Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8]=1[S:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.Cl.Br[CH2:27][C:28]([NH:30][C:31]1[C:32]([S:40][CH3:41])=[N:33][C:34]([CH3:39])=[CH:35][C:36]=1[S:37][CH3:38])=[O:29]>O.C(#N)C>[N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[NH:9][C:8]=1[S:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:27][C:28]([NH:30][C:31]2[C:32]([S:40][CH3:41])=[N:33][C:34]([CH3:39])=[CH:35][C:36]=2[S:37][CH3:38])=[O:29])[CH2:21][CH2:20]1
Reactant: CSc1cc(C)nc(SC)c1NC(=O)CBr
Reactant: c1ccc2[nH]c(SCCN3CCNCC3)nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CSc1cc(C)nc(SC)c1NC(=O)CN1CCN(CCSc2nc3ccccc3[nH]2)CC1
Reaction time: 1 h
Yield: 99 %

Procedure:
Acetonitrile (450 mL) and potassium carbonate (85.7 g, 0.62 mol) were added to 1-[2-(benzimidazol-2-ylthio)ethyl]piperazine.3 hydrochloride (59.42 g, 0.16 mol) in water (180 mL). Subsequently, 2-bromo-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide (48.19 g, 0.15 mol) was gradually added thereto, and the resultant mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water (300 mL), followed by stirring for 1 hour. The crystals that precipitated were separated through filtration, followed by washing with a solvent mixture (600 mL) of acetonitrile and water (1:1), washing with water (200 mL), and drying through air blow at 40 to 50° C., to thereby yield 2-[4-[2-(benzimidazol-2-ylthio)ethyl]piperazin-1-yl]-N-[2,4-bis(methylthio)-6-methylpyridin-3-yl]acetamide as colorless crystals (75 g, yield: 99%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:11])=[C:8]([SH:10])[CH:9]=1.C(N(CC)CC)C.[Br:19][C:20]1[C:28]([O:29][CH3:30])=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=O.[OH-].[Na+]>CN1CCCC1=O>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:22]([C:21]3[CH:25]=[CH:26][CH:27]=[C:28]([O:29][CH3:30])[C:20]=3[Br:19])[S:10][C:8]=2[CH:9]=1
Reactant: COc1cccc(C(=O)Cl)c1Br
Reactant: COc1ccc(N)c(S)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: COc1ccc2nc(-c3cccc(OC)c3Br)sc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.6 %

Procedure:
5-Methoxy-2-aminobenzenethiol hydrochloride (83 g, 4.33 mmol) was dissolved in 1-methyl-2-pyrrolidinone (10 mL). After triethylamine (0.60 mL, 4.33 mmol) was added, the mixture was stirred at room temperature for 10 min. 2-Bromo-3-methoxybenzoyl chloride (1.08 g, 4.33 mmol) in 1-methyl-2-pyrrolidinone (10 mL) was then added and the mixture was heated at 100° C. for 40 min. The mixture was cooled to room temperature and 1N NaOH was added to PH 9. The mixture was extracted with ethylacetate and combined ethylacetate were washed with brine, concentrated. After chromatographic purification gave 6-methoxy-2-(2-bromo-3-methoxy-phenyl)-benzothiazole (0.98 g, 65% yield) as a yellow solid. Mass spec: MH+=350.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])=[CH:9][N:10]=1)[C:5]([OH:7])=[O:6].S(Cl)(Cl)=O.[CH3:16]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])=[CH:9][N:10]=1)[C:5]([O:7][CH3:16])=[O:6]
Reactant: O=C(O)c1cc(Br)ncc1F
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Br)ncc1F
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of 2-bromo-5-fluoroisonicotinic acid (1.5 g, 6.82 mmol) in methanol (75 ml), thionyl dichloride (2.5 ml, 34.09 mmol) was added drop-wise. The reaction mixture was stirred overnight. The solvent was removed under high vacuum. The residual solid was distilled at 90° C. under vacuum to get 1.3 g (81%) of pure methyl 2-bromo-5-fluoroisonicotinate:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[Br:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[N:21]([S:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)(=[O:29])=[O:28])[CH:20]=[C:19]2[CH2:36]Br>>[Br:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:26])[N:21]([S:27]([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)(=[O:29])=[O:28])[CH:20]=[C:19]2[CH2:36][N:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][C:11]([CH3:13])([CH3:12])[CH3:14])=[O:9])[C@@H:2]([CH3:1])[CH2:7]1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=c1c2ccc(Br)cc2c(CBr)cn1S(=O)(=O)c1ccccc1
Product: C[C@H]1CN(Cc2cn(S(=O)(=O)c3ccccc3)c(=O)c3ccc(Br)cc23)CCN1C(=O)OC(C)(C)C

