Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=CC=C(O)C=1C=O.C(=O)C1C(=CC=CC=1)O.[Cl:20][C:21]1[C:26]2[CH:27]=[C:28]([C:30](=O)[C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[O:29][C:25]=2[CH:24]=[CH:23][CH:22]=1.O.NN>>[Cl:20][C:21]1[C:26]2[CH:27]=[C:28]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=3)[O:29][C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: COc1ccc(C(=O)c2cc3c(Cl)cccc3o2)cc1
Agent: NN
Agent: O=Cc1c(O)cccc1Cl
Solvent: O=Cc1ccccc1O
Solvent: O
Product: COc1ccc(Cc2cc3c(Cl)cccc3o2)cc1

Procedure:
When an equivalent amount of 6-chlorosalicylaldehyde is used as a starting material in the procedure of Example 15 in place of salicylaldehyde and the product 4-chloro-2-(4'-methoxybenzoyl)benzofuran is reduced with hydrazine hydrate, 4-chloro-2-(4'-methoxybenzyl)benzofuran is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:10])[CH:5]=[N:6][C:7]=1[Cl:8].C(N(CC)CC)C.Cl[CH2:19][O:20][CH3:21]>C(Cl)Cl>[Cl:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([CH2:9][O:10][CH2:19][O:20][CH3:21])=[CH:5][N:6]=1
Reactant: COCCl
Reactant: OCc1cnc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCOCc1cnc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a stirred solution of (5,6-dichloropyridin-3-yl)methanol (commercially available) in CH2Cl2 (0.2 M) at 0° C. was added triethylamine (3 eq.) and chloro(methoxy)methane (2 eq.). After stirring at 0° C. for 3 hours the reaction mixture was concentrated and the crude was purified by chromatography (silica gel, 20-50% EtOAc in hexanes) to afford 2,3-dichloro-5-((methoxymethoxy)methyl)pyridine as a colorless oil.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([OH:12])(=[O:11])=[O:10])=[CH:5][CH:4]=1)N.[CH3:13][CH:14]([C:23](=O)[CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][S:19]([OH:22])(=[O:21])=[O:20]>C(O)(=O)C>[CH3:24][C:23]1[C:14]([CH3:13])([CH2:15][CH2:16][CH2:17][CH2:18][S:19]([OH:22])(=[O:21])=[O:20])[C:8]2[C:3](=[CH:4][CH:5]=[C:6]([S:9]([OH:12])(=[O:11])=[O:10])[CH:7]=2)[N:1]=1
Reactant: NNc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)C(C)CCCCS(=O)(=O)O
Solvent: CC(=O)O
Product: CC1=Nc2ccc(S(=O)(=O)O)cc2C1(C)CCCCS(=O)(=O)O

Procedure:
4-Hydrazinobenzenesulfonic acid (1.88 g), 5-methyl-6-oxoheptanesulfonic acid (2.5 g) and acetic acid (50 ml) were mixed and heated under reflux for 6 hrs. The solvent was evaporated under vacuum, then the residue was triturated with 2-propanol to yield the crude product as a yellow solid. This was purified by HPLC as required (RPC18. Water+0.1% TFA). 1H-nmr (D2O) δ0.8-1.0 (2H, m), 1.55-1.65 (5H,=3H, s+2H, m), 2.16 (1H, ddd), 2.29 (1H, ddd), 2.75 (2H, m), 2.81 (partially d-exchanged methyl singlet), 7.71 (1H, d), 7.94 (1H, d) and 8.01 (1H, d). UV/Vis (Water+0.1% TFA): 269, 229 nm. MS (LCMS): MH+362. Acc. Mass: Found, 362.0729. MH+=C14H20NO6S2 requires 362.0732 (−0.8 ppm).
Reaction SMILES: S1C=CN=C1.Cl.[OH:7]/[N:8]=[C:9](/[C:15]1[N:16]=[C:17]([NH:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:18][CH:19]=1)\[C:10]([O:12]CC)=[O:11].C(=O)([O-])[O-].[K+].[K+].[CH2:46]([O:48][CH2:49][CH2:50]Br)[CH3:47]>CN(C=O)C.O>[CH2:46]([O:48][CH2:49][CH2:50][O:7]/[N:8]=[C:9](/[C:15]1[N:16]=[C:17]([NH:20][C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[S:18][CH:19]=1)\[C:10]([OH:12])=[O:11])[CH3:47]
Reactant: CCOCCBr
Reactant: CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOCCO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 240 h

