Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[CH2:15]([CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:32])[C:29](Cl)=[O:30])[CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)(Cl)Cl>[CH2:15]([CH:22]1[CH2:23][CH2:24][N:25]([C:28](=[O:32])[C:29]([NH:1][C:2]2[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]3[NH:6][C:7](=[O:9])[O:8][C:4]=3[CH:3]=2)=[O:30])[CH2:26][CH2:27]1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cc2oc(=O)[nH]c2cc1[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cc2oc(=O)[nH]c2cc1[N+](=O)[O-])C(=O)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of 3.23 g (16.56 mmol) of 6-amino-5-nitro-3H-benzoxazole-2-one (step a), 2.58 ml (18.5 mmol) of trethylamine and 100 ml of chloroform 5.25 g (19.75 mmol) of (4-benzylpiperidin-1-yl)oxoacetyl chloride in 20 ml of chloroform is added dropwise at 20° C., then the mixture is stirred at room temperature for 2 h. The mixture is washed with water, the organic layer is dried and concentrated. The residue is purified by column chromatography using Kieselgel 60 as adsorbent (Merck) and toluene:methanol=4:1 as eluent to yield 3.3 g (47%) of the title compound. Mp.: foam.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([F:17])[CH:10]=1)=[O:5])[CH3:2].B(Br)(Br)Br.CO>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([F:17])[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC1c1ccc(OC)c(F)c1
Agent: BrB(Br)Br
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)C1CC1c1ccc(O)c(F)c1
Temperature: -78 °C
Reaction time: 3 h
Yield: 91.3 %

Procedure:
After 2-(3-fluoro-4-methoxy-phenyl)-cyclopropanecarboxylic acid ethyl ester (0.494 g, 2.07 mmol) obtained in Step B was dissolved in anhydrous DCM (7 mL), BBr3 1 M DCM solution (3 mL, 3.11 mmol) was added thereto at −78° C., and the mixture was stirred at room temperature for 3 hours. After the termination of the reaction, the reactant was added with MeOH, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex=1/2) to obtain the title compound (0.424 g, 91%).
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[C:5]([C:20]([F:23])([F:22])[F:21])[CH:4]=1)#[N:2].[NH2:24][OH:25]>C(O)C>[OH:25][N:24]=[C:1]([C:3]1[CH:19]=[CH:18][C:6]([CH2:7][N:8]([CH3:17])[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[C:5]([C:20]([F:21])([F:23])[F:22])[CH:4]=1)[NH2:2]
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1C(F)(F)F
Reactant: NO
Solvent: CCO
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)cc1C(F)(F)F
Yield: 77 %

Procedure:
A solution of tert-butyl 2-((4-cyano-2-(trifluoromethyl)benzyl)(methyl)amino)acetate (0.541 g, 1.65 mmol) and 50% aqueous hydroxylamine (0.50 mL) in ethanol (2 mL) was heated at 75° C. for 2 hours. The solvent was evaporated in vacuo. The residue was partitioned between DCM and water. The organic phase was passed through a hydrophobic frit and evaporated in vacuo to afford the title compound (0.460 g, 77%). 1H NMR (CDCl3, 400 MHz,) δ 7.97 (1H, d, J=8.1 Hz), 7.89 (1H, s), 7.78 (1H, d, J=8.1 Hz), 4.86 (2H, br s), 3.86 (2H, s), 3.23 (2H, s), 2.37 (3H, s), 1.48 (9H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:10].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>>[C:9]([C:3]1[CH:4]=[C:5]([Br:8])[CH:6]=[CH:7][C:2]=1[NH:1][S:25]([C:22]1[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[CH:24][CH:23]=1)(=[O:27])=[O:26])(=[O:10])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Nc1ccc(Br)cc1C(=O)c1ccccc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Product: COc1ccc(S(=O)(=O)Nc2ccc(Br)cc2C(=O)c2ccccc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 138 mg of (2-Amino-5-bromo-phenyl)phenyl-methanone and 103 mg of 4-Methoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 3.78 (s, 3H), 6.83 (d, 2H, J=9.2 Hz), 7.39 (b, 1H), 7.49 (d, 2H, J=6.4 Hz), 7.68 (m, 4H), 8.85 (d, 2H, J=6.0 Hz), 9.96 (b, 1H). MS: m/z 447.0 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]2[C:10](=O)[NH:11][CH2:12][CH2:13][C:8]=2[N:7]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH:6]=1)=[O:4].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:27]>N1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:9]2[C:10](=[S:27])[NH:11][CH2:12][CH2:13][C:8]=2[N:7]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[CH:6]=1)=[O:4]
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: COC(=O)c1cn(CCc2ccc([N+](=O)[O-])cc2)c2c1C(=O)NCC2
Solvent: c1ccncc1
Product: COC(=O)c1cn(CCc2ccc([N+](=O)[O-])cc2)c2c1C(=S)NCC2
Temperature: 65 °C
Reaction time: 2 h

