Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]([F:14])([F:13])[F:12])=[CH2:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Cl[C:16](=[N:27][OH:28])[C:17]1[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([CH3:26])[CH:18]=1.C(=O)([O-])[OH:30].[K+].O>O1CCCC1>[CH:17]([O:30][CH:9]([CH3:10])[CH3:11])([CH3:22])[CH3:16].[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:11]([F:14])([F:12])[F:13])[O:28][N:27]=[C:16]([C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([CH3:26])[CH:18]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: C=C(c1cc(Cl)cc(Cl)c1)C(F)(F)F
Reactant: Cc1cc(C(Cl)=NO)ccc1[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)OC(C)C
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 113.2 %

Procedure:
In a solution of 1.31 g of 3,5-dichloro-1-(1-trifluoromethylethenyl)benzene synthesized in Step 1 of Synthetic Example 3 and 1.17 g of α-chloro-3-methyl-4-nitrobenzaldoxime in 10 ml of tetrahydrofuran, 1.15 g of potassium hydrogen carbonate and 1.50 g of water were added, and stirred at room temperature for 18 hours. After the completion of the reaction, tetrahydrofuran was removed from the reaction mixture, 3 ml of water was added, and stirred under cooling with ice for further 30 minutes. Precipitated crystal was filtered off, washed with 5 ml of water and then 5 ml of diisopropyl ether to obtain 1.29 g of the aimed product as white crystal.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]=[O:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH3:16]I.Cl>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH:12]=[O:13])=[CH:8][N:9]2[CH3:16])=[CH:5][CH:4]=1
Reactant: CI
Reactant: COc1ccc2c(C=O)c[nH]c2c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(C=O)cn(C)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of 6-methoxy-1H-indole-3-carboxaldehyde (1.65, 9.4 mm) in DMF (10 mL) was cooled to 0° C., and treated with NaH(11.3 mm). After stirring at room temperature for 1 hour, the mixture was cooled to 0° C., treated with CH3I (0.7 mL, 11.3 mm), then allowed to warm to room temperature overnight. After pouring into H2O (200 mL), the mixture was acidified with HCl and extracted with EtOAc (100 mL×2). The combined organic fractions were dried over MgSO4, filtered and evaporated to afford 6-methoxy-1-methyl-1H-indole-3-carboxaldehyde (1.78 g, 99%).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:12](=[S:14])=[S:13]>N1C=CC=CC=1>[C:2]1([C:1]2[S:8][S:14][C:12](=[S:13])[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: S=C=S
Reactant: NC(=S)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: c1ccncc1
Product: S=c1nc(-c2ccccc2)ss1
Temperature: -10 °C
Reaction time: 3 h
Yield: 24 %

Procedure:
