Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>N1C=CC=CC=1>[S:9]1[C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=[C:8]1[C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])=[CH:7][CH:6]=1
Reactant: Nc1ccc(-c2nc3ccccc3s2)cc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)Nc2ccc(-c3nc4ccccc4s3)cc2)cc1

Procedure:
To 2-(4-aminophenyl)-benzothiazole (0.5 g, 2.2 mmol) in pyridine (6 mL) was added para-toluenesulphonyl chloride (0.506 g, 2.7 mmol, 1.5 equiv.) in pyridine (4 mL). The reaction mixture was heated at reflux for 10 mins, then cooled and water (10 mL) added. The white precipitate formed was collected on a filter, washed with water and dried under vacuum to give N-[(4-benzothiazol-2-yl)phenyl]-4-methylbenzenesulfonamide as a white solid. The yield was 0.807 g (96%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](N)=[N:6][C:7]=1[CH3:8].Br.[Br:11]C1C=CC(N)=NC=1C.Br.BrBr.N([O-])=O.[Na+].[OH-].[Na+]>O>[Br:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[C:7]([CH3:8])[N:6]=1
Reactant: Cc1nc(N)ccc1Br
Agent: Br
Agent: BrBr
Agent: O=N[O-]
Solvent: O
Product: Cc1nc(Br)ccc1Br
Temperature: 2 °C
Reaction time: 1 h
Yield: 183.1 %

Procedure:
5-Bromo-2-amino-6-picoline (7.0 kg) and 5-bromo-2-amino-6-picoline hydrobromide (7.0 kg) (based on the starting material analyses, this was equal to 11 kg or 41 mol of starting material) are dissolved into 48% hydrobromic acid (107.0 kg, 635 mol, 15.49 eq) at <35° C. The solution was cooled to 2° C. and bromine (27.3 kg, 171 mol, 4.17 eq) was charged over 45 min at 0-5° C. A solution of sodium nitrite (8.1 kg, 117 mol, 2.86 eq) in 20 L of water was charged over 1.5 hours at −1 to 5° C. The contents were held one hour and the pH was adjusted to 12.5 using 50% aqueous sodium hydroxide (70.0 kg). The contents were warmed to 20° C. over one hour and the solids were collected in a polypropylene bag on a centrifuge. The solids were washed with water (75 L) to produce 12.0 kg of moist 2,5-dibromo-6-picoline, determined to be 83 wgt % product (68% yield). Part of this was dried for the purposes of recording the 13C NMR spectrum: 13C NMR (400 MHz, CDCl3) δ 158.8, 141.9, 139.4, 126.7, 120.6, 24.7.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH2:25][C:26]([NH2:28])=[O:27])=[C:9]([CH2:23][CH3:24])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18](Cl)[CH:17]=1.ClC1C=C(CN2C3C(=C(O)C=CC=3)C(CC(N)=O)=C2CC)C=CC=1.[H-].[Na+].BrCC(OC)=O>CN(C=O)C>[CH3:1][O:2][C:3](=[O:29])[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[C:8]([CH2:25][C:26]([NH2:28])=[O:27])=[C:9]([CH2:23][CH3:24])[N:10]2[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCc1c(CC(N)=O)c2c(OCC(=O)OC)cccc2n1Cc1cccc(Cl)c1
Agent: CCc1c(CC(N)=O)c2c(O)cccc2n1Cc1cccc(Cl)c1
Agent: COC(=O)CBr
Agent: [H-]
Solvent: CN(C)C=O
Product: CCc1c(CC(N)=O)c2c(OCC(=O)OC)cccc2n1Cc1ccccc1

