Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.[SH:10][C:11]1[S:12][C:13]([CH3:16])=[N:14][N:15]=1>C(O)C.[OH-].[K+]>[N+:7]([C:4]1[S:3][C:2]([S:10][C:11]2[S:12][C:13]([CH3:16])=[N:14][N:15]=2)=[N:6][CH:5]=1)([O-:9])=[O:8].[SH:10][C:11]1[S:12][C:13]([CH3:16])=[N:14][N:15]=1
Reactant: O=[N+]([O-])c1cnc(Br)s1
Agent: Cc1nnc(S)s1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nnc(Sc2ncc([N+](=O)[O-])s2)s1

Procedure:
Alternatively, 2-[(5-nitrothiazol-2-yl)mercapto]-5-methyl-1,3,4-thiadiazole is prepared by the general method of J Bourdais, P Dauvillier, P Gayral, M-C Rigothie, P Timon-David et al, 1981. Eur. J. Chem. Chim. Ther. 16: 233-240. 2-Bromo-5-nitrothiazole (2.09 g) and 1.32 g of 2-mercapto-5-methyl-1,3,4-thiadiazole in 10 mL of ethanol and 10 mL of 1 N potassium hydroxide are stirred at room temperature overnight. The precipitated solid is collected by vacuum filtration, washed with water and crystallized from ethyl acetate/hexane to give 1 g of the title compound as an off-white solid.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][CH2:7][C@H:6]([NH:9]C(=O)OC(C)(C)C)[CH2:5]1)(=[S:3])[NH2:2].[Cl:17][CH2:18][C:19](=O)[CH3:20].Cl>C(O)C>[ClH:17].[CH3:20][C:19]1[N:2]=[C:1]([C@@H:4]2[CH2:8][CH2:7][C@H:6]([NH2:9])[CH2:5]2)[S:3][CH:18]=1
Reactant: CC(=O)CCl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](C(N)=S)C1
Agent: Cl
Solvent: CCO
Product: Cc1csc([C@@H]2CC[C@H](N)C2)n1

Procedure:
To a solution of Example 120B (100 mg, 0.41 mmol) in ethyl alcohol (3 mL) was added chloroacetone (0.036 mL, 0.45 mmol). The reaction mixture was stirred at reflux overnight, then 2 mL of 2N aqueous HCl was and the mixture was stirred at reflux for 4 h. The mixture was concentrated and the residue triturated in diethyl ether to provide the title compound as a 2:1 cis/trans mixture of diastereomers. MS (ESI+) M/Z 145 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].S(Cl)([Cl:28])=O>ClCCl>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([Cl:28])=[O:25])[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCc1ccc(C2CC(C(=O)Cl)CN(C(=O)N3CCOCC3)C2)cc1
Reaction time: 2 h

Procedure:
150 mg (0.43 mmol) of the compound from Example 38A were initially charged in 3 ml of dichloromethane, and 63 μl (103 mg, 0.87 mmol) of thionyl chloride were added. The reaction mixture was stirred under RF for 2 h, concentrated under reduced pressure, and then three times toluene was added and the mixture was in each case concentrated again under reduced pressure.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[OH:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20].N1C=CC=CC=1>ClCCl>[CH3:11][C:1]1[CH:6]=[CH:5][C:4]([S:7]([O:12][CH2:13][CH2:14][N:15]2[CH2:19][CH2:18][CH2:17][C:16]2=[O:20])(=[O:9])=[O:8])=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C1CCCN1CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCN2CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
p-Toluenesulfonylchloride (1 g) is added portionwise to a solution of 1-(2-hydroxyethyl)pyrrolidin-2-one (500 μL) and pyridine (1.5 mL) in dichloromethane (8 mL) chilled in an ice bath. The mixture is stirred at room temperature for 12 hours and partitioned between 1 M hydrochloric acid and diethylether. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (ethyl acetate) to give the title compound. Yield: 390 mg; Mass spectrum (ESI+): m/z=284 [M+H]+.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([OH:16])(=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.Cl>>[Cl:1][S:2]([C:12]1[CH:13]=[CH:14][C:9]([CH:8]=[CH:7][C:6]([OH:16])=[O:15])=[CH:10][CH:11]=1)(=[O:5])=[O:3]
Reactant: O=C(O)C=Cc1ccccc1
Reactant: O=S(=O)(O)Cl
Agent: Cl
Product: O=C(O)C=Cc1ccc(S(=O)(=O)Cl)cc1
Temperature: 42 °C
Reaction time: 3 h