Procedure:
In a round bottom flask under N2 atm. are the 1-[2-(4-Nitro-phenyl)-ethyl]-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-3-carboxylic acid methyl ester (48.64 mmol), P4S10 (24.32 mmol) and 240 mL pyridine combined and heated at 65° C. for 8 hours. After cooling to RT it is poured over ˜600 mL ice and stirred for 2 hours. The yellow solid is filtered off, washed (2×) with water and dried on the high vacuum for 18 h to yield 1-[2-(4-Nitro-phenyl)-ethyl]-4-thioxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-C]pyridine-3-carboxylic acid methyl ester, 10.24 g, as a yellow solid (65%): 1H NMR (CD3OD) 2.43 (t, 2H), 3.16 (t, 2H), 3.28-3.33 (m, 2H), 3.75 (s, 3H), 4.21 (t, 2H), 7.16 (s, 1H), 7.30 (d, 2H), 8.13 (d, 2H); LRMS calcd 359.41, found [M+H] 360.2.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([Sn](C)(C)C)=[CH:3][CH:2]=1.Br[C:13]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:14]=1[C:15]#[N:16]>C1(C)C=CC=CC=1.CCOC(C)=O.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>[C:15]([C:14]1[CH:17]=[C:18]([N+:21]([O-:23])=[O:22])[CH:19]=[CH:20][C:13]=1[C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)#[N:16]
Reactant: Cc1ccc([Sn](C)(C)C)cc1
Reactant: N#Cc1cc([N+](=O)[O-])ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccc([N+](=O)[O-])cc2C#N)cc1
Temperature: 25 °C
Yield: 73.6 %

Procedure:
To a solution of p-tolyltrimethyltin (389 mg, 1.525 mmol) in dry toluene (5 mL) under N2 was added 2-bromo-5-nitro-benzonitrile (276 mg, 1.22 mmol) and Pd(PPh3)4 (176 mg; 10 mol %). The reaction was stirred at reflux under N2 for 24 hours and then cooled to room temperature. The mixture was diluted with EtOAc and the solid was removed by filtration through a pad of celite. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography on a silica column eluting with Hex/EtOAc (10:1) to afford 214 mg (74%) of the titled compound as a slightly yellow solid. 1H NMR (300 MHz, CDCl3) δ2.42 (s, 3H), 7.32 (d, 2H), 7.48 (d, 2H), 7.69 (d, 1H), 8.45 (dd, 1H), 8.61 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[CH:10]([O:14][CH3:15])[C:11]([OH:13])=O.[NH2:16][CH2:17][C:18]1[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=1>>[C:17]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22][NH:23][C:11](=[O:13])[CH:10]([C:3]2[CH:4]=[CH:5][C:6]([O:8][CH3:9])=[CH:7][C:2]=2[F:1])[O:14][CH3:15])=[CH:20][CH:19]=1)#[N:16]
Reactant: N#Cc1ccc(CN)cc1
Reactant: COc1ccc(C(OC)C(=O)O)c(F)c1
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)c(F)c1

Procedure:
(RS)-(2-Fluoro-4-methoxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(2-fluoro-4-methoxy-phenyl)-2-methoxy-acetamide. Colorless oil. MS 329.2 ([M+H]+)
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12].C([O-])([O-])=O.[K+].[K+].O>CN(C)C(=O)C>[O:7]([C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccccc1F
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=Cc1ccccc1Oc1ccccc1