Procedure:
The subtitle compound was prepared by the method of Example 11e using (S)-tert-butyl 2-methylpiperazine-1-carboxylate and 6-bromo-4-(bromomethyl)-2-(phenylsulfonyl)isoquinolin-1(2H)-one (Example 11d)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([N:12]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH2:17][CH2:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>ClCCl>[C:36]([N:18]1[C:19]2[C:15](=[CH:14][C:13]([N:12]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[S:9]([C:4]3[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])=[CH:21][CH:20]=2)[CH2:16][CH2:17]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CC(C)(C)OC(=O)CN(c1ccc2c(c1)CCN2)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Reactant: O=C(Cl)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN(c1ccc2c(c1)CCN2C(=O)c1ccccc1)S(=O)(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
150 mg tert.butyl [(3,5-dichloro-phenylsulphonyl)-(2,3-dihydro-1H-indol-5-yl)-amino]-acetate are dissolved in 5 ml dichloromethane. 110 mg potassium carbonate and 45 μl benzoyl chloride are added, the mixture is stirred for 3 hours at ambient temperature and then divided between dichloromethane and water. The organic phase is washed with water and then dried on magnesium sulphate. The solvents are eliminated in vacuo.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:5]=1N)([O-:3])=[O:2].[I:14]CI>>[I:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:10][CH:9]=[CH:8][C:7]=1[N+:11]([O-:13])=[O:12]
Reactant: Nc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: ICI
Product: O=[N+]([O-])c1cccc([N+](=O)[O-])c1I
Temperature: 25 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
To a dispersion of 2,6-dinitroaniline (4.00 g, 0.021 mol) in diiodomethane (24 mL, 0.297 mol) isoamylnitrite (15 mL, 0.112 mol) was added (Smith et al., 1990, which is incorporated herein by reference). The mixture was stirred at room temperature for one hour, and then heated at 105° C. for eight hours. The excess of diiodomethane was removed in high vacuo. The residue was diluted with acetyl acetate (10 mL). Silica (ca 30 mL, mesh 230-400 Å) was added; the mixture was concentrated in vacuo and purified by column chromatography to yield 1-iodo-2,6-dinitrobenzene (3.21 g, 52%). 1H NMR (400 MHz, CDCl3): δ 7.84 (d, 2 H, J=8.0 Hz), 7.67 (t, 1 H, J=8.0 Hz).
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[NH2:15][OH:16]>CO.C(OCC)(=O)C.[Pt].[Pt]=O>[CH2:1]([N:15]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC=O
Reactant: NO
Agent: O=[Pt]
Agent: [Pt]
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCN(O)CCCCCCCCCCCC
Yield: 49.8 %

Procedure:
A solution of dodecanal (9.2 g, 50 mmol) and hydroxylamine hydrochloride (2.0 g, 29 mmol) in 70 ml of methanol and 10 ml of ethyl acetate is shaken under hydrogen at 40-45 psi (2.8-3.15 Kg/cm2) for 2.5 hours at room temperature in the presence of a catalytic amount of 5% platinum on carbon (400 mg) and platinum oxide (15 mg). The reaction mixture is then worked up as described in Example 4 to give, after recrystallization from methanol, 4.6 g (50% yield) of the title compound as a white solid identical to that prepared in Example 4.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:14][CH3:15])=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:16]([NH2:18])=O>O>[CH3:15][O:14][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][C:9]=1[N+:11]([O-:13])=[O:12])[N:1]=[CH:16][NH:18][C:4]2=[O:6]
Reactant: COc1cc(C(=O)O)c(N)cc1[N+](=O)[O-]
Reactant: NC=O
Solvent: O
Product: COc1cc2c(=O)[nH]cnc2cc1[N+](=O)[O-]
Temperature: 0 °C
Yield: 67 %