Procedure:
[[3-(2-Amino-2-oxoethyl)-1-[(3-chlorophenyl)methyl]-2-ethyl-1H-indol-4-yl]oxy]acetic acid methyl ester. (1-[(3-Chlorophenyl)methyl]-2-ethyl-4-hydroxy-1H-indole-3-acetamide (91 mg, 0.3 mmol) was reacted with 12 mg (0.3 mmol) of NaH/mineral oil (washed with hexanes) in 10 mL of DMF and then 0.03 mL (0.3 mmol) of methyl 2-bromoacetate as described in Example 75, Part H, to give after chromatography on silica gel (eluted with ethyl acetate) 80 mg (71% yield) of 2-[[3-(2-amino-2-oxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester.
Reaction SMILES: [F:1][C@H:2]1[C@H:6]([O:7]C(=O)C2C=CC=CC=2)[C@@H:5]([CH2:16][O:17]C(=O)C2C=CC=CC=2)[O:4][C@H:3]1[N:26]1[CH:33]=[C:32]([I:34])[C:30](=[O:31])[NH:29][C:27]1=[O:28].[OH-].[Na+]>CO.O>[F:1][C@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:16][OH:17])[O:4][C@@H:3]1[N:26]1[CH:33]=[C:32]([I:34])[C:30](=[O:31])[NH:29][C:27]1=[O:28]
Reactant: O=C(OC[C@H]1O[C@@H](n2cc(I)c(=O)[nH]c2=O)[C@@H](F)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=c1[nH]c(=O)n([C@H]2O[C@H](CO)[C@@H](O)[C@@H]2F)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A slurry of 1-(2-deoxy-2-fluoro-3,5-di-O-benzoyl-β-D-arabinofuranosyl)-5-iodouracil (4.7 g, 0.0081 mole) from Procedure 6 in 60 mL 50% MeOH/H2O is stirred at 25° C. maintained at pH 10.5 with 3N NaOH until complete dissolution of solid occurs. Progress of the hydrolysis is followed by HPLC (mobile phase=70% H2O/30% MeOH, flow rate=1 mL/min., wave length=282 nm UV detection, column=Whatman 10 ODS-3 reverse-phase 25 cm., injection volume=20 μl at ~0.5 mg/l concentration, α-IX=6.86 min., β-IX =7.98 min., and 5-iodouracil=4.5 min.). When the reaction is complete (16 hr.), 25 mL of water is added and the mixture is concentrated to approximately 30 mL. The clear aqueous concentrate is adjusted to pH 6.5 to 7.0 with 3N HCl. A solid forms, the mixture is stirred at 25° C. for 2 hrs., and at 0 to 5° C. for 5 hrs. The solid is collected by filtration, washed with 30 mL cold H2O and dried at 50° C./5 mm. The yield of product is 2.7 g (90%), mp 223°-226° [360 MHz NMR (CD3OD) 8.28, d, 1H; 6.16, dd, 1H; 5.04, m, 1H; 4.32, m, 1H; 3.95-3.7, m, 3H. Elemental analysis calculated: %C 29.05, %H 2.71, %N 7.53; Found: %C 28.86, %H 2.64, %N 7.50; IR (KBr) NH, OH 3400, 3200 cm-1 ; CO--NH--CO 1725, 1655 cm-1, C--O 1050 cm-1.]
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15](F)=[C:14]([Cl:19])[CH:13]=1.ClC1C=C(C2N=C(C(OCC)=O)SC=2)C=CC=1>>[Br:1][C:2]1[S:6][C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:19])[CH:13]=1
Reactant: CCOC(=O)c1nc(-c2ccc(F)c(Cl)c2)c(Br)s1
Agent: CCOC(=O)c1nc(-c2cccc(Cl)c2)cs1
Product: CCOC(=O)c1nc(-c2cccc(Cl)c2)c(Br)s1

Procedure:
The preparation of the title compound takes place in analogy to the synthesis of the compound from Example 4A starting with the compound of Example 3A. 1.95 g of the title compound having a purity of 65% (98% of theory) are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[Se:4][C:3]=1[C:11]([NH2:13])=[O:12].[N:14]([O-])=O.[Na+]>S(=O)(=O)(O)O>[C:7]([C:5]1[Se:4][C:3]2[C:11](=[O:12])[NH:13][N:14]=[N:1][C:2]=2[CH:6]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: O=N[O-]
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)(C)c1cc2nn[nH]c(=O)c2[se]1
Temperature: 0 °C
Reaction time: 1 h
Yield: 76.8 %

