Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]1[N:4]([CH2:26][CH3:27])[C:5]2[C:10]([C:11](=[O:24])[C:12]=1[C:13]([NH:15][CH2:16][CH:17](OCC)OCC)=[NH:14])=[CH:9][CH:8]=[C:7]([I:25])[CH:6]=2.[OH-].[Na+].[NH4+].[OH-]>O>[NH2:2][C:3]1[N:4]([CH2:26][CH3:27])[C:5]2[C:10]([C:11](=[O:24])[C:12]=1[C:13]1[NH:14][CH:17]=[CH:16][N:15]=1)=[CH:9][CH:8]=[C:7]([I:25])[CH:6]=2
Reactant: CCOC(CNC(=N)c1c(N)n(CC)c2cc(I)ccc2c1=O)OCC
Agent: Cl
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: CCn1c(N)c(-c2ncc[nH]2)c(=O)c2ccc(I)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 75 %

Procedure:
0.37 ml of a 12N HCl solution were added at 0° C. to a suspension of 0.13 .g (0.28 mmol) of 2-amino-N-(2,2-diethoxy-ethyl)-1-ethyl-7-iodo-4-oxo-1,4-dihydro-quinoline-3-carboxamidine. The reaction mixture was stirred at room temperature during 16 hours. The reaction mixture was than diluted with 0.55 ml of water, basified with 0.32 ml of 1N NaOH solution, and 0.134 ml of an NH4OH solution. The mixture was then filtered and the resulting solid was washed with water, acetonitrile and pentane to give 0.08 g (0.21 mmol) of a brown solid.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[CH2:21]Br)=[O:12])(=O)C.[C:23]1(=[O:33])[NH:27][C:26](=[O:28])[C:25]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:24]12.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:11](=[O:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[OH:4])=[C:15]([CH2:21][N:27]2[C:23](=[O:33])[C:24]3[C:25](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:26]2=[O:28])[CH:16]=1
Reactant: CC(=O)Oc1ccccc1C(=O)Nc1ccc(Cl)cc1CBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Cl)cc1CN1C(=O)c2ccccc2C1=O)c1ccccc1O
Temperature: 50 °C
Reaction time: 8 h
Yield: 47.5 %

Procedure:
Compound 1-3 (6.0 g 0.015 moles) was dissolved in 50 mL of DMF. To that pthalimide (3.31 g 0.023 moles), K2CO3 (6.2 g 0.045 moles) and a catalytic amount of KI were added and allowed to stir at 50° C. overnight. Upon completion the reaction was diluted with ethyl acetate and then washed with brine (6×25 mL's) to afford 2.9 grams of 1-4 in a crude mixture, which was then purified by normal phase chromatography. 1H NMR (300 MHz, CDCl3): 4.83 ppm (2H, S); 7.05 ppm (2H, m); 7.36 ppm (1H, dd, J=2.4 Hz, 8.6 Hz); 7.50 ppm (1H, dt, J=1.5 Hz, 8.5 Hz); 7.59 ppm (1H, d, J=2.4 Hz); 7.75 ppm (3H, m); 7.91 ppm (2H, m); 8.18 ppm (1H, d, 7.2 Hz); 10.17 ppm (1H, s); 12.27 ppm (1H,s) Analytical LCMS: single peak (214 nm) at 3.633 min (CH3CN/H2O/1% TFA, 4 min gradient), HRMS calc'd for C22H15N2O4Cl (M+H), 407.0799; found 407.0793 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[N:41]1([CH2:45][C@@H:46]([NH:50][CH3:51])[CH2:47][CH2:48][CH3:49])[CH2:44][CH2:43][CH2:42]1>CN(C=O)C>[N:41]1([CH2:45][C@@H:46]([N:50]([CH3:51])[C:4](=[O:6])[C:3]2[CH:7]=[CH:8][C:9]([Cl:11])=[CH:10][C:2]=2[Cl:1])[CH2:47][CH2:48][CH3:49])[CH2:44][CH2:43][CH2:42]1
Reactant: O=C(O)c1ccc(Cl)cc1Cl
Reactant: CCC[C@@H](CN1CCC1)NC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCC[C@@H](CN1CCC1)N(C)C(=O)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 62 %

