Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][O:8][CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[CH:5][CH:4]=1.[Si:17](Cl)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][CH2:9][CH2:10][CH:11]([OH:14])[CH2:12][O:13][Si:17]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18])=[CH:15][CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1ccc(COCCC(O)CO)cc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(COCCC(O)CO[Si](C)(C)C(C)(C)C)cc1
Temperature: 25 °C
Yield: 80.5 %

Procedure:
Combine 4-(p-methoxybenzyloxy)-1,2-butandiol (42.43 g, 187.5 mmol) with DMF (700 mL) and cool in an ice bath before adding t-butyldimethylsilyl chloride (31.1 g, 206 mmol), triethylamine (31.4 mL, 225 mmol), and 4-dimethylaminopyridine (5.8 g, 47 mmol). Stir the mixture in the ice bath for 5 minutes and then allow to warm to ambient temperature and stir for sixteen hours. Filter and wash the filter cake with diethyl ether. Separate the aqueous layer and extract twice with ether. Combine the organic layers extract with water and saturated sodium chloride solution, dry over MgSO4, filter and concentrate in vacuo. Chromatograph on silica gel eluting with 2/8 ethyl acetate/hexane to give 51.4 g of the title compound the as an oil. Rf =0.25; silica gel, 2/8 ethyl acetate/hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:7]2.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C)C=O>[NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:9](=[O:12])[CH:8]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:19])[CH3:18])[CH2:7]2
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1Cc2cccc(N)c2NC1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1Cc2cccc(N)c2N(Cc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 8-amino-2-oxo-1,2,3,4-tetrahydroquinolin-3-ylcarbamate produced in Example 6 (10 g) was added to N,N-dimethylformamide (100 mL), and sodium hydride (1.65 g) was added thereto under cooling on ice. The mixture was stirred at room temperature for one hour. Subsequently, under cooling on ice, benzyl bromide (6.48 g) was added to the mixture, and stirring was performed at room temperature for one hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure, to thereby recover a residue. The residue was purified through silica gel column chromatography (ethyl acetate:n-hexane=1:2), whereby the title compound (10.8 g) was yielded.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]([CH3:7])=[C:4]([C:8]([N:10]([CH3:12])[CH3:11])=O)[NH:3]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:14]>N1C=CC=CC=1.O>[O:1]=[C:2]1[NH:6][C:5]([CH3:7])=[C:4]([C:8](=[S:14])[N:10]([CH3:12])[CH3:11])[NH:3]1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Reactant: Cc1[nH]c(=O)[nH]c1C(=O)N(C)C
Solvent: c1ccncc1
Solvent: O
Product: Cc1[nH]c(=O)[nH]c1C(=S)N(C)C

Procedure:
A suspension of 3.4 g (20 mmol) of 2,3-dihydro--N,N,5-trimethyl-2-oxo-1H-imidazole-4-carboxamide (prepared in example 3) and 4.4 g cf phosphorus pentasulfide in 100 ml of dry pyridine is stirred at reflux temperature for 6 hours. The mixture is allowed to cool overnight and is diluted with water. The precipitate is collected and recrystallized from 50% aqueous ethanol to give the title compound.
Reaction SMILES: [N+:1]([C:4]1[C:9]2[NH:10][C:11](=S)[O:12][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:14]1([C:20]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[CH2:23]([O:22][C:20]([N:14]1[CH2:19][CH2:18][N:17]([C:11]2[O:12][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:9]=3[N:10]=2)[CH2:16][CH2:15]1)=[O:21])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(OCc1ccccc1)N1CCNCC1
Reactant: O=[N+]([O-])c1cccc2oc(=S)[nH]c12
Product: O=C(OCc1ccccc1)N1CCN(c2nc3c([N+](=O)[O-])cccc3o2)CC1