A solution of thiobenzamide (100 g, 0.74 mol, Alfa Aesar, Ward Hill, Mass.) was added dropwise to a stirred suspension of NaH (22 g, 0.74 mol, 60% suspension in mineral oil) in pyridine (1 L) at −15° C. followed by the addition of carbon disulfide (122 g, 1.6 mol). The reaction mixture was stirred for 3 h at −10° C. and the solvent was evaporated. The residue was treated with ether, the solution was removed, and the insoluble material was treated in water (1 L). The precipitate was filtered off, and the clear solution was cooled to 0-4° C. and acidified with dilute hydrochloric acid. The crystalline precipitate was collected, washed with water, and dried to yield compound 7 (37.5 g, 24%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:19]2[CH:28]=[CH:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=2)[C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[CH:4][CH:3]=1.C([Li])CCC.C(O[B:38]1[O:42][C:41]([CH3:44])([CH3:43])[C:40]([CH3:46])([CH3:45])[O:39]1)(C)C.O>C1COCC1.C(Cl)(Cl)Cl>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[N:8]([C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)[C:5]1[CH:4]=[CH:3][C:2]([B:38]2[O:39][C:40]([CH3:45])([CH3:46])[C:41]([CH3:43])([CH3:44])[O:42]2)=[CH:7][CH:6]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Brc1ccc(N(c2ccc3ccccc3c2)c2ccc3ccccc3c2)cc1
Agent: [Li]CCCC
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)OB(c2ccc(N(c3ccc4ccccc4c3)c3ccc4ccccc4c3)cc2)OC1(C)C
Temperature: -78 °C
Reaction time: 24 h
Yield: 77.4 %

Procedure:
8.5 g (20 mmol) of (4-bromophenyl)dinaphthalene-2-ylamine was dissolved in 100 ml of THF and was cooled to −78° C. 9.6 ml (24 mmol) of 2.5M n-butyllithium was added slowly to the THF solution and maintained at the same temperature as above for an hour to allow reaction. 4.4 g (24 mmol) of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane was added to the reaction solution, and was maintained at the same temperature as above for an hour. The reaction solution was heated to room temperature (RT) and stirred for 24 hours. Water was added to end the reaction. 300 ml of chloroform was added to the solution and washed with 200 ml of water. The resulting organic layer was dried with anhydride magnesium sulfate. 7.3 g of dinaphthalen-2-yl-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolane-2-yl)phenyl]amine (intermediate B) was obtained through silica chromatography with a yield of 77%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:28]#[N:29])[C:17]([O:19][CH2:20][CH2:21][N:22]([CH2:24][CH2:25][O:26][CH3:27])[CH3:23])=[CH:18][C:13]=2[NH:12][C:11](=S)[CH2:10][N:9]=1.CO[C:33](OC)([N:35](C)C)[CH3:34].[NH2:40]N>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:28]#[N:29])[C:17]([O:19][CH2:20][CH2:21][N:22]([CH2:24][CH2:25][O:26][CH3:27])[CH3:23])=[CH:18][C:13]=2[N:12]=[C:11]2[NH:40][NH:35][C:33]([CH3:34])=[C:10]2[N:9]=1
Reactant: COCCN(C)CCOc1cc2c(cc1C#N)C(c1ccccc1Cl)=NCC(=S)N2
Reactant: NN
Reactant: COC(C)(OC)N(C)C
Product: COCCN(C)CCOc1cc2c(cc1C#N)C(c1ccccc1Cl)=NC1=C(C)NNC1=N2

Procedure:
5-(2-chlorophenyl)-7-cyano-1,2-dihydro-8-(2-((2-methoxyethyl)methylamino)-ethoxy)-3-methyl-pyrazolo[3,4-b][1,4]benzodiazepine (IVv) was prepared by reacting 0.0005 moles of 5-(2-chlorophenyl)-7-cyano-1,3-dihydro-8-(2-((2-methoxyethyl)methylamino)-ethoxy)-2H-1,4-benzodiazepin-2-thione (IIv) with 1,1-dimethoxy-N,N-dimethyl-ethanamine and then hydrazine in a manner analogous to Example 55. MH+/Z=465.