Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[Sn](CCCC)(CCCC)CCCC)[CH3:2].Br[C:24]1[S:25][CH:26]=[CH:27][N:28]=1.FC1C=C(C2N(CC3NC4C=NC=CC=4N3CC)C=CN=2)C=CC=1.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:3][CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[C:6]1[C:24]1[S:25][CH:26]=[CH:27][N:28]=1)[CH3:2]
Reactant: Brc1nccs1
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccn1COCC
Agent: CCN1c2ccncc2NC1Cn1ccnc1-c1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOCn1ccnc1-c1nccs1
Temperature: 25 °C
Yield: 26 %

Procedure:
A solution of crude 1-ethoxymethyl-2-tributylstannanyl-1H-imidazole (previous experimental), 2-bromothiazole (1.05 mL, 11.6 mmol, 1.0 eq based on integration of 1H NMR of crude 1-ethoxymethyl-2-tributylstannanyl-1H-imidazole), and Pd (PPh3) 4 (0.67 g, 0.58 mmol) in toluene (20 mL) is stirred at 80° C. for 18 h. After cooling to room temperature, the reaction mixture is poured into saturated aqueous NaHCO3 and extracted twice with CH2Cl2. The combined extracts are dried over Na2SO4 and concentrated in vacuo. The residue is purified by flash chromatography on silica gel, eluting with 2:1 hexanes-EtOAc (+0.5% Et3N). Fractions containing product are concentrated and resubjected to flash chromatography on silica gel. Elution with 2:1 hexanes-EtOAc (+0.5% Et3N) affords (26%) of 2-(1-ethoxymethyl-1H-imidazol-2-yl)-thiazole as a bright yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.82 (d, J=3.2 Hz, 1H), 7.33 (d, J=3.2 Hz, 1H), 7.20 (d, J=1.2 Hz, 1H), 7.15 (d, J=1.2 Hz, 1H), 6.03 (s, 2H), 3.56 (q, J=7.2 Hz, 2H), 1.17 (t, J=7.2 Hz, 3H) ppm.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:17]=[CH:16][C:15]3[NH:14][C:13]4[CH2:18][CH2:19][N:20]([C:22]5[N:27]=[CH:26][C:25]([C:28](OC)=[O:29])=[CH:24][N:23]=5)[CH2:21][C:12]=4[C:11]=3[CH:10]=2)[CH2:4][CH2:3]1.C(Cl)Cl.[NH2:35][OH:36].[OH-].[Na+]>CO.O>[OH:36][NH:35][C:28]([C:25]1[CH:24]=[N:23][C:22]([N:20]2[CH2:19][CH2:18][C:13]3[NH:14][C:15]4[CH:16]=[CH:17][C:9]([CH2:8][N:5]5[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]5)=[CH:10][C:11]=4[C:12]=3[CH2:21]2)=[N:27][CH:26]=1)=[O:29]
Reactant: NO
Reactant: COC(=O)c1cnc(N2CCc3[nH]c4ccc(CN5CCN(C)CC5)cc4c3C2)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(Cc2ccc3[nH]c4c(c3c2)CN(c2ncc(C(=O)NO)cn2)CC4)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 0° C. solution of methyl 2-{8-[(4-methylpiperazin-1-yl)methyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxylate (0.1 g) in MeOH:DCM (5:2 mL) was added 50% aqueous hydroxylamine solution (2 mL) and to the mixture was added a solution of NaOH (0.08 g) in water (1 mL). The reaction mixture was stirred at room temperature for 1 hr and the progress of the reaction was monitored by TLC and upon completion of the reaction the solvent was removed under reduced pressure. The pH of the mixture was adjusted to 7.5 using 1N HCl and the obtained solid was filtered and washed with water followed by diethyl ether. After filtering, the solid was dried under vacuum to give N-hydroxy-2-{8-[(4-methylpiperazin-1-yl)methyl]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b]indol-2-yl}pyrimidine-5-carboxamide (0.075 g). 1H NMR (DMSO-D6, 200 MHz) δ: 10.91 (2H, bm), 8.74 (2H, s), 7.64-7.01 (3H, m), 4.91 (2H, s), 4.19 (2H, s), 3.50-2.88 (10H, m), 2.87 (3H, s); m/e=422.9 (M+1).
Reaction SMILES: [OH:1][CH:2]([C:6]1[C:14]2[S:13][CH:12]=[CH:11][C:10]=2[C:9]([OH:15])=[CH:8][CH:7]=1)C(O)=O.C(O)C.S(=O)(=O)(O)O.C(OC(C)C)(=O)C>O>[OH:15][C:9]1[C:10]2[CH:11]=[CH:12][S:13][C:14]=2[C:6]([CH:2]=[O:1])=[CH:7][CH:8]=1
Reactant: O=C(O)C(O)c1ccc(O)c2ccsc12
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)OC(C)C
Solvent: CCO
Product: O=Cc1ccc(O)c2ccsc12
Temperature: 57.5 °C
Reaction time: 5 h

