Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([NH:17][CH:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:16])=[O:15])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[C:31](Cl)(Cl)=[S:32].[C:35]1([NH2:42])[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[NH2:41]>C1(C)C=CC=CC=1.O1CCCC1.C1(C)C=CC=CC=1>[NH2:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[NH:42][C:31]([NH:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([S:14]([NH:17][CH:18]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])(=[O:16])=[O:15])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1)=[S:32]
Reactant: CCOC(=O)CC(NS(=O)(=O)c1cccc(-c2cccc(N)c2)c1)c1ccccc1
Reactant: S=C(Cl)Cl
Reactant: Nc1ccccc1N
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC(NS(=O)(=O)c1cccc(-c2cccc(NC(=S)Nc3ccccc3N)c2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
31.84 g (75 mmol) ethyl 3-{[(3′-amino[1,1′-biphenyl]-3-yl)sulfonyl]amino}-3-phenyl-propanoate 10.1.2 were dissolved in 600 ml toluene and 8.62 g thiophosgene were added. The mixture was refluxed for 2 h, evaporated and the residue dissolved in 200 ml toluene. This solution was added dropwise to a solution of o-phenylendiamine (12.2 g 113 mmol) in 500 ml tetrahydrofurane/toluene (1/1) at 40° C. The mixture was stirred for 12 h at room temperature, concentrated and purified (flash chromatography: dichloromethane/acetic acid ethyl ester10+1) to yield 43 g (100%).
Reaction SMILES: [C:1]([C:3]1[C:9]2[CH:10]=[C:11]([Cl:14])[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[CH:4]=1)#[CH:2].C([Mg]Br)C.[CH2:23]=[O:24].[Cl-].[NH4+]>O1CCCC1>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]2[S:7][C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[CH:4]=[C:3]([C:1]#[C:2][CH2:23][OH:24])[C:9]=2[CH:10]=1
Reactant: C#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Reactant: C=O
Agent: CC[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: OCC#CC1=Cc2ccccc2Sc2ccc(Cl)cc21
Temperature: 50 °C

Procedure:
A solution of 13.5 g. of 10-ethynyl-8-chloro-dibenzo[b,f]thiepin in 150 ml. of absolute tetrahydrofuran is treated dropwise at room temperature with 52 ml. of a 1-M solution of ethylmagnesium bromide solution in tetrahydrofuran. After stirring the mixture for an additional hour, 1.85 g. of paraformaldehyde are pyrrolyzed and led through the mixture in gaseous form. The solution, having now warmed to about 50° C., is stirred for an additional 30 minutes and then poured onto a saturated, aqueous ammonium chloride solution. By extraction with benzene and subsequent chromatography on silica gel using benzene/methanol (20:1) as the eluant, there is obtained 3-(8-chloro-dibenzo[b,f]thiepin-10-yl)-2-propyn-1-ol which melts at 111°-113° C. after recrystallization from ethyl acetate/petroleum ether.
Reaction SMILES: CC1(C)[O:6][CH:5]2[CH:7]([N:12]3[C:16]4[N:17]=[C:18]([S:31][CH2:32][CH2:33][CH3:34])[N:19]=[C:20]([NH:21][CH:22]5[CH2:24][CH:23]5[C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=5)[C:15]=4[N:14]=[N:13]3)[CH2:8][CH:9](CO)[CH:4]2[O:3]1.F[C:37](F)(F)[C:38]([OH:40])=O.[CH:43]1(N=C=NC2CCCCC2)CCCCC1.COC(=O)C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C(O)=O>CS(C)=O.C(OCC)(=O)C.N1C=CC=CC=1>[OH:40][CH2:38][CH:37]=[CH:43][CH:9]1[CH2:8][CH:7]([N:12]2[C:16]3[N:17]=[C:18]([S:31][CH2:32][CH2:33][CH3:34])[N:19]=[C:20]([NH:21][CH:22]4[CH2:24][CH:23]4[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:15]=3[N:14]=[N:13]2)[CH:5]([OH:6])[CH:4]1[OH:3]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: O=C(O)C(F)(F)F
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(CO)C4OC(C)(C)OC43)c2n1
Agent: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)C(=O)O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C=CCO)C(O)C3O)c2n1
Reaction time: 5 h
Yield: 196.9 %