Procedure:
To a solution of phenol (1.8888 g, 0.0201 mol) and 2-fluorobenzaldehyde (2.14 mL, 0.0203 mol) in N,N-dimethylacetamide (20 mL) was added anhydrous K2CO3 (3.0798 g, 0.0223 mol). The resulting heterogenous mixture was refluxed for 3 h. The resulting green mixture was then treated with H2O (100 mL) and extracted with EtOAc (2×100 mL). The combined organic extracts were washed with H2O (4×100 mL), dried over Na2SO4, filtered and concentrated. The resulting dark residue was purified by flash chromatography on silica gel (10% EtOAc in hexane) to yield 2-phenoxybenzaldehyde as a light yellow oil.
Reaction SMILES: [CH:1](/[C:9]1[C:17]2[C:12](=[CH:13][C:14]([CH:18]=O)=[CH:15][CH:16]=2)[NH:11][N:10]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][C:21]1=[O:29].N1CCCCC1>CO>[CH:1](/[C:9]1[C:17]2[C:12](=[CH:13][C:14](/[CH:18]=[C:22]3/[C:21](=[O:29])[NH:20][C:28]4[C:23]/3=[CH:24][CH:25]=[CH:26][CH:27]=4)=[CH:15][CH:16]=2)[NH:11][N:10]=1)=[CH:2]\[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=Cc1ccc2c(/C=C/c3ccccc3)n[nH]c2c1
Reactant: O=C1Cc2ccccc2N1
Solvent: CO
Solvent: C1CCNCC1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(/C=C/c3ccccc3)n[nH]c2c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 11.9 %

Procedure:
A solution of (E)-3-styryl-1H-indazole-6-carbaldehyde (27 mg, 0.109 mmol) and oxindole (15 mg, 0.109 mmol) in MeOH (1.0 mL) was treated with piperidine (1 uL. 0.011 mmol) and the reaction stirred at 60° C. for 4 hours. The MeOH was removed and the residue purified by prep-HPLC to give 4.7 mg, 12% of a yellow powder. 1H NMR (400 MHz, CD3OD) δ 8.26 (d, J=8.38 Hz, 2H), 7.91-7.86 (m, 2H), 7.71-7.64 (m, 3H), 7.60-7.49 (m, 2H), 7.42 (t, J=7.41 Hz, 2H), 7.31 (t, J=7.49 Hz, 1H), 7.26 (t, J=7.89 Hz, 1H), 6.94 (d, J=7.75 Hz, 1H), 6.89 (t, J=6.86 Hz, 1H); MS ESI 364.2 [M+H]+, calcd for [C24H17N3O+H]+ 364.14.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[CH2:18]1COCC1>C(O)=O>[NH:8]1[C:7]2[CH:6]=[CH:5][C:4]([O:9][C:10]3[CH:15]=[CH:14][C:13]([CH2:16][OH:17])=[CH:12][CH:11]=3)=[CH:3][C:2]=2[N:1]=[CH:18]1
Reactant: Nc1ccc(Oc2ccc(CO)cc2)cc1N
Reactant: C1CCOC1
Solvent: O=CO
Product: OCc1ccc(Oc2ccc3[nH]cnc3c2)cc1

Procedure:
{4-[(3,4-diaminophenyl)oxy]phenyl}methanol (3.21 g of crude material) was dissolved in 20 ml THF and 10 ml of formic acid. The reaction was heated in a 100 degree Centigrade oil bath for approximately 22 hours. The reaction was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed 5 times with saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was dissolved in 30 ml of THF and 10 ml of 10% aqueous LiOH and heated at 100 degrees Centigrade for 30 minutes. The reaction was diluted with water and ethyl acetate. The organic layer was washed with brine three times, dried over MgSO4, and concentrated under reduced pressure onto basic alumina. The compound was purified by silica gel column chromatography (100% dichloromethane to 10% (2M NH3 in methanol) in dichloromethane gradient) to give 1.26 g of [4-(1H-benzimidazol-5-yloxy)phenyl]methanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)[CH:5]=[CH:4][C:3]1=2.C(=O)([O-])[O-].[K+].[K+].I[CH2:33][CH3:34].O>CC(=O)CC>[CH3:1][C:2]1([CH3:25])[CH2:11][CH2:10][C:9]([CH3:12])([CH3:13])[C:8]2[CH:7]=[C:6]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]([O:24][CH2:33][CH3:34])=[O:23])=[CH:20][CH:21]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(OCc3ccc(C(=O)O)cc3)ccc21
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)c1ccc(COc2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Yield: 40.9 %

