Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:4]=[C:5]([C:11]([O-:13])=O)[C:6]([O:8]CC)=[O:7])C.[Cl:14][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][CH:24]=1)[NH:21][CH2:20][CH2:19][CH2:18]2.C(O)C.[OH-].[Na+]>O>[Cl:14][C:15]1[CH:24]=[C:23]2[C:22]3[N:21]([CH:4]=[C:5]([C:6]([OH:8])=[O:7])[C:11]2=[O:13])[CH2:20][CH2:19][CH2:18][C:17]=3[CH:16]=1
Reactant: CCOC=C(C(=O)[O-])C(=O)OCC
Reactant: Clc1ccc2c(c1)CCCN2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cn2c3c(cc(Cl)cc3c1=O)CCC2
Temperature: 140 °C
Yield: 111.3 %

Procedure:
4.9 g of ethyl ethoxymethylenemalonate was added to 4 g of 6-chloro-1,2,3,4-tetrahydroquinoline and the mixture was heated on an oil bath at 110° C. during which time distillation of ethanol was observed. After heating the mixture at the same temperature as above for 30 minutes, 30 g of polyphosphoric acid was added thereto followed by heating at 140° C. for 30 minutes. After completion of the reaction, the reaction mixture was poured into 200 ml of water and the resulting mixture was rendered neutral with a 40% aqueous sodium hydroxide solution to precipitate light brown crystals. Without further purification, the crystals were mixed with 100 ml of a 10% aqueous sodium hydroxide solution and the mixture was heat-refluxed for 40 minutes during which time the crystals were dissolved to form a uniform solution. The solution was treated with activated carbon while hot and filtered. The filtrate was allowed to cool and adjusted pH value to pH 2 to obtain 7.0 g of 9-chloro-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as light yellow crystals having a melting point of 282° to 286° C.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=[O:24])([O-:19])=[O:18]>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:23]([C:22]2[CH:26]=[CH:27][CH:28]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=2)[OH:24])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1cccc([N+](=O)[O-])c1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 3-nitrobenzoic acid
Reaction SMILES: [CH3:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[F:12][C:13]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=1[CH:15]=O>>[F:12][C:13]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:14]=1[CH2:15][NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[C:8]([N+:9]([O-:11])=[O:10])[C:2]=1[CH3:1]
Reactant: O=Cc1ccc(F)cc1F
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Product: Cc1c(NCc2ccc(F)cc2F)cccc1[N+](=O)[O-]

Procedure:
2-Methyl-3-nitroaniline and 2,4-difluorobenzaldehyde were processed as described in Example 1C to provide the title compound.
Reaction SMILES: [OH:1]O.[N:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][C:10]#[N:11])[CH:4]=1.O>C(O)(=O)C>[CH:7]1[CH:8]=[N+:3]([O-:1])[CH:4]=[C:5]([CH2:9][C:10]#[N:11])[CH:6]=1
Reactant: OO
Reactant: N#CCc1cccnc1
Solvent: CC(=O)O
Solvent: O
Product: N#CCc1ccc[n+]([O-])c1
Temperature: 95 °C
Reaction time: 72 h

