Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([NH:12][NH:13][C:14]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][C:18]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:17]1=2)=[O:15])=[O:11])([O:6]CC)=[O:5])[CH3:2].CO.[OH-].[Na+]>C1COCC1>[CH2:1]([O:3][P:4]([CH2:9][C:10]([NH:12][NH:13][C:14]([N:16]1[CH2:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[O:19][C:18]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:17]1=2)=[O:15])=[O:11])([OH:6])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOP(=O)(O)CC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reaction time: 24 h

Procedure:
To a stirring solution of 0.58 g (1.2 mmol) of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[(diethoxyphosphinyl)acetyl]hydrazide (20), prepared as described above in Example 20, in 5 mL of THF:methanol (THF:MeOH) (3:2) was added 2 mL of N NaOH. After 24 hours of stirring, an additional 2 mL of NaOH was added to the reaction. After 7 days of stirring, the reaction mixture was filtered, and the resulting filtrate was extracted with 25 mL of EtOAc. The aqueous layer was neutralized with N HCl to pH 2, and was extracted with 25 mL of dichloromethane (DCM). The organic layer was dried over Na2SO4 anhydrous, filtered, and then concentrated in vacuo. The yield of 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[(ethoxyhydroxyphosphinyl)acetyl]hydrazide (27), which was a beige foam, was 0.20 g (37%). Analysis calculated for C18H19N3O6PCl. 025 H2O (M.W. 443.30): C, 48.66; H, 4.42; N, 9.46. Found: C, 48.62; H, 4.37; N, 9.24.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1.Br[CH2:40][CH2:41][CH2:42][CH2:43][O:44][C:45]1[C:50]([O:51][CH3:52])=[CH:49][CH:48]=[CH:47][C:46]=1[O:53][CH3:54]>>[CH3:54][O:53][C:46]1[CH:47]=[CH:48][CH:49]=[C:50]([O:51][CH3:52])[C:45]=1[O:44][CH2:43][CH2:42][CH2:41][CH2:40][O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:10][CH:9]2[O:21][CH2:22][C:23]2[CH:32]=[C:31]3[C:26]([CH2:27][CH2:28][C:29](=[O:38])[N:30]3[CH2:33][CH2:34][CH2:35][O:36][CH3:37])=[CH:25][CH:24]=2)=[CH:4][CH:3]=1
Reactant: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(O)cc3)cc21
Reactant: COc1cccc(OC)c1OCCCCBr
Product: COCCCN1C(=O)CCc2ccc(COC3CN(C(=O)OC(C)(C)C)CCC3c3ccc(OCCCCOc4c(OC)cccc4OC)cc3)cc21

Procedure:
Analogously to Method I, 0.100 g of tert-butyl 4-(4-hydroxyphenyl)-3-[1-(3-methoxypropyl)-2-oxo-1,2,3,4-tetrahydroquinolin-7-ylmethoxy]piperidine-1-carboxylate (Example 44d) and 0.066 g of 2-(4-bromobutoxy)-1,3-dimethoxybenzene are used to prepare the title compound. Rf=0.22 (2:1 EtOAc-heptane); Rt=5.73.
Reaction SMILES: C([N:8]1[C:12]([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:16]=2[CH3:22])O)=[CH:11][N:10]=[CH:9]1)C1C=CC=CC=1.O.[ClH:24].[H][H]>[Pd].C(O)C>[ClH:24].[CH3:22][C:16]1[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:15]=1[CH2:13][C:12]1[N:8]=[CH:9][NH:10][CH:11]=1
Reactant: Cc1cccc(C(O)c2cncn2Cc2ccccc2)c1C
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cccc(Cc2c[nH]cn2)c1C
Temperature: 3 °C
Reaction time: 2 h

