Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:10]([CH:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18](=[O:40])[CH2:19][C@H:20]([NH:32]C(=O)OC(C)(C)C)[CH2:21][C:22]4[CH:31]=[CH:30][C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH:23]=4)[CH2:13]3)=[N:11][C:6]2=[CH:5][CH:4]=1.ClCCl.[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52]>CO.CC#N.O>[NH2:32][C@H:20]([CH2:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=1)[CH2:19][C:18]([N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([C:10]2[N:9]([CH2:41][CH2:42][CH2:43][O:44][CH3:45])[C:7]3=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]3[N:11]=2)[CH2:13]1)=[O:40].[F:49][C:50]([F:55])([F:54])[C:51]([OH:53])=[O:52]
Reactant: COCCCn1c(C2CCCN(C(=O)C[C@@H](Cc3ccc4ccccc4c3)NC(=O)OC(C)(C)C)C2)nc2ccc(OC)nc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COCCCn1c(C2CCCN(C(=O)C[C@H](N)Cc3ccc4ccccc4c3)C2)nc2ccc(OC)nc21

Procedure:
(R)-tert-Butyl 4-(3-(5-methoxy-3-(3-methoxypropyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-1-yl)-1-(naphthalen-2-yl)-4-oxobutan-2-ylcarbamate (33E) (0.069 mmol, 0.042 g) was added to a 10 mL round-bottomed flask equipped for stirring under nitrogen. Dichloromethane (1 mL) and trifluoroacetic acid (1 mL) were then added and the resultant solution was allowed to stir under nitrogen for 4 hr. The solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in methanol (3 mL), filtered, and then purified by preparative LC/MS (5-55% CH3CN in H2O). The resultant fractions were collected and the solvent was removed in-vacuo affording a clear colored oil. This oil was re-dissolved in CH3CN (1 mL) and water (2 mL). The resultant solution was frozen and lyophilized to afford (R)-3-amino-1-(3-(5-methoxy-3-(3-methoxypropyl)-3H-imidazo[4,5-b]pyridin-2-yl)piperidin-1-yl)-4-(naphthalen-2-yl)butan-1-one (100) as its trifluoroacetic acid salt and as a white flocculent solid (0.067 mmol, 0.035 g, 98% yield) 1H NMR (400 MHz, DMSO-d6) δ ppm 1.37-1.58 (m, 1 H) 1.68-2.14 (m, 5H) 2.57-2.89 (m, 2H) 2.89-3.23 (m, 8H) 3.24-3.48 (m, 2H) 3.92 (d, J=2.53 Hz, 5H) 4.02-4.35 (m, 2H) 4.36-4.62 (m, 1H) 6.63-6.76 (m, 1 FI) 7.35-7.59 (m, 3 H) 7.72-8.02 (m, 5H). ESI-MS: m/z 516.2 (M+H)+.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH:10][C@H:11]([C:13]([OH:15])=O)[CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][NH:21]1>>[CH3:17][O:18][C:19](=[O:25])[C@@H:20]1[CH2:24][CH2:23][CH2:22][N:21]1[C:13](=[O:15])[C@H:11]([CH3:12])[NH:10][C:8](=[O:9])[CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: C[C@H](NC(=O)Cc1ccccc1)C(=O)O
Agent: Cl
Product: COC(=O)[C@@H]1CCCN1C(=O)[C@H](C)NC(=O)Cc1ccccc1

Procedure:
Following General Procedure A and using N-(phenylacetyl)-L-alanine (from Example B1 above) and L-proline methyl ester hydrochloride (Bachem), the title compound was prepared as an oil. The reaction was monitored by tlc (Rf=0.12 in 50% EtOAc/hexanes).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:14]([C:16]1[N:20]([CH3:21])[C:19](B(O)O)=[CH:18][CH:17]=1)#[N:15].[F-].[K+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:14]([C:16]1[N:20]([CH3:21])[C:19]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1)#[N:15]
Reactant: CCNS(=O)(=O)c1ccc(Br)cc1
Reactant: Cn1c(C#N)ccc1B(O)O
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: CCNS(=O)(=O)c1ccc(-c2ccc(C#N)n2C)cc1
Reaction time: 16 h
Yield: 13 %