Procedure:
To neat chlorosulfonic acid (26.5 mL, 0.4 mol) at 18° C. temperature slowly cinnamic acid (7) (7.35 g, 0.05 mol) was added. As the reaction proceeded, hydrogen chloride gas evolved. The reaction mixture was stirred successively at 20° C. for 3 hours and at 42° C. for 3 hours. The dark, viscous syrup was poured into ice water, and the precipitated solid was filtered and washed with water. The title compound was obtained (6.8 g, 55%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 6.55 (1H, d, J=16.0 Hz); 7.58 (1H, d, J=16.0 Hz); 7.65 (4H, s); 8.15 (1H, br s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9](=[N:17][OH:18])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1.[CH2:19]([O:21][C:22](OCC)([CH3:24])[CH3:23])[CH3:20]>C1(C)C(C)=CC=CC=1>[CH2:19]([O:21][C:22]([O:18][N:17]=[C:9]([C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:10][C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)([CH3:24])[CH3:23])[CH3:20]
Reactant: CCOC(C)(C)OCC
Reactant: ON=C(Cc1cccnc1)c1c(F)cccc1F
Solvent: Cc1ccccc1C
Product: CCOC(C)(C)ON=C(Cc1cccnc1)c1c(F)cccc1F
Temperature: 80 °C
Reaction time: 6 h

Procedure:
A solution of 7.45 g of 2',6'-difluoro-2-(3-pyridyl)acetophenone oxime in 170 ml of xylene is mixed with 8.00 g of diethoxypropane and then heated to 80° C. with stirring. After a clear solution has formed, 0.20 g of pulverised Amberlyst® A15 is added and the entire mixture is heated to reflux temperature. After 6 hours, the reaction mixture is subjected to clarifying filtration through Celite® and the filtrate is freed of excess solvent at 60° C. in a water jet vacuum. After drying in a high vacuum, 2',6'-difluoro-2-(3-pyridyl)acetophenone O-(1-ethoxy-1-methylethyl)oxime is obtained as an E/Z isomer mixture in the form of a yellow oil. On chromatographic separation on silica gel using n-hexane/ethyl acetate (3:1), the E isomer [1H-NMR (CDCl3, 200 MHz): 1.428 ppm (s, --C(CH3)2)] is obtained first in the form of slightly yellowish oils.
Reaction SMILES: [OH:1][C:2]1([CH2:15][C:16]#[C:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.FC(F)(F)C(O)=O.O.[OH-].[Na+]>C(Cl)(Cl)Cl>[C:18]1([C:17]#[C:16][CH2:15][C:2]2([OH:1])[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CC#Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Solvent: O
Product: OC1(CC#Cc2ccccc2)CCNCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 99.4 %

Procedure:
To a solution of Compound 256b (179 mg, 0.57 mmol) in CHCl3 (3 mL) was added trifluoroacetic acid (0.219 mL, 2.84 mmol) and the reaction mixture was then stirred at 25° C. for 24 h until the complete conversion of the reagent was observed by LC-MS. Afterwards, to the reaction mixture was added water, followed by aq. 2 N NaOH to give alkaline pH. Separation of the organic layer and extraction of the aqueous layer with CH2Cl2, washing the combined organic layers with brine and drying over Na2SO4 afforded the title compound (122 mg).
Reaction SMILES: [CH3:1][N:2]([C:7]1[CH:8]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=[C:11]([CH:16]=1)[C:12]([O:14]C)=[O:13])[S:3]([CH3:6])(=[O:5])=[O:4].[OH-].[Na+]>C1COCC1.CO.O>[CH3:20][O:19][C:17]([C:9]1[CH:10]=[C:11]([CH:16]=[C:7]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])[CH:8]=1)[C:12]([OH:14])=[O:13])=[O:18]
Reactant: COC(=O)c1cc(C(=O)OC)cc(N(C)S(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(C(=O)O)cc(N(C)S(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.3 %