Procedure:
1-Benzyl-5-(2,3-dimethylphenylhydroxymethyl)imidazole (20 kg), water (225 l), 30% HCl (20 l), ethanol (5 l) and palladium on charcoal 10% (4.4 kg) are charged. The mixture is stirred under 2.2 bar overpressure of hydrogen at 75±5° C. for 24 hours. The reaction mixture is filtered at 45±3° C. and the filter cake is washed with water (30 l). 170 l of water is distilled off under reduced pressure and 30% HCl (8 l) is added. The solution is cooled to 3±3° C. during 2 h. The solution is seeded with crystals of detomidine HCl at 40±5° C., 30±5° C., 20±5° C. and at 10±5° C., until the crystallization starts. The mixture is agitated for two hours. The crystalline compound is collected by centrifugation and washed with toluene. The crude product and water (250 l) are charged. The solution is heated to about 50° C. and stirred for 1 hour. The solution is cooled to 10° C. during 1.5 hour. The solution is filtered and 180 l of water is distilled off under vacuum. 30% HCl (20 l) is added and the solution is warmed to 60° C., and then cooled to 3±3° C. during 2 hours. The solution is seeded as above until the crystallization starts and agitated for two hours. The crystalline compound is collected by centrifugation and washed with toluene. The product is dried under vacuum at 39±5° C. for 20 hours, at 61±5° C. for 6 hours and at 85±5° C. for 16 hours. The yield is 10.5 kg (78%).
Reaction SMILES: C(NC(C)C)(C)C.C([Mg]Br)C.[C:12]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])(=[O:14])[CH3:13].[Br:20][C:21]1[CH:22]=[C:23]([C:27]#[N:28])[CH:24]=[N:25][CH:26]=1.[Cl-].[NH4+]>C(OCC)C>[NH2:28][C:27]([C:23]1[CH:24]=[N:25][CH:26]=[C:21]([Br:20])[CH:22]=1)=[CH:13][C:12]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14]
Reactant: CC(=O)OC(C)(C)C
Reactant: N#Cc1cncc(Br)c1
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C=C(N)c1cncc(Br)c1
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
Diisopropylamine (9.2 mL, 65 mmol) was added at 0° C. to a 3M solution of ethyl magnesium bromide in diethyl ether (10.9 mL, 32.7 mmol) and additional diethyl ether (20 mL). After one hour at 0° C. tert-butyl acetate (4.3 mL, 32.7 mmol) was added and stirring was continued for 30 minutes. 5-Bromopyridine-3-carbonitrile (2.0 g, 10.9 mmol) in diethyl ether (42 mL) was added at 0° C. After two hours at 0° C. saturated aqueous ammonium chloride solution was added. Phases were separated and the aqueous phase was extracted with diethyl ether. The combined extracts were washed with brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by chromatography on silica gel (ethyl acetate in hexane, 0 to 60%) to yield 1.12 g tert-butyl 3-amino-3-(5-bromopyridin-3-yl)prop-2-enoate.
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][CH2:4][C:3]1=[O:19].[CH2:20]=[O:21].[OH-].[Na+]>C(OCC)(=O)C>[OH:21][CH2:20][CH:4]1[N:5]=[C:6]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:2]([CH3:1])[C:3]1=[O:19]
Reactant: C=O
Reactant: CN1C(=O)CN=C(c2ccccc2)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CN1C(=O)C(CO)N=C(c2ccccc2)c2ccccc21
Yield: 15 %

Procedure:
A reaction mixture of 1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (J. Org. Chem. 52, 3232, (1987)) (12.6 g, 50 mmol), formaline-solution (37% in water, 75 mL) and sodium hydroxide (4.4 g, 110 mmol) was heated to reflux for 4.5 hours. Then additional formaline solution (35 mL) and sodium hydroxide (2.2 g) was added and the reaction mixture was heated for 4 hours. The cooled suspension was diluted with ethyl acetate, the organic layer separated, washed with water and dried over Na2SO4. The organicsolution was evaporated in vacuum and the residue flash-chromatographed on silica gel using toluene/ethanol (3.5%) as eluant to give 1,3-dihydro-3-hydroxymethyl-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one (2.15 g, 15%).
Reaction SMILES: O.[CH3:2]/[C:3](/[CH2:9][CH2:10]/[CH:11]=[C:12](\[CH3:19])/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:4]\[CH2:5][N:6]=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:2]/[C:3](/[CH2:9][CH2:10]/[CH:11]=[C:12](\[CH3:19])/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])=[CH:4]\[CH2:5][NH2:6]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CN=[N+]=[N-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)=CCC/C(C)=C/CC/C(C)=C/CN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Water (46 μL) was added to a stirred mixture of (E,E)-3,7,11-trimethyl-2,6,10-dodecatrienylazide (0.8 g, 3.2 mmol) and triphenylphosphine (0.94 g, 3.62 mmol) in THF (3 mL) and stirred at room temperature overnight. An additional amount of water (46 ML) was added and stirred for another two hours. The reaction mixture was evaporated to dryness and the residue was redissolved in methylene chloride, then MgSO4 was added and filtered. The filtrate was concentrated in vacuo to give the crude title compound as an oily solid which was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([C:11]([OH:13])=O)=[CH:4][CH:3]=1.N1C=CC=CC=1.N1C(F)=NC(F)=NC=1[F:22]>ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH3:10])[C:5]([C:11]([F:22])=[O:13])=[CH:4][CH:3]=1
Reactant: Fc1nc(F)nc(F)n1
Reactant: CCNc1nc(Cl)ccc1C(=O)O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCNc1nc(Cl)ccc1C(=O)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 98.5 %