Procedure:
The thiazole acid starting material was prepared as follows. Ethyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetate hydrochloride (9.87 g.) was suspended in DMF (50 ml.) and treated with potassium carbonate (5.52 g.) and 2-bromoethyl ethyl ether (2.25 ml.). After stirring for 10 days at ambient temperature the mixture was diluted with water and worked up conventionally by extraction into EtOAc followed by chromatography on silica, eluting with 98:2 (v/v) CH2Cl2 : EtOAc. The ethyl ester was dissolved in 1,2-dimethoxyethane (12 ml.), 2N aqueous NaOH solution (8.9 ml.) added, and the mixture heated under reflux for 2 hours. The mixture was cooled to 0°, the precipitate filtered, washed with a mixture of dimethoxyethane/water (1:1, v/v, 2×10 ml.) then dimethoxyethane/ether (1:1, v/v, 10 ml.). The precipitate was suspended in DMSO (50 ml.), acidified with 2NHCl (10 ml.), and diluted with water (500 ml.). The precipitate was filtered, washed well with water, and dried to give 2-((Z)-2-ethoxyethoxyimino)-2-(2-tritylaminothiazol-4-yl)acetic acid, having the following n.m.r. in CDCl3 :-1.07(t, 3H); 3.43(q, 2H); 3.62(t, 2H); 4.23(t, 2H); 6.5(s, 1H); 7.27(s, 15H).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]2[CH2:5][N:6](C(OC(C)(C)C)=O)[CH2:7][CH2:8][C:9]=2[N:10]=1.[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21]>ClCCl>[F:18][C:19]([F:24])([F:23])[C:20]([OH:22])=[O:21].[Br:1][C:2]1[S:3][C:4]2[CH2:5][NH:6][CH2:7][CH2:8][C:9]=2[N:10]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Br)sc2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Brc1nc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 0.02 h

Procedure:
2-Bromo-5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (890 mg) was dissolved in dichloromethane (2 ml), and to the solution trifluoroacetic acid (15 ml) was added, and the mixture was stirred at room temperature for 1 minute. The reaction mixture was concentrated under reduced pressure, and diethyl ether was added to the residue. Precipitated solid materials were collected by filtration to obtain the title compound (867 mg) as a colorless solid.
Reaction SMILES: C([N:8]1[CH2:16][CH:15]2[CH:10]([C:11]([CH2:27][OH:28])([CH3:26])[CH2:12][CH2:13][C:14]2([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])[OH:17])[CH2:9]1)C1C=CC=CC=1>[OH-].[OH-].[Pd+2].C(O)C>[OH:28][CH2:27][C:11]1([CH3:26])[CH:10]2[CH:15]([CH2:16][NH:8][CH2:9]2)[C:14]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[O:24][CH3:25])([OH:17])[CH2:13][CH2:12]1
Reactant: COc1ccccc1C1(O)CCC(C)(CO)C2CN(Cc3ccccc3)CC21
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: COc1ccccc1C1(O)CCC(C)(CO)C2CNCC21
Temperature: 50 °C
Yield: 56.1 %

Procedure:
A mixture of 3.5 g of (3aRS,4RS,7SR,7aRS)-2-benzyl-7-(hydroxymethyl)-4-(2-methoxyphenyl)-7-methyl-4-perhydroisoindolol, 2.0 g of 20% palladium hydroxide on charcoal and 75 cm3 of ethanol is heated to 50° C. After sparging with hydrogen for two hours, the reaction mixture is cooled to room temperature and flushed with a stream of nitrogen, filtered and concentrated under reduced pressure (2.7 kPa). 1.5 g of (3aRS,4RS,7SR,7aRS)-7-(hydroxymethyl)-4-(2-methoxyphenyl)-7-methyl-4-perhydroisoindolol are obtained in the form Of a white solid.
Reaction SMILES: C([NH:4][C@@H:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][C:8]=1[N:17]=[N+:18]=[N-:19])[CH3:6])(=O)C>Cl>[N:17]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][C:7]=1[C@H:5]([NH2:4])[CH3:6])[C:11]([OH:13])=[O:12])=[N+:18]=[N-:19]
Reactant: COC(=O)c1ccc([C@@H](C)NC(C)=O)c(N=[N+]=[N-])c1
Agent: Cl
Product: C[C@@H](N)c1ccc(C(=O)O)cc1N=[N+]=[N-]
Yield: 135.1 %

