Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH2:12]Br)=[O:5])[CH3:2].[CH2:14]([O:16][C:17](=[O:31])[CH2:18][NH:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]([Br:11])=[N:8][C:7]=1[CH2:12][N:19]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=1[O:29][CH3:30])[CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:31])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNCc1ccc(OC)cc1OC
Reactant: CCOC(=O)c1sc(Br)nc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1ccc(OC)cc1OC)Cc1nc(Br)sc1C(=O)OCC
Temperature: 25 °C
Reaction time: 17 h
Yield: 96.3 %

Procedure:
A mixture of 2-bromo-4-bromomethyl-thiazole-5-carboxylic acid ethyl ester (3.57 g, 10.91 mmole), (2,4-dimethoxy-benzylamino)-acetic acid ethyl ester (2.76 g, 10.91 mmole) and potassium carbonate (2.26 g, 16.36 mmole) in anhydrous dimethylformamide (25 ml) was stirred at room temperature for 17 h before it was quenched with water, extracted with ethyl acetate. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with a gradient of ethyl acetate and hexanes to give the title compound as a yellow oil (5.27 g): MS: (+) m/z 523.11, 525.04 (M+Na+, 79Br/81Br)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[CH:6]=[CH:5]2.[NH2:20][OH:21].Cl>CCO>[OH:21][NH:20][C:16](=[NH:17])[C:15]1[CH:14]=[CH:13][C:12]([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[N:8]=2)=[CH:19][CH:18]=1
Reactant: N#Cc1ccc(-c2ccc3cc(O)ccc3n2)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: N=C(NO)c1ccc(-c2ccc3cc(O)ccc3n2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 77.8 %

Procedure:
See Scheme 4, route B. 4-(6-hydroxyquinolin-2-yl)benzonitrile (900 mg, 3.68 mmol) was dissolved in 25 mL of EtOH and to it was added NH2OH.HCl (500 mg, 7.36 mmol) and TEA (1.5 mL). The mixture was stirred at 80° C. for 2 hours followed by concentration in vacuo. The crude solids were then suspended in 25 mL of H2O and stirred for 1 hour. Filtration and drying of the solids yielded desired product (800 mg, 78% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][NH:6][N:7]=2)[C:3]=1[C:11]([O:13][CH3:14])=[O:12].F[B-](F)(F)F.[CH3:20][O+](C)C>C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[C:4](=[CH:5][N:6]([CH3:20])[N:7]=2)[C:3]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: C[O+](C)C
Reactant: COC(=O)c1c(Cl)ccc2n[nH]cc12
Agent: F[B-](F)(F)F
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1c(Cl)ccc2nn(C)cc12
Reaction time: 5 h
Yield: 79.1 %

Procedure:
To a solution of methyl 5-chloro-2H-indazole-4-carboxylate (3.80 g, 18.0 mmol) in ethyl acetate (72 mL) was added trimethyloxonium tetrafluoroborate (3.47 g, 23.5 mmol) at room temperature, and the mixture was stirred for 5 hr. The reaction solution was diluted with water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residue was purified by flash silica gel column chromatography (ethyl acetate/hexane=1/3) to give the title compound (3.20 g, yield 79%).
Reaction SMILES: [I:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[C:13](#[N:17])[CH2:14][C:15]#[N:16]>N1CCCCC1.C(O)C>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([CH:9]=[C:2]([I:1])[C:3]=1[OH:12])[CH:7]=[C:14]([C:13]#[N:17])[C:15]#[N:16]
Reactant: COc1cc(C=O)cc(I)c1O
Reactant: N#CCC#N
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(C=C(C#N)C#N)cc(I)c1O