Procedure:
Dimethyl 5-(N-methylmethylsulfonamido)isophthalate (0.842 g, 2.8 mmol) was dissolved in THF:MeOH (1:1) (8 mL) and H2O (3 mL). Solid NaOH (0.112 g, 2.8 mmol) was added and stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. Saturated NaHCO3 (10 mL) was added to the reaction mixture and extracted with toluene (to remove <10% unreacted starting material). The aqueous solution was acidified with dilute HCl (10%), extracted with EtOAc, and dried over anhydrous Na2SO4. The solvent was evaporated and dried under reduced pressure to give 3-(methoxycarbonyl)-5-(N-methylmethylsulfonamido)benzoic acid as a white solid (75%, 0.598 g), which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[CH:6][C:7]2[O:11][C:10](=[O:12])[NH:9][C:8]=2[CH:13]=1.[H-].[Na+].Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].FC(F)(F)C(O)=O>O1CCCC1.CC#N.O>[O:12]=[C:10]1[N:9]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:8]2[CH:13]=[C:4]([O:3][C:2]([F:1])([F:14])[F:15])[CH:5]=[CH:6][C:7]=2[O:11]1
Reactant: O=c1[nH]c2cc(OC(F)(F)F)ccc2o1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(=O)oc2ccc(OC(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58.8 %

Procedure:
A solution of 5-[(trifluoromethyl)oxy]-1,3-benzoxazol-2(3H)-one (1.12 g, 5.1 mmol) dissolved in 6 mL of anhydrous tetrahydrofuran was added drop-wise to a mixture of sodium hydride (60% by weight in mineral oil, 0.22 g, 5.6 mmol) suspended in 11 mL of anhydrous tetrahydrofuran under argon. The mixture was allowed to stir at room temperature for 10 minutes and then ethyl bromoacetate (0.68 mL, 6.1 mmol) was added to the mixture and stirred vigorously for 18 hours before it was determined to be complete by LCMS (two Aquasil C18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=2.8 min and m/e 306 [M+1]+. The reaction was quenched by adding 5 mL of a 4 M solution of hydrochloric acid in dioxane. After allowing the mixture to stir for one hour, all of the volatiles were removed by rotary evaporation, and the crude residue was purified by silica gel chromatography (40 g Redisep column, silica, 40 um, 60 Å, 35 mL/min, A: methylene chloride, B: methanol, B: 0% to 35% over 30 min; detection at 214 nm) to give ethyl [2-oxo-5-[(trifluoromethyl)oxy]-1,3-benzoxazol-3(2H)-yl]acetate (0.96 g, 3.0 mmol, 62%) of a pink oil. MS (ES) m/e 306 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[O:17][CH:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:15][CH2:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[Cl:27]C1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1>>[Cl:27][C:25]1[CH:26]=[C:21]([CH:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][CH:20]=[C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)[CH:12]=3)[O:17]2)[CH:22]=[CH:23][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2ccccc2)O3)nc1
Reactant: Oc1ccc2c(c1)CCC(c1cccc(Cl)c1)O2
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(c2)CCC(c2cccc(Cl)c2)O3)nc1

Procedure:
2-[2-(3-Chlorophenyl)chroman-6-yloxy]-5-nitropyridine was prepared as described for 5-nitro-2-(2-phenylchroman-6-yloxy)pyridine in Example 1(b) starting from 590 mg of 2-(3-chlorophenyl)chroman-6-ol. The product was recrystallised from a 3:1 mixture of 2-propanol and ethyl acetate. 1H NMR (400 MHz, CDCl3) δ: 9.04 (d, 1H, J 2.9 Hz), 8.60 (dd, 1H, J 9.0, 2.9 Hz), 7.53 (s, 1H), 7.467-7.42 (m, 3H), 7.20 (d, 1H, J 9.0 Hz), 7.00 (dd, 1H, J 8.7, 2.7 Hz), 6.97 (d, 1H, J 2.7 Hz), 6.94 (d, 1H, J 8.7 Hz), 5.18 (dd, 1H, J 10.2, 2.2 Hz), 2.97 (ddd, 1H, J −17.0, 11.5, 5.9 Hz), 2.83 (ddd, 1H, J −17.0, 8.1, 4.5 Hz), 2.21 (m, 1H), 2.00 (m, 1H).
Reaction SMILES: C(=O)=O.CC(O)C.[OH:8][CH:9]([CH2:22][CH2:23][OH:24])[CH2:10][NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([O:13][C:12](=[O:21])[NH:11][CH2:10][C@@H:9]([OH:8])[CH2:22][CH2:23][OH:24])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=C(NCC(O)CCO)OCc1ccccc1
Agent: O=C=O
Solvent: CC(C)O
Product: O=C(NC[C@@H](O)CCO)OCc1ccccc1