Procedure:
Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed 2-hydroxy-2-(4-hydroxy-1-benzothiophen-7-yl)acetic acid (500 mg, 2.01 mmol, 1.00 equiv, 90%), Fe2(SO4)3 (750 mg, 1.88 mmol, 1.15 equiv), ethanol (0.75 mL), sulfuric acid(0.4N) (3.75 mL). The resulting solution was stirred for 5 h at 55-60° C. in an oil bath. After cooling to 25° C., 15 mL of isopropyl acetate and 5 ml of water were added under stirring, then the organic phase was separated and organic phase was diluted by 10 ml of water (pH was 3), then used NaOH (2N) solution were added dropwise at 20 degree C. until a pH of 12-12.5 was reached. The organic phase was removed and to the aqueous phase were added H2SO4 (2N) solution until a pH was 4-4.5. The product precipitated during the addition. The suspension was stirred overnight at 25° C., then for 1.2 h in an ice bath and then filtered. This resulted in 200 mg (53%) of 4-hydroxy-1-benzothiophene-7-carbaldehyde as a gray solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.[C:12]1([CH3:18])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[OH2:19].[C:20]1(C)C=CC=CC=1>>[C:1]1([C:11]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:17]=2[CH2:12][CH:18]([OH:19])[CH2:20]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Reactant: Cc1ccccc1
Product: OC1Cc2cccc(-c3ccccc3)c2C1

Procedure:
A solution of the 79.6 g of oil and 0.1 g of p-toluene-sulfonic acid in 350 ml of toluene was heated at reflux for 15-20 minutes during which a toluene/water azeotrope collected in a Dean-Stark trap. The mixture was cooled, placed on a silica gel chromatography column, and eluted first with toluene, then with 1:1 toluene/ethyl acetate. Appropriate fractions were combined and concentrated to give, after crystallization from toluene, 44.5 g of 4-phenyl-2-indanol, mp 71°-73° C. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:21]=[CH:20][C:9]2[NH:10][C:11]([CH2:16][C:17]([OH:19])=O)=[N:12][S:13](=[O:15])(=[O:14])[C:8]=2[CH:7]=1)(=[O:4])=[O:3].[CH2:22]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[NH:32][CH2:33][C:34]1[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=1)=[O:26])[CH3:23].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[CH2:22]([O:24][C:25]([C@@H:27]1[CH2:31][CH2:30][CH2:29][C@@H:28]1[N:32]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=1)[C:17](=[O:19])[CH2:16][C:11]1[NH:10][C:9]2[CH:20]=[CH:21][C:6]([NH:5][S:2]([CH3:1])(=[O:3])=[O:4])=[CH:7][C:8]=2[S:13](=[O:14])(=[O:15])[N:12]=1)=[O:26])[CH3:23]
Reactant: CS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1NCc1ccc(F)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CCOC(=O)[C@@H]1CCC[C@@H]1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2cc(NS(C)(=O)=O)ccc2N1
Temperature: 25 °C
Reaction time: 16 h
Yield: 28.6 %