Procedure:
2 g (6 mmol) of 4-carboxybenzyl 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl ether, 2.7 g (19.6 mmol) of anhydrous potassium carbonate and 19 g (12.4 mmol) of iodoethane in 18 ml of butanone were refluxed for 7 h. The mixture was then poured into water and extracted with ether, and the organic phase was washed with water, dried over Na2SO4 and concentrated. Recrystallization from methanol resulted in 0.9 g of the title compound of melting point 76°-77° C.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:55]([CH:63]1[C:70]2[CH:69]=[C:68]([C:71]([O:73]C)=[O:72])[NH:67][C:66]=2[CH2:65][CH2:64]1)[CH2:56][C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1>C(#N)C.O>[Br:1][C:69]1[C:70]2[CH:63]([CH2:55][CH2:56][C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[CH2:64][CH2:65][C:66]=2[NH:67][C:68]=1[C:71]([OH:73])=[O:72]
Reactant: COC(=O)c1cc2c([nH]1)CCC2CCc1ccccc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CC#N
Product: O=C(O)c1[nH]c2c(c1Br)C(CCc1ccccc1)CC2
Reaction time: 8 h

Procedure:
Tetrabutylammonium tribromide (114 mg, 0.24 mmol) was added to a solution of methyl 4-phenethyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (53 mg, 0.2 mmol) in 5 mL of acetonitrile at room temperature. After reacting overnight, the reaction was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated with silica gel. Purification by column chromatography (Isco CombiFlash) eluting with a gradient of 0-30% EtOAc/heptane gave the title compound. 54.2 mg. 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.69-1.80 (m, 1H), 2.10-2.22 (m, 2H), 2.56-2.71 (m, 4H), 2.72-2.83 (m, 1H), 3.00-3.09 (m, 1H), 3.80 (s, 3H), 7.11-7.16 (m, 1H), 7.17-7.21 (m, 2H), 7.22-7.27 (m, 2H); LCMS-MS (ESI+) 372.0 (M+Na).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[N:24]=1>>[CH3:29][C:25]1[N:24]=[C:23]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:3]3)[CH2:6]2)[CH:28]=[CH:27][CH:26]=1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Reactant: Cc1cccc(Cl)n1
Product: Cc1cccc(N2CC3CN(C(=O)c4ccccc4-c4cccs4)CC3C2)n1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-6-methyl-pyridine. MS (ESI): mass calculated for C23H23N3OS, 389.52; m/z found 390.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 7.56-7.47 (m, 1H), 7.45-7.10 (m, 6H), 7.07-6.91 (m, 1H), 6.43 (d, J=7.2, 1H), 6.04 (s, 1H), 3.96-2.57 (m, 10H), 2.38 (s, 3H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[F:11][CH:12]([F:15])[CH2:13][OH:14]>>[F:11][CH:12]([F:15])[CH2:13][O:14][C:2]1[N:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1
Reactant: OCC(F)F
Reactant: CC(=O)c1ccc(Cl)nc1
Product: CC(=O)c1ccc(OCC(F)F)nc1
Yield: 71 %

Procedure:
The title compound is prepared in 71% yield (1.34 g, a white solid) from 1-(6-chloropyridin-3-yl)ethanone (1.5 g, 9.64 mmol) and 2,2-difluoroethanol instead of 2,2,2-trifluoroethanol by the similar manner in Step-1 of Amine-2.
Reaction SMILES: [CH3:1]/[C:2](/[C:5]([CH3:7])=[O:6])=[N:3]\[OH:4].[CH:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[CH:18]=O.Cl>C(O)(=O)C>[CH3:1][C:2]1[N+:3]([O-:4])=[C:18]([C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[O:6][C:5]=1[CH3:7]
Reactant: CC(=O)/C(C)=N/O
Reactant: O=Cc1ccc2ccccc2c1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1oc(-c2ccc3ccccc3c2)[n+]([O-])c1C