Procedure:
The title compound was prepared by chiral separation (Preparative chiral SFC, ChiralPak® IC-H, 250×30 mm, mobile phase: CO2/iPrOH (75:35), flow rate: 60 mL/min, back pressure: 100 bar, column temperature: 38° C., wavelength: 210 nm, cycle time: ˜3.0 min) of a racemic mixture of benzyl (2,4-dihydroxybutyl)carbamate (Stage 97.2), slower eluting isomer (Peak 2). Analytical chiral SFC (ChiralCel® OD-3, 150×4.6 mm, eluent: CO2/iPrOH+0.05% DEA (8:2), flow rate: 2.4 mL/min, back pressure: 100 bar, temperature: 33° C., 210 nm): tR=3.77 min.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[Br:16].Cl[C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C>C(Cl)Cl>[F:23][C:20]([F:21])([F:22])[C:18]1[CH:17]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:24])[F:25])[CH:19]=1)[CH2:6][N:7]([CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[Br:16])[C:27](=[O:28])[O:29][CH3:30]
Reactant: Fc1ccc(Br)c(CNCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(F)ccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [3,5-bis(trifluoromethyl)benzyl](2-bromo-5-fluorobenzyl)amine from Step A (0.14 g) in methylene chloride at room temperature, excess methyl chloroformate (0.1 ml) and triethyl amine (0.1 ml) were added. The solution was stirred at room temperature for 2 h and the solvent was removed under reduced pressure. The title compound was obtained by flash column chromatography using EtOAc/hexane (1:9) as the eluant. 1H NMR (CDCl3, 500 MHz) δ 7.80 (s, 1H), 7.68 (s, 1H), 7.60 (s, 1H), 7.48 (m, 1H), 6.88 (m, 2H), 4.60 (m, 4H), 3.81 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:23])C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[N+:12]([O-:23])[CH:13]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2ccc(F)cc2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1ccc(-c2ccc(F)cc2)c[n+]1[O-]

Procedure:
To a solution of 5-(4-fluorophenyl)-2-methylpyridine (420 mg, 2.2 mmol) in CH2C2 (25 mL) is added m-chloroperbenzoic acid (600 mg, 3.4 mmol). After 16 hours the reaction mixture is diluted with CH2Cl2 (50 mL) and the resulting solution washed with 5N NaOH (2×75 mL). The organic phase is then dried with Na2SO4 and concentrated in vacuo to give 5-(4-fluorophenyl)-2-methylpyridine-N -oxide.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])[CH:27]=1.[OH:49][CH:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1>>[OH:49][CH:50]1[CH2:55][CH2:54][N:53]([C:30]([C:29]2[CH:33]=[CH:34][C:26]([Br:25])=[CH:27][C:28]=2[NH:35][S:36]([C:39]2[C:40]3[N:41]=[CH:42][CH:43]=[N:44][C:45]=3[CH:46]=[CH:47][CH:48]=2)(=[O:38])=[O:37])=[O:31])[CH2:52][CH2:51]1
Reactant: O=C(O)c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12
Reactant: OC1CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc(Br)cc1NS(=O)(=O)c1cccc2nccnc12)N1CCC(O)CC1