Procedure:
A solution of the product of Example 1, step (a) (1.6 g) in dimethylsulphoxide (15 ml) was treated with pyridine (0.25 g) followed by trifluoroacetic acid (0.18 g). To this mixture was added 1,3-dicyclohexylcarbodiimide (1.99 g). After stirring for 5 hours at the reaction mixture was treated with methyl(triphenylphosphoranylidene)acetate (1.72 g) and then stirred for a further 18 hours. The mixture was poured into ethyl acetate (300 ml) and treated with oxalic acid (1.59 g). After stirring for 30 minutes the mixture was filtered and the ethyl acetate solution was washed with dilute aqueous sodium bicarbonate and then with dilute aqueous brine, before being dried and concentrated. Purification (SiO2, ethyl acetate:isohexane 1:4 as eluant) afforded the subtitle compound (1.5 g).
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]=[C:10]=[O:11])=[N:6][N:5]=2)[CH2:3][CH2:2]1.[CH3:12][C:13]([NH2:17])(C)[CH:14]=[O:15].[C:18](OCC)(=O)C>>[CH3:18][N:17]([CH:13]([CH3:12])[CH:14]=[O:15])[C:10]([NH:9][C:7]1[S:8][C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][N:6]=1)=[O:11]
Reactant: CCOC(C)=O
Reactant: O=C=Nc1nnc(C2CC2)s1
Reactant: CC(C)(N)C=O
Product: CC(C=O)N(C)C(=O)Nc1nnc(C2CC2)s1

Procedure:
A mixture of 5-cyclopropyl-1,3,4-thiadiazol-2-yl isocyanate dimer (7 grams), the dimethyl acetal of 2-methyl-aminopropionaldehyde (6 grams) and ethyl acetate (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer and reflux condenser. The reaction mixture is heated at reflux for a period of about 2 hours. After this time the mixture is stripped of solvent under reduced pressure to yield the desired product the dimethyl acetal of 2-[1-methyl-3-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)ureido]-propionaldehyde.
Reaction SMILES: C(OC([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15]([CH:22]=O)=[C:14]([F:24])[CH:13]=3)[CH2:9]1)=O)(C)(C)C.Cl.[CH3:26][O:27][NH2:28]>C(O)C>[NH3:8].[CH3:26][O:27][N:28]=[CH:22][C:15]1[N:16]=[C:17]2[C:12](=[CH:13][C:14]=1[F:24])[CH2:11][C@H:10]1[N:18]2[C@H:19]([CH3:21])[CH2:20][NH:8][CH2:9]1
Reactant: CON
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3cc(F)c(C=O)nc3N21
Agent: Cl
Solvent: CCO
Product: CON=Cc1nc2c(cc1F)C[C@@H]1CNC[C@@H](C)N21
Product: N
Reaction time: 18 h
Yield: 145.8 %