Procedure:
18.4 g of diacetyl monoxime and 31.2 g of 2-naphthaldehyde are added to 50 ml of glacial acetic acid, and HCl gas is introduced with ice-cooling for 30 minutes. The product is precipitated as the hydrochloride by addition of methyl tert-butyl ether and filtered off with suction, and the precipitate is washed with methyl tert-butyl ether. The precipitate is suspended in a mixture of dichloromethane and water, and a basic pH is established using ammonia. The mixture is extracted three times with in each case 500 ml of dichloromethane and ethyl acetate, the combined organic phases are dried over MgSO4 and the solvent is then removed under reduced pressure. This gives 40.3 g of 4,5-dimethyl-2-naphthalen-2-yloxazole 3-oxide as a yellow solid.
Reaction SMILES: C(O[C:5](=[O:33])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]2[CH2:13][C:14](=[O:32])[NH:15][C:16]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27]C=[C:25]([CH2:29][F:30])[CH:24]=4)[C:20](C)=[CH:19][C:17]=3[N:18]=2)[CH:7]=1)C=C.O.[NH2:35][NH2:36]>CO.O>[F:30][C:29]1[CH:27]=[CH:28][C:23]([C:21]2[CH:20]=[CH:19][C:17]3[N:18]=[C:12]([C:8]4[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=4)[C:5]([NH:35][NH2:36])=[O:33])[CH2:13][C:14](=[O:32])[NH:15][C:16]=3[CH:22]=2)=[CH:24][CH:25]=1
Reactant: C=CCOC(=O)c1cccc(C2=Nc3cc(C)c(-c4cccc(CF)c4)cc3NC(=O)C2)c1
Reactant: NN
Solvent: O
Solvent: CO
Product: NNC(=O)c1cccc(C2=Nc3ccc(-c4ccc(F)cc4)cc3NC(=O)C2)c1
Temperature: 60 °C
Reaction time: 15 h
Yield: 33 %

Procedure:
To a suspension of 3-[7-(3-fluoromethyl-phenyl)-8-methyl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzoic acid allyl ester (Starting material 8a-1) (207 mg, 0.5 mmol) in MeOH (3.5 mL) was added hydrazine hydrate (0.25 mL, 5 mmol). The mixture was stirred at 60° C. for 15 h, then cooled to 23° C. and diluted with H2O (35 mL). The precipitate was collected by filtration and dried, and the crude product was purified by chromatography on silica gel using ethyl acetate/hexane (1:1) as eluent. The purified product was crystallized from Et2O/hexane to give the title compound as light yellow solid (64 mg).
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=1)[CH:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1)=[O:6]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: NCC(c1ccc(Cl)cc1)C1CCOCC1
Product: O=C(NCC(c1ccc(Cl)cc1)C1CCOCC1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-(4-chlorophenyl)-2-(tetrahydro-2H-pyran-4-yl)ethanamine. LCMS (MH+): m/z=396.1, tR (minutes, Method G)=2.36
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C1(P(=[CH:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[N:5]1[CH:6]=[CH:7][C:2](/[CH:1]=[CH:28]/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:3][CH:4]=1
Reactant: O=Cc1ccncc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1ccncc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.3 %

Procedure:
To a solution of isonicotinaldehyde (0.811 mL, 8.61 mmol) in DCM (30 mL) was added ethyl (triphenylphosphoranylidene)acetate (3.00 g, 8.61 mmol) in DCM (5 mL) dropwise. The reaction mixture was allowed to stir at rt for 5 h and then concentrated. The residue was purified by column chromatography to give ethyl (2E)-3-pyridin-4-ylacrylate (1.47 g, 96%). LCMS: (FA) ES+ 178.3.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].C(S)C.[CH:8]([C:11]1[CH:21]=[C:20]([O:22]C)[CH:19]=[C:18]2[C:12]=1[C:13](=[O:24])[NH:14][S:15]2(=[O:17])=[O:16])([CH3:10])[CH3:9].Cl>C(Cl)(Cl)Cl>[OH:22][C:20]1[CH:19]=[C:18]2[C:12]([C:13](=[O:24])[NH:14][S:15]2(=[O:17])=[O:16])=[C:11]([CH:8]([CH3:10])[CH3:9])[CH:21]=1
Reactant: COc1cc(C(C)C)c2c(c1)S(=O)(=O)NC2=O
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCS
Solvent: ClC(Cl)Cl
Product: CC(C)c1cc(O)cc2c1C(=O)NS2(=O)=O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 97.8 %