Procedure:
To a solution of (7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in Example 1j, 0.140 g, 0.241 mmol) and cis-2-(4-fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (0.064 g, 0.241 mmol) in N,N-dimethylformamide (10 mL) was added a 2.0 M solution of N,N′-dicyclohexylcarbodiimide in N,N-dimethylformamide (121 μL, 0.241 mmol) and the reaction mixture was stirred at 25° C. for 16 h. The solvent was removed in vacuo and the residue was purified by flash column chromatography (Teledyne Isco RediSep Flash Column 4 g; 0-10% methanol in dichloromethane) to afford the desired product, cis-2-{(4-fluoro-benzyl)-[2-(7-methanesulfonylamino-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-amino}-cyclopentanecarboxylic acid ethyl ester (0.04 g, 0.0689 mmol, 28.6%). LC-MS (ESI) calcd for C25H29FN4O7S2 580.15, found 581.2 [M+H+].
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[C:7]2=[N:6][CH:5]=1.Cl.[F:17][C:18]1[CH:32]=[CH:31][C:21]2[C:22]([CH:25]3[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]3)=[N:23][O:24][C:20]=2[CH:19]=1.[CH3:33]C(NC(C)C)C>CO>[F:17][C:18]1[CH:32]=[CH:31][C:21]2[C:22]([CH:25]3[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][C:4]4[C:9](=[O:10])[N:8]5[CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[C:7]5=[N:6][C:5]=4[CH3:33])[CH2:29][CH2:30]3)=[N:23][O:24][C:20]=2[CH:19]=1
Reactant: CC(C)NC(C)C
Reactant: O=c1c(CCCl)cnc2n1CCCC2O
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: Cl
Solvent: CO
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2O
Temperature: 60 °C
Reaction time: 8 h
Yield: 21.1 %

Procedure:
A mixture of 12.5 parts of 3-(2-chloroethyl)-6,7,8,9-tetrahydro-9-hydroxy-4H-pyrido[1,2-a]pyrimidin-4-one, 10.0 parts of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole monohydrochloride, 10 parts of N-(1-methylethyl)-2-propanamine and 120 parts of methanol was stirred overnight at 60° C. The reaction mixture was evaporated and the oily residue was taken up in trichloromethane and washed with water. The organic layer was dried, filtered and evaporated. The residue was purified twice by column chromatography over silica gel first using a mixture of trichloromethane and methanol (95:5 by volume) and then a mixture of trichloromethane and methanol, saturated with ammonia (95:5 by volume) as eluents. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanone. After cooling, the precipitated product was filtered off, washed with a mixture of 2-propanol and 2,2'-oxybispropane and recrystallized from 2-propanol. The product was filtered off and dried, yielding 3.6 parts (21.1%) of 3-[ 2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-9-hydroxy-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one; mp. 179.8° C. (Compound 1)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=C[CH:14]=1)[CH:8]=[CH:7]2.BrC1C=CC=C2C=1[N:28]=C(Cl)C=C2.N1C=CC=C(N)C=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]1[CH:14]=[N:28][CH:16]=[CH:17][CH:18]=1)[CH:8]=[CH:7]2
Reactant: Brc1cccc2ccc(Nc3ccccc3)nc12
Reactant: Clc1ccc2cccc(Br)c2n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Nc1cccnc1
Agent: [Li+]
Product: Brc1cccc2ccc(Nc3cccnc3)nc12
Yield: 57 %

Procedure:
This compound (1.03 g, 57% yield) as a tan crystalline solid was prepared similarly to that described in the preparation of 165c, using 8-bromo-2-chloroquinoline (Biofine International, Vancouver, BC; 1.46 g, 6.02 mmol), pyridin-3-amine (Aldrich; 0.68 g, 7.22 mmol), and LiHMDS (1.0 M solution in THF; 15.05 mL, 15.05 mmol) as starting materials. 1H NMR (400 MHz, DMSO-D6) δ ppm 9.93 (1H, s), 9.20 (1H, d, J=2.3 Hz), 8.84 (1H, d, J=8.4 Hz), 8.24-8.13 (2H, m), 7.99 (1H, d, J=7.6 Hz), 7.82 (1H, d, J=7.6 Hz), 7.39 (1H, dd, J=8.4, 4.7 Hz), 7.26 (1H, t, J=7.7 Hz), 7.18 (1H, d, J=8.8 Hz). m/z (ESI, +ve) 300/302 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:6](=[CH2:7])[CH2:5][C:4]2([CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[O:3]1.[C:14]([OH:23])(=[O:22])[C@@H:15]([C@H:17]([C:19]([OH:21])=[O:20])[OH:18])[OH:16]>C(O)C>[OH2:3].[C:19]([C@@H:17]([C@H:15]([C:14]([OH:23])=[O:22])[OH:16])[OH:18])([OH:21])=[O:20].[CH3:1][C@H:2]1[C:6](=[CH2:7])[CH2:5][C:4]2([CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8]2)[O:3]1
Reactant: C=C1CC2(CCN(C)CC2)OC1C
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCO
Product: C=C1CC2(CCN(C)CC2)O[C@H]1C
Product: O
Temperature: 60 °C