Procedure:
A mixture of 4-nitro-3H-benzoxazole-2-thione (7.00 g, 35.7 mmol) and benzyl 1-piperazinecarboxylate (15.72 g, 71.36 mmol) in xylenes was heated at reflux temperature overnight, cooled and concentrated in vacuo to provide the title compound which was used, without further purification, in Example 8.
Reaction SMILES: [OH-].[K+].[CH2:3]([O:6][C:7]1[C:16]([C:17](=[O:19])[CH3:18])=[C:15]2[C:10]([C:11](=[O:27])[C:12]([CH3:26])=[C:13]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[O:14]2)=[CH:9][CH:8]=1)[CH:4]=[CH2:5].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([CH:35]=[CH:36][CH:37]=1)[CH:33]=O>C(O)C.O>[CH3:26][C:12]1[C:11](=[O:27])[C:10]2[C:15](=[C:16]([C:17](=[O:19])[CH:18]=[CH:33][C:32]3[CH:35]=[CH:36][CH:37]=[C:30]([O:29][CH3:28])[CH:31]=3)[C:7]([O:6][CH2:3][CH:4]=[CH2:5])=[CH:8][CH:9]=2)[O:14][C:13]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COc1cccc(C=O)c1
Reactant: C=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCOc1ccc2c(=O)c(C)c(-c3ccccc3)oc2c1C(=O)C=Cc1cccc(OC)c1
Temperature: 25 °C
Yield: 70.7 %

Procedure:
A solution of KOH 50% (3 ml) is added to an equimolar solution of 7-allyloxy-8acetyl -3-methylflavone (2.5 g, 0.0075 mol) and 3-methoxy-benzaldehyde (1.01 g, 0.0075 mol) in ethanol 95%; the addition is performed under energetic stirring at room temperature. The reaction is left under stirring for one night and then diluted with water and acidified; the precipitate is separated by filtration and dried under vacuum. The compound is crystallized by methanol to give 2.4 g of product m.p. 90-92° C., 1H-NMR (CDCl3)δ:2.20 (s, 3H); 3.84 (s, 3H); 4.74 (d, 2H, J=5.1 Hz); 5.1-5.3 (m, 2H); 5.91-6.02 (m, 1H); 6.96-7.18 (m, 4H); 7.31 (d, 1H, J=16 Hz); 7.32-7.35 (m, 1H); 7.36-7.43 (m, 3H); 7.55-7.59 (m, 2H); 8.34 (d, 1H, J=8.9Hz).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:3]=1[CH:4]=[O:5].[Cl:12][C:13]1[CH:14]=[C:15]([N+:20]([O-])=O)[C:16](I)=[N:17][CH:18]=1>>[NH2:20][C:15]1[C:16]([C:4]([C:3]2[C:6]([O:10][CH3:11])=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])=[O:5])=[N:17][CH:18]=[C:13]([Cl:12])[CH:14]=1
Reactant: COc1cccc(F)c1C=O
Reactant: O=[N+]([O-])c1cc(Cl)cnc1I
Product: COc1cccc(F)c1C(=O)c1ncc(Cl)cc1N

Procedure:
(3-Amino-5-chloro-pyridin-2-yl)-(2-fluoro-6-methoxy-phenyl)-methanone was prepared from 2-fluoro-6-methoxybenzaldehyde and 5-chloro-2-iodo-3-nitro-pyridine in three steps according to the General Procedure C. MS m/z: 281.0 (M+Na).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[C:8]=2[OH:18])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:26][CH3:27]>C(#N)C>[CH2:26]([N:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:16])([F:17])[F:15])[C:8]=2[OH:18])[CH2:3][CH2:2]1)[CH3:27]
Reactant: CCI
Reactant: Oc1c(OC(F)(F)F)cccc1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CCC(c2cccc(OC(F)(F)F)c2O)CC1

