c1)C(F)(F)F
Product: CC(C)(O)C#Cc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
In analogy to example 13.1, Trifluoro-methanesulfonic acid 3-(4-bromo-phenyl)-benzo[d]isothiazol-6-yl ester and 2-Methyl-3-butyn-2-ol were converted to yield 4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yl]-2-methyl-but-3-yn-2-ol as light yellow semisolid, MS: 371 (M, 1Br).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@@H:13]([OH:21])[CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.[CH2:22](Br)[C:23]#[CH:24].C(=O)([O-])[O-].[K+].[K+].ClCCl>CC(C)=O.CO>[CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][C@@H:13]([OH:21])[CH2:14][N:15]3[CH2:16][CH2:17][N:18]([CH2:24][C:23]#[CH:22])[CH2:19][CH2:20]3)=[CH:7][C:5]=2[N:6]=1
Reactant: Cc1nc2cc(OC[C@@H](O)CN3CCNCC3)ccc2s1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Solvent: ClCCl
Product: C#CCN1CCN(C[C@H](O)COc2ccc3sc(C)nc3c2)CC1
Reaction time: 5 h
Yield: 55.7 %

Procedure:
To a solution of (2S)-1-(2-methylbenzothiazol-5-yloxy)-3-piperazinylpropan-2-ol (800 mg, 2.6 mmol) in acetone (20 ml) was added propargyl bromide (80% solution, 0.290 ml, 2.6 mmol) and potassium carbonate (720 mg, 5.2 mmol). The solution was heated to reflux and stirred for 5 hours. Thin layer chromatography (10:1 dichloromethane:methanol) showed formation of product. The solution was cooled and filtered. The filtrate was concentrated and purified by preparative chromatography (dichloromethane:methanol) to yield (2S)-1-(2-methylbenzothiazol-5-yloxy)-3-(4-prop-2-ynylpiperazinyl)propan-2-ol (500 mg, M+1=346.2). B. Preparation of a Compound of Formula I
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[H-].[Na+].[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CN(C=O)C>[C:14]1([S:20]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]([CH:10]=[O:11])=[CH:2]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=Cc1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=Cc1cn(S(=O)(=O)c2ccccc2)c2ccccc12
Reaction time: 0.5 h

Procedure:
A stirred solution of 1H-indole-3-carboxaldehyde (1 g, 6.89 mmol), in DMF (25 mL) was treated with sodium hydride (0.357 g, 60% in mineral oil, 8.95 mmol) under nitrogen at room temperature, stirred for 30 minutes, treated with benzene sulfonyl chloride (1.09 mL, 8.25 mmol), stirred at room temperature for 3-5 hrs. After the completion of reaction (T. L. C.), the reaction mixture was quenched with 25 mL ice-cold water and diluted with 25 mL ethyl acetate. The organic phase was separated, washed sequentially with water and brine, dried over anhydrous MgSO4 and concentrated in vacuo. The resultant residue was purified by flash chromatography (silica gel, EtOAc/Hexane, 2/8) to afford the title compound as an off-white foam, which was latter identified by IR, NMR and mass spectral data.
Reaction SMILES: [CH3:1]/[CH:2]=[C:3](/[C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@@H:28]4[C@:32]6([OH:38])[C@H:36]([O:37][C@H:26]5[CH2:27]4)[O:35][CH:34]=[CH:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([O:48]C(C)=O)[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])\[CH3:4].C[O-].[Na+]>>[CH3:1]/[CH:2]=[C:3](/[C:5]([O:7][C@@H:8]1[C@:16]23[C@H:20]([C@@:21]([C@:25]45[O:30][C@@:29]4([CH3:31])[C@@H:28]4[C@:32]6([OH:38])[C@H:36]([O:37][C@H:26]5[CH2:27]4)[O:35][CH:34]=[CH:33]6)([CH3:24])[C@H:22]([OH:23])[C@H:14]4[C@H:15]2[C@:11]([C:44]([O:46][CH3:47])=[O:45])([CH2:12][O:13]4)[C@H:10]([OH:48])[CH2:9]1)[C@@:19]([OH:43])([C:39]([O:41][CH3:42])=[O:40])[O:18][CH2:17]3)=[O:6])\[CH3:4]
Reactant: C/C=C(\C)C(=O)O[C@H]1C[C@@H](OC(C)=O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@H]4C[C@@H]5O[C@@H]5OC=C[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32
Agent: C[O-]
Agent: [Na+]
Product: C/C=C(\C)C(=O)O[C@H]1C[C@@H](O)[C@@]2(C(=O)OC)CO[C@H]3[C@@H](O)[C@@](C)([C@]45O[C@@]4(C)[C@H]4C[C@@H]5O[C@@H]5OC=C[C@@]54O)[C@H]4[C@]1(CO[C@]4(O)C(=O)OC)[C@@H]32