Procedure:
The title compound was prepared from the HATU-mediated coupling of 4-bromo-2-(quinoxaline-5-sulfonylamino)benzoic acid (EXAMPLE 1, Step G) and 4-hydroxypiperidine and purified as described in EXAMPLE 1, Step K. MS (ESI): mass calculated for C20H19BrN4O4S, 490.0; m/z found, 491/493 [M+H]+, 513/515 [M+Na]+. HPLC (reverse phase): RT=7.68 min. 1H NMR (400 MHz, CDCl3, rotameric broadening): 9.08 (d, J=1.8 Hz, 1H), 9.02 (d, J=1.8 Hz, 1H), 8.95 (br s, 1H), 8.52-8.50 (m, 1H), 8.38-8.36 (m, 1H), 7.92-7.88 (m, 1H), 7.75 (d, J=1.6 Hz, 0.7H), 7.68 (d, J=1.6 Hz, 0.3H), 7.20-7.17 (m, 1H), 6.96-6.92 (m, 1H), 3.96-3.91 (m, 1H), 3.85-3.75 (m, 1H), 3.2-2.8 (m, 3H), 2.05-1.95 (m, 2H), 1.7-1.3 (m, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:11].S(Cl)(Cl)=O.C([O-])(O)=O.[Na+].[CH2:21](O)[CH3:22]>ClCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:21][CH3:22])=[O:7])=[CH:4][C:3]=1[OH:11]
Reactant: CCO
Reactant: O=C(O)c1ccc(F)c(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)c1ccc(F)c(O)c1
Yield: 93 %

Procedure:
To a solution of 4-fluoro-3-hydroxy-benzoic acid (2 g, 12.81 mmol) in absolute ethanol (30 ml) was added thionyl chloride (1 ml) drop wise at 0° C. After refluxing for overnight, the solvents were driven off, the residue was dissolved in dichloromethane (50 ml), cooled on ice bath, neutralized slowly with 1M NaHCO3, and the layers were separated. The aqueous layer was extracted with dichloromethane (50 ml) for one more time. Combined organic extracts were dried (Na2SO4), filtered, concentrated, and purified by flash column chromatography using dichloromethane to yield 2.2 g (93%) of product. MS (ESI+) m/z 185 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]3(O)[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1>ClCCl>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2cc3c(Cl)cccc3s2)CC1
Solvent: ClCCl
Product: Clc1cccc2sc(C3=CCNCC3)cc12
Yield: 88.7 %

Procedure:
A solution of 0.29 gm (0.79 mMol) 4-chloro-2-(4-hydroxy-1-(tert-butoxycarbonyl)piperidin-4-yl)benzothiophene in 4.0 mL dichloromethane was subjected to the reaction conditions described in Example 51, providing 0.175 gm (88%) of 4-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzothiophene as a tan powder.
Reaction SMILES: [CH:1]1([C:6](Cl)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:26]2[C:25]3[CH:24]=[CH:23][C:22]([Br:27])=[CH:21][C:20]=3[N:19]=[C:18]([NH2:28])[C:17]=2[N:16]=[C:15]1[CH2:29][O:30][CH2:31][CH3:32].C(N(CC)CC)C>C(Cl)(Cl)Cl>[NH2:28][C:18]1[C:17]2[N:16]=[C:15]([CH2:29][O:30][CH2:31][CH3:32])[N:14]([CH2:13][CH2:12][CH2:11][CH2:10][NH:9][C:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])[C:26]=2[C:25]2[CH:24]=[CH:23][C:22]([Br:27])=[CH:21][C:20]=2[N:19]=1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCN
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCCNC(=O)C1CCCC1
Reaction time: 2.5 h
Yield: 64.2 %

Procedure:
Cyclopentanecarbonyl chloride (0.80 mL, 6.6 mmol) was added dropwise over a period of five minutes to a suspension of 1-(4-aminobutyl)-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (2.00 g, 5.1 mmol) and triethylamine (0.78 mL, 5.6 mmol) in chloroform (200 mL). The reaction was stirred for 2.5 hours and then stored for three days in a refrigerator. Additional cyclopentanecarbonyl chloride (0.18 mL) was added, and the reaction was stirred for 30 minutes and treated as described for Examples 558–583. The crude product was recrystallized from isopropanol (13 mL/g), isolated by filtration, and dried overnight on the filter funnel to provide 1.60 g of N-{4-[4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl]butyl}cyclopentanecarboxamide as a white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:14])=[C:10](F)[CH:11]=2)[C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4]1)[CH3:2].[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][NH:24][CH2:23]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[NH2:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][N:24]([C:10]1[CH:11]=[C:12]3[C:7]([C:6](=[O:15])[C:5]([C:16]([OH:18])=[O:17])=[CH:4][N:3]3[CH2:1][CH3:2])=[CH:8][C:9]=1[F:14])[CH2:23]2
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)cc21
Reactant: Nc1ccc2c(c1)CNC2
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3Cc4ccc(N)cc4C3)cc21
Yield: 24.5 %