Procedure:
Preparation according to Example 1: 2-piperidin-4-yl-6-(trifluoromethoxy)phenol (0.01 g), acetonitrile (2 ml), potassium carbonate (0.01 g) and 2-iodoethane (0.01 g). MS m/z (relative intensity, 70 eV) 289 (M+, 45), 288 (20), 275 (15), 274 (bp), 84 (26).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:17])[C:12](=[O:18])[CH2:11][C:10]2([CH3:20])[CH3:19].[CH3:21][O:22]C(Cl)Cl>C(Cl)Cl>[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[CH:21]=[O:22])[N:13]([CH3:17])[C:12](=[O:18])[CH2:11][C:10]2([CH3:20])[CH3:19]
Reactant: COc1ccc2c(c1)C(C)(C)CC(=O)N2C
Reactant: COC(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc2c(cc1C=O)N(C)C(=O)CC2(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a flame dried round bottom flask equipped with a nitrogen cap was added 89 mg (66 mmol) aluminum chloride and 5 ml of methylene chloride (CHCl2). The mixture was stirred at ambient temperature for 0.25 hour and then cooled to 0° C. followed by the addition of 75 mg (0.34 mmol) 6-methoxy-1,4,4-trimethyl-3,4-dihydro-1H-quinolin-2-one. The reaction mixture was stirred for 10 minutes at this temperature and was then treated with 84 μl (0.93 mmol) of α,α-dichloromethyl methyl ether before allowing the reaction to slowly warm to room temperature over 16 hours. The reaction mixture was quenched with 30 ml of 2M HCl and extracted with ethyl acetate (3×30 ml). The combined organics were then washed with saturated aqueous bicarbonate solution and brine followed by drying over sodium sulfate and evaporation in vacuo. The crude residue was purified on silica gel eluting with 1:1 ethyl acetate/hexane to afford two products. The more polar material was identified as the desired product: Mass spectrum APCI m/e 248 (p+1). The less polar product was identified as 7-Dichloromethyl-6-methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one (Mass spectrum APCI m/e 302 (p+1)) from which the desire product was isolated after a brief stirring in pH 7 phosphate buffer. Total yield 56 mg (66%).
Reaction SMILES: [F:1][C:2]1([F:14])[O:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[O:4][C:3]1([F:13])[F:12].C([Li])CCC.[Br:20]C(F)(F)C(F)(F)Br.[Cl-].[Na+]>O1CCCC1.O>[Br:20][C:11]1[C:5]2[O:4][C:3]([F:12])([F:13])[C:2]([F:1])([F:14])[O:7][C:6]=2[CH:8]=[CH:9][CH:10]=1
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: FC1(F)Oc2ccccc2OC1(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FC1(F)Oc2cccc(Br)c2OC1(F)F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,2,3,3-tetrafluoro-2,3-dihydro-1,4-benzodioxin (5.00 g, 24.0 mmol) in dry tetrahydrofuran (150 mL) is cooled to -78° C. under a nitrogen atmosphere. A solution of n-butyllithium (10.6 mL, 26.4 mmol of a 2.5M solution in hexanes) is added dropwise while maintaining the reaction temperature below -65° C. The reaction mixture is stirred at -78° C. for 30 min and then 1,2-dibromotetrafluoroethane (3.16 mL, 26.4 mmol) is added dropwise. After this addition is complete, the reaction mixture is allowed to come to room temperature. A small mount of water is slowly added to the mixture which is then poured into water. The aqueous mixture is saturated with sodium chloride and is extracted with diethyl ether. The combined organic extracts are dried (MgSO4), filtered, and concentrated under reduced pressure to afford the title compound of Step A.
Reaction SMILES: N#N.Br[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][CH2:20][CH3:21])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.[Li]CCCC.CN([CH:30]=[O:31])C>C1COCC1>[CH2:18]([C:15]1[CH:16]=[CH:17][C:12]([C:11]#[C:10][C:7]2[CH:8]=[CH:9][C:4]([CH:30]=[O:31])=[CH:5][CH:6]=2)=[CH:13][CH:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CN(C)C=O
Reactant: CCCCc1ccc(C#Cc2ccc(Br)cc2)cc1
Agent: N#N
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCc1ccc(C#Cc2ccc(C=O)cc2)cc1
Reaction time: 2 h
Yield: 77.7 %

Procedure:
To a dry 2 L three-necked flask under a flow of N2 containing 1-bromo-4-[(4-butylphenyl) ethynyl] benzene (VIIe) (100 g; 0.319 mol) in dry THF (1000 mL) at −78° C. was added n-BuLi (2.5M in hexane, 153.25 mL, 0.383 mol) and the reaction mixture was stirred at this temperature for 2 h. The reaction mixture went dark-green after 5 minutes of the addition of butyl lithium. To this reaction mixture was added DMF (29.56 mL, 0.383 mol) and the resulting mixture was stirred for an additional 1 h at −78° C. The reaction mixture turned black-blue after the addition of DMF. The reaction mixture was then quenched with 1.5M HCl (750 ml) at this temperature and the product was extracted with MTBE (3×500 mL). The combined organic layer were washed with 10% sodium bicarbonate solution (500 ml), water, brine and dried. The solvent was evaporated under reduced pressure to afford the title compound (m=65 g) as a white solid in a 77% yield. Melting point: 76-78° C.
Reaction SMILES: [C:1]1([CH2:7][C:8](=[O:10])[CH3:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11](OCC)=[O:12].[O-]CC.[Na+]>C1COCC1.O>[OH:12]/[CH:11]=[C:7](/[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)\[C:8]([CH3:9])=[O:10]
Reactant: CCOC=O
Reactant: CC(=O)Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)/C(=C\O)c1ccccc1