Procedure:
To a solution of 0.047 g (4R,9aR)-7-fluoro-6-formyl-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester in 1 mL ethanol was added 0.014 g O-methylhydroxylamine hydrochloride and the mixture was stirred at ambient for 18 temperature for 18 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was washed with 10% citric acid, 10% sodium bicarbonate and brine, then concentrated and purified by chromatography on silica gel with heptane:ethyl acetate=2:1. The product was treated with 1 mL trifluoroacetic acid at room temperature for 30 min. The solvent was evaporated and the residue was purified by chromatography on silica gel with dichloromethane:methanol:satd. ammonia (9:1:0.1) to yield 0.027 g (4R,9aR)-7-fluoro-4-methyl-1,2,3,4,9,9a-hexahydro-2,4a,5-triaza-fluorene-6-carbaldehyde O-methyl-oxime as a light yellow solid.
Reaction SMILES: [OH-:1].[Na+].[CH:3]([N:6]1[C:10]([C:11]([F:14])([F:13])[F:12])=[C:9](CC#N)[CH:8]=[N:7]1)([CH3:5])[CH3:4].[CH3:18][CH2:19][OH:20]>>[CH:3]([N:6]1[C:10]([C:11]([F:14])([F:13])[F:12])=[C:9]([CH2:18][C:19]([OH:1])=[O:20])[CH:8]=[N:7]1)([CH3:5])[CH3:4]
Reactant: [OH-]
Reactant: CCO
Reactant: CC(C)n1ncc(CC#N)c1C(F)(F)F
Agent: [Na+]
Product: CC(C)n1ncc(CC(=O)O)c1C(F)(F)F
Temperature: 60 °C
Yield: 75 %

Procedure:
Aqueous sodium hydroxide (150 mL of a 1 M solution) was added to [1-isopropyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]acetonitrile (Preparation 184, 6.2 g, 28.6 mmol) in EtOH (150 mL) and the mixture was heated at 60° C. for 16 hours. The mixture was evaporated in vacuo and the residue was dissolved in water (50 mL) then washed with EtOAc (100 mL). The aqueous phase was acidified to pH 5 using 1N HCl and extracted with 10% IPA in DCM (4×100 mL). The combined organic phases were dried over sodium sulphate and evaporated in vacuo to afford the title compound as a white solid in 75% yield, 5.0 g.
Reaction SMILES: [CH:1]1([S:4]([NH:7][C@H:8]2[C@@H:13]3[C@@:11]([CH3:14])([CH2:12]3)[C@@H:10]([C:15]([O:17]CC)=[O:16])[CH2:9]2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH:20]1([S:23]([NH:26][C@@H:27]2[C@H:32]3[C@:30]([CH3:33])([CH2:31]3)[C@H:29]([C:34]([O:36]CC)=[O:35])[CH2:28]2)(=[O:25])=[O:24])[CH2:22][CH2:21]1>>[CH:1]1([S:4]([NH:7][C@H:8]2[C@@H:13]3[C@@:11]([CH3:14])([CH2:12]3)[C@@H:10]([C:15]([OH:17])=[O:16])[CH2:9]2)(=[O:5])=[O:6])[CH2:2][CH2:3]1.[CH:20]1([S:23]([NH:26][C@@H:27]2[C@H:32]3[C@:30]([CH3:33])([CH2:31]3)[C@H:29]([C:34]([OH:36])=[O:35])[CH2:28]2)(=[O:24])=[O:25])[CH2:21][CH2:22]1
Reactant: CCOC(=O)[C@@H]1C[C@H](NS(=O)(=O)C2CC2)[C@@H]2C[C@]12C
Reactant: CCOC(=O)[C@H]1C[C@@H](NS(=O)(=O)C2CC2)[C@H]2C[C@@]12C
Product: C[C@@]12C[C@@H]1[C@H](NS(=O)(=O)C1CC1)C[C@@H]2C(=O)O
Product: C[C@]12C[C@H]1[C@@H](NS(=O)(=O)C1CC1)C[C@H]2C(=O)O
Yield: 100 %

