Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([C:22]2[O:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][N:26]=2)=[N:20][C:19](Br)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:34][S:35]([CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)(=[O:37])=[O:36]>CN(C=O)C>[O:5]([C:6]([N:8]([C:16]1[C:21]([C:22]2[O:23][C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[N:25][N:26]=2)=[N:20][C:19]([N:43]2[CH2:42][CH2:41][N:40]([CH2:39][CH2:38][S:35]([CH3:34])(=[O:36])=[O:37])[CH2:45][CH2:44]2)=[CH:18][N:17]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:7])[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)CCN1CCNCC1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(Br)nc1-c1nnc(-c2ccccc2)o1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1ncc(N2CCN(CCS(C)(=O)=O)CC2)nc1-c1nnc(-c2ccccc2)o1
Temperature: 100 °C
Yield: 100 %

Procedure:
tert-butyl N-tert butoxycarbonyl-5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-ylcarbamate (75 mg, 0.13 mmol) was dissolved in DMF (1 mL) and 1-(2-(methylsulfonyl)ethyl)piperazine (77 mg, 0.40 mmol) was added. The reaction mixture was heated at 100° C. in a sealed tube overnight. The reaction mixture was cooled to room temperature and partitioned between CH2Cl2 and water and the layers separated using a phase separation cartridge. The organic layer was concentrated in vacuo to give the product (84.01 mg, 0.13 mmol)
Reaction SMILES: C[N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28](=[NH:31])[NH:29][OH:30])=[C:24](F)[CH:23]=3)[C:13]3[CH2:14][C:15]([CH3:18])([CH3:17])[O:16][C:12]=3[CH:11]=2)=[O:9])=[N:3]1.C[N:34]1N=C(NC(C2C=C(OC3C=CC(C#N)=CC=3)C3CC(C)(C)OC=3C=2)=O)C=N1>>[CH3:6][N:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[CH:20]=[C:19]([O:21][C:22]3[CH:23]=[CH:24][C:25]([C:28](=[NH:31])[NH:29][OH:30])=[CH:26][CH:27]=3)[C:13]3[CH2:14][C:15]([CH3:17])([CH3:18])[O:16][C:12]=3[CH:11]=2)=[O:9])[CH:5]=[N:34]1
Reactant: Cn1ccc(NC(=O)c2cc(Oc3ccc(C(=N)NO)c(F)c3)c3c(c2)OC(C)(C)C3)n1
Reactant: Cn1ncc(NC(=O)c2cc(Oc3ccc(C#N)cc3)c3c(c2)OC(C)(C)C3)n1
Product: Cn1ncc(NC(=O)c2cc(Oc3ccc(C(=N)NO)cc3)c3c(c2)OC(C)(C)C3)n1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 185a, from 4-(4-cyano-phenoxy)-2,2-dimethyl-2,3-dihydro-benzofuran-6-carboxylic acid (2-methyl-2H-[1,2,3]triazol-4-yl)-amide (188a) (130 mg, 0.334 mmol) and used without further purification for the next step.
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[F:42])=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=2)=[CH:18][C:17]=1[F:43])(=[O:15])=[O:14])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)(C)(C)C.[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48]>ClCCl>[F:45][C:46]([F:51])([F:50])[C:47]([OH:49])=[O:48].[Cl:22][C:20]1[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=3[F:42])=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][N:33]([CH3:35])[CH:34]=2)=[CH:18][C:17]([F:43])=[C:16]([S:13]([NH:7][C:8]2[N:9]=[CH:10][S:11][CH:12]=2)(=[O:14])=[O:15])[CH:21]=1
Reactant: Cn1cc(-c2cc(-c3ccccc3F)ncc2Oc2cc(F)c(S(=O)(=O)N(C(=O)OC(C)(C)C)c3cscn3)cc2Cl)cn1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1cc(-c2cc(-c3ccccc3F)ncc2Oc2cc(F)c(S(=O)(=O)Nc3cscn3)cc2Cl)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 35 %