Procedure:
Phenylacetone (Aldrich Chem. Co. 13,538-0; Beilstein 7, 303), XXVIa (101 g, 0.75 mol) was combined with 100 g (1.35 mol) of ethyl formate and added all at once to a suspension of 50 g (0.75 mol) of sodium ethoxide in 500 ml of THF. After 3 hours at room temperature the brown solution was diluted with 400 ml of H2O. Following extraction with benzene to remove unreacted starting material, the aqueous phase was acidified with dilute HCl. The product was extracted with benzene, washed with H2O, dried over MgSO4, and concentrated to give an oil. Distillation gave 39 g (0.24 mol) of (Z)-1-hydroxymethylene-1-phenylacetone, XXVIIa, as a colorless oil, bp 65°-69° C (0.3 mm).
Reaction SMILES: [CH3:1][C:2]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13](O)=[O:14])=[CH:8][CH:7]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:34][C:35]1[S:36][S:37][C:38](=[S:40])[N:39]=1.O>O1CCCC1>[CH3:1][C:2]([CH2:16][CH2:17][CH:18]=[C:19]([CH3:21])[CH3:20])=[CH:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][C:13]([NH:34][C:35]2[S:36][S:37][C:38](=[S:40])[N:39]=2)=[O:14])=[CH:8][CH:7]=1
Reactant: CC(C)=CCCC(C)=CCOc1ccc(CC(=O)O)cc1
Reactant: Nc1nc(=S)ss1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)=CCCC(C)=CCOc1ccc(CC(=O)Nc2nc(=S)ss2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 16.5 %

Procedure:
2-{4-[(3,7-Dimethyl-2,6-octadienyl)oxy]phenyl}acetic acid (1.00 g,3.47 mmol) was dissolved in tetrahydrofuran (12 ml), and 1,1′-carbonyldiimidazole (0.68 g, 4.16 mmol) was added thereto. The mixture was stirred for 1 hour at room temperature, and then 3-amino-1,2,4-dithiazole-5-thione (0.42 g, 2.70 mmol) was added thereto. After being stirred for 3 hours at room temperature, the mixture, with water added thereto, was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over MgSO4, and then concentrated. The obtained residue was purified by silica gel chromatography (chloroform), to give 2-{4-[(3,7-dimethyl-2,6-octadienyl)oxy]phenyl}-N-(3thioxo-3H-1,2,4-dithiazol-5-yl)acetoamide (Compound 2) (0.187 g, 18%).
Reaction SMILES: [Li]CCCC.[CH2:6]([N:8]([CH2:19][CH3:20])[C:9]([O:11][C:12]1[C:13]([F:18])=[N:14][CH:15]=[CH:16][CH:17]=1)=[S:10])[CH3:7].[CH2:21]([N:23]([CH2:27][CH3:28])[C:24](Cl)=[O:25])[CH3:22].Cl>C1COCC1.O>[CH2:21]([N:23]([CH2:27][CH3:28])[C:24](=[O:25])[C:12]1([O:11][C:9](=[S:10])[N:8]([CH2:6][CH3:7])[CH2:19][CH3:20])[CH:17]=[CH:16][CH:15]=[N:14][CH:13]1[F:18])[CH3:22]
Reactant: CCN(CC)C(=O)Cl
Reactant: CCN(CC)C(=S)Oc1cccnc1F
Agent: Cl
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)C(=O)C1(OC(=S)N(CC)CC)C=CC=NC1F
Temperature: -10 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
250 ml (400 mmol) of n-BuLi (1.6M in hexane) are added to a solution of 57.9 g (410 mmol) of TMP in 750 ml of THF at -10° C. After the mixture has been stirred for 1 hour at -10° C., a solution of 64 g (280 mmol) of 3-diethylthiocarbamoyloxy-2-fluoropyridine in 200 ml of THF is added dropwise at -78° C. in the course of 30 minutes. After the mixture has been stirred for 1 hour at -78° C., 81.4 g (600 mmol) of diethylcarbamoyl chloride are added in the course of 1 minute, the mixture is stirred at -78° C. for 2 hours and heated to -20° C., 130 ml of 3N HCl are added, and the mixture is diluted with 1 l of water and brought to pH 7. The organic phase is washed 3 times with water. The combined aqueous phases are extracted twice using Et2O, and the combined organic phases are washed twice with water, dried over Na2SO4 and concentrated in vacuo at 60° C.: 116 g of a brown oil. Chromatography (ethyl acetate/hexane 1:1) gives 60 g (65% ) of beige crystals of m.p. 87°-92° C.
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C@@H:8]([CH2:13][NH2:14])[CH2:7][CH2:6]2.[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>O1CCCC1>[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C@@H:8]([CH2:13][NH:14][C:23](=[O:24])[O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][CH2:6]2
Reactant: NC[C@H]1CCc2cc(I)ccc2O1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NC[C@H]1CCc2cc(I)ccc2O1)OCc1ccccc1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a mixture of (R)-6-iodo-chroman-2-methylamine hydrochloride of Example 10 (3.3 g, 10 mmol) and benzylchloroformate (1.57 mL, 11 mmol) in tetrahydrofuran (30 mL), cooled in an ice-water bath, was added slowly 1N aqueous sodium hydroxide in 20 minutes. The resulting mixture was stirred for 1 hour. The organic layer was separated and concentrated in vacuo. The aqueous layer was extracted with ethyl acetate (50 mL×2). The combined ethyl acetate layer was combined with the above residue and washed with water (50 mL), brine (50 mL), and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded the crude product as a white solid (4.2 g, 99%).
Reaction SMILES: [CH3:1][N:2](S(C1C=CC=CC=1)(=O)=O)[N:3]=[C:4](Cl)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11].[Cl:22][C:23]1[CH:30]=[C:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][N:33]=2)[CH:28]=[CH:27][C:24]=1[C:25]#[N:26].ClC1C=CC=CC=1Cl>C(Cl)(Cl)Cl.[Fe](Cl)(Cl)Cl>[Cl:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:4]1[N:26]=[C:25]([C:24]2[CH:27]=[CH:28][C:29]([O:31][C:32]3[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:39])[F:40])=[CH:34][N:33]=3)=[CH:30][C:23]=2[Cl:22])[N:2]([CH3:1])[N:3]=1
Reactant: CN(N=C(Cl)c1ccccc1Cl)S(=O)(=O)c1ccccc1
Reactant: N#Cc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1Cl
Agent: Cl[Fe](Cl)Cl
Solvent: Clc1ccccc1Cl
Solvent: ClC(Cl)Cl
Product: Cn1nc(-c2ccccc2Cl)nc1-c1ccc(Oc2ccc(C(F)(F)F)cn2)cc1Cl
Temperature: 140 °C
Reaction time: 0.5 h
Yield: 67.3 %