Procedure:
To an ice cold solution (0° C.) of 3-amino-5-(tert-butyl)selenophene-2-carboxamide (3.0 g, 12.2 mmol) in concentrated sulfuric acid (50 mL) was added a cold (0° C.) solution of sodium nitrite (0.92 g, 13.4 mmol) in concentrated sulfuric acid (10 mL) for 10 min (while adding, the temperature should keep between −5-0° C.). After addition, the mixture was stirred at 0° C. for 1 h and at rt for 1 h. The reaction mixture was cooled and poured into crushed ice slowly with stirring for 15 min and stirred at the same temperature for 15 min. The solid was filtered, washed with ice cold water and dried to give the product as a off-white color solid (2.4 g, 77%), mp 158-160° C. 1H NMR (400 MHz, CDCl3): δ 7.67 (1H, s, H-7), 1.50 (9H, s, tert-butyl); LC-MS (negative ion mode): m/z 254, 256 (M−H)—.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:12][C:11]([CH2:27][C:28](OC)=[O:29])=[C:10]1[C:32]([O:34][CH3:35])=[O:33].[OH-].[Na+].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1.Cl.C(N=C=NCCCN(C)C)C>ClCCl.CCOCC.O.CO>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[NH:12][C:11]([CH2:27][C:28]([N:42]2[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]2)=[O:29])=[C:10]1[C:32]([O:34][CH3:35])=[O:33]
Reactant: COC(=O)CC1=C(C(=O)OC)C(c2c(Cl)cccc2Cl)C(C(=O)OC)=C(CCc2ccccc2)N1
Reactant: CN1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: CO
Product: COC(=O)C1=C(CCc2ccccc2)NC(CC(=O)N2CCN(C)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 59.6 %

Procedure:
A mixture of dimethyl 4-(2,6-dichlorophenyl)-2-methoxycarbonylmethyl-6-(2-phenylethyl)-1,4-dihydropyridine-3,5-dicarboxylate (3.9 g, 7.52 mmol), methanol(35 ml), water (5 ml), and 6N NaOH (2.51 ml, 15.05 mmol) was stirred at room temperature for 1.25 h. The reaction mixture was diluted with dichloromethane (100 ml) followed by addition of 6 NHCl (3 ml) and water (100 ml). The organic layer separated was washed twice with water and brine, dried over Na2SO4, and concentrated to 50 ml. To this solution was added N-methylpiperazine (1.25 ml, 11.28 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2.162 g, 11.28 mmol) at 0° C. and stirred for 0.5 h, then ice bath was removed and stirring was continued at room temperature overnight. The reaction mixture was washed with water, NaHCO3 aqueous solution and brine, and dried over Na2SO4. The solvent was evaporated and the crude product was chromatographed on 234 g silica gel (dichloromethane/ethyl acetate: 22/3 as eluent) to give 3.48 g. This was taken up in 17 ml ether and stirred, giving 2.63 g of crystals after drying under high vacuum at 78° C., mp 138°-139° C.
Reaction SMILES: [C:1]([N:5]1[CH:9]=[C:8]([CH:10]=[O:11])/[C:7](=[N:12]/[C:13](=[O:23])[C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])/[S:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][Mg]Br>C1COCC1>[C:1]([N:5]1[CH:9]=[C:8]([CH:10]([OH:11])[CH3:24])/[C:7](=[N:12]/[C:13](=[O:23])[C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=2[O:21][CH3:22])/[S:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1C=O
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sn(C(C)(C)C)cc1C(C)O
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 46.6 %

Procedure:
The product from Example 21A (450 mg, 1.28 mmol) in THF (20 mL) was treated dropwise with methylmagnesium bromide (0.85 mL, 2.55 mmol) at −40° C. The reaction was stirred at −40° C. for 1.5 hrs, quenched with saturated NH4Cl and the mixture was extracted with EtOAc (2×). The organics were combined, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 10-80% ethyl acetate/hexane) to afford 220 mg (47%) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 1.64 (d, J=6.44 Hz, 3 H) 1.67 (s, 9 H) 3.70-3.78 (m, 1 H) 3.93 (s, 3 H) 5.19 (q, J=6.44 Hz, 1 H) 6.93 (d, J=8.90 Hz, 1 H) 7.37 (dd, J=8.59, 2.76 Hz, 1 H) 7.97 (s, 1 H) 8.06 (d, J=2.76 Hz, 1 H); MS (DCI/NH4+) m/z 369 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH2:11][O:12][CH3:13])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][Si:22](Cl)([CH3:24])[CH3:23]>>[CH2:14]([C:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)([CH2:9][O:10][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH2:11][O:12][CH3:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[Si](C)(C)Cl
Reactant: COCC(CO)(Cc1ccccc1)Cc1ccccc1
Product: COCC(CO[Si](C)(C)C)(Cc1ccccc1)Cc1ccccc1