Procedure:
A solution of methyl (R)-4-(1-acetylaminoethyl)-3-azidobenzoate (1.6 g) in 2N hydrochloric acid (25 ml) was refluxed under heating for 8 hours. After the reaction, the mixture was concentrated under reduced pressure, and boiled with toluene to give crude (R)-3-azido-4-(1-aminoethyl)benzoic acid (1.7 g). Then, the mixture was added to a solution of sodium hydroxide (0.85 g) in water (25 ml). Benzyloxycarbonyl chloride (1.56 g) was dropwise added, and the mixture was stirred at room temperature for 5 hours. After the reaction, the solution was adjusted to have pH 4 with conc. hydrochloric acid. The mixture was extracted with chloroform, washed with water, and dried. The solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to give 1.6 g of pale-yellow (R)-3-azido-4-(1-benzyloxycarbonylaminoethyl)benzoic acid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[CH:3]=1.CON(C)[C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)=[O:13]>C1COCC1>[F:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:12]([C@@H:14]1[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1)=[O:13]
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cccc(Br)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cccc(F)c2)C1
Temperature: 55 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
A solution of 1-bromo-3-fluoro-benzene (57.7 g, 0.33 mol) in anhydrous THF (480 mL) was added dropwise to Mg (10.6 g, 0.44 mol) at rt under nitrogen. The mixture was stirred at 50-60° C. for 1 hr. The resulting Grignard reagent was used for the next step. The Grignard reagent was added dropwise to a solution of (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (60 g, 0.22 mol) in anhydrous THF (600 mL) at −78° C. under nitrogen. After addition, the mixture was allowed to stir at rt for 1.5 hr. The mixture was quenched with saturated NH4Cl solution (300 mL) and extracted with ethyl acetate (3×200 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to give crude (R)-tert-butyl 3-(3-fluorobenzoyl)piperidine-1-carboxylate (67.5 g, 100%), which was used immediately in the next step without purification.
Reaction SMILES: C(O[C:4](=[O:17])[C:5](=[N:8][NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Br:16])[C:6]#[N:7])C.[CH3:18][NH2:19]>O>[Br:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][N:8]=[C:5]([C:6]#[N:7])[C:4]([NH:19][CH3:18])=[O:17]
Reactant: CCOC(=O)C(C#N)=NNc1ccccc1Br
Reactant: CN
Solvent: O
Product: CNC(=O)C(C#N)=NNc1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[(2-Bromophenyl)-hydrazono]-cyanoacetic acid ethyl ester (15.28 g, 51.60 mmol) was dissolved in 40% methylamine in water (67.5 mL) and stirred at room temperature overnight. The reaction mixture was concentrated to dryness, slurried in diethyl ether, and filtered. After drying under high vacuum at 40° C., the title compound was obtained as a yellow solid (11.16 g, 77%). 1H NMR (300.132 MHz, CDCl3) δ 7.68 (dd, J=8.2, 1.4 Hz, 1H), 7.54 (dd, J=8.1, 1.3 Hz, 1H), 7.35 (t, J=7.9 Hz, 1H), 7.01 (td, J=7.7, 1.5 Hz, 1H), 6.29 (s, 1H), 2.98 (d, J=4.9 Hz, 3H). MS APCI, m/z=281/283 (M+H). HPLC 4.08 min.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([OH:24])[CH:10]=[C:11]([C:13]2[NH:14][C:15]([C:18]3[O:19][CH2:20][C@@H:21]([CH3:23])[N:22]=3)=[CH:16][CH:17]=2)[CH:12]=1)[CH3:5].Br[C:26]1[CH:31]=[N:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][N:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(#N)C>[CH3:1][O:2][CH2:3][C@@H:4]([O:6][C:7]1[CH:8]=[C:9]([CH:10]=[C:11]([C:13]2[NH:14][C:15]([C:18]3[O:19][CH2:20][C@@H:21]([CH3:23])[N:22]=3)=[CH:16][CH:17]=2)[CH:12]=1)[O:24][C:26]1[CH:31]=[N:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][N:27]=1)[CH3:5]
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=N[C@H](C)CO3)[nH]2)c1
Reactant: CS(=O)(=O)c1cnc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COC[C@H](C)Oc1cc(Oc2cnc(S(C)(=O)=O)cn2)cc(-c2ccc(C3=N[C@H](C)CO3)[nH]2)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 91 %