Procedure:
To a suspension of 10.5 g (52.3 mmol) of the compound obtained in step 1.1 in dichloromethane (250 ml) are successively added 4.2 ml (52.3 mmol) of pyridine and 8.4 ml (99.6 mmol) of cyanuric fluoride. The mixture is stirred for 3 hours at room temperature and then filtered. The solid is rinsed with dichloromethane (100 ml) and the filtrate is washed twice with ice-cold water (60 ml). The organic phase is dried over Na2SO4 and then concentrated under reduced pressure. 10.44 g of product are obtained, the form of an orange-coloured oil. Yield=99%. The product is used without purification in the following step.
Reaction SMILES: I[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[NH:15][S:16]([CH3:19])(=[O:18])=[O:17].[CH3:20][C:21]([C:23]#[CH:24])=[CH2:22]>>[C:21]([C:23]1[N:15]([S:16]([CH3:19])(=[O:18])=[O:17])[C:3]2[C:2]([CH:24]=1)=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[C:5]([C:11]([F:14])([F:13])[F:12])[CH:4]=2)([CH3:22])=[CH2:20]
Reactant: C#CC(=C)C
Reactant: CS(=O)(=O)Nc1cc(C(F)(F)F)c([N+](=O)[O-])cc1I
Product: C=C(C)c1cc2cc([N+](=O)[O-])c(C(F)(F)F)cc2n1S(C)(=O)=O

Procedure:
This compound was prepared using the general Sonagashira conditions as described in general Example C, starting from N-(2-iodo-4-nitro-5-trifluoromethyl-phenyl)-methanesulfonamide (9.0 g, 21.9 mmol) and 2-methyl-1-buten-3-yne (6.25 mL, 65.7 mmol) to yield the title compound as a reddish-brown solid.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([NH:9][C@H:10]([C:18]([OH:20])=O)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:8])[CH2:3][CH2:2]1.[NH2:21][C@H:22]([C:29]([NH:31][C@H:32]([C@@H:40]([OH:46])[CH2:41][CH2:42][CH:43]([CH3:45])[CH3:44])[CH2:33][CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:30])[CH2:23][C:24]1[N:28]=[CH:27][NH:26][CH:25]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(CC)CC)C>CN(C)C=O>[O:1]1[CH2:2][CH2:3][N:4]([C:7]([NH:9][C@H:10]([C:18]([NH:21][C@H:22]([C:29]([NH:31][C@H:32]([C@@H:40]([OH:46])[CH2:41][CH2:42][CH:43]([CH3:44])[CH3:45])[CH2:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:30])[CH2:23][C:24]2[N:28]=[CH:27][NH:26][CH:25]=2)=[O:20])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[CH2:5][CH2:6]1
Reactant: O=C(O)[C@H](Cc1ccccc1)NC(=O)N1CCOCC1
Reactant: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@@H](N)Cc1c[nH]cn1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)CC[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)N1CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To a solution of N-morpholinocarbonyl-L-phenylalanine (114 mg) and 2(S)-(L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (150 mg) in dry N,N-dimethylformamide (20 ml) which was cooled to 0° C., were added a solution of diphenyl phosphorylazide (125 mg) in dry N,N-dimethylformamide (5 ml) and triethylamine (46 mg). The mixture was stirred overnight at ambient temperature. After evaporation of the solvent, the residue was dissolved in ethyl acetate (30 ml) and the solution was washed with saturated sodium bicarbonate solution and water successively, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (2% methanol in chloroform as eluent) to give 2(S)-(N-morpholinocarbonyl-L-phenylalanyl-L-histidyl)amino-1-cyclohexyl-3(S)-hydroxy-6-methylheptane (174 mg) as an amorphous powder.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:11].[N+:12]([O-])([O-:14])=[O:13].[K+]>OS(O)(=O)=O>[F:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=1
Reactant: Cc1cc(C(=O)O)ccc1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc(C(=O)O)c([N+](=O)[O-])cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.6 %