Procedure:
2,4-Dichlorobenzoic acid (92 mg, 0.48 mmol) and TBTU (162 mg, 0.50 mmol) was mixed in DMF (1.5 mL). The mixture was cooled to 0° C. and NMM (0.063 mL, 0.58 mmol) was dropwise added. After 10 min at 0° C. was (S)-1-(azetidin-1-yl)-N-methyl-pentan-2-amine (Compound J1) (75 mg, 0.48 mmol) added. The resultant mixture was stirred at 0° C. for 30 min and at rt for 16 h. The mixture was concentrated and the residue dissolved in DCM (5 mL). The organic phase was washed with NaHCO3 (saturated, 2×5 mL), filtered through a phase separator and concentrated under reduced pressure. The residue was purified by preparative HPLC to give the title compound (98 mg, 62%). Mixture of rotamers: 1H NMR (400 MHz, DMSO-d6): 0.59-0.87, 0.90, 0.98-1.66, 1.72-2.11, 2.22-2.47, 2.5, 2.78, 4.26-4.70, 7.24-7.36, 7.43-7.64, 7.65-7.79. Total no of protons: 22. HRMS (M+H)+: calculated 329.1187. found 329.1161
Reaction SMILES: [C:1]([O-:4])(=O)[CH3:2].[K+].C(O)(=O)C.[I-].[Na+].ClC(C)[C:14]([C:16]1[CH:21]=[C:20]([F:22])[C:19]([O:23][CH3:24])=[C:18]([F:25])[CH:17]=1)=[O:15]>CC(C)=O.O>[F:22][C:20]1[CH:21]=[C:16]([CH:14]([OH:15])[CH:1]([OH:4])[CH3:2])[CH:17]=[C:18]([F:25])[C:19]=1[O:23][CH3:24]
Reactant: CC(=O)[O-]
Reactant: COc1c(F)cc(C(=O)C(C)Cl)cc1F
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: COc1c(F)cc(C(O)C(C)O)cc1F

Procedure:
Potassium acetate (3.0 g) then glacial acetic acid (5 ml) and then sodium iodide (1.0 g) were added to a solution of 2-chloro-1-(3,5-difluoro-4-methoxyphenyl) propan-1-one (6.5 g) in acetone (50 ml). The mixture was stirred and heated under reflux for 4 hours, cooled and treated with water (150 ml) the acetone was evaporated and the aqueous residue was extracted into dichloromethane. The organic phase was washed with sodium bicarbonate solution, dried (magnesium sulphate), and concentrated under reduced pressure, the residual oil was dissolved in ethanol (150 ml) cooled in ice and treated with excess sodium borohydride (1.5 g). The solution was stirred for 2 hours at ambient temperature, the ethanol and the residue partitioned between dilute hydrochloric acid and ethyl acetate. The ethyl acetate layer was dried (magnesium sulphate) and evaporated to give 1-(3,5-difluoro-4-methoxy-phenyl)propane 1,2-diol as an oil which was used in the next stage without further purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1.[Cl:16][C:17]1[CH:36]=[C:35]([OH:37])[CH:34]=[C:33]([Cl:38])[C:18]=1[CH2:19][C@@H:20]1[CH2:24][CH2:23][N:22]([N:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)[C:21]1=[O:32]>CS(C)=O.C(OCC)(=O)C>[Cl:16][C:17]1[CH:36]=[C:35]([CH:34]=[C:33]([Cl:38])[C:18]=1[CH2:19][C@@H:20]1[CH2:24][CH2:23][N:22]([N:25]2[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]2)[C:21]1=[O:32])[O:37][C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][CH:9]=1
Reactant: O=C1[C@H](Cc2c(Cl)cc(O)cc2Cl)CCN1N1CCC(O)CC1
Reactant: N#Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(Oc2cc(Cl)c(C[C@@H]3CCN(N4CCC(O)CC4)C3=O)c(Cl)c2)cc1
Yield: 49.7 %

