Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C#C.[CH2:3]([Li])[CH2:4]CC.C(O[C@@H:12]1[C@H:17]2[C@H:18]3[C@H:28]([CH2:29][CH2:30][C@:15]2([CH3:16])[C:14](=[O:33])[CH2:13]1)[C@:26]1([CH3:27])[C:21]([CH:22]=[C:23]([O:31]C)[CH2:24][CH2:25]1)=[CH:20][CH2:19]3)(=O)C.[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[C:3]([C@:14]1([OH:33])[CH:13]=[CH:12][C@H:17]2[C@H:18]3[C@H:28]([CH2:29][CH2:30][C@:15]12[CH3:16])[C@:26]1([CH3:27])[C:21](=[CH:22][C:23](=[O:31])[CH2:24][CH2:25]1)[CH2:20][CH2:19]3)#[CH:4]
Reactant: [Li]CCCC
Reactant: COC1=CC2=CC[C@H]3[C@@H]4[C@@H](OC(C)=O)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Agent: C#C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C#C[C@]1(O)C=C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 2 h

Procedure:
Acetylene is introduced at 0° C. for 45 minutes into 200 ml of butyllithium solution (1.6 molar in hexane) in 600 ml of tetrahydrofuran. Then, 20.0 g of 15α-acetoxy-3-methoxyandrosta-3,5-dien-17-one in 400 ml of tetrahydrofuran is added thereto. After 2 hours, the mixture is gently combined with saturated ammonium chloride solution, diluted with ethyl acetate, washed with water, dried, and concentrated under vacuum. At room temperature, 14 ml of concentrated hydrochloric acid is added dropwise to the crude product in 400 ml of methanol and 50 ml of water. After 1.5 hours, the reaction mixture is stirred into ice/water. The thus-precipitated product is suctioned off, washed with water, dissolved in ethyl acetate, dried, and concentrated under vacuum. The crude product is chromatographed on silica gel with a hexane-ethyl acetate gradient, thus obtaining 9.5 g of 17α-ethynyl-17β-hydroxyandrosta-4,15-diene-3-one, mp 206.4° C. (from acetone/hexane).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[CH2:13][CH2:12][C:11](=[O:14])[CH:10]=[CH:9]1.C(O[CH2:27][N:28]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[CH2:29][Si](C)(C)C)CCC.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O.ClCCl>[CH2:34]([N:28]1[CH2:29][CH:10]2[CH:9]([C:8]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[CH2:13][CH2:12][C:11]2=[O:14])[CH2:27]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C1C=CC(c2ccccc2F)(c2ccccc2F)CC1
Reactant: CCCCOCN(Cc1ccccc1)C[Si](C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC(c2ccccc2F)(c2ccccc2F)C2CN(Cc3ccccc3)CC12
Reaction time: 16 h

Procedure:
Trifluoroacetic acid (3 drops) is added to a solution of 4,4-bis(2-fluorophenyl)cyclohexenone (4.3 g) and N-butoxymethyl-N-(trimethylsilylmethyl)benzylamine (5.8 cc) in dry dichloromethane (30 cc). The reaction mixture is brought to reflux and then stirred for 16 hours after the temperature has been allowed to return to 25° C. N-Butoxymethyl-N-(trimethylsilylmethyl)benzylamine (2.5 cc) and trifluoroacetic acid (3 drops) are added and the mixture is stirred for 3 hours under reflux. The reaction mixture is treated with potassium carbonate (3 g) and stirred for 15 minutes. After filtration and concentration to dryness under reduced pressure (2.7 kPa), the residue is chromatographed on a column of silica gel (particle size 0.04-0.063 mm, diameter 4 cm, height 32 cm), eluting under a nitrogen pressure of 0.5 bar with a mixture of cyclohexane and ethyl acetate (85:15) and collecting 20-cc fractions. Fractions 13 to 22 are combined and concentrated to dryness under reduced pressure (2.7 kPa) to give (3aRS,7aRS)-2-benzyl-7,7-bis(2-fluorophenyl)perhydro-4-isoindolone (2.28 g). M.p. 138° C.
Reaction SMILES: C([N:11]([CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)(OCC1C=CC=CC=1)=O.C(N(CC)CC)C.[C:42]([OH:50])(=[O:49])[CH:43]([CH2:45][C:46]([OH:48])=[O:47])[OH:44].[H][H]>O1CCCC1.CCOCC>[CH:29]1([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([O:49][C:42](=[O:50])[CH:43]([CH2:45][C:46]([OH:48])=[O:47])[OH:44])=[O:17])=[CH:14][CH:13]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: [H][H]
Reactant: O=C(Cl)c1ccc(N(CCCCCCCCC2CCCCC2)C(=O)OCc2ccccc2)cc1
Reactant: O=C(O)CC(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)CC(O)C(=O)OC(=O)c1ccc(NCCCCCCCCC2CCCCC2)cc1