Procedure:
A solution of 2-amino-5-methoxy-4-nitrobenzoic acid (1 6.6 g, 78 mmol) in formamide (250 ml) was heated at reflux for 4.5 hours. The reaction mixture was cooled to 0° C., diluted with water and the resulting precipitate collected by filtration, washed with water and dried under vacuum to give 6-methoxy-7-nitro-3,4-dihydroquinazolin-4-one ( 11.56 g, 67%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[N:3]=1.[CH2:13]([NH2:15])[CH3:14].[OH-].[Na+]>>[Cl:8][C:6]1[N:7]=[C:2]([NH:15][CH2:13][CH3:14])[N:3]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[N:5]=1
Reactant: CC(C)Nc1nc(Cl)nc(Cl)n1
Reactant: CCN
Agent: [Na+]
Agent: [OH-]
Product: CCNc1nc(Cl)nc(NC(C)C)n1

Procedure:
In stage (b) the 2,4-dichloro-6-isopropylamino-s-triazine obtained in stage (a), ethylamine and sodium hydroxide, are reacted to produce 2-chloro-4-ethylamino-6-isopropylamino-s-triazine according to the scheme: ##STR4##
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[C-:14]#[N:15].[Na+].O=O.C1(OC)C=CC=CC=1>O.[Cu]I>[NH2:1][C:2]1[C:11]([CH3:12])=[CH:10][C:9]([C:14]#[N:15])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1cc(Br)cc(C)c1N
Reactant: [C-]#N
Agent: [Cu]I
Agent: O=O
Agent: [Na+]
Solvent: O
Solvent: COc1ccccc1
Product: CNC(=O)c1cc(C#N)cc(C)c1N
Temperature: 153 °C

Procedure:
A 100-mL, four-necked flask equipped with a magnetic stirrer, thermocouple and condenser was charged with copper(I) iodide (1.01 g, 5.3 mmol), 2-amino-5-bromo-N,3-dimethylbenzamide (prepared by the method of Reference Example 1) (5.00 g, 20.6 mmol), powdered sodium cyanide (1.27 g, 25.1 mmol, 97% purity), oxygen-free 4-picoline (1.92 g, 20.6 mmol) and oxygen-free anisole (10 mL) under a nitrogen atmosphere in a glovebox. The reaction mixture was heated at about 153° C. for 12 h and allowed to cool to room temperature overnight. The solid reaction mixture was then heated at 125° C. and more anisole (10 mL) was added. A solution of sodium cyanide (0.505 g, 10.0 mmol) in water (20 mL) was added to the reaction mixture at about 105° C., and then the mixture was taken out of the glovebox and allowed to cool to room temperature while stirring. The reaction mixture was filtered, and the solid collected was washed with water (2×10 mL, 1×5 mL) and toluene (2×10 mL), and then dried in a vacuum-oven at 55° C. to give the title compound as an off-white solid (3.66 g).
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].I[C:8]1[S:9][C:10]([CH3:13])=[CH:11][CH:12]=1>C(N(CC)CC)C.C(OCC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][C:8]1[S:9][C:10]([CH3:13])=[CH:11][CH:12]=1
Reactant: Cc1ccc(I)s1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1ccc(C#C[Si](C)(C)C)s1
Yield: 92.6 %