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[C:12](OC2C(OC)=CC(NC)=C(N)C=2)[CH:11]=[CH:10][N:9]=1)=[O:7])(C)(C)C.NC(N)=S.IC.C(OC(C1C=C([O:45][C:46]2[CH:63]=[CH:62][C:49]3[N:50]([CH3:61])[C:51]([NH:53][C:54]4[CH:59]=[CH:58][C:57]([Cl:60])=[CH:56][CH:55]=4)=[N:52][C:48]=3[CH:47]=2)C=CN=1)=O)(C)(C)C.FC(F)(F)[C:66](O)=[O:67]>CO.C(Cl)Cl>[Cl:60][C:57]1[CH:56]=[CH:55][C:54]([NH:53][C:51]2[N:50]([CH3:61])[C:49]3[CH:62]=[C:63]([O:67][CH3:66])[C:46]([O:45][C:8]4([C:6]([OH:7])=[O:5])[CH:13]=[CH:12][CH:11]=[CH:10][NH:9]4)=[CH:47][C:48]=3[N:52]=2)=[CH:59][CH:58]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CNc1cc(OC)c(Oc2ccnc(C(=O)OC(C)(C)C)c2)cc1N
Reactant: Cn1c(Nc2ccc(Cl)cc2)nc2cc(Oc3ccnc(C(=O)OC(C)(C)C)c3)ccc21
Agent: NC(N)=S
Solvent: CI
Solvent: CO
Solvent: ClCCl
Product: COc1cc2c(cc1OC1(C(=O)O)C=CC=CN1)nc(Nc1ccc(Cl)cc1)n2C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To tert-butyl4-[3-amino-6-methoxy-4-(methylamino)phenoxy]pyridine-2-carboxylate (1 eq) in methanol was added 4-chlorobenzeneisothiocyanate (1 eq) and stir at ambient temperature for 16 h. Formation of the corresponding thiourea was followed by LC/MS. To it was then added iodomethane (1 eq) and heated to 60° C. for 2 h. Formation of tert-butyl4-(2-{[4-chlorophenyl]amino)-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylate was followed by LC/MS. To it in methylene chloride was added trifluoroacetic acid and stirred at ambient temperature overnight. Resulting 4-(2-{[4-chlorophenylamino)-6-methoxy-1-methylbenzimidazol-5-yloxy)pyridine-2-carboxylic acid was purified by preparative chromatography. MS: MH+=424.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[C:12]=1[C:13]([O:15][CH3:16])=[O:14].[C:22](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O.ClCCl>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:10][C:11]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[C:12]=2[C:13]([O:15][CH3:16])=[O:14])=[CH:3][CH:4]=1)=[O:7]
Reactant: COC(=O)c1c(O)cccc1O
Reactant: O=C([O-])[O-]
Reactant: O=Cc1ccc(F)cc1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1c(OC)cccc1Oc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.1 %

Procedure:
4-Fluorobenzaldehyde (1.00 g, 8.06 mmol) and methyl 2,6-dihydroxybenzoate (2.03 g, 12.1 mmol) were dissolved in N,N-dimethylformamide (50 mL) and potassium carbonate (1.11 g, 8.06 mmol) was added. The reaction was stirred at room temperature overnight. The reaction was diluted with water (25 mL) and the layers separated. The aqueous phase was extracted twice with ethyl acetate (25 mL) then twice with diethyl ether (50 mL). The organic phases were combined and dried over MgSO4. The solution was filtered and the solvent evaporated then placed under high vacuum. The mixture was chromatographed, eluted with 25–50% ethyl acetate/hexanes. The desired fractions were combined and concentrated to give a light yellow oil. The product was redissolved in a minimum amount of dichloromethane, triturated with hexane and the solvent evaporated to give an oily yellow solid (0.21 g, 9%). 1H NMR (400 MHz, CDCl3): δ 9.93 (s, 1H), 7.84 (m, 2H), 7.38 (t, J=8.4 Hz, 1H), 7.08 (m, 2H), 6.81 (d, J=8.3 Hz, 1H), 6.63 (d, J=8.2 Hz, 1H), 3.89 (s, 3H), 3.78 (s, 3H); LCMS found for C16H15O5 (M+H)+: m/z=287.0.