Procedure:
Add potassium carbonate (0.385 g, 2.8 mmol) and 4-fluorobenzonitrile (0.253 g, 2.1 mmol) to a solution of (R)-3-(2,6-dichloro-4-hydroxy-benzyl)-1-(4-hydroxy-piperidin-1-yl)-pyrrolidin-2-one (0.5 g, 1.4 mmol) in DMSO. Stir the reaction at 80° C. for 3 hours. Cool the reaction, dilute with ethyl acetate, and wash three times with water and one time with brine. After drying the organic layer over sodium sulfate, filter and concentrate under vacuum. Purify the residue by silica gel chromatography with 50% ethyl acetate/hexane to 100% ethyl acetate gradient to afford 0.32 g (50%) of the title compound. MS (m/z): 460 (M+).
Reaction SMILES: CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[C:30]([NH:31][C:32]2[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=2[C:34]([OH:36])=O)=[CH:29][CH:28]=[N:27]1.[OH-].[Na+]>O>[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[C:30]2[NH:31][C:32]3[C:33]([C:34](=[O:36])[C:29]=2[CH:28]=[N:27]1)=[CH:37][CH:38]=[CH:39][CH:40]=3
Reactant: O=C(O)c1ccccc1Nc1ccnn1-c1ccccn1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Solvent: O
Product: O=c1c2ccccc2[nH]c2c1cnn2-c1ccccn1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.4 %

Procedure:
A solution of methanesulfonic acid (20 mL, 0.31 mol) in phosphorus pentoxide (5.00 g, 35.2 mmol) was heated at 100° C. The mixture was stirred at the same temperature, while powdery 2-[[1-(2-pyridinyl)-1H-pyrazol-5-yl]amino]benzoic acid (1.94 g, 6.92 mmol) was added in small portions. The reaction mixture was heated and stirred at the same temperature for 10 minutes. The mixture was allowed to cool to room temperature, and iced water was added thereto. The solution was made basic by the addition of an aqueous sodium hydroxide solution, and the organic matter was extracted with ethyl acetate. The extract was washed with saturated brine and water, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform:methanol=99:1) to give the title compound (1.35 g, 74% yield).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:7])[CH3:6].[Cl-].[CH3:18][O:19][C:20](=[O:26])[CH2:21][CH2:22][C:23](O)=[O:24]>C(Cl)Cl>[O:24]=[C:23]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][NH:8][C:5](=[O:7])[CH3:6])=[CH:12][CH:13]=1)[CH2:22][CH2:21][C:20]([O:19][CH3:18])=[O:26]
Reactant: COC(=O)CCC(=O)O
Reactant: CC(=O)NCCc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)CCC(=O)c1ccc(CCNC(C)=O)cc1
Temperature: 25 °C

Procedure:
272.7 g. (2.04 mol) aluminium chloride are introduced portionwise at 0° C. into a solution of 110.97 g. (0.68 mol) N-acetylphenethylamine and 93 ml. (0.75 mol) succinic acid methyl ester chloride in 1200 ml. anhydrous methylene chloride, the reaction mixture is further stirred for 1 hour at 0° C. and then warmed to ambient temperature. The reaction mixture is poured into hydrochloric acid/ice water, the organic phase is separated off, dried over anhydrous magnesium sulphate and evaporated. The residue is stirred up with hot diethyl ether, filtered off with suction and afterwashed with a little cold diethyl ether. Yield 154 g. (82% of theory); colourless crystals; m.p. 119.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][C:12](O)=[O:13].S(C)C>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13]
Reactant: O=C(O)Cc1ccc([N+](=O)[O-])cc1F
Solvent: CSC
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CCO)c(F)c1
Temperature: 25 °C
Reaction time: 10 h
Yield: 95.8 %