Procedure:
To a solution of 4-fluoro-3-methylbenzoic acid (3.7 g, 24 mmol) in conc. H2SO4 (50 mL) at 0° C. was added KNO3 (3.6 g, 36 mmol) in one portion and the mixture was stirred at rt for 2 h. The reaction mixture was poured into ice water (200 mL) and extracted with DCM (100 mL×2). The organic layer was washed with brine, dried and concentrated to give the crude 4-fluoro-5-methyl-2-nitrobenzoic acid (5 g) as white solid. It was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Br)=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH:12]([NH2:15])([CH3:14])[CH3:13]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:15][CH:12]([CH3:14])[CH3:13])[C:5]2=[N:4][CH:3]=1
Reactant: Brc1cncc2ncc(Br)n12
Reactant: CC(C)N
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)Nc1nccn2c(Br)cnc12
Temperature: 70 °C
Yield: 68.1 %

Procedure:
To a solution of 3,5-dibromo-imidazo[1,2-a]pyrazine (D) (200 mg, 0.72 mmol) in THF (3.6 ml) was added isopropylamine (1.3 ml, 14.4 mmol). The mixture was heated at 70° C. overnight. The mixture was then cooled to rt, diluted with DCM. The organic layer was washed with water, brine, dried and concentrated. The residue was purified on a silica gel column to afford 125 mg (yield 68%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[C:20]1([CH3:29])[CH:25]=[CH:24][CH:23]=[C:22]([N:26]=[C:27]=[O:28])[CH:21]=1>>[C:20]1([CH3:29])[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27](=[O:28])[NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[C:16]4[C:11](=[N:12][CH:13]=[CH:14][CH:15]=4)[NH:10][C:9]=3[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=2)[CH:21]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: NC(=O)c1[nH]c2ncccc2c1-c1ccc(N)cc1
Product: Cc1cccc(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4ncccc34)cc2)c1

Procedure:
62.5 mg of solid beige-coloured 3-[4-(3-m-tolylureido)phenyl]-1H-pyrrolo[2,3-b]pyridine-2-carboxamide are prepared as described in Example 7 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide and m-tolyl isocyanate.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][CH:3]=1.[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][O:20][CH2:19][CH2:18][NH:17]1)=[O:15])[CH3:12].C(N(C(C)C)CC)(C)C>CS(C)=O>[CH2:11]([O:13][C:14]([CH:16]1[CH2:21][O:20][CH2:19][CH2:18][N:17]1[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1)=[O:15])[CH3:12]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CCOC(=O)C1COCCN1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1COCCN1c1ccc(N)cc1

Procedure:
4-Fluoronitrobenzene and morpholine-3-carboxylic acid ethyl ester were allowed to undergo the reaction at 100° C. in DMSO in the presence of diisopropylethylamine, and then the resulting compound was subjected to catalytic hydrogenation in the same manner as shown in Reference Example 3 to obtain 4-(4-aminophenyl)morpholine-3-carboxylic acid ethyl ester. ESI: 251.
Reaction SMILES: [C:1]([CH:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:2].C1C=CC=CC=1.C(O)C>Cl>[C:1]([C@@H:3]([OH:12])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:2]
Reactant: N#CC(O)CCc1ccccc1
Agent: Cl
Solvent: c1ccccc1
Solvent: CCO
Product: N#C[C@@H](O)CCc1ccccc1

Procedure:
α-Cyano-3-phenylpropyl alcohol wad hydrolyzed in concentrated hydrochloric acid (0.5 ml) at room temperature for 3 days with stirring to convert it to 1-hydroxy-4-phenyl butyric acid which was isolated by crystallization from benzene. [α]D20 =7.02° (ethanol, c=0.968).
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]1[CH:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]3[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=3)=[O:24])=[CH:18][CH:17]=2)[CH:12]=[CH:11][N:10]=1.C(N(CC)CC)C>O1CCCC1>[CH:1]1([C:5]([NH:8][C:9]2[CH:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=4)=[O:24])=[CH:18][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[O:6])[CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCC1
Reactant: Nc1cc(Oc2ccc(NC(=O)Nc3ccc(F)cc3)cc2)ccn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)cc1)Nc1ccc(Oc2ccnc(NC(=O)C3CCC3)c2)cc1
Temperature: 25 °C