Procedure:
According to the procedure as described in Example 1,2,2-dibenzyl-1-methoxy-3-[(trimethylsilyl)oxy]propane was prepared from intermediate 2,2-dibenzyl-3-methoxy-1-propanol and reagent trimethylsilyl chloride.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH2:10])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Cl:11][CH2:12][C:13]([N:16]=[C:17]=[O:18])([CH3:15])[CH3:14].CO>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:17]([NH:16][C:13]([CH3:15])([CH3:14])[CH2:12][Cl:11])=[O:18])[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(CCl)N=C=O
Reactant: Nc1ccc2ncsc2c1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CC(C)(CCl)NC(=O)Nc1ccc2ncsc2c1
Temperature: 25 °C
Yield: 18.5 %

Procedure:
Benzothiazol-6-ylamine (1.8 g, 12.00 mmol) was added portion wise to solution of 1-chloro-2-isocyanato-2-methyl-propane (2 g, 13.60 mmol) in toluene (20 mL) over a period of 5 minutes. The resulting mixture was stirred at room temperature for 2½ days. The reaction was monitored by TLC (5% MeOH in CHCl3). The reaction mixture was concentrated and extracted with ethylacetate. The organic layer was dried over Na2SO4 and concentrated. Purification by column chromatography on silica gel (1% MeOH in CHCl3) afforded 630 mg of the product (16.57% yield).
Reaction SMILES: CO.C(=O)([O-])[O-].[Na+].[Na+].Br[C:10]1[CH:11]=[C:12]([F:25])[C:13]([C:16]#[C:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])=[N:14][CH:15]=1.[Cl:26][C:27]1[CH:32]=[CH:31][C:30](OB(O)O)=[CH:29][CH:28]=1>O1CCOCC1>[Si:18]([C:17]#[C:16][C:13]1[C:12]([F:25])=[CH:11][C:10]([C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=2)=[CH:15][N:14]=1)([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19]
Reactant: CC(C)(C)[Si](C)(C)C#Cc1ncc(Br)cc1F
Reactant: OB(O)Oc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)(C)[Si](C)(C)C#Cc1ncc(-c2ccc(Cl)cc2)cc1F

Procedure:
10 mL of MeOH, 10 mL of 2N aqueous sodium carbonate solution, and 94 mg (0.13 mmol) of [1,1′-bis(diphenylphosphine)ferrocene]palladium (II) chloride were added to a solution of 1.61 g (5.14 mmol) of 5-bromo-2-[(tert-butyldimethylsilanyl)ethynyl]-3-fluoropyridine and 0.90 g (5.65 mmol) of 4-chlorophenylboric acid in 30 mL of 1,4-dioxane and the mixture was refluxed for 15 minutes. The reaction mixture was evaporated down in vacuo and diluted with EtOAc. The organic phase was washed with water and semisaturated aqueous sodium bicarbonate solution, dried over sodium sulfate, and evaporated down in vacuo. The residue was purified by column chromatography (silica gel, PE/DCM 1:1). Yield: 1.25 g (70% of theoretical); C19H21ClFNSi (M=345.913); calc.: molpeak (M+H)+: 346/348 (Cl); found: molpeak (M+H)+: 346/348 (Cl); HPLC-MS: 8.83 minutes (method B).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[N:26](C3CCCCO3)[N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:33][CH2:34][CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[Cl:19][C:16]([F:17])([F:18])[O:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([N:39]3[CH2:40][CH2:41][N:36]([CH2:35][CH2:34][F:33])[CH2:37][CH2:38]3)=[N:3][CH:4]=2)=[CH:14][CH:13]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccnn2C2CCCCO2)c1
Reactant: FCCN1CCNCC1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2CCN(CCF)CC2)c(-c2ccn[nH]2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 33 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-5-yl)nicotinamide (Stage 48.2) and 1-(2-fluoroethyl)piperazine to afford an off-white powder. HPLC (Condition 4) tR=4.57 min, UPLC-MS (Condition 3) tR=0.82 min, m/z=492.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 2.54-2.71 (m, 2H) 3.09-3.21 (m, 4H) 3.24-3.35 (m, 4H) 4.46 (t, J=4.89 Hz, 1H) 4.58 (t, J=4.89 Hz, 1H) 6.66 (br. s, 1H) 7.33 (d, J=8.60 Hz, 2H) 7.86 (d, J=8.99 Hz, 3H) 8.28-8.37 (m, 1H) 8.73 (d, J=1.95 Hz, 1H) 10.39 (br. s, 1H) 12.96-13.11 (m, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[NH:6][N:5]=1)(=[O:3])[CH3:2].[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(OCC)(=O)C>[C:1]([C:4]1[CH:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:6]([CH3:14])[N:5]=1)(=[O:3])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(C(C)=O)n[nH]1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C(C)=O)nn1C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 65.1 %