Procedure:
To a stirred solution of 2-(2-fluoro-4-nitrophenyl)acetic acid (1 g, 5.02 mmol) in tetrahydrofuran (10 mL) was added BH3.S(CH3)2 (7.5 mL, 7.53 mmol) at 0° C. The reaction mixture was allowed to stir at room temperature for 10 h. Then reaction mixture was cooled to 0° C. and the excess of borane was quenched with methanol (10 mL). The reaction mixture was concentrated under reduced pressure to obtain a crude compound which was purified by CC (eluent: ethyl acetate/n-hexane (1:1)) to give 2-(2-fluoro-4-nitrophenyl)ethanol (0.89 g, 95%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH3:13][O:14][C:15](=[O:22])[C@H:16]([CH2:18][CH2:19][S:20][CH3:21])[NH2:17]>>[CH3:13][O:14][C:15](=[O:22])[CH:16]([NH:17][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1)[CH2:18][CH2:19][S:20][CH3:21]
Reactant: O=C(O)CCc1ccc(O)cc1
Reactant: COC(=O)[C@@H](N)CCSC
Product: COC(=O)C(CCSC)NC(=O)CCc1ccc(O)cc1
Yield: 91 %

Procedure:
Following the same procedure of Example 4 except that 3-(4-hydroxyphenyl)propionic acid (1.0 g, 6.0 mmol) and methionine methyl ester (1.08 g, 6.6 mmol) were used, 1.7 g of the title compound was obtained. The compound was finally purified by silica gel column chromatography (column size: 25 mm×150 mm, silica gel 70-230 mesh, eluent: hexane/EtOAc (1/1)). The results of analyses of the compound are as follows:
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[CH2:6]1[O:16][C:15]2[CH:14]=[CH:13][C:10]([CH2:11]Cl)=[CH:9][C:8]=2[O:7]1>C(Cl)Cl>[O:16]1[C:15]2[CH:14]=[CH:13][C:10]([CH2:11][N:2]([CH3:1])[CH2:3][CH2:4][OH:5])=[CH:9][C:8]=2[O:7][CH2:6]1
Reactant: CNCCO
Reactant: ClCc1ccc2c(c1)OCO2
Solvent: ClCCl
Product: CN(CCO)Cc1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 82.3 %

Procedure:
2-(Methylamino)ethanol (22.0 g, 290 mmol) is added all at once to a stirred solution of 3,4-methylenedioxybenzyl chloride (25.0 g, 147 mmol) in DCM (45 mL) at −78° C. under nitrogen. The solution is stirred for 15 minutes at −78° C. then allowed to warm to room temperature overnight (16 h). The reaction is quenched with 1.2 M NaOH (100 mL), washed twice with water, dried of MgSO4, and filtered. Concentration under reduced pressure afforded 25.3 g (83%) of 2-(benzo[1,3]dioxol-5-ylmethyl-methyl-amino)-ethanol as a clear oil which was suitable for use in the next step.
Reaction SMILES: [SH:1][C:2]([CH3:17])([CH3:16])[C:3]([CH:5]([CH2:9][C:10](=[O:15])[C:11]([SH:14])([CH3:13])[CH3:12])[C:6](O)=[O:7])=[O:4]>O1CCCC1.B.C1COCC1>[SH:1][C:2]([CH3:17])([CH3:16])[C:3]([CH:5]([CH2:9][C:10](=[O:15])[C:11]([SH:14])([CH3:13])[CH3:12])[CH2:6][OH:7])=[O:4]
Reactant: CC(C)(S)C(=O)CC(C(=O)O)C(=O)C(C)(C)S
Agent: B
Solvent: C1CCOC1
Product: CC(C)(S)C(=O)CC(CO)C(=O)C(C)(C)S
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cold solution of 2,3-bis(mercaptoisobutryl) propionic acid 9 (Scheme 1) (1 mmol) in 10 mL of anhydrous tetrahydrofuran, 1.5 mL of 1M BH3.THF is added over a period of 5 minutes (min.). The solution is stirred for another 10 min. and evaporated to dryness. Ten ml of water is added to the residue and the mixture is extracted with ethyl acetate. The organic layer is washed with water, dried and evaporated in vacuo to give the product 21, which is purified by flash column chromatography.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:29]2[N:38]=[CH:37][C:36]3[C:31](=[C:32]([F:43])[CH:33]=[C:34]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:35]=3)[C:30]2=[O:44])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[CH:17]=[C:16]([NH:18][C:19]2[CH:20]=[C:21]3[CH2:26][CH2:25][CH2:24][N:22]3[N:23]=2)[C:15](=[O:27])[N:14]([CH3:28])[CH:13]=1)(=O)C.[OH-].[Li+].O>C1COCC1.C(O)(C)C.O>[C:39]([C:34]1[CH:35]=[C:36]2[C:31](=[C:32]([F:43])[CH:33]=1)[C:30](=[O:44])[N:29]([C:7]1[C:6]([CH2:5][OH:4])=[C:11]([C:12]3[CH:17]=[C:16]([NH:18][C:19]4[CH:20]=[C:21]5[CH2:26][CH2:25][CH2:24][N:22]5[N:23]=4)[C:15](=[O:27])[N:14]([CH3:28])[CH:13]=3)[CH:10]=[CH:9][N:8]=1)[N:38]=[CH:37]2)([CH3:42])([CH3:40])[CH3:41]
Reactant: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCC4)c(=O)n(C)c2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: Cn1cc(-c2ccnc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2cc3n(n2)CCC3)c1=O
Reaction time: 2.5 h
Yield: 33.7 %