Procedure:
20 mg (0.03 mmol) of tert-butyl((5-chloro-2-fluoro-4-((6-(2-fluorophenyl)-4-(1-methyl-1H-pyrazol-4-yl)pyridin-3-yl)oxy)phenyl)sulfonyl)(thiazol-4-yl)carbamate was dissolved in 3 mL of dichloromethane, and 30 uL of trifluoroacetic acid was added thereto, followed by stirring at room temperature for 5 hours. After completion of the reaction as checked by TLC, the solvent was removed to obtain 7.0 mg (35% yield) of the title compound.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][OH:6])[CH3:2].[H-].[Na+].Cl[C:10]1[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1.O>O1CCCC1>[CH2:1]([O:3][CH2:4][CH2:5][O:6][C:10]1[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1)[CH3:2]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CCOCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCCOc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-ethoxyethanol (1.08 g, 12 mmol) and sodium hydride (410 mg, 12 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl) pyridine (790 mg, 4 mmol) in dry tetrahydrofuran. The mixture was stirred at room temperature for 2 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[C:5]([CH2:10]Br)[C:6]([NH2:9])=[N:7][CH:8]=1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CC#N.CCOCC>[Br:2][C:3]1[CH:4]=[C:5]([CH2:10][N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:6]([NH2:9])=[N:7][CH:8]=1
Reactant: Nc1ncc(Br)cc1CBr
Reactant: C1CCNCC1
Agent: Br
Solvent: CC#N
Solvent: CCOCC
Product: Nc1ncc(Br)cc1CN1CCCCC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 53.5 %

Procedure:
An ice-cold suspension of 5-bromo-3-bromomethyl-pyridin-2-ylamine hydrobromide (10.0 g, 28.8 mmol) in MeCN (100 mL) was treated with piperidine (6.4 mL, 64.8 mmol). After stirring at room temperature for 3.5 h, the mixture was diluted with Et2O (500 mL). The solution was filtered and then concentrated to give the title compound (4.16 g, 53%) as a pale, yellow solid: MS (ESI) m/e 270 (M+H)+.
Reaction SMILES: Cl[Si:2]1(Cl)[CH2:5][CH2:4][CH2:3]1.[NH:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1>>[N:7]1([Si:2]2([N:7]3[CH2:11][CH2:10][CH2:9][CH2:8]3)[CH2:5][CH2:4][CH2:3]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Cl[Si]1(Cl)CCC1
Reactant: C1CCNC1
Product: C1CCN([Si]2(N3CCCC3)CCC2)C1
Reaction time: 48 h
Yield: 34 %

Procedure:
Bis(pyrrolidino)silacyclobutane was synthesized by reacting 1,1-dichlorosilacyclobutane with an excess amount of pyrrolidine (Equation 3). To do so, 23.7 ml (0.200 mol) 1,1-dichlorosilacyclobutane was added to 100.0 ml (1.20 mol) pyrrolidine in 1 L hexanes at −10° C. After bodying for two day at the room temperature, the reaction slurry was filtered to remove pyrrolidine hydrochloride salt. The filtrant was vacuum dried to give a liquid crude product which was then vacuum distilled. 15.4 g Product was isolated at 99.7% purity in 34% yield at 51° C. under 1 torr pressure. The structure of the product analyzed with 1H, 13C and 29Si NMR, FT-IR and GC-MS was in consistence with bis(pyrrolidino)silacyclobutane.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=[C:11](Cl)[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]([NH:27][CH2:28][CH2:29][NH2:30])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21]>>[C:1]([O:5][C:6]([NH:8][C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=[C:11]([NH:30][CH2:29][CH2:28][NH:27][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[N:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(Cl)nc1NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCN
Product: COC(=O)c1ccc(NCCNC(=O)OC(C)(C)C)nc1NC(=O)OC(C)(C)C

Procedure:
The compound is prepared from 650 mg (2.3 mmol) of methyl 2-[(tert-butoxycarbonyl)amino]-6-chloropyridine-3-carboxylate (Example 118A) and 363 mg (2.3 mmol) of N-Boc-ethylenediamine as described in Example 114A. 500 mg (50% of theory) of the product are obtained as a solid.
Reaction SMILES: [NH2:1][S:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH2:11][C:12]([NH:14][NH2:15])=O)(=[O:4])=[O:3].[OH-].[K+].[C:18](=[S:20])=[S:19]>C(O)C.O>[SH:20][C:18]1[S:19][C:12]([CH2:11][C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:2]([NH2:1])(=[O:4])=[O:3])=[N:14][N:15]=1
Reactant: S=C=S
Reactant: NNC(=O)Cc1ccccc1S(N)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: NS(=O)(=O)c1ccccc1Cc1nnc(S)s1