Reaction SMILES: [Br:1]Br.[NH2:3][C:4]1[CH:8]=[C:7]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][C:10]=2[Cl:20])[N:6]([CH3:21])[N:5]=1>C(Cl)(Cl)(Cl)Cl>[NH2:3][C:4]1[C:8]([Br:1])=[C:7]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:17])[F:18])=[CH:11][C:10]=2[Cl:20])[N:6]([CH3:21])[N:5]=1
Reactant: Cn1nc(N)cc1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: Cn1nc(N)c(Br)c1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 136.9 %

Procedure:
Bromine (0.12 g) was added to a solution of 0.3 g of 3-amino-5-(2,6-dichloro-4-trifluoromethylphenyl)-1-methylpyrazole in 5 ml of anhydrous carbon tetrachloride at room temperature, and the mixture was stirred at room temperature for 10 minutes. The solvent was distilled off under reduced pressure to obtain a residue, which was then purified by column chromatography on silica gel (eluent: ether/hexane=1/5), affording 0.4 g of the desired compound in the form of white crystals (quantitative yield).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-])=[O:7])=[CH:4][C:3]=1[S:11]([OH:13])=[O:12].[Na+].[Na+].Cl[C:17]1C=CC(C([O-])=O)=CC=1S(O)=O.CI.CN(C)[CH:33]=[O:34]>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:34][CH3:33])=[O:7])=[CH:4][C:3]=1[S:11]([CH3:17])(=[O:13])=[O:12]
Reactant: O=C([O-])c1ccc(Cl)c(S(=O)O)c1
Reactant: CN(C)C=O
Agent: [Na+]
Solvent: CI
Product: COC(=O)c1ccc(Cl)c(S(C)(=O)=O)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
250 g of disodium 4-chloro-3-hydroxysulfinylbenzoate were suspended in 500 ml of abs. dimethylformamide at RT, 218 ml of methyl iodide (3.5 mol) were added and the reaction mixture was heated to 60° C. It was subsequently stirred at this temperature for 4 hours, then allowed to stand at RT overnight. The mixture became solid on cooling. It was warmed to 70° C., diluted with 250 ml of abs. dimethylformamide and subsequently stirred at 70° C. for a further 3 hours. The solvent was distilled off, the residue was taken up in 1000 ml of water, stirred for 30 minutes in an ice bath, filtered off with suction and washed 3 times with about 200 ml of water each time, sucked dry and dried in vacuo (50° C.).
Reaction SMILES: [H-].[Na+].[CH2:3]([C:5]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[O:7][N:6]=1)[CH3:4].[CH2:19]([CH:21]1[O:23][CH2:22]1)Br.[Cl-].[Na+]>>[CH2:3]([C:5]1[CH:9]=[C:8]([CH:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[O:18][CH2:19][CH:21]2[O:23][CH2:22]2)[O:7][N:6]=1)[CH3:4]
Reactant: CCc1cc(C=Cc2ccccc2O)on1
Reactant: BrCC1CO1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Product: CCc1cc(C=Cc2ccccc2OCC2CO2)on1

Procedure:
This compound is prepared, using the method described in Example V, from 5.1 g of 55% strength sodium hydride (0.116 mole), 25.0 g (0.116 mole) of 3-ethyl-5-(2-hydroxystyryl)-isoxazole and 15.9 g (0.116 mole) of epibromohydrin. The reaction mixture is poured into sodium chloride solution and the batch is extracted by shaking with diethyl ether. The ether solution is dried with anhydrous sodium sulfate and evaporated down. 29.2 g (93% of theory) of a colorless oil are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].C([O-])([O-])=O.[K+].[K+]>CC#N>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)CBr
Reactant: Oc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)COc1ccccc1Br
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 2-bromophenol (2 g, 0.0116 mol) in MeCN (10 mL) was added ethyl bromoacetate (2.12 g, 0.0128 mol) and K2CO3 (4.81 g, 0.035 mol). The mixture was stirred at 80° C. for 4 h, filtered and concentrated. The crude product was used in the next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.O.C(OC([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[C:27]([Br:29])[CH:28]=2)[C@@H:18]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:17]1)=O)(C)(C)C>ClCCl>[Br:29][C:27]1[CH:28]=[C:23]([CH2:22][N:19]2[CH2:20][CH2:21][NH:16][CH2:17][C@@H:18]2[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:24]=[N:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cncc(Br)c2)[C@@H](c2ccc(F)cc2)C1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc([C@H]2CNCCN2Cc2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 200.3 %

Procedure:
A mixture of trifluoroacetic acid and water (TFA:water=19:1, 10 mL) was added to a solution of (S)-4-(5-bromo-pyridin-3-ylmethyl)-3-(4-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (300 mg, 0.67 mmol) in 3 mL of dichloromethane and the resulting mixture stirred at ambient temperature for 1.5 h, and then the volatiles were removed in vacuo to leave 470 mg of product. LC/MS: Retention time, 2.13 min; (M+H)=351.