Procedure:
To a solution of 162d (50 mg, 0.080 mmol) in THF/i-propanol/water (1/1/0.5 ml) was added lithium hydroxide (19 mg, 0.80 mmol) at room temperature. After the reaction was stirred for 2.5 h, LCMS indicated the reaction was complete. Then the mixture was poured into water (15 mL) and extracted with dichloromethane (3×20 mL). The combined organic layer was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue solid was purified by reverse-phase prep-HPLC (A: 1% NH4HCO3/water, B: acetonitrile) to afford 162 (15 mg, 33.3%) as white solid. MS-ESI: [M+H]+ 556.3. 1H NMR (500 MHz, CDCl3) δ 8.62 (d, J=5.0 Hz, 1H), 8.32 (s, 1H), 7.93 (d, J=2.0 Hz, 1H), 7.55-7.47 (m, 4H), 7.26 (s, 1H), 5.74 (s, 1H), 4.47 (d, J=4.0 Hz, 2H), 4.07 (t, J=2.0 Hz, 2H), 3.70 (s, 3H), 2.87 (t, J=6.5 Hz, 2H), 2.55-2.52 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5](N)=[CH:4][C:3]1=2.[H+].[B-](F)(F)(F)[F:23].N([O-])=O.[Na+]>O>[CH3:1][C:2]1([CH3:20])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]([F:23])=[CH:4][C:3]1=2
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)c1cc2c(cc1N)C(C)(C)CCC2(C)C
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1cc2c(cc1F)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
In an ice bath, ethyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-3-aminonaphthalene-2-carboxylate (Compound C, 150 mg, 0.55 mmol) was added 0.24 ml of HBF4 (48% solution in water), followed by a solution of NaNO2 (81 mg, 1.16 mmol) in 1 ml of water. The slurry was left in a refrigerator for 3 days. The reaction mixture was washed successively with ethyl acetate until TLC showed no UV visible spot at the baseline. The ethyl acetate layer was dried with MgSO4 and the solution was concentrated to an oil. The oil was further dissolved in 1 ml of toluene and the mixture was heated under reflux for 2 h. After the reaction cooled to room temperature, solvent was evaporated and the residue was passed through a column (silica gel, ethyl acetate/hexane 1/10) to give the title compound as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[CH:12]=[C:11]([C:13]([OH:15])=O)[NH:10][C:7]2=[N:8][CH:9]=1)([O-:3])=[O:2].[CH3:16][N:17](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.CN>CN(C=O)C>[CH3:16][NH:17][C:13]([C:11]1[NH:10][C:7]2=[N:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[C:6]2[CH:12]=1)=[O:15]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: O=C(O)c1cc2cc([N+](=O)[O-])cnc2[nH]1
Agent: CN
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc2cc([N+](=O)[O-])cnc2[nH]1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77 %