Procedure:
A preferred method of synthesis of (E)-1-cyano-3- (3-iodo-4,5-hydroxyphenyl)acrylonitrile (Compound 2) is as follows: The compound was prepared as described in Ohmichi et al., 1993, Biochemistry 32:4650 in two steps. First, 3-methoxy-4-hydroxy-5-iodobenzylidene malononitrile was prepared by adding 3 drops of piperidine to 1.4 g of 5-iodovanillin and 0.4 g of malononitrile in 25 ml of ethanol and refluxing the mixture for 4 hours. 0.8 g (49% yield) of a yellow solid resulted.
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)(=[O:20])=[O:19])[CH2:14][C@@H:13]2[CH2:26][NH:27][CH:28]([CH3:30])[CH3:29])=[CH:8][CH:7]=1)([OH:5])[CH3:4].[C:33](Cl)(=[O:35])[CH3:34].CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH3:30][CH:28]([N:27]([CH2:26][C@H:13]1[CH2:14][N:15]([S:18]([C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)(=[O:20])=[O:19])[CH2:16][CH2:17][N:12]1[C:9]1[CH:8]=[CH:7][C:6]([C:3]([OH:5])([CH3:4])[C:2]([F:1])([F:31])[F:32])=[CH:11][CH:10]=1)[C:33](=[O:35])[CH3:34])[CH3:29]
Reactant: CC(C)NC[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N(C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1c1ccc(C(C)(O)C(F)(F)F)cc1)C(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a solution of 1,1,1-trifluoro-2-(4-((2S)-2-(((1-methylethyl)amino)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.150 g, 0.305 mmol, Example 195, Step 1) in CH2Cl2 (5.0 mL) was added 4-dimethylaminopyridine (7.46 mg, 0.061 mmol), acetyl chloride (0.043 mL, 0.610 mmol), Hünig's base (0.159 mL, 0.915 mmol). The resulting mixture was stirred at room temperature. After 20 min, the solvent was concentrated and the crude product was purified by column chromatography (24 g of silica, 10 to 40% acetone in hexanes) to afford N-(1-methylethyl)-N-(((2S)-4-(2-thiophenylsulfonyl)-1-(4-(2,2,2-trifluoro-1-hydroxy-1-methylethyl)phenyl)-2-piperazinyl)methyl)acetamide as a mixture of two isomers.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH2:19][CH3:20])=[C:9]([CH3:18])[C:10]=1[CH2:11][CH2:12][C:13]([O:15]CC)=[O:14])(OCC)=O.[CH3:21]C1OC(C)OC(C)O1>>[CH2:1]([C:6]1[NH:7][C:8]([CH2:19][CH3:20])=[C:9]([CH3:18])[C:10]=1[CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH3:21]
Reactant: CCOC(=O)CCc1c(C(=O)OCC)[nH]c(CC)c1C
Reactant: CC1OC(C)OC(C)O1
Product: CCc1[nH]c(CC)c(CCC(=O)O)c1C

Procedure:
2-Carbethoxy-3-carbethoxyethyl-4-methyl-5-ethyl-pyrrole was reductively alkylated with paraldehyde to yield 2,5-diethyl-3-carboxyethyl-4-methyl-pyrrole. ##STR114##
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[CH:6]=O.[CH2:13]([C:15]1[O:16][CH2:17][C:18]([CH2:22]C)([CH2:20]C)[N:19]=1)[CH3:14]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:13]([C:15]2[O:16][CH2:17][C:18]([CH3:22])([CH3:20])[N:19]=2)[CH3:14])[CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1
Reactant: CCC1=NC(CC)(CC)CO1
Reactant: COc1cc(C=O)cc(OC)c1
Product: COc1cc(C=C(C)C2=NC(C)(C)CO2)cc(OC)c1

Procedure:
3,5-Dimethoxybenzaldehyde was reacted with 2,4,4-triethyl-2-oxazoline to produce 2-[2-(3,5-dimethoxyphenyl)-1-methylethenyl]-4,4-dimethyl-2-oxazoline (P-1641), b.p. 171°-173° at 0.25 mm. It was administered to mice to determine the acute oral toxicity and a trained observer studied the animals for tranquilizing activity. The oral LD0 was determined to be over 5 g/kg and the animals receiving it were observed to be highly tranquilized. The compound is administered orally to animals in need of tranquilizing in a dosage of from about 100 to about 1000 mg/kg.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:28][CH3:29])=[CH:9][C:10]3[C:11]4[N:19]([CH2:20][CH:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)[C:18](=O)[NH:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:30])[O:4][N:3]=1.O=P(Cl)(Cl)[Cl:33].P(Cl)(Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Cl:33][C:18]1[N:19]([CH2:20][CH:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[C:11]2[C:10]3[CH:9]=[C:8]([O:28][CH3:29])[C:7]([C:6]4[C:2]([CH3:1])=[N:3][O:4][C:5]=4[CH3:30])=[CH:16][C:15]=3[N:14]=[CH:13][C:12]=2[N:17]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cc2c(cc1-c1c(C)noc1C)ncc1[nH]c(=O)n(CC3CCOCC3)c12
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nc(Cl)n(CC3CCOCC3)c12
Temperature: 120 °C
Yield: 6.18 %