Procedure:
To a suspension of 22 g of the hydrazide prepared in Example 1 in 175 ml of absolute ethanol was added a solution of 5.4 g of potassium hydroxide in 40 ml of water. After stirring several minutes, 9.2 g of carbon disulfide was added dropwise. The suspension was refluxed 4 hours then concentrated in vacuo. After water (about 200 ml) was added to the residue and the suspension stirred several minutes, the suspension was filtered, and the filtrate was acidified with concentrated hydrochloric acid (red to litmus paper). The mixture was filtered and the solid isolated was suction-dried to give 5 g of the crude subject compound; m.p. 173°-197° C.
Reaction SMILES: ON=[CH:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH2:11][CH2:10]2)=[O:5].S(=O)(=O)(O)[OH:17]>>[NH:6]1[C:7]2[C:15](=[CH:14][C:13]3[CH2:12][CH2:11][CH2:10][C:9]=3[CH:8]=2)[C:3](=[O:17])[C:4]1=[O:5]
Reactant: O=S(=O)(O)O
Reactant: O=C(C=NO)Nc1ccc2c(c1)CCC2
Product: O=C1Nc2cc3c(cc2C1=O)CCC3
Temperature: 80 °C
Yield: 77 %

Procedure:
Add 2-Hydroxyimino-N-indan-5-yl-acetamide (4.66 g, 22.84 mmol) in small portions at 65° C. to concentrated sulfuric acid (22 mL) and heat the mixture at 80° C. for 15 minutes. Cool to room temperature, pour into ice water (200 mL) and filter the precipitate. Dissolve the solid in warmed ethanol and leave to cool overnight. Filter the precipitate and wash with ethyl ether. Dry the solid to yield the title compound (3.3 g, 77%). 1H NMR (DMSO-d6, 300 MHz) δ 1.98 (quintuplet, J=7.7 Hz, 2H), 2.76 (t, J=7.7 Hz, 2H), 2.85 (t, J=7.7 Hz, 2H), 6.74 (s, 1H), 7.28 (s, 1H). MS (ES−): 186 (M−H).
Reaction SMILES: [CH3:1][NH:2][S:3](Cl)(=[O:5])=[O:4].[CH3:7][C:8]1([CH3:24])[C:12]2[CH:13]=[C:14]([OH:17])[CH:15]=[CH:16][C:11]=2[O:10][CH:9]1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.C(N(CC)CC)C>O1CCCC1>[CH3:1][NH:2][S:3]([O:17][C:14]1[CH:15]=[CH:16][C:11]2[O:10][CH:9]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:8]([CH3:24])([CH3:7])[C:12]=2[CH:13]=1)(=[O:5])=[O:4]
Reactant: CC1(C)c2cc(O)ccc2OC1N1CCOCC1
Reactant: CNS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CNS(=O)(=O)Oc1ccc2c(c1)C(C)(C)C(N1CCOCC1)O2

Procedure:
At 0° to 5°C and while stirring, 36 parts (by weight) of methylaminosulfonyl chloride was added to a solution of 48.8 parts of 2,3-dihydro-3,3-dimethyl-2-morpholino-5-hydroxybenzofuran and 27.3 parts of triethylamine in 130 parts of tetrahydrofuran. The reaction mixture was stirred for 1 hour at room temperature and then filtered. The filtrate was concentrated in vacuo and the residue dissolved in 250 parts of methanol. After addition of 100 parts of water and treatment of the solution with activated carbon, crystallization was initiated by cooling. The mush of crystals was suction filtered, washed with 50wt% aqueous methanol and dried in vacuo. The crude product melted at 125° to 128°C. Pure 2,3-dihydro-3,3-dimethyl-2-morpholinobenzofuran-5-yl methylaminosulfonate was obtained by recrystallizing a sample from 80% methanol.
Reaction SMILES: [OH:1][C@H:2]([C@@H:24]([NH:32][C:33](=[O:43])[C@H:34]([CH:40]([CH3:42])[CH3:41])[NH:35][C:36]([O:38][CH3:39])=[O:37])[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:3][N:4]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[NH:5][C:6](=[O:16])[C@H:7]([CH:13]([CH3:15])[CH3:14])[NH:8][C:9]([O:11][CH3:12])=[O:10].[CH3:44][O:45][CH2:46][C:47](Cl)=[O:48]>O1CCOCC1.N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH3:44][O:45][CH2:46][C:47]([O:1][C@H:2]([C@@H:24]([NH:32][C:33](=[O:43])[C@H:34]([CH:40]([CH3:42])[CH3:41])[NH:35][C:36]([O:38][CH3:39])=[O:37])[CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[CH2:3][N:4]([CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[NH:5][C:6](=[O:16])[C@H:7]([CH:13]([CH3:14])[CH3:15])[NH:8][C:9]([O:11][CH3:12])=[O:10])=[O:48]
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(CC1CCCCC1)NC(=O)[C@@H](NC(=O)OC)C(C)C)C(C)C
Reactant: COCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: COCC(=O)O[C@@H](CN(CC1CCCCC1)NC(=O)[C@@H](NC(=O)OC)C(C)C)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C