Procedure:
5-nitro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (1.3 g, 6.5 mmoles), HATU (1.2 eq) and DIEA (5 eq) were dissolved in dry DMF under argon. After stirring at RT for 15 minutes, methylamine hydrochloride (3 eq) was added and the mixture was allowed to stir at RT overnight. The mixture was concentrated and washed by a saturated solution of sodium carbonate. The precipitate was filtered off, washed with water and diethyl ether to obtain a brownish solid (1.1 g, 5 mmoles). Yield=77%. ESI-MS: m/z 221 ([M+H]+). HPLC purity: 98%.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([NH2:11])=[CH:6][CH:5]=2.Cl[C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[CH:19]=[C:20]([C:22]3[C:23]([CH3:35])=[N:24][C:25]([N:28]4[C:32]([CH3:33])=[CH:31][CH:30]=[C:29]4[CH3:34])=[CH:26][CH:27]=3)[S:21][C:14]=12>>[CH3:33][C:32]1[N:28]([C:25]2[N:24]=[C:23]([CH3:35])[C:22]([C:20]3[S:21][C:14]4[C:15](=[N:16][CH:17]=[CH:18][C:13]=4[NH:11][C:7]4[CH:8]=[C:9]5[C:4](=[CH:5][CH:6]=4)[NH:3][C:2]([CH3:1])=[CH:10]5)[CH:19]=3)=[CH:27][CH:26]=2)[C:29]([CH3:34])=[CH:30][CH:31]=1
Reactant: Cc1cc2cc(N)ccc2[nH]1
Reactant: Cc1nc(-n2c(C)ccc2C)ccc1-c1cc2nccc(Cl)c2s1
Product: Cc1cc2cc(Nc3ccnc4cc(-c5ccc(-n6c(C)ccc6C)nc5C)sc34)ccc2[nH]1

Procedure:
The title compound was prepared from 2-methyl-5-aminoindole and 7-chloro-2-[6-(2,5-dimethyl-pyrrol-1-yl)-2-methyl-pyridin-3-yl]-thieno[3,2-b]pyridine by the procedure analogous to example 148(c) above. 1H NMR (400 MHz, CD3OD) δ8.08 (s, 1H), 7.82 (d, 1H), 7.40 (s, 1H), 7.30 (s, 1H), 7.25 (d, 1H), 7.07 (d, 1H), 6.92 (dd, 1H), 6.58 (d, 1H), 6.07 (s, 1H), 5.80 (s, 2H), 2.60 (s, 3H), 2.36 (s, 3H), 2.05 (s, 6H); RP18-HPLC RT: 6.55 minutes; API MS: 464 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][CH:15]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[S:22]1[CH2:26][C:25](=[O:27])[NH:24][C:23]1=[O:28].C1(C)C=CC=CC=1>N1CCCCC1.C(O)(=O)C.O>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][O:13][C:14]2[CH:15]=[CH:16][C:17]([CH:20]=[C:26]3[S:22][C:23](=[O:28])[NH:24][C:25]3=[O:27])=[CH:18][CH:19]=2)=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: O=C1CSC(=O)N1
Reactant: CS(=O)(=O)c1ccc(CCOc2ccc(C=O)cc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CC(=O)O
Product: CS(=O)(=O)c1ccc(CCOc2ccc(C=C3SC(=O)NC3=O)cc2)cc1
Yield: 67.6 %