Procedure:
30% Hydrogen peroxide (12 mL) was added to a solution of 3-pyridylacetonitrile (7.50 g, 63.5 mmol) in acetic acid (40 mL) and the mixture heated at 95° C. for 20 hours. The reaction mixture was then cooled and stirred at room temperature for 72 hours. Water (35 mL) was then added and the solution concentrated under reduced pressure. Water (2×100 mL) was added to the residue and solution concentrated under reduced pressure. Residual water was removed azeotropically using toluene (2×100 mL) to yield the title compound (I115) (8.3 g, 97%) as a pale yellow solid which was used without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:18])([F:17])[F:16])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[CH:3]=1.[Cl:30]N1C(=O)CCC1=O>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([S:13][CH2:14][C:15]([F:16])([F:17])[F:18])[C:10]([CH3:19])=[CH:9][C:8]=2[F:20])[N:5]=[C:4]([O:21][CH2:22][C:23]([F:28])([F:29])[C:24]([F:25])([F:27])[F:26])[C:3]=1[Cl:30]
Reactant: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2N)cc1SCC(F)(F)F
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)c(Cl)c2N)cc1SCC(F)(F)F
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
0.9 g of 5-amino-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole was dissolved in 10 mL of acetonitrile, and 0.3g of N-chlorosuccinimide was added under cooling with ice. After stirring for 10minutes under cooling with ice, the solvent was distilled off under reduced pressure, extraction with ethyl acetate was carried out, and the organic layer was dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane=1:4) to obtain 0.9 g of 5-amino-4-chloro-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)pyrazole.
Reaction SMILES: Cl[C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH2:19][CH2:20][CH2:21][OH:22]>CN(C=O)C.CCOC(C)=O>[OH:22][CH2:21][CH2:20][NH:19][C:2]1[C:3](=[O:18])[N:4]([CH:15]([CH3:17])[CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NCCO
Reactant: CC(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)N1C(=O)C(NCCO)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 98.8 %

Procedure:
4-Chloro-2-isopropyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide (1.10 g, 3.85 mmol) was dissolved in dry DMF (10 mL) under nitrogen atmosphere. 2-Aminoethanol (0.28 g, 4.62 mmol) was added followed by TEA (0.58 g, 5.77 mmol). The reaction mixture was heated in a microwave reactor at 120° C. for 15 mins. The mixture was diluted with EtOAc, washed with saturated aqueous NaHCO3, dried with Na2SO4, filtered and evaporated. The residue was purified on a Biotage Horizon HPFC system using Heptane and EtOAc as eluant and TEA as additive affording the title compound (1.18 g, 99.1%). 1H NMR (500 MHz, CDCl3): δ 1.59 (d, 6H), 3.02 (q, 2H), 3.57 (t, 2H), 4.38-4.46 (m, 1H), 5.71 (bs, 1H), 7.43-7.46 (m, 3H), 7.50-7.53 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 20.38, 46.11, 47.76, 60.78, 107.46, 125.22, 128.96, 129.89, 131.70, 135.84, 158.67; Mass Spectrum: M+H+ 311.
Reaction SMILES: Cl.[N+:2]([C:5]1[C:6]([NH:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:7][CH:8]=[CH:9][CH:10]=1)([O-:4])=[O:3].Cl[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1>CN1CCCC1.O>[S:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[N:15]1[CH2:16][CH2:17][CH:12]([NH:11][C:6]2[C:5]([N+:2]([O-:4])=[O:3])=[CH:10][CH:9]=[CH:8][N:7]=2)[CH2:13][CH2:14]1
Reactant: Clc1nc2ccccc2s1
Reactant: O=[N+]([O-])c1cccnc1NC1CCNCC1
Agent: CN1CCCC1
Agent: Cl
Solvent: O
Product: O=[N+]([O-])c1cccnc1NC1CCN(c2nc3ccccc3s2)CC1
Temperature: 180 °C
Yield: 33.9 %

Procedure:
A mixture of 3-nitro-N-(piperidin-4-yl)pyridine-2-amine hydrochloride (intermediate 58, 500 mg, 2.24 mmol) and 2-chloro-benzo[d]thiazole (379 mg, 2.24 mmol) in N-methylpyrrolidine (5 mL) was heated at 180° C. in microwave for 2 hours. The mixture was diluted with water (60 mL) and extracted with ethyl acetate (2×50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. Purification by silica chromatography gave N-(1-(benzo[d]thiazol-2-yl)piperidin-4-yl)-3-nitropyridin-2-amine (270 mg, 0.76 mmol, 33.8% yield).
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([Br:12])[CH:11]=1)[C:6](O)=[O:7].C[N:16](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.N>CN(C)C=O.O>[Br:12][C:10]1[CH:9]=[C:5]([CH:4]=[C:3]([C:2]([F:14])([F:13])[F:1])[CH:11]=1)[C:6]([NH2:16])=[O:7]
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Reactant: CCN=C=NCCCN(C)C
Agent: N
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: NC(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.7 %