Procedure:
7-(3,5-Dimethyl-4-isoxazolyl)-8-(methyloxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1,3-dihydro-2H-imidazo[4,5-c]quinolin-2-one (for a preparation see Intermediate 14) (220 mg, 0.539 mmol) was dissolved in POCl3 (2 ml, 21.46 mmol), PCl5 (0.2 g, 0.960 mmol) was added and the mixture was heated at 120° C. for 24 h. The reaction mixture was evaporated in vacuo to give a beige solid. This was dissolved in DCM (3 ml) and loaded onto a 25 g silica column, then eluted with 0-10% 2M methanolic ammonia/DCM (25 column volumes) and product containing fractions were evaporated in vacuo to give 2-chloro-7-(3,5-dimethyl-4-isoxazolyl)-8-(methyloxy)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-imidazo[4,5-c]quinoline (14.2 mg, 0.033 mmol, 6.18% yield) as beige solid. LCMS (formate) Rt 0.81 min, MH+ 427.
Reaction SMILES: [OH:1][C:2]1[C:11]([C:12]([O:14]C)=O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.[CH3:16][N:17]([CH2:19][CH2:20][CH2:21][NH2:22])[CH3:18]>C1(C)C=CC=CC=1>[CH3:16][N:17]([CH3:18])[CH2:19][CH2:20][CH2:21][NH:22][C:12]([C:11]1[C:2]([OH:1])=[CH:3][C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=1)=[O:14]
Reactant: COC(=O)c1cc2ccccc2cc1O
Reactant: CN(C)CCCN
Solvent: Cc1ccccc1
Product: CN(C)CCCNC(=O)c1cc2ccccc2cc1O

Procedure:
The coupling component used in this Example was obtained by reacting methyl 2-hydroxy-3-naphthoate with dimethylamino propylamine in toluene to obtain N,N-dimethyl-N-3-(3-hydroxy-2-naphthamido)propylamine, and converting the amide compound isolated by filtration, with dimethylsufuric acid in methanol, to a quaternary ammonium form. Further, the amide compound may also be readily prepared via 2-hydroxy-3-napthoic acid chloride.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14](O)[CH3:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:14]([N:40]1[C:36](=[O:46])[C:37]2[C:38](=[CH:42][CH:43]=[CH:44][CH:45]=2)[C:39]1=[O:41])[CH3:15]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)c1nc2ccc(F)cn2c(=O)c1Br
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1nc2ccc(F)cn2c(=O)c1Br)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-bromo-7-fluoro-2-(1-hydroxyethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (1.238 g, 4.31 mmol), triphenylphosphine (1.357 g, 5.17 mmol), phthalimide (0.761 g, 5.17 mmol), and THF (28.7 mL) was stirred at rt for 5 min to dissolve all reactants. The mixture was then cooled to 0° C. and to the cooled homogenous mixture was added dropwise over 3 min diisopropyl azodicarboxylate (1.019 mL, 5.17 mmol) at 0° C. After stirring at 0° C. for 30 min, the cooling bath was removed and the mixture was stirred at rt. After 1.5 h, the mixture was partitioned between EtOAc (50 mL) and water (50 mL). The insoluble solid was filtered, washed with water (50 mL) and EtOAc (50 mL), and dried under vacuum to give the desired product 2-(1-(3-bromo-7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)isoindoline-1,3-dione as a white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.92-9.00 (1 H, m), 8.12 (1 H, ddd, J=9.9, 7.1, 2.9 Hz), 7.82-7.92 (4 H, m), 7.75 (1 H, dd, J=9.8, 5.5 Hz), 5.56-5.66 (1 H, m), 1.85 (3 H, d, J=7.0 Hz); Mass Spectrum (ESI) m/e=416.0 [M+1 (79Br)] and 418.0 [M+1 (81Br)]. To the filtrate was added brine (50 mL) and the organic layer was separated, dried over Na2SO4, filtered and concd under reduced pressure to give the crude material as a yellow solid. The yellow solid was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 50% gradient of EtOAc in hexane over 25 min and 50% isocratic of EtOAc for 10 min as eluent to give the desired product 2-(1-(3-bromo-7-fluoro-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)-ethyl)isoindoline-1,3-dione as a light yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.95 (1 H, td, J=3.1, 1.6 Hz), 8.12 (1 H, ddd, J=9.9, 7.1, 2.9 Hz), 7.83-7.93 (4 H, m), 7.71-7.79 (1 H, m), 5.57-5.65 (1 H, m), 1.85 (3 H, d, J=7.0 Hz); Mass Spectrum (ESI) m/e=416.0 [M+1 (79Br)] and 418.0 [M+1 (81Br)].
Reaction SMILES: [F:1][C:2]1([F:15])[O:14][C:5]2=[CH:6][C:7]3[NH:11][C:10]([SH:12])=[N:9][C:8]=3[CH:13]=[C:4]2[O:3]1.Cl[CH2:17][C:18]1[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=1>>[F:15][C:2]1([F:1])[O:14][C:5]2=[CH:6][C:7]3[NH:11][C:10]([S:12][CH2:17][C:18]4[C:23]([CH3:24])=[C:22]([O:25][CH3:26])[C:21]([CH3:27])=[CH:20][N:19]=4)=[N:9][C:8]=3[CH:13]=[C:4]2[O:3]1
Reactant: COc1c(C)cnc(CCl)c1C
Reactant: FC1(F)Oc2cc3nc(S)[nH]c3cc2O1
Product: COc1c(C)cnc(CSc2nc3cc4c(cc3[nH]2)OC(F)(F)O4)c1C
Yield: 86 %