Procedure:
1 g (3.3 mmole) 4-[2-(4-formylphenoxy)ethyl]phenyl methyl sulfone, 0.96 g (8.2 mmole) 2,4-thiazolidinedione, 5 drops of piperidine, 6 drops of acetic acid and toluene were refluxed with water separation in a Dean-Stark apparatus for 1 hour. The heat was removed and the yellow precipitate was filtered off. A slurry of the precipitate and dichloromethane:methanol (95:5) was refluxed. The product was collected by filtration giving 0.9 g (yield 67.6%) of 5-(4-[2-(4-methanesulfonylphenyl)ethoxy]benzylidene)thiazolidine-2,4-dione.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[NH:5][C:4]([NH2:8])=[N:3][CH:2]=1.[CH3:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[O:17])=[CH:12][N:11]=1.Cl>>[NH2:8][C:4]1[NH:3][CH:2]=[C:1]([CH:16]([C:13]2[CH:12]=[N:11][C:10]([CH3:9])=[CH:15][CH:14]=2)[OH:17])[C:6](=[O:7])[N:5]=1
Reactant: Cc1ccc(C=O)cn1
Reactant: Nc1nccc(=O)[nH]1
Agent: Cl
Product: Cc1ccc(C(O)c2c[nH]c(N)nc2=O)cn1

Procedure:
Isocytosine is reacted with 2-methyl-5-formyl pyridine in refluxing concentrated hydrochloric acid for 24 hours to give 2-amino-5-((6-methyl-3-pyridyl)hydroxymethyl)-4(1H)-pyrimidinone.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[SH:12])=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:13](I)[CH3:14]>[OH-].[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[S:12][CH2:13][CH3:14])=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Nc1cnc2ccccc2c1S
Reactant: CCI
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: CCSc1c(N)cnc2ccccc12
Temperature: 60 °C
Yield: 84.7 %

Procedure:
17.62 g (0.1 mole) of 3-amino-4-quinoline-thiol are dissolved in 50 ml of a 2 molar sodium hydroxide solution whereupon some sodium pyrosulfite crystals are added to the solution. At a temperature below 60° C. 22 g (0.14 mole) of ethyl iodide are added dropwise. The reaction mixture is stirred at 60° C., the product is extracted with chloroform, clarified with activated charcoal and evaporated. Thus 17.3 g of 3-amino-4-ethylthio-quinoline are obtained, yield 85%, b. p.: 147° C./26.6 N.m-2.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8](Cl)[CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#[N:5].CCO.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:29][N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=[C:31]1[CH:39]([OH:48])[CH2:40][NH:41][CH:42]1[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]1>CCOC(C)=O>[Cl:1][C:2]1[N:9]=[C:8]([N:45]2[CH2:46][CH2:47][CH:42]([NH:41][CH2:40][CH:39]([OH:48])[C:31]3[N:30]([CH3:29])[C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=4[N:32]=3)[CH2:43][CH2:44]2)[CH:7]=[C:6]([C:11]([F:14])([F:13])[F:12])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c(C(F)(F)F)cc(Cl)nc1Cl
Reactant: Cn1c(C(O)CNC2CCNCC2)nc2ccccc21
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(C(O)CNC2CCN(c3cc(C(F)(F)F)c(C#N)c(Cl)n3)CC2)nc2ccccc21
Reaction time: 2 h
Yield: 62.5 %

Procedure:
2,6-Dichloro-4-trifluoromethyl-nicotinonitrile (277 mg, 1.15 mmol) was dissolved into 10 mL of absolute EtOH and cooled in a wet ice bath. To this was added DIPEA (1.74 mL, 10 mmol) and 1-(1-methyl-1H-benzoimidazol-2-yl)-2-(piperidin-4-ylamino)-ethanol dihydrochloride (400 mg, 1.15 mmol). The mixture was stirred for 2 h. LC-MS anlysis indicated formation of the product. The reaction mixture was concentrated on a rotary evaporator and the residue was dissolved in CH2Cl2 and applied to a SiO2 column and purified (0–10% MeOH/CH2Cl2) to give an oil, still contaminated with DIPEA. Trituration with EtOAc gave 344 mg, 62.4% of 6′-chloro4-[2-hydroxy-2-(1-methyl-1H-benzoimidazol-2-yl)-ethylamino]-4′-trifluoromethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-carbonitrile.