Procedure:
In an analogous manner to general procedure B, 4-bromo-N-ethylbenzenesulfonamide (105 mg, 0.40 mmol), 5-cyano-1-methyl-1H-pyrrol-2-ylboronic acid (72 mg, 0.48 mmol), potassium fluoride (76 mg, 1.3 mmol), and tris(dibenzylideneacetone)dipalladium(0) (10 mg, 0.01 mmol) were placed in an oven dried flask under nitrogen and dry THF (1.0 mL) was added. Tri-t-butylphosphine (60 μL, 0.02 mmol, 10 wt % in hexane) was added and the reaction was stirred for 16 hours. 4-(5-cyano-1-methyl-1H-pyrrol-2-yl)-N-ethylbenzenesulfonamide (15 mg, 13%) was provided after purification. MS (ESI) m/z 289. HPLC purity 100.0% at 210-370 nm, 9.6 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]([CH2:12][CH2:13][OH:14])C(O)=O)=[CH:4][CH:3]=1.[N:15]([O-])=O.[Na+]>OS(O)(=O)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH2:15])[CH2:12][CH2:13][OH:14])=[CH:4][CH:3]=1
Reactant: O=N[O-]
Reactant: O=C(O)[C@@H](CCO)c1ccc(F)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: N[C@@H](CCO)c1ccc(F)cc1
Temperature: 2.5 °C

Procedure:
The hydrazide of (S)-2-(4-fluorophenyl)-4-hydroxybutanoic acid (0.5 gram) is reacted with a solution of 0.5 grams of sodium nitrite in 10 ml of 5% H2SO4. The reaction mixture is maintained for 1 hour at 0-5° C., followed extraction of the reaction mixture with ethyl acetate, followed by basification of the resulting aqueous solution with NaOH, extraction with methyl t-butyl ether, drying of the extracts over MgSO4, filtration, and the removal of solvent by rotary evaporation. The product (S)-1-(4-fluorophenyl)-3-hydroxypropylamine is isolated as a light yellow oil.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]=[C:11]([N:14]2CCCC2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br.Br[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)=O.O>C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][C:22]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[CH:21][C:10]=2[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccncc1
Reactant: C1=C(N2CCCC2)CCN(Cc2ccccc2)C1
Agent: Br
Solvent: O
Solvent: c1ccccc1
Product: c1ccc(CN2CCc3[nH]c(-c4ccncc4)cc3C2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To 70 mL of a solution of 1-benzyl-4-(pyrrolidin-1-yl)-1,2,3,6-tetrahydropyridine in benzene was added dropwise a solution 13 g of 4-bromoacetyl pyridine bromohydride in 150 mL of benzene at 0° C. over 1 hour, followed by stirring at 0° C. for 1 hour and then at room temperature for 15 hours. To the reaction mixture was added water, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane/methanol), and to the obtained 1.86 g of 1-benzyl-3-[2-oxo-2-(pyridin-4-yl)ethyl]piperidine-4-one were added 20 mL of acetic acid and 605 mg of ammonium acetate, followed by heating and refluxing for 1 hour. The reaction mixture was cooled to room temperature and the pH was adjusted to about 9 with a 10% aqueous sodium hydroxide solution, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane/methanol) to obtain 1.26 g of 5-benzyl-2-(pyridin-4-yl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][N:3]=1.[CH:9]([B-](F)(F)F)=[CH2:10].[K+].C(N(CC)CC)C.C(O)C>[Pd+2].ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(OCC)(=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([CH:9]=[CH2:10])=[N:3][CH:4]=1
Reactant: C=C[B-](F)(F)F
Reactant: Clc1ccc(Cl)nc1
Agent: [Fe+2]
Agent: [Pd+2]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: CCO
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=Cc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
A mixture of 2,5-dichloropyridine (10.0 g), potassium vinyltrifluoroborate (10.86 g), dichloromethane complex (2.5 g) of dichloro-1,1′-bis(diphenylphosphino)-ferrocene palladium (II), triethylamine (14.13 mL) and ethanol (150 mL) was stirred overnight under reflux. After cooling the system to room temperature, ethyl acetate was added, followed by washing with saturated aqueous sodium hydrogencarbonate solution and saturated brine and drying over anhydrous sodium sulfate. Concentrating the solvent under reduced pressure, the resulting residue was distilled under reduced pressure (63° C., 8 mmHg) to provide the title compound (6.50 g, 69%).
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]([OH:8])=[O:7])([O-:3])=[O:2].S(Cl)(Cl)=O.[CH2:13](O)[CH3:14]>C(Cl)(Cl)Cl>[N+:1]([CH2:4][CH2:5][C:6]([O:8][CH2:13][CH3:14])=[O:7])([O-:3])=[O:2]
Reactant: CCO
Reactant: O=C(O)CC[N+](=O)[O-]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CCOC(=O)CC[N+](=O)[O-]