Procedure:
To a warm solution of N-carbobenzyloxy-4-(8-cyclohexyloctylamino)benzoyl chloride and 1.3 g. triethylamine in 100 ml. ether is treated with 2 g. malic acid. An immediate precipitate forms, but the mixture is refluxed for one hour and filtered while hot. The solid is washed several times with hot ether, then the ether is evaporated to yield a white solid. The product is dissolved in tetrahydrofuran (100 ml.) and hydrogenated ove 600 mg. 10% Pd(C) at 50 psi until hydrogen uptake stops. The catalyst is filtered, the solution is evaporated, and the residue is crystallized from acetic acid to yield the title compound as a tan, crystalline mass.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.C(N(CC)CC)C.[CH3:14][C:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[S:17][C:16]=1[CH:24]=O.[CH2:26]([O:28][C:29](=[O:34])[CH2:30][C:31]([CH3:33])=O)[CH3:27]>C(O)C>[CH3:33][C:31]1[NH:1][C:2]2[N:3]([N:4]=[N:5][N:6]=2)[CH:24]([C:16]2[S:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:15]=2[CH3:14])[C:30]=1[C:29]([O:28][CH2:26][CH3:27])=[O:34]
Reactant: Cc1c(C=O)sc2ccccc12
Reactant: Nc1nnn[nH]1
Reactant: CCOC(=O)CC(C)=O
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)C1=C(C)Nc2nnnn2C1c1sc2ccccc2c1C
Temperature: 25 °C
Yield: 40 %

Procedure:
The 5-aminotetrazole (850 mg; 10.0 mmole) was dissolved in hot ethanol (25 ml) with triethylamine (1.8 mmole; 0.25 ml). When all solids were dissolved (about ten minutes of heating at 82° C.), 3-methyl-2-benzothiophenecarboxaldehyde (1.76 g; 10.0 mmole) was added followed by ethylacetoacetate (1.28 ml; 10.0 mmole). The clear solution was maintained at reflux for 15 h. At which time a white precipitate had filled the flask and the mixture was cooled to room temperature where it was filtered and the material washed with ethanol then ethyl ether to provide the desired product (1.42 g; 41%) as a white powder. 1H NMR (400 MHz; CDCl3) δ 11.2 (bs, 1H); 7.73 (d, 1H, J=7.8 Hz); 7.69 (d, 1H, J=7.8 Hz); 7.39 (ddd, 1H, J=7.0, 7.0, 0.78 Hz); 7.32 (ddd, 1H, J=8.2, 7.0, 1.5 Hz); 4.17-4.05 (m, 2H); 2.71 (s, 3H); 2.69 (s, 3H); 1.14 (at, J=7.0 Hz). LC MS shows MH+ at 356 and 2 MH+ at 711.
Reaction SMILES: [Se](=O)=O.[OH:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][N:13]=1)[C:9]#[N:10].ClCCl>O1CCOCC1>[CH:5]([C:6]1[CH:7]=[C:8]([CH:11]=[CH:12][N:13]=1)[C:9]#[N:10])=[O:4]
Reactant: N#Cc1ccnc(CO)c1
Agent: O=[Se]=O
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1ccnc(C=O)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.8 %