Procedure:
Under a dry nitrogen atmosphere 3.0 grams (0.031 mole) of trimethylsilylacetylene was added to a stirred mixture of 5.5 grams (0.025 mole) of 2-iodo-5-methylthiophene in 50 ml of triethylamine. To this mixture was added approximately 0.05 gram of dichlorobis(triphenylphosphine)palladium (II) and approximately 0.05 gram of copper (I) iodide. The resultant mixture was stirred at room temperature for approximately 18 hours. The triethylamine was removed from the mixture by evaporation under reduced pressure leaving a residue. This residue was dissolved in diethyl ether and the resultant solution was washed in succession with an aqueous, 10% ammonium chloride solution, water, and an aqueous, saturated sodium chloride solution. The washed organic solution was dried over anhydrous sodium sulfate and was filtered. The filtrate was evaporated under reduced pressure leaving a residue. This residue was purified by column chromatography on silica gel, eluting with n-hexane, to yield 4.5 grams of 1-trimethylsilyl-2-(5-methylthien-2-yl)ethyne as an oil.
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C[Mg]Br.[C:17](#[N:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>C(OCC)C>[CH:8]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:17](=[NH:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: N#Cc1ccccc1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: N=C(c1ccccc1)N(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Dicyclohexylamine (18.1 g, 0.10 mmol) was dissolved in diethylether (150 ml). The solution was heated to reflux temperature and a solution of methylmagnesiumbromide (33 ml, 3.0 M in diethylether, 0.10 mol) was added dropwise over a period of 20 minutes. After the addition, the reaction mixture was stirred for 3 hours at room temperature. Benzonitrile (10.3 g, 0.10 mol) was added and the reaction mixture was stirred for 20 hours at room temperature. A solution of ammoniumchloride (10% in water, 100 ml) was added. The water and organic layers were separated and the water layer was extracted twice with diethylether (150 ml). The combined ether layers were dried over sodium sulphate, filtered and the solvent was evaporated from the filtrate resulting in a yellow wax (23.6 g). The product was further purified by short path distillation (kugelrohr, P=0.8 mbar, T=150° C.). Yield 19.5 g (69%). The product was characterized by 1H NMR 300 MHz (CDCl3) δ (ppm): 7.3 (dd, 3H), 7.2 (dd, 2H), 5.7 (bs, 1H), 3.1 (tt, 2H), 2.0 (bq, 3H), 1.7 (m, 8H), 1.5 (d, 2H), 1.1 (m, 6H) and by 13CNMR 75 MHz (CDCl3) δ (ppm): 169.3, 131.9, 128.7, 128.3, 126.2, 58.6, 31.6, 27.0, 25.8
Reaction SMILES: [Cl:1][C:2]1[N:6]([CH:7]([F:9])[F:8])[C:5]([CH3:10])=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1.[N+:18]([O-])([OH:20])=[O:19]>>[Cl:1][C:2]1[N:6]([CH:7]([F:8])[F:9])[C:5]([CH3:10])=[N:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([N+:18]([O-:20])=[O:19])[CH:12]=1
Reactant: Cc1nc(-c2ccc(Cl)cc2)c(Cl)n1C(F)F
Reactant: O=[N+]([O-])O
Product: Cc1nc(-c2ccc(Cl)c([N+](=O)[O-])c2)c(Cl)n1C(F)F
Temperature: 0 °C
Reaction time: 2 h