Procedure:
A suspension of 116 g (0.97 mole) β-nitropropanoic acid (CAS number 504-88-1) in chloroform (1 l) is stirred and treated with 127.5 g (1.07 mole) thionyl chloride. A rapid evolution of gas takes place and the mixture is stirred one hour at room temperature. Ethanol (50 g, 1.07 mole) is added dropwise followed by rapid gas evolution. The mixture is stirred 72 hours, concentrated and distilled to yield ethyl β-nitropropanoate, bp 95°-105° C. at 15 mm. A solution of 182 g (1.84 mole) ethyl acrylate [CAS number 140-88-5] in t-butanol (150 ml) and 10 ml of Triton B is treated at 40° C. with 135.5 g (0.92 mole) of ethyl β-nitropropanoate. Additional portions of Triton B (2 ml×3) and ethyl acrylate (25 g×3) are added over a five-hour period. The mixture is cooled and poured into a solution of 100 ml of concentrated hydrochloric acid in water (1 l). The diethyl-γ-nitro-γ-carboethoxymethylpimelate is extracted using dichloromethane (4×500 ml). The combined extracts are dried over anhydrous magnesium sulfate, filtered, and concentrated to yield an oil. The oil (160 g) is dissolved in ethanol (1.5 l) and treated with hydrogen in the presence of 7 g 20% Pd/C. The mixture is filtered through filter aid and concentrated to yield a mixture of 5-carboethoxyethyl-5carboethoxymethyl-2-pyrrolidinone (major product), 5-carboethoxymethyl-5-carboxyethyl-2-pyrrolidinone, and 5-carboethoxyethyl-5-carboxymethyl-2-pyrrolidinone as an oil. The oil dissolved in 1 l of 50% ethanol is titrated with a solution of 50% sodium hydroxide with stirring at reflux accompanied by removal of ethanol. The hydrolyzed mixture is neutralized with concentrated hydrochloric acid to yield 5-carboxyethyl-5-carboxymethyl-2-pyrrolidinone in water. The water is removed at reduced pressure and the resulting solid is added to acetic anhydride (1 kg) with stirring. The mixture is heated at 100° C. for 16 hours. The mixture is filtered through filter aid and concentrated at reduced pressure to yield tetrahydro-3,5-dioxo-1H-pyrrolizine-7a(5H)acetic acid anhydride with acetic acid as an oil. The oil is dissolved in a minimum amount of acetonitrile, an equivalent amount of water is added, and the mixture is stirred 16 hours. The mixture is concentrated at reduced pressure to yield a solid. The solid is recrystallized from acetonitrile to yield tetrahydro-3,5 -dioxo-1H-pyrrolizine-7a(5H)-acetic acid with a melting point of 177°-180° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])[CH:5]=[C:6]([F:8])[CH:7]=1.[Li]CCCC.[S:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1>C1COCC1>[CH3:15][C:10]1[N:9]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([C:24]3([OH:27])[CH2:25][CH2:26][S:21][CH2:22][CH2:23]3)=[C:6]([F:8])[CH:5]=2)[C:13]([CH3:14])=[CH:12][CH:11]=1
Reactant: O=C1CCSCC1
Reactant: Cc1ccc(C)n1-c1cc(F)cc(F)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(F)c(C2(O)CCSCC2)c(F)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To the solution of 1-(3,5-difluorophenyl)-2,5-dimethyl-1H-pyrrole (Step 1, 16.7 g, 80.6 mmol) in anhydrous THF (161 mL) at −78° C. under N2 is added n-BuLi (1.6 M in hexanes, 51.8 mL, 82.9 mmol) dropwise. After stirring at −78° C. for 1 h, the reaction mixture is treated with tetrahydrothiopyran-4-one (5.35 g, 46.1 mmol) in anhydrous THF (46 mL) dropwise and then stirred at −78° C. for 2 h and at 0° C. for 3 h. The reaction is then quenched by the slow addition of saturated aqueous ammonium chloride (50 mL), diluted with H2O (50 mL) and Et2O (50 mL) and the layers are separated. The organic phase is washed with H2O (50 mL) and saline (50 mL), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure, and the residue is purified by silica gel chromatography (650 mL, 10–20% EtOAc/Hexanes eluent) to give the title compound, mp 125–126° C.; MS (ESI+) for C17H19F2NOS m/z 324 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][N:8]2[C:13]3[CH:14]=[CH:15][C:16]([N+:18]([O-])=O)=[CH:17][C:12]=3[O:11][CH2:10][C:9]2=[O:21])[N:3]=1.C(O)C.[OH-].[K+]>Cl>[NH2:18][C:16]1[CH:15]=[CH:14][C:13]2[N:8]([CH2:7][C:4]3[N:3]=[C:2]([CH3:1])[O:6][N:5]=3)[C:9](=[O:21])[CH2:10][O:11][C:12]=2[CH:17]=1
Reactant: Cc1nc(CN2C(=O)COc3cc([N+](=O)[O-])ccc32)no1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(CN2C(=O)COc3cc(N)ccc32)no1
Yield: 38.3 %