Procedure:
3-{[(2S)-1-Methoxypropan-2-yl]oxy}-5-{5-[(4R)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (340 mg, 1.03 mmol) synthesized in Example (107c) was dissolved in acetonitrile (10 mL), and 2-bromo-5-(methylsulfonyl)pyrazine (300 mg, 1.27 mmol) synthesized in Example (107d) and cesium carbonate (850 mg, 2.61 mmol) were added at room temperature, followed by stirring at room temperature for 4.5 hours under nitrogen atmosphere. To this reaction solution, water (20 mL) was added, and extraction was carried out with methylene chloride (30 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate=100%) to afford the desired compound (456 mg, yield 91%) as a white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14]([C:20]1[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=1)=[N:13][C@H:12]1[C@@H:7]2[CH2:8][O:9][CH2:10][CH2:11]1)[CH3:2].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[NH:60]1[CH2:65][CH2:64][O:63][CH2:62][CH2:61]1>ClCCl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:15](=[CH:16][C:17]=1[O:18][CH3:19])[C:14]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([N:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)=[O:26])=[CH:27][CH:28]=1)=[N:13][C@H:12]1[C@@H:7]2[CH2:8][O:9][CH2:10][CH2:11]1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCOC[C@H]21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N3CCOCC3)cc1)=N[C@@H]1CCOC[C@H]21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 1 mmol of 4-((4aR,10aR)-6-Ethoxy-7-methoxy-1,4,4a,10a-tetrahydro-2H-3-oxa-10-aza-phenanthren-9-yl)-benzoic acid, 5 mmol of triethyl amine and 1.1 mmol of O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluoro-phosphate (HBTU) in 20 ml of dichloromethane is stirred for 30 min at RT. After addition of 1.1 mmol of morpholine the suspension is stirred for 60 min at RT. The mixture is concentrated under reduced pressure and the solid residue is purified by column chromatography on SiO2 (n-hexane/ethyl acetate/triethylamine 4/5/1 vol/vol/vol), the main product fraction is separated and concentrated yielding the title compound as grayish solid foam. M.p. 116-120° C. (unsharp, enamel-like shrinking starting at about 61° C.)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])CCC.[C:17]1([CH2:23][CH:24]=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1.CCCCCC>[C:17]1([CH2:23][C:24]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: FC(F)(F)c1ccc(Br)cc1
Reactant: O=CCc1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccccc1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Yield: 24 %

Procedure:
To a solution of 45.0 g of 1-bromo-4-(trifluoromethyl)benzene in 300 mL of THF cooled to -78° C. was added 77.0 mL of 2.5M n-butyl lithium in hexane dropwise. An exothermic reaction to -55° C. was observed. The reaction was then stirred for 20 minutes after which time phenyl acetaldehyde (23.5 mL, 0.2 mol) was added dropwise. The reaction was then stirred for an additional hour with gradual warming to room temperature. The mixture was then partitioned between ether and water, dried over anhydrous magnesium sulfate and concentrated to 52.6 g of a yellow oil. The crude oil was dissolved in 600 mL of methylene chloride and 100 g of pyridinium dichromate was added in several portions over 20 minutes and the mixture was then stirred at room temperature overnight. The reaction was then diluted with ether and filtered through magnesium sulfate and concentrated. The crude product was dissolved in hot n-butyl chloride, insoluble material was filtered off and the mixture was cooled to 0° C. Filtration and drying of the precipitate afforded 12.7 g of the title compound as a white solid, mp 127°-128° C.
Reaction SMILES: [O:1]1[CH2:20][CH:2]1[CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:9]2>C(N)(C)C>[OH:1][CH:2]([CH2:20][NH:9][CH:8]([CH3:15])[CH3:7])[CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH3:14])[CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[NH:9]2
Reactant: CCOC(=O)c1cc2c(OCC3CO3)cc(C)cc2[nH]1
Solvent: CC(C)N
Product: CCOC(=O)c1cc2c(OCC(O)CNC(C)C)cc(C)cc2[nH]1
Reaction time: 48 h
Yield: 131.7 %