Reaction SMILES: [CH2:1]([N:8]([CH2:10][C:11]1[N:15]=[C:14]([CH2:16][C:17]#[N:18])[O:13][N:12]=1)[CH3:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:19]([C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=1)[CH:25]=[C:26]([C:31]([CH3:33])=[O:32])[C:27]([O:29][CH3:30])=[O:28])([O-:21])=[O:20].N1CCCCC1>C(O)C>[NH2:18][C:17]1[O:32][C:31]([CH3:33])=[C:26]([C:27]([O:29][CH3:30])=[O:28])[CH:25]([C:24]2[CH:34]=[CH:35][CH:36]=[C:22]([N+:19]([O-:21])=[O:20])[CH:23]=2)[C:16]=1[C:14]1[O:13][N:12]=[C:11]([CH2:10][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH3:9])[N:15]=1
Reactant: CN(Cc1ccccc1)Cc1noc(CC#N)n1
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Solvent: CCO
Solvent: C1CCNCC1
Product: COC(=O)C1=C(C)OC(N)=C(c2nc(CN(C)Cc3ccccc3)no2)C1c1cccc([N+](=O)[O-])c1
Yield: 33.4 %

Procedure:
To a stirred mixture of 1.21 g of 3-(N-benzyl-N-methylamino)methyl-5-cyanomethyl-1,2,4-oxadiazole prepared in Example 95 and 1.25 g of methyl 2-(3-nitrobenzylidene)acetoacetate in 10 ml of ethanol was added 0.1 ml of piperidine. The reaction mixture was heated under reflux for 3 hours and then concentrated in vacuo. The residue was triturated with 10 ml of ethyl acetate and the insoluble crystals were collected by filtration. Treatment of a solution of this base in chloroform with etherial hydrogen chloride afforded 820 mg of methyl 2-amino-3-[3-(N-benzyl-N-methylamino)methyl-1,2,4-oxadiazol-5-yl]-6-methyl-4-(3-nitrophenyl)-4H-pyran-5-carboxylate as pale yellow powder, m.p. 201.5° C. (decomp.).
Reaction SMILES: [C:1](=[S:3])=[S:2].OS(O[CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[NH:11]1)(=O)=O>[OH-].[Na+]>[CH2:9]1[CH:10]2[CH2:18][C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]2[C:1](=[S:3])[S:2]1
Reactant: S=C=S
Reactant: O=S(=O)(O)OCC1Cc2ccccc2N1
Agent: [Na+]
Agent: [OH-]
Product: S=C1SCC2Cc3ccccc3N12
Temperature: 20 °C
Reaction time: 2 h

Procedure:
Carbon disulphide (65 cc) is added to a suspension of (RS)-2-hydroxysulphonyloxymethylindoline (45.8 g) in 1.5 N aqueous sodium hydroxide solution (400 cc). After stirring for 2 hours at a temperature of about 20° C., a solution is obtained and the formation of beige crystals is then observed; stirring is continued for 12 hours. The crystals formed are filtered off, washed with water and then recrystallised from ethanol (850 cc). (RS)-9,9a-dihydrothiazolo[3,4-a]indole-3-thione (31.3 g) is thus obtained in the form of white crystals melting at 132° C.