Procedure:
8 g (28 mmol) of 5-chloro-4-(4-chlorophenyl)-1-difluoromethyl-2-methyl-1H-imidazole were cooled to (−40)° C., and 100 ml of concentrated nitric acid were added. After 2 hours at (−20)° C., the mixture was poured into ice-water, whereupon the solid product of value was filtered off, washed with water and dried. Yield: 7 g.
Reaction SMILES: I.[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9](=[NH:11])[NH2:10])[CH2:5][CH2:4]1.[Na].CO[C:15]1[C:16](=O)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1>C(O)C>[CH3:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[N:10]=[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=[C:21]3[N:11]=2)[CH2:5][CH2:4]1
Reactant: COc1cccccc1=O
Reactant: CN1CCN(C(=N)N)CC1
Agent: I
Agent: [Na]
Solvent: CCO
Product: CN1CCN(c2nc3cccccc-3n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Methyl-1-piperazinecarboximidamide hydroiodide (17.8 g) was suspended in ethanol (15 ml). Sodium (1.5 g) in ethanol (47.8 ml) was added to it. The mixture was stirred at room temperature for 30 min. A solution of 2-methoxy-2,4,6-cycloheptatrien-1-one in ethanol (12 ml) was added dropwise. The mixture was refluxed for 3 hr and evaporated. The residue was taken in water and extracted with ethyl acetate in a continuous extractor. The organic layer was dried and evaporated. The residue was chromatographed through a column of silica gel using 5% methanol in chloroform and the eluates were evaporated. The residue was taken up in diethyl ether and filtered. The precipitate was crystallized from diethyl ether-hexane to obtain the title compound (3.4 g): mp 93°-95° C.; ir (CHCl3) 1600, 1565 and 1523 cm-1 ; uv max (MeOH) 291 (ε7,280), 262(ε28,445) and 238 nm(ε23,970); nmr-(CDCl3) δ 2.3(3H,s), 2.5(4H,t), 4.0(4H,t) and 7.2-8.0(5H,m) and Anal. Calcd for C13H16N4 : C, 68.39 % H, 7.06% N, 24.54% N, 24.54% and Found: C, 68.45% H, 6.99% N, 24.27%.
Reaction SMILES: [CH3:1][S:2][C:3]1[S:4][CH:5]=[CH:6][C:7]=1[C:8]1[N:12]([CH2:13][C:14]([OH:16])=[O:15])[N:11]=[N:10][N:9]=1.S(=O)(=O)(O)O.[CH2:22](O)[CH2:23][OH:24]>>[OH:24][CH2:23][CH2:22][O:15][C:14](=[O:16])[CH2:13][N:12]1[C:8]([C:7]2[CH:6]=[CH:5][S:4][C:3]=2[S:2][CH3:1])=[N:9][N:10]=[N:11]1
Reactant: CSc1sccc1-c1nnnn1CC(=O)O
Reactant: OCCO
Agent: O=S(=O)(O)O
Product: CSc1sccc1-c1nnnn1CC(=O)OCCO
Temperature: 90 °C
Reaction time: 2.5 h
Yield: 88.1 %

Procedure:
To a solution of 920 mg (3.6 mM) of [5-(2-methylthio-3-thienyl)tetrazol-1-yl]acetic acid in 5 ml of ethylene glycol was added 0.5 ml of sulfuric acid. After the addition, the mixture was stirred at 90° C. for 2.5 hrs. The mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant residue was subjected to silica gel column chromatography (eluent: chloroform/methyl alcohol=50/1) for separation and purification, to give 950 mg (yield 88.1%) of [5-(2-methylthio-3-thienyl)tetrazol-1-yl] acetic acid 2-hydroxyethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:31])=[CH:4][C:5]([C:27]([F:30])([F:29])[F:28])=[C:6]([CH:26]=1)[C:7]([N:9]([CH:23]([CH3:25])[CH3:24])[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11]1)=[O:8].Br[CH:33]([CH:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1)[C:34](Cl)=[O:35]>>[CH:23]([N:9]([C:7]([C:6]1[C:5]([C:27]([F:30])([F:28])[F:29])=[CH:4][C:3]2[O:31][CH:33]([CH:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)[C:34](=[O:35])[NH:1][C:2]=2[CH:26]=1)=[O:8])[C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:11]1)([CH3:24])[CH3:25]
Reactant: CC(C)N(C(=O)c1cc(N)c(O)cc1C(F)(F)F)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(Cl)C(Br)C1CCOCC1
Product: CC(C)N(C(=O)c1cc2c(cc1C(F)(F)F)OC(C1CCOCC1)C(=O)N2)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1

Procedure:
Using tert-butyl (3R)-3-[[5-amino-4-hydroxy 2-(trifluoromethyl)benzoyl](isopropyl)amino]-piperidine-1-carboxylate and bromo (tetrahydro-2H-pyran-4-yl)acetyl chloride, the title compound was obtained in a similar manner to Reference Example 55.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]2[CH:27]=[CH:26][C:9]3[C:10]4[N:11]=[C:12]([C:18]5[N:19]([CH:23]([CH3:25])[CH3:24])[N:20]=[CH:21][N:22]=5)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH2:3]1.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>>[CH:23]([N:19]1[C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([CH:4]5[CH2:5][N:2]([S:29]([CH3:28])(=[O:31])=[O:30])[CH2:3]5)[CH:27]=[CH:26][C:9]=4[C:10]=3[N:11]=2)=[N:22][CH:21]=[N:20]1)([CH3:25])[CH3:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CNC3)ccc1-2
Agent: Cl
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(S(C)(=O)=O)C3)ccc1-2