Procedure:
Analogously to Example 105, 200 mg (0.33 mmol) of 1-[2(S)-hydroxy-3(S)-(N-(methoxycarbonyl)-(L)-valyl)amino-4-phenyl-butyl]-1-[cyclohexylmethyl]-2-[N-methoxycarbonyl-(L)-valyl]-hydrazine (Example 73a) in 2.6 ml of dioxane and 0.4 ml of pyridine are reacted with 50 μl (0.495 mmol) of methoxyacetic acid chloride and 2 mg (0.017 mmol) of DMAP. To complete the reaction a further 0.5 equivalents of methoxyacetic acid chloride and a few granules of DMAP are added and the mixture is stirred. Extraction and digestion from DIPE/hexane in an ultrasound bath yields the pure title compound: TLC Rf (O)=0.48; tRet (V)=15.6 min; FAB-MS (M+H)+ =678.
Reaction SMILES: [C:1]1(=O)[C:6]2=[CH:7][N:8]=[CH:9][CH:10]=[C:5]2[CH2:4][CH2:3][O:2]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:21])=CC=1>C1(C)C=CC=CC=1>[C:1]1(=[S:21])[C:6]2=[CH:7][N:8]=[CH:9][CH:10]=[C:5]2[CH2:4][CH2:3][O:2]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: O=C1OCCc2ccncc21
Solvent: Cc1ccccc1
Product: S=C1OCCc2ccncc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 120.5 %

Procedure:
3,4-dihydro-pyrano[3,4-c]pyridine-1-on (250 mg, 1.676 mmol) was dissolved in anhydrous toluene and stirred overnight at room temperature after adding Lawesson reagent (420 mg, 1.005 mmol). The mixture was evaporated under reduced pressure and a silica gel column chromatography (70% EtOAc/Hexane) was performed on the resulting residue and obtained 200 mg (72%) of 3,4-dihydro-pyrano[3,4-c]pyridine-1-thione in yellow solid.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([OH:12])=O)[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:20][C@H:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.Cl.CCN=C=NCCCN(C)C>C(Cl)(Cl)Cl>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:2]([C:10]([NH:20][C@H:21]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:12])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
In 150 ml of chloroform were dissolved 26.5 g of Boc-Phe-OH and 22.9 g of H-Phe-OEt.HCl, to which 18.4 ml of WSC was added under cooling at 0° C. This was then subjected to stirring for 2 hours at -10° C., then 15 hours at room temperature. The reaction solution was concentrated in vacuo and the residue was dissolved in 20 ml of ethyl acetate, washed successively with 1 N HCl, water, 5% aqueous NaHCO3 solution and water, dried over Na2SO4 then again concentrated in vacuo. The thus obtained residue was added to n-hexane and the resultant amorphous precipitate was collected, and was recrystallized from n-hexane, which gave 37 g (yield=84%) of the title product. m.p. 106.5°-107.5° C. [α]D25 -9.7° (C 1.3, DMF). Analysis--Calculated for C25H32O5N2 : C, 68.16; H, 7.32; N, 6.36. Found: C, 67.85; H, 7.32; N, 6.49.
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH3:7][C:8]([CH3:12])=[CH:9][CH:10]=[O:11].Cl>>[OH:11][C@@H:10]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[CH:9]=[C:8]([CH3:12])[CH3:7]
Reactant: CC(C)=CC=O
Reactant: COP([O-])OC
Agent: Cl
Product: COP(=O)(OC)[C@H](O)C=C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1 M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring at room temperature for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Then 3-methyl-2-butenal (0.40 mmol) was added thereto. After reacting for 81 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture was extracted with ethyl acetate (10 ml×three times), and the combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-1-hydroxy-3-methyl-2-butenylphosphonate as a final product in a yield of 72%. The chemical reaction in this Example is shown in chemical formula 36. ##STR30##
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([N:16]2[CH:20]=[N:19][CH:18]=[N:17]2)[C:12]([NH:21][C:22]2[CH:27]=[C:26]([NH:28][C:29](=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:25]=[CH:24][C:23]=2[Cl:44])=[N:11]1.[C:45](Cl)(=[O:49])[CH2:46][CH2:47][CH3:48].C(OCC)(=O)C>C(#N)C>[C:45]([O:15][C:14]1[N:10]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=2[Cl:9])[N:11]=[C:12]([NH:21][C:22]2[CH:27]=[C:26]([NH:28][C:29](=[O:43])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[CH:25]=[CH:24][C:23]=2[Cl:44])[C:13]=1[N:16]1[CH:20]=[N:19][CH:18]=[N:17]1)(=[O:49])[CH2:46][CH2:47][CH3:48]
Reactant: CCCC(=O)Cl
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2n2cncn2)c1
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(Nc2nn(-c3c(Cl)cc(Cl)cc3Cl)c(OC(=O)CCC)c2-n2cncn2)c1
Temperature: 25 °C