Procedure:
A mixture of N-methyl-N-(benzenesulfonyl)-2-chlorobenzohydrazonoyl chloride (2.05 g), 2-chloro-4-(5-trifluoromethylpyridine-2-yloxy)benzonitrile (1.88 g), anhydrous iron (III) chloride (1.07 g) and o-dichlorobenzene (10 ml) is stirred at an oil bath temperature of 140° C. for 30 minutes. After cooling, it is dissolved in chloroform (300 ml) and washed with dilute hydrochloric acid, dilute aqueous solution of sodium hydroxide and saline. Then, it is dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 1.87 g of desired compound (melting point: 104.0°-108.0° C.).
Reaction SMILES: [NH2:1][C:2]1[C:21]([CH2:22][N:23]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:24][CH3:25])=[CH:20][C:5]([C:6]([CH:8]([OH:19])[C@H:9]([C@H:11]([C@@H:13]([C@@H:15]([CH2:17][OH:18])[OH:16])[OH:14])[OH:12])[OH:10])=[O:7])=[CH:4][C:3]=1[Br:32].[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=1[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH2:48][C:49](O)=[O:50]>>[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([Cl:40])[C:35]=1[NH:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=1[CH2:48][C:49]([CH:17]([OH:18])[C@H:15]([C@H:13]([C@@H:11]([C@@H:9]([CH:8]([C:6](=[O:7])[C:5]1[CH:20]=[C:21]([CH2:22][N:23]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]2)[CH2:24][CH3:25])[C:2]([NH2:1])=[C:3]([Br:32])[CH:4]=1)[OH:19])[OH:10])[OH:12])[OH:14])[OH:16])=[O:50]
Reactant: CCN(Cc1cc(C(=O)C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO)cc(Br)c1N)C1CCCCC1
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Product: CCN(Cc1cc(C(=O)C(O)[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)C(O)C(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc(Br)c1N)C1CCCCC1