Procedure:
To a solution (18 mL) of 3-trifluoromethyl-5-bromobenzoic acid (5.0 g, 19 mmol) in N,N-dimethylformamide were added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide (4.3 g, 22 mmol), 1-hydroxybenzotriazole (3.4 g, 22 mmol) and 28% aqueous ammonia (1.7 mL, 28 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was to recrystallized (hexane-ethyl acetate) to give the title compound (3.7 g, 74%) as colorless crystals.
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH:22]3[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]3)[CH:17]=[C:16]([C:29]#[C:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH:15]=2)=[CH:9][C:8]=1[Cl:38])C.[OH-].[Na+].Cl>C(O)C>[Cl:38][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH:22]3[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]3)[CH:17]=[C:16]([C:29]#[C:30][C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:39])=[O:3]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(Cl)cc3)cc(OCC3CCN(C)CC3)c2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN1CCC(COc2cc(C#Cc3ccc(Cl)cc3)cc(Sc3ccc(OCC(=O)O)c(Cl)c3)c2)CC1
Reaction time: 16 h

Procedure:
{2-Chloro-4-[3-(4-chloro-phenylethynyl)-5-(1-methyl-piperidin-4-ylmethoxy)-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (60 mg; 0.10 mmol) was dissolved in ethanol (7 mL), and aqueous 1N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 16 h, acidified with 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried, evaporated to dryness and purified by prep. HPLC (method B). Yield: 20 mg. HPLC-MS: m/z: 556.5 (M+); Rt: 2.10 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]([O:10][CH2:11][CH3:12])=[O:9].C(OCC)(=O)C>N1C=CC=CC=1>[C:8]([NH:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1)([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)Cl
Reactant: Nc1nccs1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nccs1
Reaction time: 24 h
Yield: 43.4 %

Procedure:
To a stirred solution of 15.1 g (151 mmole) of 2-aminothiazole in 200 ml of dry pyridine is added slowly 18.8 g (173 mmole) of ethyl chloroformate. After approximately 1 day, insolubles are removed by filtration and discarded and the filtrate is concentrated at reduced pressure. The resultant gum is dissolved in aqueous ethanol and redried in vacuo to a sticky solid. The crude product is dissolved in a boiling mixture of 100 ml of ethanol and 25 ml of water, clarified by filtration, and allowed to cool. The resultant crystalline solid is collected and washed thoroughly with water, giving 11.3 g (65.6 mmole) of 2-carbethoxyaminothiazole as a tlc-homogeneous (ethyl acetate eluent on silica gel plates) substance. Structure assignment is supported by the nmr spectrum.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](O)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:18]>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([Cl:18])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1O
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
7-Bromo-3-nitroquinolin-4-ol (42 g, 156 nmmol) was suspended in POCl3 (130 mL) and brought to 102° C. under an atmosphere of N2. After 45 min, all of the solids had dissolved, so the reaction was cooled to room temperature. The resulting solids were collected by filtration, washed with H2O, and then partitioned with CH2Cl2 (3 L) and 2M Na2CO3 (500 mL). The organic layer was separated, washed with H2O (1×), dried over Na2SO4, filtered, and concentrated to afford 33.7 g of 7-bromo-4-chloro-3-nitroquinoline as a beige solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH2:9][NH:10][CH:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:22][C:23]1[N:28]=[C:27](Cl)[C:26]([N+:30]([O-:32])=[O:31])=[CH:25][N:24]=1>CC(C)=O>[CH2:1]([O:3][C:4]([C:6]1([CH2:9][N:10]([C:25]2[C:26]([N+:30]([O-:32])=[O:31])=[CH:27][N:28]=[C:23]([Cl:22])[N:24]=2)[CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15]2)[CH2:7][CH2:8]1)=[O:5])[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C1(CNC2CCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C1(CN(c2nc(Cl)ncc2[N+](=O)[O-])C2CCCC2)CC1