Procedure:
Following the procedure for 395, 8-azetidin-3-yl-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene hydrochloride salt and methanesulfonyl chloride were reacted. The reaction mixture was loaded directly onto a silica column with no aqueous work-up to give 259 isolated as a white solid (67 mg, 84%). LCMS: RT=10.97 min, [M+H]+=446. 1H NMR δ (ppm) (CDCl3): 8.36 (1 H, d, J=8.20 Hz), 7.90 (1 H, d, J=0.68 Hz), 7.16 (1 H, dd, J=8.24, 1.88 Hz), 7.02 (1 H, d, J=1.85 Hz), 5.93-5.83 (1 H, m), 4.42-4.36 (2 H, m), 4.30-4.22 (2 H, m), 4.10-4.03 (2 H, m), 3.83-3.73 (1 H, m), 3.43-3.37 (2 H, m), 2.90 (3 H, s), 1.61 (6 H, d, J=6.63 Hz)
Reaction SMILES: [C:1]([C:3]([OH:29])([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1)#[CH:2].[H][H]>[Pd].C1C=CC=CC=1>[CH2:1]([C:3]([OH:29])([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=1[Cl:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13][N:14]([CH2:18][CH2:19][CH3:20])[CH2:15][CH2:16][CH3:17])=[CH:6][CH:5]=1)[CH3:2]
Reactant: [H][H]
Reactant: C#CC(O)(c1ccc(OCCCN(CCC)CCC)cc1)c1ccc(Cl)cc1Cl
Agent: [Pd]
Solvent: c1ccccc1
Product: CCCN(CCC)CCCOc1ccc(C(O)(CC)c2ccc(Cl)cc2Cl)cc1

Procedure:
21.7 g. of α-ethinyl-α-(2,4-dichlorophenyl)-4-[3-(dipropylamino)-propoxy]-benzylalcohol are dissolved in 210 ml. of benzene, and the solution is hydrogenated in the presence of 1.1 g. of a 10% palladium-on-charcoal catalyst. When the uptake of the calculated amount of hydrogen is complete (about 3 hours), catalyst is filtered off and benzene is distilled off. The crude product weighing 21 g. is distilled in vacuo, to yield a product boiling at 194° to 196° C./6.6 Pa.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([NH2:24])[CH:6]([C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[CH2:19][O:20][C:21](=[O:23])[CH3:22])[NH:12][CH:11]=1)[CH2:7][O:8][CH3:9])[CH3:2].O.[C:27]([OH:31])(=[O:30])[CH:28]=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.O>[CH2:1]([O:3][C:4]([CH:5]1[CH:6]([CH2:7][O:8][CH3:9])[C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[CH2:19][O:20][C:21](=[O:23])[CH3:22])[NH:12][C:11]=2[CH:28]([C:27]([OH:31])=[O:30])[NH:24]1)=[O:25])[CH3:2]
Reactant: CCOC(=O)C(N)C(COC)c1c[nH]c2cccc(COC(C)=O)c12
Reactant: O=CC(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1NC(C(=O)O)c2[nH]c3cccc(COC(C)=O)c3c2C1COC
Temperature: 0 °C

Procedure:
A solution of 3-(4-acetoxymethylindol-3-yl)-2-amino-4-methoxy-butyric acid ethyl ester (8.7 g) in ethyl acetate (40 ml) is slowly added drop by drop to a solution of glyoxylic acid monohydrate (2.4 g) in water (30 ml), cooled to 0° C., under argon protection and with stirring. The pH of the solution is adjusted to 4 by addition of potassium carbonate (about 1 g). Then the mixture is stirred for 2 hours, whereby it is allowed to warm to room temperature. Ethyl acetate and water phases are separated, the water phase is shaken out three times with ethyl acetate. The combined ethyl acetate extracts, for their part, are washed once with water, dried with sodium sulfate and evaporated. 9 g of the title compound remains.