Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14](OC(C)(C)C)[CH2:13][C@H:12]1[C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC([N:40]1C[C@@H](N)C[C@H]1C1OC=CN=1)=O)C1C=CC=CC=1>>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([NH2:40])[CH2:13][C@H:12]1[C:21]1[O:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](c2nc3ccccc3o2)N(C(=O)OCc2ccccc2)C1
Reactant: N[C@H]1C[C@@H](c2ncco2)N(C(=O)OCc2ccccc2)C1
Product: N[C@H]1C[C@@H](c2nc3ccccc3o2)N(C(=O)OCc2ccccc2)C1

Procedure:
(2S,4S)-4-amino-2-benzooxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester was prepared from (2S,4R)-2-benzooxazol-2-yl-4-tert-butoxy-pyrrolidine-1-carboxylic acid benzyl ester in a similar reaction sequence used in the preparation of (2S,4S)-4-amino-2-oxazol-2-yl-pyrrolidine-1-carboxylic acid benzyl ester. MS calcd. for C19H20N3O3 [(M+H)+] 338, obsd. 338.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]=2[CH:13]=1.[Mg].[CH:15](N1CCOCC1)=[O:16].[NH4+].[Cl-]>C1COCC1>[CH:15]([C:2]1[CH:3]=[CH:4][C:5]2[S:10][CH2:9][CH2:8][C:7]([CH3:12])([CH3:11])[C:6]=2[CH:13]=1)=[O:16]
Reactant: CC1(C)CCSc2ccc(Br)cc21
Reactant: O=CN1CCOCC1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)CCSc2ccc(C=O)cc21
Temperature: -10 °C
Reaction time: 1 h
Yield: 96.9 %

Procedure:
The 6-bromo-4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyran (2.62 g, 10 mmol) prepared in the previous step (b) and in solution in 5 ml of anhydrous THF, is added at 66° C. to magnesium (0.30 g, 12 mmol) in 1 ml of anhydrous THF. The mixture is agitated at reflux of the THF until quasi-complete consumption of the magnesium (30 minutes). The reaction medium is then cooled to −10° C. and at this temperature, the N-formylmorpholine (1.2 ml, 12 mmol) in 2 ml of THF is added. At the end of the addition, the reaction medium is brought to ambient temperature for 1 hour. After hydrolysis by 10 ml of an aqueous saturated NH4Cl solution at 0° C. and extraction with ethyl ether (5×30 ml), the organic phase is dried over MgSO4, filtered and evaporated. The raw product is purified by flash chromatography on silica (eluent petroleum ether:ethyl ether:100:5). 2.00 g of 6-formyl-4,4-dimethyl-3,4-dihydro-2H-1-benzothiopyran is obtained (yield=61%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:18]=[C:17]3[C:12]([CH:13]=[CH:14][C:15](=O)[NH:16]3)=[CH:11][CH:10]=2)[CH:4]=1.P(Cl)(Cl)([Cl:22])=O>>[Cl:22][C:15]1[CH:14]=[CH:13][C:12]2[C:17](=[CH:18][C:9]([C:5]3[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][N:6]=3)=[CH:10][CH:11]=2)[N:16]=1
Reactant: COc1ccnc(-c2ccc3ccc(=O)[nH]c3c2)c1
Reactant: O=P(Cl)(Cl)Cl
Product: COc1ccnc(-c2ccc3ccc(Cl)nc3c2)c1

Procedure:
A suspension of 7-(4-methoxypyridin-2-yl)-2-quinolone (130 mg) in phosphorus oxychloride (5 ml) was refluxed for 2 hours. The mixture was evaporated under reduced pressure. The residue was poured into a saturated aqueous sodium hydrogencarbonate solution and extracted with dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure to give 2-chloro-7-(4-methoxypyridin-2-yl)quinoline (140mg).
Reaction SMILES: [NH:1]([C:4]1[CH:5]=[C:6]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:8][CH:9]=1)[C:2]#[N:3].Cl.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>ClCCl>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:2]([NH:1][C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([C:10]([F:11])([F:12])[F:13])[CH:5]=2)=[NH:3])=[CH:18][CH:17]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: N#CNc1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Product: N=C(NCc1ccc(Cl)cc1)Nc1cccc(C(F)(F)F)c1
Temperature: 150 °C
Reaction time: 40 h

Procedure:
A mixture of 3-cyanamidobenzotrifluoride (1.20 g, 6.45 mmol) and 4-chlorobenzylamine hydrochloride (1.26 g, 7.09 mmol) was stirred at 150° C. for 40 h. Dichloromethane (100 ml) was added and the mixture was washed with saturated aqueous sodium hydrogen carbonate (100 ml). The organic phase was purified by chromatography using silica gel and a mixture of methanol (10%) and dichloromethane as eluent. The product was isolated as the free base. Yield 1.05 g, 50%. M.p. 103-105° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[O:15][C:6]2=[CH:7][C:8]3[C:9]([CH:14]=[C:5]2[CH:4]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]1[OH:22])=[N:10][O:11][N+:12]=3[O-].C(O)CO.[N-]=[N+]=[N-].[Na+]>O>[CH3:1][C:2]1([CH3:23])[O:15][C:6]2=[CH:7][C:8]3[C:9]([CH:14]=[C:5]2[CH:4]([N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:3]1[OH:22])=[N:10][O:11][N:12]=3
Reactant: CC1(C)Oc2cc3c(cc2C(N2CCCCC2)C1O)no[n+]3[O-]
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: OCCO
Product: CC1(C)Oc2cc3nonc3cc2C(N2CCCCC2)C1O
Temperature: 140 °C
Yield: 29.8 %