Procedure:
A mixture of (1R,2S,4R,5S)-ethyl 4-(cyclopropanesulfonamido)-1-methylbicyclo[3.1.0]hexane-2-carboxylate and (1S,2R,4S,5R)-ethyl 4-(cyclopropanesulfonamido)-1-methyl-bicyclo[3.1.0]hexane-2-carboxylate (0.109 g, 0.379 mmol) was hydrolyzed using General Procedure GG to give (1R,2S,4R,5S)-4-(cyclopropanesulfonamido)-1-methyl-bicyclo[3.1.0]hexane-2-carboxylic acid and (1S,2R,4S,5R)-4-(cyclopropanesulfonamido)-1-methylbicyclo[3.1.0]hexane-2-carboxylic acid (0.113 g, 100%): LC/MS (Table 2, Method a) Rt=1.57 min; MS m/z: 258 (M−H)−.
Reaction SMILES: Cl.[C:2]([NH2:10])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(O[CH:14]=[C:15]([CH3:18])[CH:16]=O)C.C[O-].[Na+].O>CO>[CH3:18][C:15]1[CH:14]=[N:9][C:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[N:10][CH:16]=1
Reactant: N=C(N)c1ccccc1
Reactant: CCOC=C(C)C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cnc(-c2ccccc2)nc1
Reaction time: 0.5 h

Procedure:
To a solution of benzamidine hydrochloride (500 mg, 3.19 mmol) and 3-ethoxy-2-methylacrylaldehyde (400 mg, 3.51 mmol) in Methanol (10 mL) was added a NaOMe-solution (30 percent in methanol) dropwise under stirring over 30 minutes. After stirring for 4 hours water (20 mL) was added and mixture was stirred for further 30 minutes at room temperature. After filtration the obtained precipitate was washed with water and dried. White solid. Yield: 220 mg, 41%. 1H NMR (CDCl3, 500 MHz): δH (ppm)=2.34 (s, 3H), 7.44-7.54 (m, 3H), 8.37-8.45 (m, 2H), 8.64 (d, J=0.6 Hz, 2H); 13C NMR (CDCl3, 125 MHz): δC (ppm)=15.7, 128.1, 128.5, 128.8, 130.6, 137.9, 157.6, 162.7; (ESI): m/z=170.97 [M+H]+.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1.[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][CH2:43][C@@H:42]1[CH2:46]O)=[O:40])([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl>[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][CH2:43][C@H:42]1[CH2:46][Br:1])=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CBr
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 30.5 %

Procedure:
To a solution of N-bromosuccinimide (1.33 g, 7.45 mmol, 3 eq) in DCM (15 ml) was added drop wise a solution of triphenylphosphine (1.82 g, 6.94 mmol, 2.8 eq) in DCM (15 ml). The solution was stirred at room temperature for 15 minutes. Pyridine (0.015 ml, 1.2 eq) was added followed by dropwise addition of (R)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (0.50 g, 2.48 mmol, 1 eq) in DCM (15 ml). The solution was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was triturated in diethyl ether (2×5 0 ml) and 10% ethyl acetate in heptane. The solvents from trituration were combined and concentrated under reduced pressure to give a pale pink solid. The product was purified using column chromatography eluting with ethyl acetate/heptane to give the title compound (0.20 g, 30% yield).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([OH:9])=O)=[O:4].[NH2:20][C@H:21]([C:31]([NH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:32])[CH2:22][CH2:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27].S(O)(C1C=CC(C)=CC=1)(=O)=O.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:2][C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([NH:20][C@H:21]([C:31]([NH:33][CH2:34][C:35]([O:37][CH3:38])=[O:36])=[O:32])[CH2:22][CH2:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:9])=[O:4]
Reactant: COC(=O)CNC(=O)[C@@H](N)CCC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Product: COC(=O)CNC(=O)[C@H](CCC(=O)OC(C)(C)C)NC(=O)[C@@H]1CCCN1C(=O)CNC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
2.7 g (10 mmoles) of Boc-Gly-Pro-OH and 4.5 g (10 mmoles) of H-Glu(O-But)-Gly-OMe.TosOH are dissolved in 20 ml of dimethylformamide. 1.28 ml (10 mmoles) of N-ethylmorpholine and 2.2 g (10.6 mmoles) of dicyclohexylcarbodiimide are added and the mixture is left to stand at room temperature overnight. The dicyclohexylurea is then filtered off, the solvent is distilled off in vacuo, the residue is taken up in ethyl acetate and the solution is washed with citric acid, bicarbonate solution and water, as described above, dried over sodium sulfate and evaporated to dryness. The residue is dissolved in ether and a precipitate is obtained with petroleum ether and filtered off.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:4]=[C:5]([C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]#[N:19])=[C:13]3[NH:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(OCC)(=O)C>[Pd].C(O)(=O)C>[F:20][C:2]([F:1])([F:21])[C:3]1[CH:4]=[C:5]([CH:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]#[N:19])=[C:13]3[NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: N#Cc1cnn2c1NCC=C2c1cccc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#Cc1cnn2c1NCCC2c1cccc(C(F)(F)F)c1
Reaction time: 4.5 h