Procedure:
Ethyl 3-acetyl-1H-pyrazole-5-carboxylate (Chem. Commun., 2004, 394-395) (4.82 g) was dissolved in N,N-dimethylformamide (80 ml). To the solution, potassium carbonate (4.39 g) and iodomethane (1.98 ml) were added under ice cooling, and the mixture was stirred at room temperature for 3 hours and 50 minutes. The reaction solution was diluted with ethyl acetate. The organic layer was washed with saturated saline, water, and saturated saline in this order and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane-ethyl acetate) to obtain the title compound (3.38 g).
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.[Cl:16][C:17]1[C:18]([F:28])=[C:19]([O:26][CH3:27])[CH:20]=[C:21]2[C:25]=1[NH:24][CH2:23][CH2:22]2>>[Cl:8][C:6]1[N:7]=[C:2]([N:24]2[C:25]3[C:21](=[CH:20][C:19]([O:26][CH3:27])=[C:18]([F:28])[C:17]=3[Cl:16])[CH2:22][CH2:23]2)[C:3](=[O:15])[N:4]([C@@H:9]([CH:12]2[CH2:14][CH2:13]2)[CH2:10][CH3:11])[CH:5]=1
Reactant: COc1cc2c(c(Cl)c1F)NCC2
Reactant: CC[C@H](C1CC1)n1cc(Cl)nc(Cl)c1=O
Product: CC[C@H](C1CC1)n1cc(Cl)nc(N2CCc3cc(OC)c(F)c(Cl)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1R)-1-cyclopropylpropyl]-2(1H)-pyrazinone and 7-chloro-6-fluoro-5-methoxyindoline as the starting materials. mp 128-130° C.; 1H NMR (300 MHz, CDCl3): δ 6.96 (s, 1 H), 6.79 (d, J=7.3 Hz, 1 H), 4.33 (t, J=7.9 Hz, 2H), 4.08-4.00 (m, 1 H), 3.86 (s, 3 H), 3.08 (t, J=7.7 Hz, 2 H), 1.94-1.74 (m, 2 H), 1.07-0.97 (m, 1 H), 0.92 (t, J=7.3 Hz, 3 H), 0.80-0.73 (m, 1 H), 0.55-0.44 (m, 2 H), 0.34-0.27 (m, 1H); HRMS (ESI) calcd for C19H21N3O2Cl2F (M+H)+: 412.0995; found m/z 412.1019.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].N1C=CC=CC=1.[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1>CN(C)C=O>[F:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:26])=[CH:23][CH:22]=1
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)C(NC(=O)c1ccc(F)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 15 h
Yield: 69.8 %

Procedure:
To a solution of diethyl aminomalonate hydrochloride (5.0 g, 23.6 mmol) in pyridine (7.64 ml, 94.5 mmol) and dimethylformamide (60 ml) was added p-fluorobenzoyl chloride (4.19 ml, 35.4 mmol). The reaction mixture was stirred at room temperature for 15 hours. After removing the solvents, the residue was redissolved in dichloromethane, washed with water, brine and dried over Na2SO4. After removing the solvents, the crude residue was purified by flash chromatography on silica (CH2Cl2/MeOH 30:1) to yield the title compound as a white solid (4.9 g, 70%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[Cl-].[Cl-].[Cl-].[Al+3].[CH3:15][C:16]1[C:21]2[NH:22][C:23](=[O:25])[O:24][C:20]=2[CH:19]=[CH:18][CH:17]=1>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:18]2[CH:17]=[C:16]([CH3:15])[C:21]3[NH:22][C:23](=[O:25])[O:24][C:20]=3[CH:19]=2)=[O:9])[CH:3]=1
Reactant: Cc1cccc2oc(=O)[nH]c12
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: [Al+3]
Agent: [Cl-]
Product: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)[nH]c12
Temperature: 130 °C