Procedure:
2.0 g 4-(2,3-epoxypropoxy)-2-ethoxycarbonyl-6-methyl indole are dissolved in 25 ml isopropylamine. The solution is kept for two days at room temperature and then heated to boiling for 8 to 10 hours. Excessive isopropyl amine is removed in vacuum and the residue triturated with ether. The crude product is dissolved in small amounts of isopropanol during heating. After the addition of 0.42 ml glacial acetic acid, the solution is allowed to cool. The precipitated deposit is aspirated and recrystallized from small amounts of isopropanol. There is obtained 1.6 g (55% of theory) 4-(2-hydroxy-3-isopropylamino-propoxy)-2-ethoxycarbonyl-6-methylindole as acetate; m.p. 163°-165° C.
Reaction SMILES: [K].[S:2]([CH2:6][NH:7][C:8](=[S:11])SC)([OH:5])(=[O:4])=[O:3].[N-:12]=[N+:13]=[N-:14].[Na+]>O>[S:2]([CH2:6][N:7]1[C:8]([SH:11])=[N:14][N:13]=[N:12]1)([OH:5])(=[O:4])=[O:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CSC(=S)NCS(=O)(=O)O
Agent: [K]
Agent: [Na+]
Solvent: O
Product: O=S(=O)(O)Cn1nnnc1S

Procedure:
A mixture of 45.3 g. (0.19 mol.) of methyl sulfomethyldithiocarbamate potassium salt and 16.9 g. (0.26 mol.) of sodium azide in 425 ml. of water was heated at 80° for 4.75 hours. The reaction mixture was passed through an Amberlite IR-120H ion exchange resin column and eluted with water until the pH of the eluant became 3.5. The eluant was extracted with ether and the aqueous solution was evaporated to dryness to give 1-sulfomethyltetrazole-5-thiol.
Reaction SMILES: [S-2:1].[Na+:2].[Na+].[SH-].[Na+].[C:6]([Cl:15])(=[O:14])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>O.[Cl-].C[N+](CCCCCCCC)(CCCCCCCC)CCCCCCCC>[S-2:1].[Na+:2].[Na+:2].[C:6]([O-:14])(=[S:1])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[Na+:2].[Cl-:15].[Na+:2]
Reactant: CCCCCCCC(=O)Cl
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Product: CCCCCCCC([O-])=S

Procedure:
A 20 weight percent aqueous solution of sodium sulfide was prepared by dissolving sodium sulfide (116 grams, 1.48 moles) in the form of hydrated flakes (193 grams, 60%) into 385 grams of water in a 5-liter round-bottomed flask. This solution was then cooled by means of an ice-water bath and converted to an aqueous solution of sodium hydrosulfide (NaSH) by saturating it with an excess of hydrogen sulfide by adding hydrogen sulfide with stirring until no more was absorbed. A dropping funnel was charged with octanoyl chloride (241 grams, 1.48 moles). With the temperature of the sodium hydrosulfide solution in the 5-liter flask at 9° C., the addition of the octanoyl chloride to the 5-liter flask was begun with stirring of the contents of the 5-liter flask with a mechanical stirrer, immediately after the addition of 1.7 grams of a 10% aqueous solution of methyltrioctylammonium chloride to the 5-liter flask. The addition of the octanoyl chloride was completed over the course of 1.8 hours with a final temperature of 13° C. The content of the 5-liter flask was kept between 8 and 19° C. during the course of the addition. The content of the 5-liter flask was then allowed to reach ambient temperature and stirring was stopped, yielding a clear, slightly viscous, one-phase aqueous solution of sodium thiooctanoate and sodium chloride.
Reaction SMILES: Cl[C:2]1[C:11]([Cl:12])=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH2:13]([S:16]([NH2:19])(=[O:18])=[O:17])[CH2:14][CH3:15].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CS(C)=O>[Cl:12][C:11]1[C:2]([NH:19][S:16]([CH2:13][CH2:14][CH3:15])(=[O:18])=[O:17])=[N:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Clc1nc2ccccc2nc1Cl
Reactant: CCCS(N)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCCS(=O)(=O)Nc1nc2ccccc2nc1Cl
Temperature: 150 °C
Reaction time: 1 h
Yield: 84 %