Procedure:
To 90% aqueous ethanol (water:ethanol =1:9, v/v), 7 g of (±)-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane and 5.79 g of L-tartaric acid were added and dissolved by heating at 60° C. The resulting solution was allowed to cool and maintained at about 4° C. for 15 hours. The resulting crystals were collected by filtration and, without drying, recrystallized from 9 ml of 90% aqueous ethanol. This recrystallization procedure was repeated further twice and the crystals obtained were dried under reduced pressure to give 3.22 g of (-)-(S)-2,8-dimethyl-3-methylene-1-oxa-8-azaspiro[4.5]decane L-tartrate monohydrate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:15][C:16]([O-:18])=[O:17])[CH:5]=[C:6]([Cl:14])[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.[F-].[Cs+].CO[CH2:36][CH2:37]OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:14][C:6]1[CH:5]=[C:4]([CH2:15][C:16]([O:18][CH2:36][CH3:37])=[O:17])[CH:3]=[C:2]([C:24]2[CH:25]=[CH:26][C:21]([C:20]([F:31])([F:30])[F:19])=[CH:22][CH:23]=2)[C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11]
Reactant: O=C([O-])Cc1cc(Cl)c(OCC(F)(F)F)c(Br)c1
Reactant: COCCOC
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Product: CCOC(=O)Cc1cc(Cl)c(OCC(F)(F)F)c(-c2ccc(C(F)(F)F)cc2)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A mixture of 2-(3-bromo-5-chloro-4-(2,2,2-trifluoroethoxy)phenyl)-acetate (0.750 g, 2.0 mmol), 4-trifluoromethyl phenylboronic acid (0.567 g, 3.0 mmol), Pd (PPh3)4 (0.231 g, 0.2 mmol), cesium fluoride (0.604 g, 4.0 mmol) in DME (10 ml) was stirred overnight at 100° C., upon which the precipitates were removed by filtration. The filtrate was diluted with water and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with water followed by brine and dried over Na2SO4. The crude residue was purified by flash column chromatography to give ethyl 2-(5-chloro-6-(2,2,2-trifluoroethoxy)-4′-(trifluoromethyl)biphenyl-3-yl)acetate (0.525 g, 73.6%) as an off white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18].[CH3:25][O:26][C:27]([CH2:29]P(OC)(OC)=O)=[O:28]>>[CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:29][C:27]([O:26][CH3:25])=[O:28])=[CH:5][C:4]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:16][C:17]=1[CH3:18]
Reactant: COc1ccc(C=O)cc1OCc1nc(-c2ccccc2)oc1C
Reactant: COC(=O)CP(=O)(OC)OC
Product: COC(=O)C=Cc1ccc(OC)c(OCc2nc(-c3ccccc3)oc2C)c1