Procedure:
A well stirred mixture of 2.34 g (13.2 mmol) 6-chloropyrimidine-4-carboxylic acid chloride, 8.00 g (60.0 mmol) aluminium trichloride and 1.79 g (12.0 mmol) 4-methyl-3H-benzoxazol-2-one was heated to 130° C. for 1.5 h. After cooling to RT the mixture was decomposed with ice water, then extracted with ethyl acetate, the organic phase was dried on sodium sulphate and evaporated down i. vac. The crude product left as a solid was triturated with diethyl ether, suction filtered and dried in the air.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)[N:10]=2)[CH2:5][CH2:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:33][CH:34]1[O:38][CH2:37][CH2:36][O:35]1.O>CN(C)C=O>[CH2:1]([N:3]1[CH2:4][CH2:5][N:6]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:33][CH:34]4[O:38][CH2:37][CH2:36][O:35]4)=[CH:23][CH:24]=3)[N:10]=2)[CH2:7][CH2:8]1)[CH3:2]
Reactant: BrCC1OCCO1
Reactant: CCN1CCN(c2nc(-c3ccc(O)cc3)cc3ccccc23)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCN(c2nc(-c3ccc(OCC4OCCO4)cc3)cc3ccccc23)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
The resulting 1-(4-ethylpiperazin-1-yl)-3-(4-hydroxyphenyl)isoquinoline (0.53 g) was dissolved in N,N-dimethylformamide (5 ml), to which were added potassium carbonate (0.24 g) and 2-bromomethyl-1,3-dioxolane (250 ml), and the mixture was stirred at 90° C. overnight. Water was added to the reaction solution, and then the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol system), to give 0.47 g of the title compound as a pale yellow oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([N:8]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH2:11][CH:10]([C:24](O)=[O:25])[CH2:9]2)=[O:7])[CH2:3]1.[Cl:27][C:28]1[CH:29]=[C:30]([C:34](=[N:36]O)[NH2:35])[CH:31]=[CH:32][CH:33]=1>>[Cl:27][C:28]1[CH:29]=[C:30]([C:34]2[N:36]=[C:24]([CH:10]3[CH2:11][CH:12]([C:14]4[CH:15]=[CH:16][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:19]=4)[CH2:13][N:8]([C:6]([N:4]4[CH2:3][CH:2]([OH:1])[CH2:5]4)=[O:7])[CH2:9]3)[O:25][N:35]=2)[CH:31]=[CH:32][CH:33]=1
Reactant: NC(=NO)c1cccc(Cl)c1
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CC(O)C2)C1
Product: O=C(N1CC(O)C1)N1CC(c2ccc(C(F)(F)F)cc2)CC(c2nc(-c3cccc(Cl)c3)no2)C1

Procedure:
90.0 mg (0.242 mmol) of 1-[(3-hydroxyazetidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 101A) and 45.4 mg (0.266 mmol) of 3-chloro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 34.7 mg (28% of theory).
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4]/[C:5](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:33])[C:24]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:25])[CH:18]=2)=[CH:13][CH:12]=1)/[C:6]([O:8]C)=[O:7].C(O)(=O)C>O1CCCC1>[CH3:3][O:4]/[C:5](=[CH:10]\[C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([N:23]([CH3:33])[C:24]([NH:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[O:25])[CH:18]=2)=[CH:15][CH:16]=1)/[C:6]([OH:8])=[O:7]
Reactant: COC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Nc3ccccc3)c2)cc1)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CO/C(=C\c1ccc(-c2cccc(N(C)C(=O)Nc3ccccc3)c2)cc1)C(=O)O
Temperature: 68 °C
Reaction time: 4 h
Yield: 59.9 %

Procedure:
2.5 mL (2.5 mmol) of aqueous 1 N sodium hydroxide solution are added to a solution of 0.7 g (1.7 mmol) of methyl (Z)-2-methoxy-3-[3′-(1-methyl-3-phenylureido)biphenyl-4-yl]acrylate in 12 mL of tetrahydrofuran. The reaction medium is heated at 68° C. and stirred for 4 hours. The reaction medium is acidified with 2.6 mL of 1 N acetic acid solution and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is filtered from hot ethanol. 410 mg (60%) of (Z)-2-methoxy-3-[3′-(1-methyl-3-phenylureido)biphenyl-4-yl]acrylic acid are obtained in the form of a white solid with a melting point of 223° C.