Procedure:
To a stirred solution of Ethyl1-[(cyclopentylamino)methyl]cyclopropane-1-carboxylate in acetone (700 mL) at room temperature was added potassium carbonate (29.0 g, 209.6 mmol) followed by the 2,4-dichloro-5-nitropyrimidine (Frontier Scientific; 29.81 g, 153.7 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[C:14](F)[CH:13]=[C:12]([F:17])[C:11]=1[N+:18]([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH2:29]([OH:31])C>O>[F:17][C:12]1[CH:13]=[C:14]([O:31][CH3:29])[CH:15]=[C:10]([NH:9][C:3]2[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=2[F:1])[C:11]=1[NH2:18]
Reactant: CCO
Reactant: O=[N+]([O-])c1c(F)cc(F)cc1Nc1ccc(I)cc1F
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Product: COc1cc(F)c(N)c(Nc2ccc(I)cc2F)c1
Temperature: 70 °C

Procedure:
A suspension of 2-fluoro-N-(3,5-difluoro-2-nitrophenyl)-4-iodobenzenamine (Intermediate 17, 550 mg, 1.35 mmol) in ethanol (12 mL) was stirred at 70° C. to obtain a clear solution. To this hot solution was added dropwise a freshly prepared solution of Na2S2O4 (707 mg, 4.0 mmol) in water (2 mL) and stirred the reaction mixture at 90° C. for 1 h. The progress of reaction was monitored by TLC. After completion, the reaction mixture was concentrated and residue dissolved in ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated to yield 3-fluoro-N1-(2-fluoro-4-iodophenyl)-5-methoxybenzene-1,2-diamine (448 mg). 1H-NMR (400 MHz, CDCl3): δ 3.86 (3H, s), 6.43-6.50 (2H, m), 6.56-6.61 (1H, m), 7.26-7.27 (1H, m), 7.37 (1H, d, J=10.0).
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH2:54][CH2:55][C:56]1[O:60][C:59]([C:61]2[CH:66]=[CH:65][C:64]([C:67]3[C:72]([CH3:73])=[CH:71][CH:70]=[C:69]([C:74]([NH:76][CH:77]4[CH2:79][CH2:78]4)=[O:75])[CH:68]=3)=[CH:63][CH:62]=2)=[N:58][N:57]=1>CN(C=O)C>[CH:77]1([NH:76][C:74]([C:69]2[CH:68]=[C:67]([C:64]3[CH:65]=[CH:66][C:61]([C:59]4[O:60][C:56]([CH2:55][NH:54][C:8](=[O:10])[CH2:7][C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[N:57][N:58]=4)=[CH:62][CH:63]=3)[C:72]([CH3:73])=[CH:71][CH:70]=2)=[O:75])[CH2:79][CH2:78]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CN)o2)cc1
Reactant: O=C(O)Cc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(-c2nnc(CNC(=O)Cc3ccccc3)o2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Phenylacetic acid (12 mg) and HATU (33 mg) in DMF (1 ml) were stirred for 10 minutes at room temperature. To this solution was added HOBt (11.6 mg), DIPEA (.0.45 ml) and 4′-[5-(aminomethyl)-1,3,4-oxadiazol-2-yl]-N-cyclopropyl-6-methyl-1,1′-biphenyl-3-carboxamide (Example 53) (30 mg) in DMF (2 ml) and the reaction stirred at room temperature for 18 hours. The solvent was evaporated under vacuum and the residue dissolved in DMSO (0.25 ml), methanol (0.25 ml) was added and the precipitate produced isolated by filtration to give N-cyclopropyl-6-methyl-4′-(5-{[(phenylacetyl)amino]methyl}-1,3,4-oxadiazol-2-yl)-1,1′-biphenyl-3-carboxamide.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1/[CH:7]=[CH:8]/[C:9]([OH:11])=O.S(Cl)([Cl:14])=O>>[CH3:1][C:2]1[O:3][CH:4]=[CH:5][C:6]=1/[CH:7]=[CH:8]/[C:9]([Cl:14])=[O:11]
Reactant: O=S(Cl)Cl
Reactant: Cc1occc1/C=C/C(=O)O
Product: Cc1occc1/C=C/C(=O)Cl