Reaction SMILES: [CH:1]([N:4]1[CH2:11][CH:10]2[CH2:12][CH:6]([CH2:7][NH:8][CH2:9]2)[CH2:5]1)([CH3:3])[CH3:2].[OH-].[Na+].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:20](Cl)=[O:21].O>C(Cl)Cl>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:20]([N:8]1[CH2:9][CH:10]2[CH2:12][CH:6]([CH2:5][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:11]2)[CH2:7]1)=[O:21]
Reactant: COc1ccc(C(=O)Cl)cc1OC
Reactant: CC(C)N1CC2CNCC(C2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CC3CC(C2)CN(C(C)C)C3)cc1OC
Reaction time: 3 h
Yield: 73.3 %

Procedure:
A 25-mL, three-necked, round-bottomed flask was equipped with a magnetic stirrer, a standard condenser with a N2 inlet, a 10-mL addition funnel, and two glass stoppers. To a mixture of the amine (31, 0.60 g, 3.57 mmol) in CH2Cl2 (5 mL) and 10% NaOH (3.58 g, 8.93 mmol) was added dropwise a solution of 3,4-dimethoxybenzoyl chloride (0.80 g, 3.92 mmol) in CH2Cl2 (10 mL) over 15 min. Stirring of the mixture was continued for an additional 3 h under N2. An aqueous mixture, formed upon addition of H2O (30 mL), was extracted (CH2Cl2, 4×25 mL). Combined extracts were dried (Na2SO4, 2 h), filtered and concentrated to give a viscous yellow oil. Chromatography of the oil was performed on neutral alumina (74 g, 1.7 cm×32 cm) using 60:40 ethyl acetate/hexanes as eluant. Fractions (Rf = 0.31) were saved and concentrated (rotary evaporator then vacuum pump, overnight, RT/0.2 mm Hg) to give 0.87 g (73.1%) of off-white solid (34); mp 67.5°-69.5° C. IR (KBr) cm-1 3055 (Ar C--H), 2950, 2915, 2845, 2820, 2770, 2750, 2710 (C--H), 1625 (C=O); 1H NMR (DCCl3) δ0.96 (d, 3 H, CH3, J=6.4 Hz), 1.06 (d, 3 H, CH3, J=6.5 Hz), 1.62-1.75 [m, 3 H, H(5) and H(9)], 1.96 [bs, 1 H, H(1)], 2.43 [bd, 1 H, H(4)ax, J=9.7 Hz], 2.51 [bd, 1 H, H(6)ax, J=10.5 Hz], 2.62 [heptet, 1 H, CH(CH3)2, J=6.4 Hz], 2.74 [bd, 1 H, H(6)eq, J=9.9 Hz], 3.00-3.09 [m, 2 H, H(4)eq and H(2)ax ], 3.32 [bd, 1 H, H(8)ax, J=13.2 Hz], 3.83-3.94 [m, 7 H, H(8)eq and OCH3 ], 4.77 [bd, 1 H, H(2)eq, J=13.3 Hz], 6.84-6.94 (m, 3 H, Ar--H); 13C NMR (DCCl3) ppm 16.46, 19.15 (CH3), 29.13 [C(1)], 29.86 [C(5)], 32.36 [C(9)], 46.71 [C(2)], 52.25 [C(4)], 52.65 [C(8)], 54.35 [CH(CH3)2 ], 54.68 [C(6)], 55.88, 55.93 (OCH3), 110.50, 119.64, 130.23, 148.78, 149.39 (Ar--C), 169.90 (C=O). Anal. Calcd. for C19H28N2O3 : C, 68.65; H, 8.49. Found: C, 68.58; H, 8.47.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH3:12])(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH3:22][O:23][CH2:24][C@H:25]([CH3:45])[O:26][C:27]1[CH:28]=[C:29]([OH:44])[CH:30]=[C:31]([C:33]2[NH:34][C:35]([C:38]3[O:39][C@@H:40]([CH3:43])[CH2:41][N:42]=3)=[CH:36][CH:37]=2)[CH:32]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:21][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][N:11]([CH3:12])[S:8]([C:5]2[CH:4]=[CH:3][C:2]([O:44][C:29]3[CH:30]=[C:31]([C:33]4[NH:34][C:35]([C:38]5[O:39][C@@H:40]([CH3:43])[CH2:41][N:42]=5)=[CH:36][CH:37]=4)[CH:32]=[C:27]([O:26][C@@H:25]([CH3:45])[CH2:24][O:23][CH3:22])[CH:28]=3)=[CH:7][N:6]=2)(=[O:10])=[O:9])=[CH:15][CH:16]=1
Reactant: COC[C@H](C)Oc1cc(O)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Reactant: COc1ccc(CN(C)S(=O)(=O)c2ccc(Cl)cn2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(=O)(=O)N(C)Cc3ccc(OC)cc3)nc2)cc(-c2ccc(C3=NC[C@H](C)O3)[nH]2)c1