Procedure:
In substantially the same manner as in Reference Example 16, 4-methoxy-3-(5-methyl-2-phenyl-4-oxazolyl methoxy)benzaldehyde was allowed to react with trimethyl phosphonoacetate to yield methyl 4-methoxy-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)cinnamate, which was recrystallized from ethyl acetate-ether to give colorless needles, m.p.135-136° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]([CH2:16][OH:17])[CH2:14][OH:15])=[CH:4][N:3]=1.O.[C:19]1(C)[CH:24]=CC(S(O)(=O)=O)=C[CH:20]=1.COC(OC)(C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH:13]2[CH2:16][O:17][C:19]([CH3:24])([CH3:20])[O:15][CH2:14]2)=[CH:4][N:3]=1
Reactant: Nc1ncc2ncn(CCC(CO)CO)c2n1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COC(C)(C)OC
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCC(CCn2cnc3cnc(N)nc32)CO1
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a suspension of 2-amino-9-(4-hydroxy-3-hydroxymethylbut-1-yl)purine (240 mg, 1.0 mmol) in N,N-dimethylformamide (3 ml) were added p-toluenesulphonic acid monohydrate (210 mg,1.1 mmol) and 2,2-dimethoxypropane (0.62 ml, 5.0 mmol) and the solution was stirred for 30 minutes. Potassium carbonate (110 mg, 0.8 mmol) was added and the solution was stirred for a further 30 minutes. Water (10 ml) was added and the solution was extracted with chloroform (3×8 ml). The organic layers were combined, dried (magnesium sulphate) and the solvent removed. Trituration with toluene-ether afforded 2-amino-9-[2-(2,2-dimethyl-1,3-dioxan-5-yl)ethyl]purine as a white crystalline solid (262 mg, 94%) which was recrystallised from ethyl acetate-hexane (216 mg, 78%), m.p. 118+-120°; λmax (MeOH) 221 (27,200), 244 (4,920), and 308 (7,130)nm; νmax (KBr) 3450, 3140, 1635, 1615, 1580, and 1435 cm-1 ; &H [(CD3)2SO] 1.26 (3H, s, CH3), 1.33 (3H, s, CH3), 1.58 (1H, m, 3'-H), 1.74 (2H, q, J 7.1Hz, 2'-H), 3.54 (2H, dd, J 11.8Hz and 8.5Hz, 2×Hax), 3.78 (2H, dd, J 11.8Hz and 4.4Hz, 2×Heq), 4.07 (2H, t, J 7.2Hz, 1'-H), 6.46 (2H, s, D2O exchangeable, 2-NH2), 8.09 (1H, s, 8-H), and 8.56 (1H, s, 6-H); (Found: C, 56.09; H, 6.91; N, 24.88%. C13H19N5O2 requires C, 56.30; H, 6.91; N, 25.25%).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1.[NH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+].N[C@H](C(O)=O)[C@@H](C)O>C(#N)C.ClCCl>[CH2:8]([C:4]1[CH:5]=[N:6][CH:7]=[C:2]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[N:3]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Clc1cncc(Cc2ccccc2)n1
Reactant: C1CNCCN1
Agent: C[C@@H](O)[C@H](N)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: c1ccc(Cc2cncc(N3CCNCC3)n2)cc1
Temperature: 85 °C
Reaction time: 8.5 h
Yield: 57 %

Procedure:
A mixture of the product from step 1 above (0.83 g, 4.0 mmol), piperazine (1.1 g, 12.8 mmol) and K2CO3 (0.62 g, 4.49 mmol) in acetonitrile (7 mL) was stirred at 85° C. for 8.5 h. Thr reaction mixture was diluted with dichloromethane, filtered and concentrated in vacuo. The semi-solid residue was purified by silica gel chromatography (20×4 cm) using CHCl3/MeOH (9:1) as eluent. The resulting oil was redissolved in CHCl3 and filtered through a short (4 cm) plug of alumina using ether/MeOH (96:4) as eluent. Solvent removal in vacuo furnished 0.59 g (57%) of the title compound as an oil which became semi-solid upon refrigeration. HRMS m/z calcd for C15H18N4 (M)+ 254.1531, found 254.1527. Anal. (C15H18N4) C, H, N.
Reaction SMILES: [Cl:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[CH2:6]([O:8][CH:9]([O:31][CH2:32][CH3:33])[C:10]1[N:14]2[C:15]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:16]=3[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][CH2:19][C:13]2=[N:12][N:11]=1)[CH3:7]>CC(C)=O.CO>[CH2:32]([O:31][CH:9]([O:8][CH2:6][CH3:7])[C:10]1[N:14]2[C:15]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:16]=3[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:18][CH2:19][C:13]2=[N:12][N:11]=1)[CH3:33].[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2]
Reactant: [O-][Cl+3]([O-])([O-])O
Agent: CCOC(OCC)c1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2
Solvent: CO
Solvent: CC(C)=O
Product: [O-][Cl+3]([O-])([O-])[O-]