Procedure:
20 g of 1-(2,4,6-trichlorophenyl)-3-(2-chloro-5-tetradecanamidoanilino)-4-(1,2,4-triazol-1-yl)-5-oxo-2-pyrazoline (prepared by the method described in U.S. Pat. No. 4,076,533) was suspended in 100 ml of acetonitrile and 3.7 g of butanoyl chloride was added to the mixture, followed by refluxing for 3 hours. After cooling to room temperature, 500 ml of ethyl acetate was added to the reaction mixture and washed several times with water. The ethyl acetate layer was dried with anhydrous sodium sulfate and concentrated. Upon crystallization of the residue from a solvent mixture of acetonitrile and benzene, 16 g of Coupler (1) was obtained. The melting point of the coupler was 89° to 95° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]1[N:15]=[C:16]([C:20]([O:22]CC)=O)[NH:17][C:18](=[O:19])[C:7]1=[CH:6]2.[CH3:25][NH2:26]>C(O)C>[CH3:25][NH:26][C:20]([C:16]1[NH:17][C:18](=[O:19])[C:7]2[C:8]([N:15]=1)=[N:9][C:10]1[C:5]([CH:6]=2)=[CH:4][C:3]([O:2][CH3:1])=[C:12]([O:13][CH3:14])[CH:11]=1)=[O:22]
Reactant: CCOC(=O)c1nc2nc3cc(OC)c(OC)cc3cc2c(=O)[nH]1
Reactant: CN
Solvent: CCO
Product: CNC(=O)c1nc2nc3cc(OC)c(OC)cc3cc2c(=O)[nH]1