Procedure:
A mixture of 1.5 parts of 4,5-dihydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile, 50 parts of ethyl acetate, 10 parts of acetic acid and 0.2 parts of 5% palladium-on-carbon catalyst was shaken on a Parr hydrogenator under about 30 pounds of hydrogen pressure for 4.5 hours. The reaction mixture was filtered, and the mother liquor was concentrated to remove the solvent. The yellow oil which was obtained was crystallized by trituration in ether. The crystalline product was recrystallized from ethyl acetate by addition of hexane. The product 4,5,6,7-tetrahydro-7-[3-(trifluoromethyl)phenyl]pyrazolo[1,5-a]pyrimidine-3-carbonitrile melted at 181°-183° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)#[N:2].[C:18](OCC)(=[O:20])[CH3:19]>C(O)C.[Pd]>[NH:9]([C:7]1[CH:6]=[CH:5][C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:3]([C:1]#[N:2])[CH:8]=1)[C:18]([CH3:19])=[O:20]
Reactant: CCOC(C)=O
Reactant: N#Cc1cc([N+](=O)[O-])ccc1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)Nc1ccc(-c2ccccc2)c(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Cyano-4-nitrobiphenyl (0.067 moles, 15.0 g.) was dissolved in 100 ml ethyl acetate/100 mi ethanol and hydrogenated at 40 psi over 3.0 g of 10% palladium on carbon. The catalyst was removed by filtering though celite. The solvents were removed in vacuo. The residue was dissolved in 175 ml of methylene chloride. Acetic anhydride (15 ml) was added. The reaction was stirred at room temperature for 30 minutes and poured over ice. The organic layer was dried, concentrated, and then purified by HPLC over silica gel eluted with a gradient of 0-10% ethyl acetate in chloroform. (MS)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[N:12]1([CH2:18][CH2:19][O:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]([NH2:31])=[CH:23][CH:22]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([NH:31][C:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21]([O:20][CH2:19][CH2:18][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[CH:22][CH:23]=1)=[O:8]
Reactant: Nc1ccc(OCCN2CCOCC2)c2ccccc12
Reactant: COc1cccc(C(=O)O)c1
Product: COc1cccc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)c1

Procedure:
Compound is prepared from 3-methoxybenzoic acid and 4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-ylamine according to conditions described in general procedure G. Mp: 105-107° C.; 1H NMR (300 MHz, DMSO-d6) δ 2.57 (t, J=4.8 Hz, 4H), 2.88 (t, J=5.7 Hz, 2H), 3.60 (t, J=4.5 Hz, 4H), 3.85 (s, 3H), 4.31 (t, J=5.4 Hz, 2H), 7.02 (d, J=8.1 Hz, 1H), 7.17 (dd, J=2.4 and 8.4 Hz, 1H), 7.42-7.68 (m, 5H), 7.85-7.89 (m, 1H), 8.19-8.22 (m, 1H), 10.24 (s, 1H); MS 407 (M+1).
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][CH2:12][NH2:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1.C(N(CC)CC)C.N>CN(C)C=O.C(Cl)Cl>[C:1]([NH:9][CH2:10][CH2:11][CH2:12][NH:13][CH2:15][CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[NH:19][CH:18]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: NCCCNC(=O)c1ccccc1
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCCCNCCc1c[nH]c2ccccc12)c1ccccc1