Procedure:
Referring to the numbered compounds of Table 1, transesterification of azadirachtin (1) with sodium methoxide gave 3-deacetylazadirachtin (2). Heating a solution of azadirachtin (1) and acetic anhydride at reflux gave a monoacetylated product, 11-O-acetylazadirachtin (4).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5](Cl)=O)[CH3:2].[NH2:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:18]=1[NH:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][CH:15]=[CH:14][CH:13]=2.C(O)C.C(N(CC)CC)C>ClCCl>[CH2:1]([O:3][CH2:4][C:5]1[N:19]([CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[CH:10][C:9]=2[N:8]=1)[CH3:2]
Reactant: CCOCC(=O)Cl
Reactant: CCOC(=O)CCCNc1c(N)cnc2ccccc12
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3ccccc3c2n1CCCC(=O)OCC
Reaction time: 1.5 h
Yield: 98.7 %

Procedure:
A solution of ethoxyacetyl chloride (7.00 g, 57.1 mmol) in dichloromethane (10 mL) was added dropwise to a stirred solution of ethyl 4-(3-aminoquinolin-4-ylamino)butyrate (prepared as described in Steps 1-2 of Example 17, 12.5 g, 45.7 mmol) in dichloromethane (100 mL) at room temperature. After 1.5 hours, the reaction mixture was concentrated under reduced pressure to afford a solid to which was added ethanol (100 mL) and triethylamine (17.4 mL, 125 mmol). The solution was left at room temperature for 5 days, then was heated at reflux for 2 hours. The solution was concentrated under reduced pressure. The residue was partitioned between dichloromethane (150 mL) and water (50 mL). The organic layer was washed with water (50 mL) and saturated aqueous sodium bicarbonate (50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to yield 15.4 g of ethyl 4-[2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]butanoate as a brown oil that was used in the next step without purification.
Reaction SMILES: [C:1]([C:3]1[C:4](I)=[C:5]([C:14]([NH:16][CH3:17])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:4]2[C:3]([C:1]#[N:2])=[C:7]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[S:6][C:5]=2[C:14]([NH:16][CH3:17])=[O:15])=[CH:22][CH:21]=1
Reactant: CNC(=O)c1sc(N2CCOCC2)c(C#N)c1I
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CNC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
A mixture of 4-cyano-3-iodo-N-methyl-5-morpholin-4-ylthiophene-2-carboxamide (0.055 g, 0.14 mmol), 4-chlorophenylboronic acid (0.046 g, 0.29 mmol), tetrakis(triphenylphosphine)palladium(0) (0.017 g, 0.014 mmol) and sodium carbonate (0.046 g, 0.44 mmol) in 1,2-dimethoxyethane (0.71 mL) and water (0.37 mL) was allowed to stir at 80° C. overnight. The reaction mixture was quenched with water and extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by column chromatography to give 3-(4-chlorophenyl)-4-cyano-N-methyl-5-morpholin-4-ylthiophene-2-carboxamide (69) (0.030 g, 57%).
Reaction SMILES: [C:1]1([CH3:16])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[N:9]=[N:10][NH:11][C:12]=2[C:13]([OH:15])=O)=[CH:3][CH:2]=1>CCO.CN(C=O)C.O>[CH3:16][C:1]1[CH:2]=[CH:3][C:4]2[NH:7][C:8]3[N:9]=[N:10][NH:11][C:12]=3[C:13](=[O:15])[C:5]=2[CH:6]=1
Reactant: Cc1ccc(Nc2nn[nH]c2C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: Cc1ccc2[nH]c3nn[nH]c3c(=O)c2c1
Yield: 71.9 %