Procedure:
Add selenium dioxide (2.69 g, 24.2 mmol) to a solution of 2-hydroxymethyl-isonicotinonitrile (5.86 g, 43.7 mmol) in dioxane (120 mL). Heat reaction to 80° C. After 4 hours, cool to room temperature. Add dichloromethane (500 mL) and celite and stir. After 15 minutes, filter through a plug of silica eluting with dichloromethane. Concentrate filtrate under reduced pressure to yield the title compound as an orange solid (5.30 g, 92%): 1H NMR (DMSO-d6) δ 8.19 (dd, 1H), 8.34 (t, 1H), 9.07 (dd, 1H), 10.01 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:51][N:17]3[C:18](=[O:50])[C@@H:19]([NH:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH:25]=[CH:26][C@@H:27]4[CH2:32][C@@:28]4([C:33](=[O:41])[NH:34][S:35]([CH:38]4[CH2:40][CH2:39]4)(=[O:37])=[O:36])[NH:29][C:30](=[O:31])[C@@H:16]3[CH2:15]1)=[O:12])[CH2:6]2.[H][H].O.S([O-])(O)(=O)=O.[K+]>C(OCC)(=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:11]([O:13][C@H:14]1[CH2:51][N:17]3[C:18](=[O:50])[C@@H:19]([NH:42][C:43]([O:45][C:46]([CH3:47])([CH3:48])[CH3:49])=[O:44])[CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][C@@H:27]4[CH2:32][C@@:28]4([C:33](=[O:41])[NH:34][S:35]([CH:38]4[CH2:40][CH2:39]4)(=[O:36])=[O:37])[NH:29][C:30](=[O:31])[C@@H:16]3[CH2:15]1)=[O:12])[CH2:6]2
Reactant: CC(C)(C)OC(=O)N[C@H]1CCOCCC=C[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Reactant: [H][H]
Agent: CC(C)(C)OC(=O)N[C@H]1CCOCC/C=C\[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCOCCCC[C@@H]2C[C@@]2(C(=O)NS(=O)(=O)C2CC2)NC(=O)[C@@H]2C[C@@H](OC(=O)N3Cc4cccc(F)c4C3)CN2C1=O
Reaction time: 16 h
Yield: 38.1 %

Procedure:
(2R,6S,13aS,14aR,16aS,Z)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxo-2,3,5,6,7,8,10,11,13a,14,14a,15,16,16a-tetradecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate (0.037 g, 0.050 mmol) and Rh/Al (5%) (0.021 g, 0.010 mmol) in Ethyl acetate (5 mL) was charged with 1 atmosphere of hydrogen and stirred for 16 hrs. Water (3 mL) and saturated potassium hydrogen sulfate (3 mL) was added and stirred for 10 minutes. The organic phase was separated and aqueous phase extracted with ethyl acetate (10 mL), washed with brine and dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (Hexane:Ethyl acetate=1:2) to give (2R,6S,13aR, 14aR,16aS)-6-(tert-butoxycarbonylamino)-14a-(cyclopropylsulfonylcarbamoyl)-5,16-dioxohexadecahydro-1H-cyclopropa(j)pyrrolo[1,2-f][1,6,9]oxadiazacyclopentadecin-2-yl 4-fluoroisoindoline-2-carboxylate as white solid (0.014 g, 38%). MS: Calcd.: 735. Found: [M+H]+ 736. 1H NMR (400 MHz, d6-DMSO) δ 1.08 (s, 1H), 8.79 (b, 1H), 7.34 (m, 1H), 7.10-7.20 (m, 3H), 5.28 (m, 1H), 4.66 (s, 4H), 4.41 (m, 1H), 4.20 (m, 1H), 3.94 (m, 1H), 3.74 (m, 1H), 3.42-3.47 (m, 2H), 2.97 (m, 1H), 0.79-2.38 (m, 28H).
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[C:9](Cl)[C:8]([CH2:12][CH3:13])=[C:7]([CH3:14])[N:6]=1)[CH2:2][CH2:3][CH3:4].[NH3:15]>>[NH2:15][C:9]1[C:8]([CH2:12][CH3:13])=[C:7]([CH3:14])[N:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[N:10]=1
Reactant: N
Reactant: CCCCc1nc(C)c(CC)c(Cl)n1
Product: CCCCc1nc(C)c(CC)c(N)n1

Procedure:
The title compound prepared from 2-butyl-4-chloro-5-ethyl-6-methylpyrimidine (from Example 18) upon treatment with alcoholic ammonia as described by Marshall and Walker (J. Chem. Soc., 1951, 1004).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]2[N:8]=[C:9]3[N:13]([C:14]=2[NH:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:12]=[CH:11][S:10]3)=[N:4][CH:3]=1.[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)#[CH:21].CCN(CC)CC>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:16]([NH:15][C:14]1[N:13]2[C:9]([S:10][CH:11]=[CH:12]2)=[N:8][C:7]=1[C:5]1[S:6][C:2]([C:21]#[C:20][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)=[CH:3][N:4]=1)([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)Nc1c(-c2ncc(Br)s2)nc2sccn12
Reactant: C#Cc1ccccn1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)Nc1c(-c2ncc(C#Cc3ccccn3)s2)nc2sccn12
Yield: 16.7 %