Temperature: 100 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
5-Chloro-N-(4-methoxybenzyl)-N-methylpyridine-2-sulfonamide (228 mg, 0.70 mmol) synthesized in Example (121b) and 3-[(1S)-2-methoxy-1-methylethoxy]-5-{5-[(5S)-5-methyl-4,5-dihydro-1,3-oxazol-2-yl]-1H-pyrrol-2-yl}phenol (220 mg, 0.67 mmol) synthesized in Example (116d) were dissolved in N,N-dimethylformamide (3 mL), and cesium carbonate (434 mg, 1.33 mmol) was added, followed by stirring at 100° C. for 3 hours under nitrogen atmosphere. The reaction solution was cooled to room temperature, water (20 mL) was added, and extraction was carried out twice with ethyl acetate (20 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: methanol/methylene chloride=0.5%-5%) to afford the desired compound (293 mg, yield 71%) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12](=O)[CH:11]([NH:16][C:17]([C:19]2[S:20][C:21]3[C:27]([N:28]4[CH2:33][CH2:32][O:31][CH2:30][CH2:29]4)=[CH:26][CH:25]=[C:24]([O:34][CH3:35])[C:22]=3[N:23]=2)=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+:40].C(=O)(O)[O-].[Na+]>O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[N:40]=[C:17]([C:19]3[S:20][C:21]4[C:27]([N:28]5[CH2:29][CH2:30][O:31][CH2:32][CH2:33]5)=[CH:26][CH:25]=[C:24]([O:34][CH3:35])[C:22]=4[N:23]=3)[NH:16][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [NH4+]
Reactant: COc1ccc(N2CCOCC2)c2sc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CCC3=O)nc12
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: COc1ccc(N2CCOCC2)c2sc(-c3nc4c([nH]3)CCN(C(=O)OC(C)(C)C)CC4)nc12
Temperature: 25 °C
Yield: 69.3 %

Procedure:
A mixture of 0.15 g 4-[(4-methoxy-7-morpholin-4-yl-benzothiazole-2-carbonyl)-amino]-5-oxo-azepane-1-carboxylic acid tert-butyl ester and 0.46 g ammonium acetate was melted at 120° C. for 3 hours and, after cooling to room temperature, suspended in a 1:1 mixture of water and saturated aqueous sodiumbicarbonate. Extraction with dichloromethane and chromatography on silicagel with dichloromethane/methanol 98:2 gave 0.10 g (72%) 2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepine-6-carboxylic acid tert-butyl ester as yellow solid; M.p.: 142–144° C.; MS (ISP): m/e=486 (M+H+).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@H:4]([C:7](O)=O)[CH2:3]1.[CH:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][C:11]=1[S:20](Cl)(=[O:22])=[O:21].[C:24]([O-:27])([O-])=[O:25].[Na+].[Na+]>O>[CH2:15]([O:1][C@H:2]1[CH2:6][N:5]([S:20]([C:11]2[CH:12]=[CH:13][C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:10]=2)(=[O:22])=[O:21])[C@H:4]([CH2:7][C:24]([OH:27])=[O:25])[CH2:3]1)[C:14]1[CH:19]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C([O-])[O-]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [Na+]
Solvent: O
Product: O=C(O)C[C@@H]1C[C@@H](OCc2ccccc2)CN1S(=O)(=O)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.62 g of (2S,4R)-4-hydroxyproline are dissolved in 15 ml of water containing 5.9 g of Na2CO3 and 5.21 g of 2-naphthalenesulphonyl chloride are added. After vigorous stirring for 18 hours at RT, the mixture is drained and the filtrate is then acidified to pH=1. The resulting mixture is again drained, washed with water and dried in order to obtain 4.1 g of the expected compound.