Procedure:
After adding 70 mg of cyclobutanecarbonyl chloride to a solution of 100 mg of N-[4-(2-aminopyridin-4-yl)oxyphenyl]-N′-(4-fluorophenyl)urea, 0.12 ml of triethylamine and 10 ml of tetrahydrofuran stirred at room temperature, the mixture was further stirred for 15 minutes. NH type silica gel was added to the reaction solution, the solvent was distilled off under reduced pressure and the reaction product was adsorbed onto the silica gel. The silica gel was charged into a dry column packed with NH type silica gel, and column purification was performed (chloroform:methanol=40:1). The obtained residue was solidified from ethyl acetate-methanol-hexane to obtain 64 mg of the target substance as a white solid.
Reaction SMILES: [Cl-:1].[Al+3].[Cl-].[Cl-].S(Cl)(Cl)(=O)=O.[CH:10]1[C:23]2[NH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[S:15][C:14]=2[CH:13]=[CH:12][C:11]=1[C:24]#[N:25]>ClCCCl>[Cl:1][C:18]1[CH:17]=[C:16]2[C:21](=[CH:20][CH:19]=1)[NH:22][C:23]1[CH:10]=[C:11]([C:24]#[N:25])[CH:12]=[CH:13][C:14]=1[S:15]2
Reactant: [Cl-]
Reactant: N#Cc1ccc2c(c1)Nc1ccccc1S2
Agent: [Al+3]
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCCl
Product: N#Cc1ccc2c(c1)Nc1ccc(Cl)cc1S2
Temperature: 25 °C
Reaction time: 48 h
Yield: 7143.1 %

Procedure:
Aluminium chloride (0.5 g) and sulphuryl chloride (39.7 cc) are added in the course of 4 hours to a solution, heated to 50° C., of 2-phenothiazinecarbonitrile (100 g) in 1,2-dichloroethane (3000 cc). The reaction mixture is brought to reflux for 2 hours, and then stirred for 48 hours at 25° C. The precipitate formed is filtered off, washed with 1,2-dichloroethane (2×200 cc) and then with ethyl ether (200 cc) and dried at 40° C. under reduced pressure (30 mm Hg; 4 kPa) to give 7-chloro-2-phenothiazinecarbonitrile (69.3 g) in the form of a yellow-green solid, m.p. 235° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][C:7]#[N:8])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[CH:12]=1.[Na]>C(O)C>[C:7]([C:6]([C:5]1[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=1)=[CH:17][C:13]1[CH:12]=[N:11][CH:16]=[CH:15][CH:14]=1)#[N:8]
Reactant: N#CCc1ccc(Cl)cc1
Reactant: O=Cc1cccnc1
Agent: [Na]
Solvent: CCO
Product: N#CC(=Cc1cccnc1)c1ccc(Cl)cc1
Reaction time: 1 h
Yield: 48 %

Procedure:
A solution of 4-chlorobenzyl cyanide (7.58 g) and pyridine-3-aldehyde (5.35 g) in absolute ethanol (50 ml) was warmed to 50° C.; 3.5 ml of a solution of sodium (2.74 g) in absolute ethanol (32 ml) was added and the mixture was left without further heating. After 1 hour, the solid product was filtered off, washed with ethanol, and then diethylether, and dried. Recrystallization of this material from ethanol (150 ml) with charcoal treatment gave 4 in 48% yield as pale yellow needles; m.p. 141°-143° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=[O:2].[CH2:12]([NH:15][CH2:16][CH2:17][CH3:18])[CH2:13][CH3:14]>>[CH2:12]([N:15]([CH2:16][CH2:17][CH3:18])[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([CH:1]=[O:2])[CH:4]=1)[CH2:13][CH3:14]
Reactant: CCCNCCC
Reactant: O=Cc1cccc(C(=O)O)c1
Product: CCCN(CCC)C(=O)c1cccc(C=O)c1

Procedure:
To 2 g (13.3 mmole) of 3-formyl benzoic acid was coupled with di-n-propylamine via Method I to give 2.5 g of the title compound as a white solid.
Reaction SMILES: S(Cl)(Cl)=O.[CH2:5]([O:12][C:13]1[CH:26]=[CH:25][C:16]([C:17]([NH:19][C:20]([CH3:24])([CH3:23])[CH2:21][OH:22])=O)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(Cl)(Cl)Cl>[CH2:5]([O:12][C:13]1[CH:26]=[CH:25][C:16]([C:17]2[O:22][CH2:21][C:20]([CH3:24])([CH3:23])[N:19]=2)=[CH:15][CH:14]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(CO)NC(=O)c1ccc(OCc2ccccc2)cc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC1(C)COC(c2ccc(OCc3ccccc3)cc2)=N1
Yield: 99 %