Procedure:
177 mg of 1-ethyl-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 113 mg of 5-aminoisoindoline, 213 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 63 mg of the target compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30](Cl)[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2].Cl.[CH2:41]([O:43][C:44](=[O:47])[CH2:45][NH2:46])[CH3:42].CCN(CC)CC.O>C1COCC1>[CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:39])[C@@H:13]([NH:23][C:24]([C:26]2[CH:31]=[C:30]([NH:46][CH2:45][C:44]([O:43][CH2:41][CH3:42])=[O:47])[N:29]=[C:28]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:27]=2)=[O:25])[CH2:14][CH2:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)c2cc(Cl)nc(-c3ccccc3)n2)CC1
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1cc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)N2CCN(C(=O)OCC)CC2)nc(-c2ccccc2)n1
Temperature: 40 °C

Procedure:
4-{(S)-4-tert-butoxycarbonyl-2-[(6-chloro-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester (40 mg), glycine ethyl ester hydrochloride (23.8 mg) and NEt3 (20 l) were dissolved in THF (0.5 ml). The mixture was stirred at 40° C. until reaction completion. Water was added to the reaction mixture which was extracted with EA. The org. layers were dried (Na2SO4) and evaporated off to give 41 mg of the desired pure compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]([CH2:17][C:18]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:16])[N:7]=[C:6]2[NH2:30].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33].C(N(CC)CC)C>ClCCl.O>[CH2:35]([O:34][C:32]([N:21]1[CH2:20][CH2:19][C:18]([CH2:17][N:15]([C:8]2[N:7]=[C:6]([NH2:30])[C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=2)[CH3:16])([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:23][CH2:22]1)=[O:33])[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: COc1cc2nc(N(C)CC3(c4ccccc4)CCNCC3)nc(N)c2cc1OC
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)N1CCC(CN(C)c2nc(N)c3cc(OC)c(OC)cc3n2)(c2ccccc2)CC1

Procedure:
A solution of 6,7-dimethoxy-N2-(4-phenyl-piperidin-4-ylmethyl)-quinazoline-2,4-diamine 11 (375 mg), ethyl chloroformate, and triethylamine (250 μl) in dichloromethane (10 ml) was stirred at room temperature for 24 hours. The mixture was diluted with water and extracted with ethyl acetate. The product was chromatographed on silica gel to yield 4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidine-1-carboxylic acid ethyl ester 20, MS: 479 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][NH2:16])[CH3:12].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>C1COCC1>[CH2:11]([N:13]([CH2:17][CH3:18])[CH2:14][CH2:15][NH:16][C:8]([C:5]1[CH:4]=[CH:3][C:2]([NH2:1])=[CH:7][N:6]=1)=[O:10])[CH3:12]
Reactant: CCN(CC)CCN
Reactant: Nc1ccc(C(=O)O)nc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)CCNC(=O)c1ccc(N)cn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The 5-amino-pyridine-2-carboxylic acid is coupled to N,N-diethyl-ethane-1,2-diamine (0.47 mL, 3.32 mmol), in the presence of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (1.26 g, 3.33 mmol), and DIPEA (0.59 mL, 3.33 mmol) in THF (10 mL). The mixture is stirred at room temperature for 48 hours. The solvent is removed in vacuo and the residue partitioned between water-EtOAc. The organic layer is dried over MgSO4, filtered and concentrated to give a residue purified by silica gel column chromatography. 5-Amino-pyridine-2-carboxylic acid (2-diethylamino-ethyl)-amide is isolated (394 mg, 100%) eluting with 96:4 DCM:NH3 (7M in MeOH).