Procedure:
A solution of 8 g N-benzoyl-1,3-diaminopropane, 6,7 g 3-(2-bromoethyl)indole and 5 ml anhydrous triethylamine in 15 ml anhydrous dimethylformamide is maintained for 72 hours in nitrogen atmosphere. A dilute ammonia solution and methylene chloride are then added to the reaction mixture and the organic phase is dried and evaporated. The residue is chromatographied on silicagel using as eluant methylene chloride+5% methanol+0.3% ammonia, to yield the title compound (M.pt. of the naphthalene-2-sulfonate 203°-204° with decomposition after crystallization from ethanol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C@H:4]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:5][C:6]1[S:7][C:8]([C:11]([CH3:13])=[CH2:12])=[CH:9][CH:10]=1>[Pd]>[CH3:1][O:2][C:3](=[O:22])[C@H:4]([NH:14][C:15]([O:17][C:18]([CH3:19])([CH3:21])[CH3:20])=[O:16])[CH2:5][C:6]1[S:7][C:8]([CH:11]([CH3:13])[CH3:12])=[CH:9][CH:10]=1
Reactant: C=C(C)c1ccc(C[C@@H](NC(=O)OC(C)(C)C)C(=O)OC)s1
Agent: [Pd]
Product: COC(=O)[C@@H](Cc1ccc(C(C)C)s1)NC(=O)OC(C)(C)C
Yield: 95.9 %

Procedure:
8.50 g of 2(R)-tert-butoxycarbonylamino-3-(5-isopropenyl-thiophen-2-yl)-propionic acid methyl ester was treated with Pd/C and H2 gas (1 atm) by the general procedure N to afford 8.20 g of 2(R)-tert-butoxycarbonylamino-3-(5-isopropyl-thiophen-2-yl)-propionic acid methyl ester. This ester was treated with HCl/dioxane (4.0 M) to afford 7.10 g of title compound.
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([CH3:10])[CH3:9])[CH:3]=1.P(Cl)(Cl)(Cl)=O.[C:16]([N:19]1[CH2:23][CH2:22][NH:21][C:20]1=O)(=[O:18])[CH3:17]>>[C:16]([N:19]1[CH2:23][CH2:22][N:21]=[C:20]1[NH:1][C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH:8]([CH3:10])[CH3:9])[CH:3]=1)(=[O:18])[CH3:17]
Reactant: CC(C)c1cc(N)n(C)n1
Reactant: CC(=O)N1CCNC1=O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)N1CCN=C1Nc1cc(C(C)C)nn1C
Reaction time: 40 h

Procedure:
5-amino-3-isopropyl-1-methyl pyrazole (described in British Pat. No. 1,057,740) (19.3 g) was dissolved in 180 ml. phosphorus oxychloride (POCl3). 1-Acetyl-2-imidazolidinone (J. Chem Soc 1964, 178) (20.1 g) was added. This reaction mixture was stirred at 55° for 40 hr. The solvents were concentrated in vacuum, ice and methylene chloride were added and the mixture neutralized with 25% sodium hydroxide in water. The methylene chloride layer was dried over MgSO4 and then concentrated and the residue crystallized from isopropyl alcohol and ether to give 12.73 g. of product, mp 145°-147° C.
Reaction SMILES: [H-].[Na+].[C:3]1([SH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[H][H].Cl[CH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH2:15]1>CN(C)C=O>[CH3:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([N:16]2[CH2:17][CH2:18][CH2:19][CH:14]([CH2:13][S:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:15]2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: [H][H]
Reactant: Cc1ccc(S(=O)(=O)N2CCCC(CCl)C2)cc1
Reactant: Sc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N2CCCC(CSc3ccccc3)C2)cc1
Reaction time: 17 h
Yield: 82 %