Procedure:
In DMSO were dissolved 2,3-dichloroquinoxaline (5.00 g, 25.1 mmol) and propane-1-sulfonamide (3.09 g, 25.1 mmol). Potassium carbonate (3.47 g, 25.1 mmol) was added and the mixture was stirred at 150° C. for 1 hour. A 1% aqueous acetic acid solution was added to the mixture and the mixture was stirred at room temperature for 3 hours. The precipitated solid was separated by filtration and the obtained solid was washed with water. The separated solid was then purified by slurrying in diisopropyl ether to give compound AA (6.01 g, 84% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.OC[CH2:27][CH2:28][NH:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[C:35]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]([F:50])([F:49])[F:48])[NH:36][C:37]2=[O:40])=[CH:32][CH:31]=1>C(Cl)Cl>[Br:24][CH2:20][CH2:27][CH2:28][NH:29][C:30]1[CH:39]=[C:38]2[C:33]([CH:34]=[C:35]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=3[C:47]([F:50])([F:48])[F:49])[NH:36][C:37]2=[O:40])=[CH:32][CH:31]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(NCCCO)cc12
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(NCCCBr)cc12
Temperature: 25 °C
Reaction time: 3 h
Yield: 41.7 %

Procedure:
Triphenylphosphine (940 mg, 3.59 mmol) and carbon tetrabromide (1.19 g, 3.59 mmol) were added to a methylene chloride solution (10 ml) that contained the 7-(3-hydroxypropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (500 mg, 1.38 mmol) obtained in step B of Example 1-49. The obtained mixture was stirred at a room temperature for 3 hours. The reaction solvent was distilled away, and the obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:2 to 1:1), so as to obtain 7-(3-bromopropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one (245 mg, 42%).
Reaction SMILES: C1(=O)[NH:5]C(=O)C2=CC=CC=C12.[ClH:12].C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H]([N:43]5[CH:48]=[C:47]([C:49]([NH2:51])=O)[CH2:46][CH:45]=[CH:44]5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1>>[ClH:12].[ClH:12].[NH2:5][CH2:44][CH2:45][CH2:46][C:47]1[CH:48]=[N:43][NH:51][CH:49]=1
Reactant: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Reactant: O=C1NC(=O)c2ccccc21
Agent: Cl
Product: NCCCc1cn[nH]c1
Temperature: 4 °C

Procedure:
This phthalimide intermediate (8.0 gram, 0.03 mole) was refluxed in 100 ml. of 6 normal hydrochloric acid overnight. The clear solution was cooled to 4° C., phthalic acid removed by filtration, and the filtrate evaporated to dryness to give a product which, after recrystallization from a mixture of ethanol and ethyl ether, amounted to 4.4 grams of a white solid identified as 4-(3-aminopropyl)-pyrazole dihydrochloride, melting point 189°-190° C. This pyrazole compound could be coupled to the activated dextran by reaction of the terminal amino group, but the resulting affinity resin, in which the coupling arm had a length of only 6 Angstrom units, had poor binding capacity for the binary complex of alcohol dehydrogenase and NAD.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][OH:11])[CH:3]=1.[OH-].[Na+]>C(O)C.[Pd]>[N:7]1[CH:2]=[CH:3][C:4]([NH:8][CH:9]([CH2:12][CH3:13])[CH2:10][OH:11])=[N:5][CH:6]=1
Reactant: CCC(CO)Nc1cc(Cl)ncn1
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(CO)Nc1ccncn1

Procedure:
2-[(6-Chloro-4-pyrimidinyl)amino]-1-butanol was dissolved in ethanol (110 mL), which was sequentially added with a 5N aqueous sodium hydroxide solution (5.5 mL) and Pd—C (hydrous product; 0.55 g), and hydrogenation was performed under hydrogen atmosphere at a normal temperature and a normal pressure. After completion of the reaction, Pd—C was filtered off, and the solvent was evaporated. The resulting residue was extracted with dichloromethane-methanol, and the solvent was removed to give the title compound (4.3 g) as white crystals.