Procedure:
A mixture of 235 mg (0.66 mmol) 6-(5-bromothiazole-2-yl)-N-tert-butylimidazo[2,1-b]thiazole-5-amine, 22 mg (0.033 mmol) bis(triphenylphosphine)-palladium-(II)-chloride, 12 mg (0.066 mmol) copper-(I)-iodide, 80 μl (0.79 mmol) 2-ethynylpyridine and 731 μl (5.28 mmol) NEt3 in DMF (2 ml) was heated in the microwave (Biotage Initiator) for 10 min to 120° C. The reaction solution was diluted with water and extracted several times with AE. The collected organic phases were washed with brine and dried over MgSO4. After filtering and removal of the solvent in a vacuum, a CC (1.TBME, 2.MeOH) was performed with the residue, whereby 43 mg (0.11 mmol, 17%) N-tert-butyl-6-(5-(pyridine-2-ylethynyl)thiazole-2-yl)imidazo[2,1-b]thiazole-5-amine was obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH:6](=O)[CH3:7].[CH:9]([C:12]1[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][CH:13]=1)([CH3:11])[CH3:10].C(O)=O.P(=O)(O)(O)O>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([NH:18][C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([CH:9]([CH3:11])[CH3:10])=[CH:13][CH:14]=1)[CH3:7]
Reactant: CC=O
Reactant: c1ccsc1
Reactant: CC(C)c1ccc(C(N)=O)cc1
Agent: O=P(O)(O)O
Solvent: O=CO
Product: CC(C)c1ccc(C(=O)NC(C)c2cccs2)cc1

Procedure:
Thiophene (100 mmol), acetaldehyde (10 mmol) and 4-isopropylbenzamide (10 mmol) were stirred in the following formic acid/phosphoric acid mixture at 20° C. for two hours to obtain N-[1-(2-thienyl)ethyl]-4-isopropylbenzamide:
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:8][OH:9].C(#N)C.[C:13]([C:19]([O:21][CH3:22])=[O:20])#[C:14][C:15]([O:17][CH3:18])=[O:16]>>[NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:8][O:9]/[C:14](=[CH:13]/[C:19]([O:21][CH3:22])=[O:20])/[C:15]([O:17][CH3:18])=[O:16].[NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:8][O:9]/[C:14](=[CH:13]\[C:19]([O:21][CH3:22])=[O:20])/[C:15]([O:17][CH3:18])=[O:16]
Reactant: ON=C1CCCCCN1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CC#N
Product: COC(=O)/C=C(/ON=C1CCCCCN1)C(=O)OC
Product: COC(=O)/C=C(\ON=C1CCCCCN1)C(=O)OC

Procedure:
To a suspension of azepan-2-one oxime in acetonitrile 1.1 eq. of dimethyl acetylenedicarboxylate were added dropwise under stirring. The mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure to afford a mixture 8/1 of dimethyl (2E)-2-[(azepan-2-ylideneamino)oxy]but-2-enedioate and dimethyl (2Z)-2-[(azepan-2-ylideneamino)oxy]but-2-enedioate as a yellow oil. To better characterize the title compounds a small amount of the crude was purified by preparative RP-HPLC, using water (0.1% TFA) and acetonitrile (0.1% TFA) as eluents (column C1-8). The pooled product fractions were lyophilized.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][C@@H:15]([C:26]([OH:28])=[O:27])[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:13])=[O:12].C(N(C(C)C)C(C)C)C.O[CH2:39][C@H:40]1[CH2:45][CH2:44][CH2:43][N:42]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:41]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[C:49]([O:48][C:46]([N:42]1[CH2:43][CH2:44][CH2:45][C@H:40]([CH2:39][O:27][C:26](=[O:28])[C@@H:15]([CH2:16][C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[NH:19][CH:18]=2)[NH:14][S:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)(=[O:13])=[O:12])[CH2:41]1)=[O:47])([CH3:52])([CH3:50])[CH3:51]
Reactant: O=C(O)[C@@H](Cc1c[nH]c2ccccc12)NS(=O)(=O)c1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H](COC(=O)[C@@H](Cc2c[nH]c3ccccc23)NS(=O)(=O)c2ccc3ccccc3c2)C1
Reaction time: 15 h
Yield: 66.7 %