Procedure:
Analogous reaction of 2,2-difluoro-5H-[1,3]-dioxolo[4,5-f]benzimidazole-6-thiol with 2-chloromethyl-4-methoxy-3,5-dimethylpyridine gives 2,2-difluoro-6-[(4-methoxy-3,5-dimethyl-2-pyridyl)methylthio]-5H-[1,3]-dioxolo[4,5-f]benzimidazole, of m.p. 148°-149° C. (from acetonitrile), in 86% yield.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[N:8]=[CH:9][CH:10]=[C:11]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=O)[O:21]C(C)(C)C)=[CH:15][CH:14]=3)[C:5]=2[N:4]=[CH:3]1.[C:27]([C:31]1[CH:35]=[C:34]([N:36]=C=O)[N:33]([C:39]2[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=2)[N:32]=1)([CH3:30])([CH3:29])[CH3:28]>>[C:27]([C:31]1[CH:35]=[C:34]([NH:36][C:20]([NH:19][C:16]2[CH:15]=[CH:14][C:13]([O:12][C:11]3[C:5]4[N:4]=[CH:3][C:2](=[O:1])[NH:7][C:6]=4[N:8]=[CH:9][CH:10]=3)=[CH:18][CH:17]=2)=[O:21])[N:33]([C:39]2[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=2)[N:32]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2N=C=O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(Oc2ccnc3[nH]c(=O)cnc23)cc1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(Oc3ccnc4[nH]c(=O)cnc34)cc2)cc1
Yield: 55 %

Procedure:
Method E1 was used with Tert-butyl 4-(3-oxo-3,4-dihydropyrido[2,3-b]pyrazin-8-yloxy)phenylcarbamate and 3-tert-butyl-5-isocyanato-1-p-tolyl-1H-pyrazole to obtain the title compound (yield 55%).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].[N:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[S:18][C:17]([S:19](Cl)(=[O:21])=[O:20])=[CH:16][CH:15]=1>[OH-].[Na+].O1CCOCC1>[CH3:6][C:2]([NH:1][S:19]([C:17]1[S:18][C:14]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][N:8]=2)=[CH:15][CH:16]=1)(=[O:20])=[O:21])([CH3:7])[C:3]([OH:5])=[O:4]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccn2)s1
Reactant: CC(C)(N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)(NS(=O)(=O)c1ccc(-c2ccccn2)s1)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 34.4 %