Procedure:
A mixture of ethyl 7,8-dimethoxypyrimido[4,5-b]quinolin-4(3H)-one-2-carboxylate (300 mg., 0.90 mM) and ethanol (75 ml.) saturated with anhydrous monomethylamine is heated at 95° C. for 24 hours in a stainless steel bomb. The bomb and contents are cooled, the contents removed and concentrated to dryness under reduced pressure. The residue is recrystallized from chloroform/ethyl acetate to give 250 mg. (88%) of product, m.p. 334° C. (dec.).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O-]CC.[Na+].C([O:16][C:17]([CH:19]1[CH:21]([CH:22]=O)[C:20]1([CH3:25])[CH3:24])=[O:18])C>C(O)C>[C:8]([C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[CH:22][C@H:21]1[C@H:19]([C:17]([OH:18])=[O:16])[C:20]1([CH3:25])[CH3:24])#[N:9]
Reactant: CCOC(=O)C1C(C=O)C1(C)C
Reactant: N#CCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC1(C)[C@@H](C=C(C#N)c2ccccc2)[C@@H]1C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Phenylacetonitrile is added to a stirred solution of sodium ethoxide in absolute ethanol (prepared from 1.1 g sodium and 100 ml of ethanol). Next, a solution of 3-formyl-2,2-dimethyl-cyclopropanecarboxylic acid ethyl ester (8.5 g) in absolute ethanol (15 ml) is added over 5 minutes. The reaction mixture is stirred for 12 hours at room temperature and then heated on a steam bath for 0.5 hour. The alcohol is removed in vacuo, and the residue washed with water (250 ml) and ether (150 ml). The aqueous layer is acidified with concentrated hydrochloric acid. The resulting cream colored slurry is filtered and the isolated product dried. The product is dissolved in ether and precipitated with hexane to afford 6.1 g of white crystals, m.p. 186°-188° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[C:25]([N:26]4[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]4)=[CH:24][CH:23]=[CH:22][C:21]=3[CH:33]3[CH2:35][CH2:34]3)=[C:14]([CH3:36])[CH:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2].[C:37]1(C)C=CC=CC=1.S(OC)(OC)(=O)=O>O>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH3:37])[N:8]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][C:20]3[C:25]([N:26]4[C:30](=[O:31])[N:29]([CH3:32])[N:28]=[N:27]4)=[CH:24][CH:23]=[CH:22][C:21]=3[CH:33]3[CH2:34][CH2:35]3)=[C:14]([CH3:36])[CH:13]=2)[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]nc(-c2ccc(OCc3c(C4CC4)cccc3-n3nnn(C)c3=O)c(C)c2)c1C
Reactant: Cc1ccccc1
Solvent: COS(=O)(=O)OC
Solvent: O
Product: CCOC(=O)c1c(C)c(-c2ccc(OCc3c(C4CC4)cccc3-n3nnn(C)c3=O)c(C)c2)nn1C
Temperature: 100 °C
Reaction time: 3 h

Procedure:
At room temperature, to a mixture of 4-{4-[2-cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-3-methyl-2,4-dioxo-butyric acid ethyl ester (described in Reference Preparation example 115) 5.5 g, tetrahydrofuran 100 ml was added hydrazine one hydrate 0.56 g and the resulting mixture was stirred for twelve hours. The reaction mixture was concentrated under reduced pressure to give 5-{4-[2-cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-4-methyl-2H-pyrazole-3-carboxylic acid ethyl ester crude product 5 g. Next, the mixture of the above-mentioned 5-{4-[2-cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-4-methyl-2H-pyrazole-3-carboxylic acid ethyl ester crude product 5 g, toluene 70 ml and dimethyl sulfate 3.8 g was stirred at 100° C. for three hours. To the reaction mixture was added water and was extracted with ethyl acetate. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give 5-{4-[2-cyclopropyl-6-(4-methyl-5-oxo-4,5-dihydro-tetrazol-1-yl)-benzyloxy]-3-methyl-phenyl}-2,4-dimethyl-2H-pyrazole-3-carboxylic acid ethyl ester 1.4 g (hereinafter, referred to as “Present compound 48”).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9](O)[C:10]2[CH:11]=[CH:12][C:13]([F:18])=[C:14]([CH:17]=2)[C:15]#[N:16])[CH:5]=[C:6]([F:8])[CH:7]=1.[I-].[Na+].Cl[Si](C)(C)C>C(#N)C.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:8])[CH:7]=1)[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([F:18])=[C:14]([CH:17]=1)[C:15]#[N:16]
Reactant: N#Cc1cc(C(O)c2cc(F)cc(F)c2)ccc1F
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: N#Cc1cc(Cc2cc(F)cc(F)c2)ccc1F
Yield: 94.3 %

Procedure:
5-[(3,5-Difluoro-phenyl)-hydroxy-methyl]-2-fluoro-benzonitrile (3.5 g, 13.3 mmol) and sodium iodide (20 g, 133 mmol) are stirred in acetonitrile (50 mL) under nitrogen at 60° C. To the reaction mixture is gradually added chlorotrimethylsilane (17 mL, 134 mmol) over a period of 8 hours. The mixture is diluted with ethyl acetate and washed with water, saturated aquoeus sodium bicarbonate, 10% aquoeus sodium thiosulfate and brine. Purification of the crude by chromatography over silica gel (EtOAc/hexane 5:100) afforded 3.1 g of the title compound (88% yield).