Procedure:
A mixture of 4-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-7-nitro-2H-1,4-benzoxazin-3(4H)-one (3.2 g) and ethanol (40 ml) was prepared. To this mixture was added a solution of stannous chloride dihydrate (11.3 g) in concentrated hydrochloric acid (44 ml) at a temperature of 10° to 20° C. The reaction mixture was stirred at a temperature of 60° to 70° C., and distilled to dryness under a reduced pressure. The resulting residue was admixed with ice (150 g). To the mixture thus obtained was added dropwise a 25% aqueous potassium hydroxide solution at a temperature of 0° to 10° C. to render the mixture alkaline. The resultant alkaline solution was extracted with dichloromethane (80 ml×2). The dichloromethane layer was washed with water, and dried over anhydrous sodium sulfate. The dichloromethane solvent was distilled off under a reduced pressure, and the resultant solid residue (1.3 g) was recrystallized from toluene, so that the aimed compound, i.e. 7-amino-4-(5-methyl-1,2,4-oxadiazol-3-ylmethyl)-2H-1,4-benzoxazin-3(4H)-one (1.1 g) was obtained. m.p. 146°-147.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:6]2)#[N:2].Cl.[NH2:20][OH:21].C(=O)([O-])O.[Na+]>C(O)C>[OH:21][NH:20][C:1](=[NH:2])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:7]=[CH:6]2
Reactant: NO
Reactant: CCOC(=O)CCn1ccc2cc(C#N)ccc21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CCn1ccc2cc(C(=N)NO)ccc21
Temperature: 50 °C
Reaction time: 72 h
Yield: 95.9 %