Procedure:
A solution of 1.0 g of N-2-naphthylsulfonyl-(D)-tryptophan in 20 ml of DMF is treated with 0.5 ml of ethyldiisopropylamine. After the addition of 0.6 g of t-butyl (S)-3-hydroxymethyl-1-piperidinecarboxylate (Example 3c) and 1.1 g of benzotriazol-1-yloxy-tris(dimethylamino)phosphoniumhexafluorophosphate the reaction mixture is stirred for 15 hours. The solvent is evaporated and the residue is taken up in water and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried and evaporated. Chromatography over silica gel with ethyl acetate gives 1.0 g of N-(2-naphthylsulfonyl)-D-tryptophan (S)-1-t-butyoxycarbonyl-3-piperidinylmethyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[C:5]([C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:14])=O.Cl.[C:19]([NH:23][NH2:24])([CH3:22])([CH3:21])[CH3:20].C(N(CC)CC)C>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)/[C:5](=[N:24]\[NH:23][C:19]([CH3:22])([CH3:21])[CH3:20])/[C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:14].[Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)/[C:5](/[C:7]1[C:12]([OH:13])=[CH:11][CH:10]=[CH:9][N+:8]=1[O-:14])=[N:24]/[NH:23][C:19]([CH3:22])([CH3:21])[CH3:20]
Reactant: O=C(c1cccc(Br)c1)c1c(O)ccc[n+]1[O-]
Reactant: CC(C)(C)NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)N/N=C(/c1cccc(Br)c1)c1c(O)ccc[n+]1[O-]
Product: CC(C)(C)N/N=C(\c1cccc(Br)c1)c1c(O)ccc[n+]1[O-]

Procedure:
A mixture of 2-(3-bromobenzoyl)-3-hydroxypyridine 1-oxide (2.13 g), t-butylhydrazine hydrochloride (3.03 g), triethylamine (3.5 mL) and ethanol (50 mL) was refluxed for 2 hours. The reaction mixture was then poured into a saturated aqueous saline solution, and subjected to extraction with ethyl acetate. The extract was washed with a saturated aqueous saline solution, and dried (sodium sulfate), followed by evaporating the solvent under reduced pressure. The residue was purified by means of a silica gel column (ethyl acetate--hexane) to afford (E)-2-(3-bromo-t-butylhydrazonobenzyl)-3-hydroxypyridine 1-oxide (0.68 g) and (Z)-2-(3-bromo-α-t-butylhydrazonobenzyl)-3-hydroxypyridine 1-oxide (0.79 g) (compounds 29 and 28).
Reaction SMILES: O=[C:2]1[C:6]2[C:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[N:8][C:9](=[O:10])[C:5]=2[C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:3]1.[C:23](=[O:26])([O-])[O-].[K+].[K+].[C:29]1(C)C=CC(S(OC)(=O)=O)=CC=1.[N+](C1C=CC=CC=1)([O-])=O>>[O:10]=[C:9]1[C:5]2=[C:4]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:3]([CH3:2])[C:23](=[O:26])[C:6]2=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]1[CH3:29]
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: O=C([O-])[O-]
Reactant: O=c1nc(-c2ccccc2)c2c(=O)nc(-c3ccccc3)c1=2
Agent: [K+]
Solvent: O=[N+]([O-])c1ccccc1
Product: CN1C(=O)C2=C(c3ccccc3)N(C)C(=O)C2=C1c1ccccc1
Temperature: 20 °C

Procedure:
14.5 Parts of 1,4-diketo-3,6-diphenylpyrrolo-[3,4-c]-pyrrole, 15 parts of anhydrous potassium carbonate, 40 parts of methyl p-toluenesulfonate and 170 parts of dry nitrobenzene are heated at 200°-205° C. for one hour, with stirring. After cooling to 20° C., the 1,4-diketo-2,5-dimethyl-3,6-diphenylpyrrolo-[3,4-c]-pyrrole obtained is filtered off, washed with toluene, then methanol and thereafter with hot water and dried. 10.85 parts of orange crystals of the compound of the formula (IX) are obtained (melting point 236°-238° C.). ##STR13##
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11](SC)=[C:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:13]#[N:14])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH:27]1([NH2:31])[CH2:30][CH2:29][CH2:28]1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH:10][C:11]([NH:31][CH:27]3[CH2:30][CH2:29][CH2:28]3)=[C:12]([S:15]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[C:13]#[N:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: NC1CCC1
Reactant: CSC(Nc1ccc2c(c1)OCO2)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Product: N#CC(=C(Nc1ccc2c(c1)OCO2)NC1CCC1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 29.1 %