Procedure:
To a suspension of 0.0808 mole of sodium hydride in 250 ml of dry dimethylformamide at room temperature and under nitrogen atmosphere was added 9.0 g (0.0818 mole) of thiophenol. After evolution of hydrogen had stopped, 14.18 g (0.0494 mole) of 3-chloromethyl-1-[(4-methylphenyl)sulfonyl]piperidine was added and the solution was stirred at 100°-110° C. for 17 hr. The solution was quenched in 500 ml of 1M sodium hydroxide and the aqueous mixture was extracted with several portions of methylene chloride. The methylene chloride solution was dried over magnesium sulfate and the solvent was removed in vacuo to give an oil which solidified on standing. Recrystallization from methylene chloride-diethyl ether-hexane gave 14.65 g (82%) of the product, m.p. 66.67° C.
Reaction SMILES: [C:1]1([CH2:7][C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[P+](O[P+](O)=O)=O.C=O.[C:20](=O)([O-])[O-].[K+].[K+]>>[CH2:20]1[C:6]2[C:1](=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH2:7][C:8](=[O:9])[NH:10]1
Reactant: O=C([O-])[O-]
Reactant: NC(=O)Cc1ccccc1
Agent: C=O
Agent: O=[P+](O)O[P+](=O)O
Agent: [K+]
Product: O=C1Cc2ccccc2CN1
Temperature: 155 °C
Yield: 21 %

Procedure:
A mixture of phenylacetamide (5 g, 37 mmol), pyrophosphonic acid (80 g, 449.5 mmol) and paraformaldehyde (1.22 g, 40.7 mmol) is heated at 155° C. for 1 h to give a viscous black solution. It is poured into ice water and treated with potassium carbonate to pH 7. The solution is extracted with ethyl acetate, and the organic solution is washed with saturated potassium carbonate, dried over magnesium sulfate, and evaporated to dryness to give 1.145 g (21%) of the product as a yellow solid; MS (ESI) m/z 148.0 (M+1). [Ref: Heterocycles 26(9), 2385 (1987)].
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:15]([CH2:16]/[CH:17]=[C:18](\[CH3:25])/[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:14]([O:26][CH3:27])[C:13]([CH3:28])=[C:12]2[C:8]=1[C:9](=[O:29])[O:10][CH2:11]2)(=O)=O.[C-:32]#[N:33].[K+].C(OCC)(=O)C>O1CCOCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:32]([C:7]1[C:15]([CH2:16]/[CH:17]=[C:18](\[CH3:25])/[CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:14]([O:26][CH3:27])[C:13]([CH3:28])=[C:12]2[C:8]=1[C:9](=[O:29])[O:10][CH2:11]2)#[N:33]
Reactant: [C-]#N
Reactant: COC(=O)CC/C(C)=C/Cc1c(OC)c(C)c2c(c1OS(=O)(=O)C(F)(F)F)C(=O)OC2
Agent: [Pd]
Agent: [K+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: COC(=O)CC/C(C)=C/Cc1c(C#N)c2c(c(C)c1OC)COC2=O
Reaction time: 18 h
Yield: 94.4 %

Procedure:
A nitrogen-flushed mixture of 5.8 g (12.4 mmol) of methyl (E)-6-(1,3-dihydro-4-trifluoromethylsulfonyloxy-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate, 1.5 g (23.0 mmol) of potassium cyanide, and 1.11 g (0.96 mmol) of tetrakis(triphenylphosphine) palladium in 100 ml of 1,4-dioxane was heated at reflux for 18 hours. Upon cooling, the mixture was partitioned between water and ethyl acetate. The organic phase was washed with water six times, with brine once, and then dried over magnesium sulfate. The solvent was evaporated under reduced pressure and the resulting solid was stirred with hexane for 18 hours and then filtered off. This solid was further purified by silica gel chromatography using 5:4 hexane:ethyl acetate to give 4.0 g (11.7 mmol) of methyl (E)-6-(1,3-dihydro-4-cyano-6-methoxy-7-methyl-3-oxoisobenzofuran-5-yl)-4-methyl-4-hexenoate, mp 87°-88° C.