Procedure:
To a solution of 2-amino-2-methylpropionic acid (2.0 grams, 19.4 mmole) in 1 N aqueous sodium hydroxide solution (45 mL) and dioxane (45 mL) was added 5-pyridin-2-ylthiophene-2-sulfonyl chloride (8.41 grams, 32.4 mmole). The resulting mixture was stirred at room temperature for 16 hours. Additional 1 N aqueous sodium hydroxide solution (45 mL) was added to the reaction mixture which was then extracted with diethyl ether. The organic extracts were discarded. The aqueous layer was acidified with 1 N hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate fractions were washed with brine, dried over magnesium sulfate and concentrated to afford 2-methyl-2-(5pyridin-2-ylthiophene-2-sulfonylamino)propionic acid as a white solid (2.18 grams, 34%).
Reaction SMILES: [O:1]([CH2:8][C:9](Cl)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([C:20]2([OH:26])[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[CH:17]=[CH:18][CH:19]=1>>[OH:26][C:20]1([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH3:12])[CH:15]=2)[CH2:25][CH2:24][CH2:23][N:22]([C:9](=[O:10])[CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:21]1
Reactant: COc1cccc(C2(O)CCCNC2)c1
Reactant: O=C(Cl)COc1ccccc1
Product: COc1cccc(C2(O)CCCN(C(=O)COc3ccccc3)C2)c1

Procedure:
The compound of Example 15 was prepared according to the general preparation protocol A from phenoxyacetyl chloride and 3-(3-methoxy-phenyl)-piperidine-3-ol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.O>C(O)C.Cl.[Fe]>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14]2)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)n2ccc3ccccc32)c1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1cccc(S(=O)(=O)n2ccc3ccccc32)c1
Temperature: 77.5 °C
Reaction time: 4 h
Yield: 133.1 %

Procedure:
To a solution of 1-(3-Nitrobenzenesulfonyl)indole (6.62 mmoles, 2.0 g) in 10 mL of ethanol in 50 mL three necked round bottomed flask, was added (33.11 mmoles, 1.85 g) of iron powder at 25° C. To the above mixture was added 2 mL water and 1-2 drops of hydrochloric acid. The reaction mixture was then stirred for 4 hour at 75-80° C. After the completion of reaction (TLC), the reaction mixture was filtered through buchner funnel and residue was washed with 20 mL×2 portions of hot ethanol. Combined ethanol layer was distilled under vacuum, the residue was quenched in 30 mL ice-cold water and basified with 40% sodium hydroxide solution. Aqueous layer was extracted with dichloromethane (50 mL×3). The combined dichloromethane extracts were then washed with water, brine and dried over anhydrous magnesium sulfate. The volatiles were removed under the reduced pressure to obtain 2.4 g crude thick oil. This compound was purified on column using neutral silica and n-hexane to 40% ethylacetate:n-hexane as eluent.
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1.[C:14]([C:18]1[CH:34]=[CH:33][C:21]([CH2:22][N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31]Cl)[CH2:25][CH2:24]2)=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15]>>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:31][CH2:30][CH2:29][N:26]3[CH2:25][CH2:24][N:23]([CH2:22][C:21]4[CH:20]=[CH:19][C:18]([C:14]([CH3:15])([CH3:17])[CH3:16])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)[CH:10]=2)[NH:5][C:4](=[O:13])[CH:3]=1
Reactant: Cc1cc(=O)[nH]c2ccc(O)cc12
Reactant: CC(C)(C)c1ccc(CN2CCN(CCCCl)CC2)cc1
Product: Cc1cc(=O)[nH]c2ccc(OCCCN3CCN(Cc4ccc(C(C)(C)C)cc4)CC3)cc12

Procedure:
In a manner analogous to that described in Example 5, by the reaction of 4-methyl-6-hydroxy-2-oxo-1,2-dihydroquinoline with 3-[4-(4-tert.-butylbenzyl)-piperazin-1-yl]-propyl chloride, there is obtained 4-methyl-6-{3-[4-(4-tert.-butylbenzyl)-piperazin-1-yl]-propoxy}-2-oxo-1,2-dihydroquinoline which, after recrystallization from ethyl acetate, melts at 171°-172° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([SH:12])[N:11]=[C:4]2[N:3]=1.[Cl:13][C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20]Br)=[CH:16][C:15]=1[F:24]>>[Cl:13][C:14]1[CH:23]=[CH:22][C:17]([O:18][CH2:19][CH2:20][S:12][C:10]2[N:11]=[C:4]3[N:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[N:5]3[N:9]=2)=[CH:16][C:15]=1[F:24]
Reactant: Cc1cc(C)n2nc(S)nc2n1
Reactant: Fc1cc(OCCBr)ccc1Cl
Product: Cc1cc(C)n2nc(SCCOc3ccc(Cl)c(F)c3)nc2n1
Yield: 75 %