Procedure:
3-(Benzo[1,3]dioxol-5-ylamino-2-(4-chloro-phenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.29 g, 0.7 mmol) was stirred in cyclobutylamine (0.6 ml 7.0 mmol) for 17 h at 100° C. under nitrogen in a sealed flask. The reaction mixture was concentrated and the residue was crystallised from ethyl acetate to give 88 mg (29%) of the title compound. Mp 189.5° C. 1H NMR (200 MHz, CDCl3): δ=1.6 (m, 2H), 1.75 (m, 2H), 2.05 (m, 2H), 3.80 (m, 1H), 6.02 (s, 2H), 6.5 (m, 2H), 6.79 (d, 2H), 7.50 (dt, 2H), 7.83 (dt, 2H). Analysis: calc. for C20H18ClN3O4S: C, 55.62%; H, 4.20%; N, 9.73%; Found: C, 55.59%; H, 4.21%; N, 9.59%.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]([CH3:14])[S:10](Cl)(=[O:12])=[O:11].[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:35][C:36](=[O:38])[CH3:37])[C:24]2[NH:25][CH:26]=[C:27]([CH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][CH3:32])[N:28]=2)=[CH:18][CH:17]=1>C(Cl)Cl.O>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH:23]([NH:35][C:36](=[O:38])[CH3:37])[C:24]2[N:25]([S:10]([N:9]([CH3:14])[CH3:8])(=[O:12])=[O:11])[CH:26]=[C:27]([CH2:29][C:30]([CH3:34])([CH3:33])[CH2:31][CH3:32])[N:28]=2)=[CH:18][CH:17]=1
Reactant: CCC(C)(C)Cc1c[nH]c(C(Cc2ccc(Br)cc2)NC(C)=O)n1
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(Cc2ccc(Br)cc2)NC(C)=O)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triethylamine (0.48 mL, 34.5 mmol) followed by dimethylsulfamoyl chloride (0.24 mL, 46 mmol) were added to an ambient temperature solution of N-{2-(4-bromophenyl)-1-[4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]ethyl}acetamide (450 mg, 11.5 mmol) in methylene chloride (10 mL). After stirring at ambient temperature overnight, the reaction mixture was diluted with water and extracted with ethyl acetate and methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-50% acetone/methylene chloride afforded N-{2-(4-bromophenyl)-1-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylbutyl)-1H-imidazol-2-yl]ethyl}acetamide.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7](N)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH2:12]=O.[BH3-][C:15]#[N:16].[Na+]>CO.O>[CH3:12][N:16]([CH3:15])[C:7]1[CH:6]=[C:5]2[C:10](=[CH:9][CH:8]=1)[N:1]=[CH:2][CH:3]=[CH:4]2
Reactant: [BH3-]C#N
Reactant: C=O
Reactant: Nc1ccc2ncccc2c1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(C)c1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 50 %

Procedure:
To a solution of quinolin-6-amine (666 mg, 4.62 mmol) in CH3OH (15 ml) was added 40% aqueous formaldehyde (1 ml), NaBH3CN (400 mg, 6.37 mmol) with stirring for 3 days at room temperature and diluted with water (150 ml), extracted with ethyl acetate (3×30 ml), dried over magnesium sulfate and concentrated in vacuo to give a residue, which was purified by a silica gel column chromatography with 5%-20% ethyl acetate in petroleum ether to give N,N-dimethylquinolin-6-amine as a solid (400 mg, 50%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](Cl)=[O:7].Cl.[O:10]1CCC[CH2:11]1>[Cl-].[Na+].O>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[O:7])[CH2:11][OH:10]
Reactant: O=C(Cl)CCCCBr
Reactant: C1CCOC1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: O=C(CO)CCCCBr
Temperature: 10 °C

Procedure:
To 191.4 g of tris-trimethylsilyloxyethylene (Example 267) containing 15 drops of stannic tetrachloride under argon with stirring at 10° C. is added 87 g of 5-bromopentanoyl chloride (Example 274) dropwise. After one-half of the acid chloride is added, the mixture is stirred until an exotherm ensues. The remaining acid chloride is added dropwise maintaining the reaction exotherm at 65° C. The mixture is then stirred for 2.5 hours. The mixture is slowly poured into a stirred mixture of 100 ml of 0.6 N hydrochloric acid and 200 ml of tetrahydrofuran. The mixture is stirred for 30 minutes and poured into brine. The mixture is extracted with ether. The ether solution is washed with saturated sodium bicarbonate and dried over magnesium sulfate. The solvent is removed. The residue is mixed with petroleum ether and cooled in dry-ice-acetone to induce crystallization. The petroleum ether is decanted and the solid is dried at reduced pressure to give 54.72 g of the title compound.