Procedure:
Thionyl chloride (11 ml, 150 mmol, 3 eq) is added to a solution of 4-(benzyloxy)-N-(2-hydroxy-1,1-dimethylethyl)benzamide ax1 (14.98 g, 50 mmol, 1 eq) in chloroform (400 ml) and the mixture is heated at reflux for 2 h. The solvent is then removed under vacuum, and the residue is dissolved into dichloromethane. The organic layer is washed with a saturated solution of aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated under vacuum to give 2-[4-(benzyloxy)phenyl]-4,4-dimethyl-4,5-dihydro-1,3-oxazole ax4 (4.3 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:7]2[CH:8]=[C:9](B(O)O)[CH:10]=[CH:11][C:6]=2[NH:5][C:4](=[O:15])[O:3]1.[Br:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[C:20](Br)[CH:19]=1>>[Br:17][C:18]1[CH:19]=[C:20]([C:9]2[CH:10]=[CH:11][C:6]3[NH:5][C:4](=[O:15])[O:3][C:2]([CH3:16])([CH3:1])[C:7]=3[CH:8]=2)[CH:21]=[C:22]([F:24])[CH:23]=1
Reactant: Fc1cc(Br)cc(Br)c1
Reactant: CC1(C)OC(=O)Nc2ccc(B(O)O)cc21
Product: CC1(C)OC(=O)Nc2ccc(-c3cc(F)cc(Br)c3)cc21

Procedure:
6-(3-Bromo-5-fluorophenyl)-4,4-dimethyl-1,4-dihydrobenzo[d][1,3]oxazin-2-one was prepared, from (1,4-dihydro-4,4-dimethyl-2-oxo-2H-3,1-benzoxazin-6-yl)boronic acid and 1,3-dibromo-5-fluorobenzene following the procedure of Example 5, as a white solid: mp 182–183° C.; 1H-NMR (DMSO-d6) δ 10.36 (s, 1H, D2O exchangeable), 7.78 (s, 1H), 7.58–7.65 (m, 3H), 7.49 (dd, 1H, J=8.3, 1.8 Hz), 6.96 (d, 1H, J=8.5 Hz), 1.69 (s, 6H); 19F-NMR (DMSO-d6) 6–112.46 (m, 1F); MS (CI) m/z 352 ([M+H]+, 78%), 350 ([M+H]+, 75%); Anal. Calc. For C16H13BrFNO2: C, 54.88, H, 3.74, N, 4.00. Found: C, 54.83, H, 3.82, N, 3.95.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Cl)[CH:2]=1.[C:18]1(=[O:28])[NH:22][C:21](=[O:23])[C:20]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:19]12.[K].[I-].[K+]>CN(C)C=O.O>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:22]2[C:18](=[O:28])[C:19]3[C:20](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:21]2=[O:23])[CH:2]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: ClCCCCCCc1cnc2ccccc2c1
Agent: [I-]
Agent: [K+]
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCCCCc1cnc2ccccc2c1
Temperature: 130 °C
Yield: 82.4 %

Procedure:
A solution of 7.8 g of 3-quinolinehexanol in 35 ml of dry dichloromethane was treated dropwise with a solution of 6.07 g of thionyl chloride in 15 ml of dichloromethane. The reaction mixture was heated to reflux for 1 hour and evaporated to dryness. The residue was dissolved in dichloromethane, washed successively with water, saturated sodium bicarbonate solution and brine, dried over potassium carbonate and evaporated to give 8.3 g of crude 6-(3-quinolinyl)hexylchloride. A suspension of 8.3 g of 6-(3-quinolinyl)hexylchloride, 12.6 g of potassium phthalimide, and 0.50 g of potassium iodide in 60 ml of dimethylformamide was heated to a bath temperature of 130° C. for one hour. The cooled mixture was diluted with water and extracted with dichloromethane. The combined organic layers were washed with water, dried over potassium carbonate and evaporated. The crude solid was crystallized from ethyl acetate-hexane to give 9.9 g (82%) of 2-[6-(3-quinolinyl)hexyl]-1H-isoindole-1,3-(2H)-dione, mp 90°-91° C. An analytical sample was obtained from toluene, mp 95.5°-96.5° C.