Procedure:
An alternative procedure was also used. To a stirred suspension of 62.74 g (0.47 mol) of AlCl3 in 500 mL of chloroform at 0° was added 43.9 g (0.7 mol) of ethanethiol. Within minutes a clear solution formed. To this a solution of 20.0 g (0.078 mol) of 4-isopropyl-6-methoxysaccharin in 550 mL of chloroform was added over a 30-min period. This solution was allowed to warm to RT and stirred for 3-4 hr at 60°. After cooling, the mixture was poured into ice-water and acidified with dilute HCl. The solid which separated was collected by filtration, washed with water and dried to give 18.4 g (97%) of 6-hydroxy-4-isopropylsaccharin.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([CH3:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[CH:2].[CH3:13][O:14][C:15](=[O:45])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[C:27][C:28]2[CH:33]=[C:32]([C:34]#[C:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:31]=[C:30](Br)[CH:29]=2)=[CH:20][C:19]=1[CH3:44]>CN(C=O)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:13][O:14][C:15](=[O:45])[CH2:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]#[C:27][C:28]2[CH:33]=[C:32]([C:34]#[C:35][CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[CH:31]=[C:30]([C:2]#[C:1][C:3]3[CH:4]=[CH:5][C:6]([S:9]([CH3:12])(=[O:10])=[O:11])=[CH:7][CH:8]=3)[CH:29]=2)=[CH:20][C:19]=1[CH3:44]
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#CCN3CCOCC3)c2)cc1C
Reactant: C#Cc1ccc(S(C)(=O)=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)COc1ccc(OCC#Cc2cc(C#CCN3CCOCC3)cc(C#Cc3ccc(S(C)(=O)=O)cc3)c2)cc1C
Temperature: 65 °C

Procedure:
A mixture of 1-ethynyl-4-methanesulfonyl-benzene (346 mg, 1.92 mmol), (4-{3-[3-bromo-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester (123 mg, 0.24 mmol, example 6), Pd(PPh3)2Cl2 (17 mg, 0.024 mmol), CuI (12 mg, 0.067 mmol) in dry DMF (2 ml) and triethylamine (2 ml) was heated in a microwave own for 1 hour at 65° C. in a sealed tube. The reaction mixture was filtered through Decalite and the filtrate was evaporated. The residue was purified on column chromatography using methylene chloride/THF mixtures to give (4-{3-[3-(4-methanesulfonyl-phenylethynyl)-5-(3-morpholin-4-yl-prop-1-ynyl)-phenyl]-prop-2-ynyloxy}-2-methyl-phenoxy)-acetic acid methyl ester in 50 mg (34%) yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[C:17]([CH3:31])=[C:18]([CH:23]=[C:24]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:32](=O)[CH3:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:32][CH3:33])[C:16]2[C:17]([CH3:31])=[C:18]([CH:23]=[C:24]([O:26][CH2:27][CH2:28][O:29][CH3:30])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COCCOc1cc(NC2CCC(NC(=O)OC(C)(C)C)CC2)c(C)c(C(=O)OC)c1
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCN(c1cc(OCCOC)cc(C(=O)OC)c1C)C1CCC(NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93.8 %

Procedure:
To a stirred solution of methyl 3-((4-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-5-(2-methoxyethoxy)-2-methylbenzoate (1.60 g, 3.67 mmol) and acetaldehyde (0.48 g, 10.9 mmol) in dichloroethane (20 mL) was added acetic acid (1.3 g, 22 mmol) and the reaction mixture stirred at room temperature for 20 minutes. Then sodium triacetoxyborohydride (2.33 g. 11.0 mmol) was added at 0° C. and the reaction was stirred at room temperature for 2 h. The reaction was quenched with aqueous sodium bicarbonate, the organic phase separated and the aqueous phase extracted with dichloromethane. The combined organic layers were washed with water, dried, concentrated under reduced pressure, the crude material was purified by column chromatography to afford the title compound (1.6 g, 94%).