Procedure:
The title compound was prepared according to the experimentals described for Example 1 above from 5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidine-2-thiol and 4-chloro-3-fluorophenoxy-ethylbromide in 75% yield; EM (calc.): 352.1; MS (ESI) m/e: 353.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]1([C:14]2[N:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]3([C:27]([F:30])([F:29])[F:28])[CH2:26][CH2:25]3)[CH2:21][NH2:22])=[CH:16][CH:15]=2)[CH2:13][CH2:12]1>>[CH:11]1([C:14]2[N:19]=[CH:18][C:17]([CH:20]([CH2:23][C:24]3([C:27]([F:30])([F:28])[F:29])[CH2:26][CH2:25]3)[CH2:21][NH:22][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=3[F:1])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1
Reactant: O=C(O)c1ccccc1F
Reactant: NCC(CC1(C(F)(F)F)CC1)c1ccc(C2CC2)nc1
Product: O=C(NCC(CC1(C(F)(F)F)CC1)c1ccc(C2CC2)nc1)c1ccccc1F

Procedure:
From 2-fluorobenzoic acid and 2-(6-cyclopropyl-pyridin-3-yl)-3-(1-trifluoromethyl-cyclopropyl)-propylamine. LCMS (MH+): m/z=407.1, tR (minutes, Method G)=2.01
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][C:17]([F:28])([CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)[CH2:18]O.N1C=CC=CC=1>ClCCl>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][CH2:18][C:17]([F:28])([F:16])[CH2:20][O:21][CH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][O:23]1)(=[O:10])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: OCC(F)(F)COC1CCCCO1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(OCC(F)(F)COC1CCCCO1)C(F)(F)F
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Triflic anhydride (1.8 ml, 11 mmol) was added to a cold (0° C.) solution of 2,2-difluoro-3-tetrahydropyranyloxy-1-propanol 91.6 g, 10 mmol), pyridine (0.9 ml, 11 mmol) in anhydrous dichloromethane (50 ml). The mixture was stirred 1 h at 0° C. and, after usual work-up, the product was purified by flash chromatography on silica gel (ethyl acetate:hexane; 15:85) (2.6 g, 80%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH:18]1[CH:19]=[C:20]([CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:21]2[C:26]=1[CH:25]=[CH:24][CH:23]=[CH:22]2>ClCCl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([C:18]2[CH:19]=[C:20]([CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:21]3[C:26]=2[CH:25]=[CH:24][CH:23]=[CH:22]3)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Reactant: CCOC(=O)CCCc1ccc2ccccn12
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CCCc1cc(C(=O)c2ccc(OC(C)=O)cc2)c2ccccn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.1 %

Procedure:
4-Acetoxybenzoyl chloride (53.6 g) was added to a suspension of aluminum chloride (36.5 g) in dichloromethane (500 ml). After the mixture was stirred for 20 minutes at room temperature, a solution of ethyl 4-(indolizin-3-yl)butyrate (57.8 g) in dichloromethane (50 ml) was added to the mixture. The mixture was stirred for 2 hours at room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate (500 ml) and washed with water. N,N-dimethylaminopropylamine (20 ml) was added to the solution. The mixture was washed with diluted hydrochloric acid, water, sodium bicarbonate aqueous solution and water. The solution was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was washed with diisopropyl ether to give ethyl 4-[1-(4-acetoxybenzoyl)indolizin-3-yl]butyrate as yellow powder (36.5 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:12])[CH:10]=[CH2:11])=[CH:4][CH:3]=1.[ClH:13].[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([C:28]2([F:35])[CH2:33][CH2:32][NH:31][CH2:30][CH:29]2[CH3:34])[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[ClH:13].[CH2:14]([O:21][C:22]1[CH:23]=[C:24]([C:28]2([F:35])[CH2:33][CH2:32][N:31]([CH2:11][CH2:10][C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=3)=[O:12])[CH2:30][CH:29]2[CH3:34])[CH:25]=[CH:26][CH:27]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C=CC(=O)Nc1ccc(Br)cc1
Reactant: CC1CNCCC1(F)c1cccc(OCc2ccccc2)c1
Agent: Cl
Product: CC1CN(CCC(=O)Nc2ccc(Br)cc2)CCC1(F)c1cccc(OCc2ccccc2)c1
Yield: 65 %

Procedure:
This material was synthesized by the reaction of N-(4-bromophenyl)acrylamide with 4-(3-benzyloxyphenyl)-4-fluoro-3-methylpiperidine hydrochloride as described in Step 1 of Example 20. The desired compound was obtained as a light yellow solid in 65% yield.