Procedure:
This compound was prepared from 1-[4-amino-3-bromo-5-(N-ethyl-cyclohexylaminomethyl)-benzoyl]-D-mannitol and 2-[(2,6-dichlorophenyl)-amino]-phenyl-acetic acid analogous to Example 4. Amorphous powder.
Reaction SMILES: [O:1]=[C:2](N1CCOC1=O)[CH2:3][CH2:4][CH:5]=O.[NH2:13][C@@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][OH:21])[CH2:16][CH2:15]1>>[OH:21][CH2:20][C@@H:17]1[CH2:18][CH2:19][C@H:14]([N:13]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:1])[CH2:15][CH2:16]1
Reactant: N[C@H]1CC[C@@H](CO)CC1
Reactant: O=CCCC(=O)N1CCOC1=O
Product: O=C1CCCN1[C@H]1CC[C@@H](CO)CC1

Procedure:
Using the method of Example 167, 4-oxo-4-(2-oxo-oxazolidin-3-yl)-butyraldehyde (Dominique Urban, Troels Skrydstrup, and Jean-Marie Beau, J. Org. Chem., 1998, 63(8), 2507-2516) (4.2 g, 24.54 mmol) and (cis-4-amino-cyclohexyl)-methanol (Thomas P. Johnston, etc. J. Med. Chem., 1977, 20(2), 279-290) (3.17 g, 24.54 mmol) yield 4.87 g (100%) of the title compound as a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([N+:11]([O-:13])=[O:12])=[C:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:7]=2[CH:20]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(O)C>[N+:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([CH2:2][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:20][C:7]=2[C:8]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O-:13])=[O:12]
Reactant: O=[N+]([O-])c1oc2ccc(CBr)cc2c1-c1ccccc1
Reactant: C1COCCN1
Solvent: CCO
Product: O=[N+]([O-])c1oc2ccc(CN3CCOCC3)cc2c1-c1ccccc1

Procedure:
Using the method of Example 1, 5-bromomethyl-2-nitro-3-phenylbenzofuran is reacted with morpholine in ethanol to provide yellow crystals of N-(2-nitro-3-phenyl-5-benzofuranylmethyl)-morpholine, m.p. 151°-154° C., having the structure ##STR13##
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]2[CH2:15][C@@H:14]3[N:16](C(OC(C)(C)C)=O)[C@H:11]2[CH2:12][CH2:13]3)=[N:7][CH:8]=1.Cl>C(Cl)Cl.O1CCOCC1>[F:25][C:2]([F:1])([F:24])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C@@H:10]2[CH2:15][C@@H:14]3[NH:16][C@H:11]2[CH2:12][CH2:13]3)=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1[C@H](Nc1ccc(C(F)(F)F)cn1)C2
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: FC(F)(F)c1ccc(N[C@@H]2C[C@H]3CC[C@@H]2N3)nc1
Reaction time: 8 h

Procedure:
To the title compound of step A (319 mg, 0.89 mmol) in DCM (8.7 mL) was added 4M HCl in dioxane (1.1 mL). The reaction was allowed to proceed overnight then concentrated and neutralized with 5% Na2CO3 (aq) and extracted with DCM (2×). The combined organics were dried (Na2SO4) to give the title compound of step B that was used without further purification.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][S:6][C:7]1[N:12]=[C:11]([Cl:13])[CH:10]=[C:9](Cl)[N:8]=1)C.[CH3:16][C:17]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(=O)([O-])[O-].[Na+].[Na+].Cl>C(O)C>[Cl:13][C:11]1[CH:10]=[C:9]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:17]=2[CH3:16])[N:8]=[C:7]([S:6][CH2:5][C:4]([OH:3])=[O:15])[N:12]=1
Reactant: Cc1cccc(N)c1C
Reactant: CCOC(=O)CSc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cccc(Nc2cc(Cl)nc(SCC(=O)O)n2)c1C
Reaction time: 4 h

Procedure:
A mixture of 21.4 g of (4,6-dichloro-2-pyrimidinylthio) acetic acid ethyl ester, 9.7 g of 2,3-dimethylaniline, 8.5 g of anhydrous sodium carbonate in 200 ml. of ethanol was heated under reflux with stirring for 4 hr. The mixture was filtered and water was added to the filtrate until precipitation occurred. This material was removed by filtration and amounted to 7.0 g. This material was treated with boiling 30% sodium hydroxide solution (30 ml.) and sufficient ethanol to obtain a clear solution. After cooling in ice the material was acidified with 30% hydrochloric acid solution. The resulting product was then recrystallized from ethanol giving 4.3 g of product, mp. 146°-151°C.