Procedure:
Cyclisation of 4-(p-tolylamino)-1,2,3-triazole-5-carboxylic acid (1 g) with 85% polyphosphoric acid (12 g) at 100° C. over 2 hrs. gave 0.66 g (72%) of the title compound of mp (EtOH-DMF-H2O) 310° C.; νmax (mull) 2720 (br.) 1655, 1600 cm-1, Δ (DMSO) 2.42 (3H, s); 7.58 (2H, s); 8.10 (1H,s), 1 low fieled broad (exchangeable). (Found; C, 59.89; H, 4.37; N, 28.09; C10H8N4O2 requires; C, 59.99 H, 4.03; N, 27.99%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH2:17][CH2:16][C@H:15]([NH:18][S:19]([C:22]4[S:30][C:29]5[C:24](=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=4)(=[O:21])=[O:20])[C:14]3=[O:31])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.C1(O)C=CC=CC=1.C([O-])(=O)C.[NH4+:43]>>[NH2:43][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH2:12][N:13]3[CH2:17][CH2:16][C@H:15]([NH:18][S:19]([C:22]4[S:30][C:29]5[C:24](=[N:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=4)(=[O:21])=[O:20])[C:14]3=[O:31])[CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: O=C1[C@@H](NS(=O)(=O)c2cc3ncccc3s2)CCN1Cc1ccc2ccnc(Cl)c2c1
Agent: CC(=O)[O-]
Solvent: Oc1ccccc1
Product: Nc1nccc2ccc(CN3CC[C@H](NS(=O)(=O)c4cc5ncccc5s4)C3=O)cc12
Temperature: 70 °C
Reaction time: 0.08 h

Procedure:
Thieno[3,2-b]pyridine-2-sulfonic acid [1-(1-chloro-isoquinolin-7-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-amide (1.36 g, 2.88 mmol) and phenol (2.22 g, 23.6 mmol) are melted together with stirring at 70° C. for 5 minutes. Ammonium acetate (2.71 g, 28.8 mmol) is added and the reaction mixture is heated to 90° C. and stirred overnight. Additional ammonium acetate (0.50 g, 5.31 mmol) is added and the reaction is heated for 20 more hours. The reaction is cooled and the residue is purified by RP-HPLC eluting in a gradient of 10% CH3CN/H2O (0.1% TFA) to 100% CH3CN. The appropriate product fractions are lyophilized to provide the title compound as a white solid. The enantiomeric purity is 90.5% ee as determined by analytical Chiralpak AS RP-HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:12].I(C1C=CC=C(C[C:22]([O-])=[O:23])C=1CC([O-])=O)=O.CS(O)(=O)=O>CO>[Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([O:23][CH3:22])=[CH:5][NH:6][C:7]2=[O:12]
Reactant: O=Ic1cccc(CC(=O)[O-])c1CC(=O)[O-]
Reactant: O=c1[nH]ccc2c(Cl)cccc12
Agent: CS(=O)(=O)O
Solvent: CO
Product: COc1c[nH]c(=O)c2cccc(Cl)c12
Yield: 87.8 %

Procedure:
To a solution of 5-choroisoquinolin-1(2H)-one (3.8 g, 21.2 mmol) in methanol (70 ml) was added iodosobenzenediacetate (7.5 g, 23.4 mmol) followed by methane sulphonic acid (2.45 g, 25.5 mmol) at room temperature. The reaction mass was heated at reflux for 3 h. The solvent was evaporated and the residue was diluted with cold water. The precipitated solid was filtered, washed with water to get crude compound (3.9 g, 88%) as a light red colored solid. 1H NMR (400 MHz, CDCl3): δ ppm 8.06-8.03 (d, J=12 Hz, 1H), 7.60-7.57 (d, J=12 Hz, 1H), 7.42 (d, J=8 Hz, 1H), 7.01-6.99 (br s, 1H), 3.51 (s, 3H); MS: MS m/z 209.1 (M++1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[N:9]([O:21][CH3:22])[C:10](=[O:20])[CH:11]=[C:12]2[C:16](=[O:17])OC(C)(C)[O:13]2)=[CH:4][CH:3]=1.C=O.[CH3:32][NH2:33].[CH3:34]O>>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH:8]([N:9]([O:21][CH3:22])[C:10]([C:11]2[CH2:32][N:33]([CH3:34])[C:16](=[O:17])[C:12]=2[OH:13])=[O:20])[C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:28][CH:27]=1
Reactant: CON(C(=O)C=C1OC(C)(C)OC1=O)C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CN
Reactant: CO
Agent: C=O
Product: CON(C(=O)C1=C(O)C(=O)N(C)C1)C(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 42 %

Procedure:
N-[Bis-(4-fluorophenyl)-methyl]-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-methoxy-acetamide, prepared using the methods described in the previous examples, was treated in methanol with paraformaldehyde and methylamine as described in the preparation of Compound 44, Method 44B, to give the title compound as a tan solid (42% yield). 1HNMR 400 MHz (DMSO-d6) δ (ppm): 2.9 (3H, broad s, NCH3), 3.1 (3H, broad s, OCH3), 4.2 (2H, broad, NCH2), 6.9 (1H, broad s, CH), 7.0–7.4 (8H, m, aromatics). HRMS (ES+) calculated for C20H22F2N3O4, [M+NH4]+: 406.157838. found: 406.158046.