Procedure:
Ethyl 3-(5-cyano-1H-indol-1-yl)propanoate (D51) (1.7 g, 7.2 mmol), hydroxylamine hydrochloride (1.0 g, 14.4 mmol) and sodium hydrogen carbonate (2.42 g, 28.9 mmol) were suspended in ethanol (100 ml) and stirred at 50° C. for 3 days. A single product formed but 15% starting material remained. Cooled, filtered off the inorganic material and evaporated off the solvent. The product was crystallised from a mixture of EtOAc, diethyl ether and hexane to yield 1.9 g of the title compound as a white solid. MS (ES) C14H17N3O3 requires 275; found 276. (MH+).
Reaction SMILES: [CH:1]([C:3]1[C:4]([B:8]([OH:10])[OH:9])=[CH:5][S:6][CH:7]=1)=[O:2].C1COCC1.Cl>>[OH:2][CH2:1][C:3]1[C:4]([B:8]([OH:10])[OH:9])=[CH:5][S:6][CH:7]=1
Reactant: O=Cc1cscc1B(O)O
Agent: Cl
Solvent: C1CCOC1
Product: OCc1cscc1B(O)O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-formyl-3-thienylboronic acid (1.0 g, 6.4 mmol) in dry THF (10 ml) sodium borohydride (0.27 g, 7.1 mmol) was added. The mixture was stirred at room temperature for 30 minutes. The reaction was then stopped by the addition of 1M hydrochloric acid and was then extracted with ethyl acetate, dried and evaporated to dryness. Yield: 0.9 g, 89%, dec. at ≈120° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].C(O)C.[S:28]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29]1>C1(C)C=CC=CC=1.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.[Pd].O>[N+:16]([C:4]1[CH:3]=[C:2]([C:30]2[CH:31]=[CH:32][S:28][CH:29]=2)[CH:7]=[CH:6][C:5]=1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])([O-:18])=[O:17]
Reactant: CC(C)(C)OC(=O)Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: OB(O)c1ccsc1
Agent: [Pd]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccsc2)cc1[N+](=O)[O-]
Temperature: 90 °C
Yield: 88 %

Procedure:
To a solution of tert-butyl 4-bromo-2-nitrophenylcarbamate obtained in step IV preparation 4 above (1.0 eq) in toluene, was added 10 mol % of tetrakis Pd, heated to 90° C. for 30 min, then aq K2CO3 and ethanol were added, followed by addition of 3-thienyl boronic acid portionwise and then reaction was refluxed overnight. Water was added to the reaction mixture and the organic layer was separated, dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford crude product, which, on purification by column chromatography afforded the desired tert-butyl 2-nitro-4-thien-3-ylphenylcarbamate. (Yield=88%)
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]=2[N:7]=[CH:6]1)[CH3:2].Cl[CH2:19][CH2:20][CH2:21][CH2:22][P:23]([O:28][CH2:29][CH3:30])(=[O:27])[O:24][CH2:25][CH3:26]>>[CH2:1]([O:3][CH2:4][N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:19][CH2:20][CH2:21][CH2:22][P:23](=[O:27])([O:28][CH2:29][CH3:30])[O:24][CH2:25][CH3:26])[C:10](=[O:15])[N:9]([CH2:16][CH3:17])[C:8]=2[N:7]=[CH:6]1)[CH3:2]
Reactant: CCOP(=O)(CCCCCl)OCC
Reactant: CCOCn1cnc2c1c(=O)[nH]c(=O)n2CC
Product: CCOCn1cnc2c1c(=O)n(CCCCP(=O)(OCC)OCC)c(=O)n2CC

Procedure:
The title substance was prepared from 0.01 5 mol of 7-ethoxymethyl-3-ethylxanthine and 0.017 mol of diethyl 4-chlorobutanephosphonate analogously to 53.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][O:39][CH:40]([O:44][CH3:45])[CH2:41][NH:42][CH3:43]>>[CH3:38][O:39][CH:40]([O:44][CH3:45])[CH2:41][N:42]([CH3:43])[C:21]1[N:20]=[C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:29]=[C:30]([N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:31]=[C:2]([F:1])[CH:3]=3)=[CH:9][CH:10]=2)[CH:24]=[CH:23][N:22]=1
Reactant: CNCC(OC)OC
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: COC(CN(C)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1)OC