Procedure:
(E)-3-(2-Methyl-3-furyl)acrylic acid (0.30 g, 2 mmol) was dissolved into thionyl chloride (5 ml) and the mixture was heated to reflux for 80 min. Volatiles were removed by evaporation to give crude (E)-3-(2-methyl-3-furyl)acryloyl chloride. The titled compound was prepared from 2-amino-4-methoxy-N-(2-pyridyl)aniline (0.43 g, 2 mmol) and (E)-3-(2-methyl-3-furyl)acryloyl chloride obtained as above according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method A). Recrystallization from a mixture of isopropyl ether (3 ml) and ethyl acetate (3 ml) to give 0.10 g (16%) of the titled compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[C@@H:34]([OH:36])[CH3:35])[NH:28][C:27](=[O:38])[CH2:26]2>>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH:32][C:33](=[O:37])[C@@H:34]([OH:36])[CH3:35])[NH:28][C:27](=[O:38])[C:26]2=[CH:20][C:3]1[NH:4][C:5]2[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]3)[C:7](=[O:19])[C:6]=2[C:2]=1[CH3:1]
Reactant: C[C@H](O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cc(NC(=O)[C@H](C)O)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCCCC1)CC2
Yield: 58.4 %

Procedure:
The title compound was prepared under the same conditions as described in Example 25 with 3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and (S)—N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-propionamide as starting materials to give (S)—N-{5-fluoro-3-[3-methyl-4-oxo-5-(2-piperidin-1-yl-ethyl)-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-ylmethylene]-2-oxo-2,3-dihydro-1H-indol-6-yl}-2-hydroxy-propionamide (44 mg, 58.4%) as an orange solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[N:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][N:3]=2)=[CH:13][CH:12]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: COc1cnc(Cl)nc1
Product: COc1cnc(-c2ccc(Cl)cc2)nc1
Yield: 40 %

Procedure:
The title compound was prepared according to the method described for Preparation 17 using 2-chloro-5-methoxy-pyrimidine and 4-chlorophenylboronic acid to afford the title compound as an off-white solid (4.05 g, 40%)
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][N:8]2[CH2:16][C:15]3[C:14]([OH:17])=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9]2)=[CH:3][CH:2]=1.C(N(CC)CC)C.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH3:25][N:26]([CH3:30])[C:27](=[O:28])[O:17][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[CH2:16][N:8]([NH:7][C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)[CH2:9]2
Reactant: Oc1cccc2c1CN(Nc1ccncc1)C2
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Oc1cccc2c1CN(Nc1ccncc1)C2
Temperature: 25 °C
Yield: 60.5 %

Procedure:
To a mixture of 2,3-dihydro-2-(4-pyridinylamino)-1H-isoindol-4-ol (1.20 g), triethylamine (1.18 g) and chloroform (35 ml), was added dimethylcarbamyl chloride (0.68 g) with stirring, at ambient temperature, under nitrogen. The reaction mixture was heated under reflux for 3 hrs, poured into dilute sodium bicarbonate solution (100 ml), and the layers were separated. The aqueous phase was extracted with chloroform, and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was chromatographed on silica, eluting with 10-15% methanol/dichloromethane. The appropriate fractions were collected and concentrated to give 953 mg (60%) of product. Recrystallization from dichloromethane-heptane gave the analytical sample, mp 183-185° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11]C(C=O)=[CH:7][CH:6]=1.[CH3:13][O:14][C:15]([O:18][CH3:19])([CH3:17])C>CO.C(Cl)Cl>[CH3:19][O:18][CH:15]([O:14][CH3:13])[C:17]1[CH:11]=[CH:12][C:5]([O:4][CH2:3][CH2:2][OH:1])=[CH:6][CH:7]=1
Reactant: COC(C)(C)OC
Reactant: O=Cc1ccc(OCCO)cc1
Solvent: ClCCl
Solvent: CO
Product: COC(OC)c1ccc(OCCO)cc1
Reaction time: 5 h
Yield: 69.9 %