Procedure:
An amount of 0.13 g (0.0013 mole) of perchloric acid is added to a solution of 0.5 g (0.00126 mole) of 6-phenyl-8-chloro-4H-s-triazolo[4,3 -a][1,4]benzodiazepine-1-carboxaldehyde-diethylacetal in 3 ml each of acetone and methanol. The salt crystallises out after the addition of 5 ml of petroleum ether. Filtration under suction is then performed and 6-phenyl-8-chloro-4H-s-triazolo[4,3-a][1,4]benzodiazepine-1-carboxaldehyde-diethylacetal-perchlorate obtained, which decomposes at 250°-265°.
Reaction SMILES: [CH2:1]([C:3](=[CH:8][CH3:9])[CH:4]=[CH:5][CH2:6][NH2:7])[CH3:2].[C:10]([N:12]=[C:13]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)OC(C)C)#[N:11].C[O-].[Na+]>CO.O>[C:10]([NH:12][C:13]([C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=[N:7][CH2:6][CH:5]=[CH:4][C:3]([CH2:1][CH3:2])=[CH:8][CH3:9])#[N:11]
Reactant: CC=C(C=CCN)CC
Reactant: CC(C)OC(=NC#N)c1cccnc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC=C(C=CCN=C(NC#N)c1cccnc1)CC
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
To a solution of crude 4-ethyl-2,4-hexadien-1-ylamine (1.38 g) and isopropyl N-cyano-3-pyridinecarboximidate (1.74 g) in methanol (35 ml) at room temperature was added 28% sodium methoxide in methanol (2.13 g). After 10 minutes, the mixture was diluted with water and extracted three times with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel (5% methanol in dichloromethane) to give N-cyano-N'-(4-ethyl-2,4-hexadien-1-yl)-3-pyridinecarboximidamide (1.89 g) as an oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=O)=[CH:30][CH:29]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].Cl.[CH2:39]([NH2:41])[CH3:40].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:37])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([CH2:27][C:28]2[CH:29]=[CH:30][C:31]([C:32]([NH:41][CH2:39][CH3:40])=[O:34])=[CH:35][CH:36]=2)[C:19]2[N:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][N:20]=2)[N:15]=1)([CH3:8])[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCN
Reactant: CCc1cnc(N(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)Cc2ccc(C(=O)O)cc2)nc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCNC(=O)c1ccc(CN(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)c2ncc(CC)cn2)cc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.8 %

Procedure:
4-{[(2-{2-[(2-tert-Butoxy-1,1-dimethyl-2-oxoethyl)thio]-1,3-thiazol-4-yl}ethyl)(5-ethylpyrimidin-2-yl)amino]methyl}benzoic acid (261 mg) synthesized in Example 437-2 and ethylamine hydrochloride (47 mg) were dissolved in N,N-dimethylformamide (2.5 mL), triethylamine (80 μL), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDC) hydrochloride (110 mg) and 1-hydroxybenztriazole (HOBt) monohydrate (86 mg) were successively added thereto, and the mixture was stirred at room temperature for 6 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=1:1) to give the title compound (268 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][CH2:8][C:9]([OH:12])([CH3:11])[CH3:10])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[C:23](OC(=O)C)(=[O:25])[CH3:24]>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:23]([O:12][C:9]([CH3:11])([CH3:10])[CH2:8][NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:13])(=[O:25])[CH3:24]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(O)CNC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)OC(C)(C)CNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 16 h
Yield: 88.4 %

Procedure:
2-Hydroxy-2-methylpropylcarbamic acid tert-butylester (510 mg, 2.69 mmol) was dissolved in dichloromethane (7 ml). The solution was cooled to 0° C. Ethyldiisopropylamine (0.70 ml, 4.04 mmol), 4-dimethylaminopyridine (33 mg, 0.27 mmol), and acetic acid anhydride (0.33 ml, 3.50 mmol) were added successively. The reaction mixture was stirred for 16 h, while slowly warming up to room temperature. It was diluted with ethyl acetate (30 ml) and extracted with 1 N hydrochloric acid (30 ml). The aqueous phase was extracted with ethyl acetate (2×20 ml). The combined organic layers were washed with saturated sodium hydrogen carbonate solution (50 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (100 g), using ethyl acetate/heptane (1:2) as eluent, to give 550 mg of 2-(tert-butoxycarbonylamino)-1,1-dimethylethyl acetate.