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and (2,2-dimethoxy-ethyl)-methylamine according to conditions described in general procedure C. Mp: 135-136° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.59-1.61 (m, 6 H), 2.82 (s, 3 H), 3.01-3.08 (m, 2 H), 3.27-3.30 (m, 10 H), 3.60 (s, 1 H), 6.25-6.40 (bd, 1H), 6.93-6.98 (m, 1H), 7.16 (d, J=8.5 Hz, 1 H), 7.40 (d, J=9.0 Hz, 1 H), 7.45 (s, 1 H), 7.54-7.59 (m, 3 H), 7.80 (s, 1 H), 7.96-7.99 (m, 1 H), 8.27 (d, J=4.4 Hz, 1 H), 10.41 (s, 1 H).
Reaction SMILES: CO[C:3](=[O:5])[O-:4].[CH2:6]([N+:8]([CH3:11])([CH3:10])[CH3:9])[CH3:7].C1(=O)[O:17][C:15](=[O:16])[CH:14]=[CH:13]1>O>[C:3]([O-:4])(=[O:5])/[CH:13]=[CH:14]\[C:15]([O-:17])=[O:16].[CH2:6]([N+:8]([CH3:11])([CH3:10])[CH3:9])[CH3:7].[CH2:6]([N+:8]([CH3:11])([CH3:10])[CH3:9])[CH3:7]
Reactant: COC(=O)[O-]
Reactant: O=C1C=CC(=O)O1
Agent: CC[N+](C)(C)C
Solvent: O
Product: O=C([O-])/C=C\C(=O)[O-]
Yield: 139.8 %

Procedure:
By following the same procedure as Example 20 (2nd step) except that 7.8 g of ethyltrimethylammonium methyl carbonate, 7.8 g of water, and 4.7 g of maleic anhydride were used, 9.7 g (yield of 99.9%) of ethyltrimethylammonium maleate was obtained. The content of monomethyl maleate was less than 0.1% and the contents of impurity ions were all less than 1 ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.[NH:30]1[C:38]2[C:33](=[CH:34][C:35]([CH2:39]O)=[CH:36][CH:37]=2)[CH:32]=[CH:31]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:39][C:35]5[CH:34]=[C:33]6[C:38](=[CH:37][CH:36]=5)[NH:30][CH:31]=[CH:32]6)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OCc1ccc2[nH]ccc2c1
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1Cc1ccc2[nH]ccc2c1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(1H-indol-5-ylmethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and (1H-indol-5-yl)methanol following General Procedure J.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[CH3:8][O:9][C:10]1[CH:15]=[C:14]([Br:16])[CH:13]=[CH:12][C:11]=1[OH:17]>>[Br:16][C:14]1[CH:13]=[CH:12][C:11]([O:17][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:10]([O:9][CH3:8])[CH:15]=1
Reactant: COc1cc(Br)ccc1O
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1ccc(Br)cc1OC

Procedure:
Prepared analogously to Intermediate product Z2a from ethyl bromo-acetate and 2-methoxy-4-bromophenol.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[C@H:25]([CH3:26])[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]2=3)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[CH3:26][C@@H:25]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:12]1[S:9]([C:6]1[CH:5]=[CH:4][C:3]([OH:2])=[CH:8][CH:7]=1)(=[O:11])=[O:10]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3[C@H]2C)cc1
Agent: BrB(Br)Br
Solvent: C1=CCCCC1
Solvent: ClCCl
Product: C[C@@H]1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)cc1

Procedure:
The title compound was prepared from (R)-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.38 g, 1.04 mmol), cyclohexene (0.27 mL, 2.61 mmol), and 1.0 M boron tribromide in dichloromethane (6.27 mL, 6.27 mmol) according to the procedure and in the same manner as described in Example 1, step b. The crude product was purified by flash column chromatography on silica gel, eluting with dichloromethane, to yield 4-{[(R)-6-methylphenanthridin-5(6H)-yl]sulfonyl}phenol* (0.26 g, 0.74 mmol, 71%) as a white, solid, single enantiomer, m.p. 181-183° C.;