Procedure:
To a solution of 4-hydroxyethoxybenzaldehyde (Bernstein et aL, J. Am. Chem. Soc., 73: 906-912 (1951); 8.5 g, 51.2 mmol), 2,2-dimethoxypropane (30 mL, 244 mmol) in a mixture of methanol (40 mL) and CH2Cl2 (100 mL) was added anhydrous Amberlyst 15 (Aldrich) (1.0 g). The mixture was stirred for 5 hrs, the catalyst was removed by filtration and the filtrate was concentrated to give the crude product contaminated with the starting aldehyde. This material was chromatographed on silica eluting with 1:1 ethyl acetate-hexane. The pure product fractions were pooled and concentrated. Drying under vacuum afforded 7.6 g (70%) of the title compound as a pale yellow, viscous liquid. 1H NMR: d 7.28 (d, J=9 Hz, 2 H), 6.92 (d, J=9 Hz, 2H), 5.31 (s, 1H), 4.86 (t, J=5.5 Hz, 1H), 3.98 (t, J=5 Hz, 2H), 3.71 (q, J=5 Hz, 2H), 3.20 (s, 3H). 13C NMR: d 158.60, 130.19, 127.74, 113.90, 102.46, 69.43, 59.52, 52.27.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])[CH3:2].C(N(CC)CC)C.[C:19](Cl)(=[O:22])[CH:20]=[CH2:21]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:19](=[O:22])[CH:20]=[CH2:21])[CH3:2]
Reactant: CCOC(=O)CCCCCO
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC(=O)OCCCCCC(=O)OCC
Reaction time: 3 h

Procedure:
A mixture of ethyl-6-hydroxyhexanoate (49.44 grams, 0.31 moles), methylene chloride (200 mL), and triethylamine (36.26 grams, 0.36 moles) was cooled in an ice bath. Acryloyl chloride (29.87 grams, 0.33 moles) was added dropwise over 60 minutes. The mixture was stirred for 3 hours and filtered. The solution was concentrated under vacuum and diluted with ethyl acetate (300 mL). The mixture was washed with saturated aqueous sodium bicarbonate and water, and then dried over magnesium sulfate. The solvent was removed under vacuum to give a crude oil that was purified by vacuum distillation. A slightly yellow oil (ethyl-6-acryloxy-hexanoate) was collected at 90-92° C. at 0.70 mm Hg (51.27 grams). A portion of this oil (40 grams) was further purified by column chromatography over silica gel using 10 volume percent ethyl acetate in hexane to give the product as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[C:11]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:12]([C:16]([F:19])([F:18])[F:17])[O:13]2)=[CH:8][CH:7]=1)([CH3:5])[CH:3]=[O:4].[O-:25]Cl=O.[Na+]>O1CCOCC1.O>[CH2:23]([O:22][C:20]([C:11]1[CH:12]([C:16]([F:19])([F:17])[F:18])[O:13][C:14]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([C:2]([CH3:1])([CH3:5])[C:3]([OH:25])=[O:4])[CH:15]=2)=[O:21])[CH3:24]
Reactant: CCOC(=O)C1=Cc2ccc(C(C)(C)C=O)cc2OC1C(F)(F)F
Reactant: [O-][Cl+][O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C1=Cc2ccc(C(C)(C)C(=O)O)cc2OC1C(F)(F)F
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To a solution of ethyl 7-(1,1-dimethyl-2-oxoethyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (500 mg, 1.46 mmoles) in 20 mL of dioxane was added a solution of 80% NaClO2 (727 mg, (582 mg), 6.43 mmoles) in 5 mL of water. The resulting mixture was stirred in an oil bath at 90° C. for 1.5 h, and cooled. The mixture was partitioned between DCM and water, further extracted, and the combined organic extracts dried over Na2SO4, filtered, and evaporated. Chromatography of the residue over silica gel using 30% EtOAc—hexane—1% HOAc as eluent gave the title compound, 400 mg, as an oil.