Procedure:
A mixture of 297 mg (0.93 m mol) of 7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(1-piperidinyl)-6H-pyrano [2,3-f] benzo-2,1,3-oxadiazole 3-oxide, 6 ml of ethylene glycol and 60 mg (0.93 m mol) of NaN3 was heated to 140° C. and reacted for 1.2 hours. After cooling, the reaction solution was poured into water and extracted thrice with chloroform. After the combined chloroform layer was dried over anhydrous sodium sulfate, the solvent was distilled off. The residue was subjected to a silica gel column chromatography using a developing solvent of ethyl acetate-hexane (1:3 (v/v)) to obtain 84 mg (yield: 30%) of the intended compound as oil. A part of the obtained compound was dissolved in ethanol-ethyl ether and added with HCl--EtOH to obtain the hydrochloride of the intended compound as pale yellow crystals.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH:5]([O:35][CH2:36][CH3:37])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[O:18])=[CH:9][CH:8]=1)C.[OH-].[Na+].Cl>C(O)C>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[NH:19][C:17](=[O:18])[N:16]([CH2:15][CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([CH2:6][CH:5]([O:35][CH2:36][CH3:37])[C:4]([OH:38])=[O:3])=[CH:12][CH:11]=1)[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCN(CCOc1ccc(CC(OCC)C(=O)OCC)cc1)C(=O)Nc1ccc(F)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCN(CCOc1ccc(CC(OCC)C(=O)O)cc1)C(=O)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
A solution of the compound obtained in Example 1, Step f (40 mg) in ethanol (2 ml) was added with 1 N aqueous sodium hydroxide (0.1 ml) and stirred at room temperature for 2 hours and then at 50° C. for 1 hour. The reaction mixture was added with 1 N hydrochloric acid (0.1 ml) and concentrated, and the resulting residue was applied on a silica gel column and eluted with methylene chloride/ethanol (10:1, containing 1% acetic acid) to obtain the title compound (35.6 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH2:5]([O:7][C:8]([C:10]1[CH:25]=[CH:24][C:13]([O:14][C:15]2[N:23]=[CH:22][CH:21]=[CH:20][C:16]=2[C:17](Cl)=[O:18])=[CH:12][CH:11]=1)=[O:9])[CH3:6]>[N+](C1C=CC=CC=1)([O-])=O>[O:18]=[C:17]1[C:16]2[C:15](=[N:23][CH:22]=[CH:21][CH:20]=2)[O:14][C:13]2[CH:12]=[CH:11][C:10]([C:8]([O:7][CH2:5][CH3:6])=[O:9])=[CH:25][C:24]1=2
Reactant: CCOC(=O)c1ccc(Oc2ncccc2C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: CCOC(=O)c1ccc2oc3ncccc3c(=O)c2c1
Temperature: 0 °C
Yield: 56.8 %

Procedure:
1.7 g of anhydrous aluminum chloride is added in small portions to a solution of 1.2 g of 2-(p-ethoxycarbonylphenoxy)nicotinoyl chloride in 5 ml of nitrobenzene at room temperature with stirring. The mixture is stirred at 80°C for 4 hours, and poured into ice water to decompose aluminum chloride. The nitrobenzene layer is separated, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is recrystallized from ethanol to give 0.6 g of ethyl 5-oxo-5H-[1]benzopyrano[2,3-b]pyridine-7-carboxylate melting at 131°-132°C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=O.FC(F)(F)C(O)=O.[CH:20]([C:23]1[S:24][CH:25]=[C:26]([C:28]([N:30]2[CH2:35][C:34]3([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3)[O:33][CH2:32][CH2:31]2)=[O:29])[N:27]=1)([CH3:22])[CH3:21].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CN1CCCC1=O.O.C(O)(=O)C>[OH:1][CH2:2][CH2:3][S:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH2:8][N:38]1[CH2:39][CH2:40][C:34]2([O:33][CH2:32][CH2:31][N:30]([C:28]([C:26]3[N:27]=[C:23]([CH:20]([CH3:21])[CH3:22])[S:24][CH:25]=3)=[O:29])[CH2:35]2)[CH2:36][CH2:37]1
Reactant: CC(C)c1nc(C(=O)N2CCOC3(CCNCC3)C2)cs1
Reactant: O=Cc1cccc(SCCO)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: CN1CCCC1=O
Product: CC(C)c1nc(C(=O)N2CCOC3(CCN(Cc4cccc(SCCO)c4)CC3)C2)cs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-(2-Hydroxyethylthio)benzaldehyde (example 65, step c) (0.16 g) was added to a solution of (2-isopropylthiazol-4-yl)(1-oxa-4,9-diazaspiro[5.5]undecan-4-yl)methanone trifluoroacetate (example 22, step b) (0.25 g) and acetic acid (0.046 mL) in N-methyl-2-pyrrolidinone (5 mL) and the resulting mixture was stirred for 1 h and cooled in an ice bath. Sodium triacetoxyborohydride (0.26 g) was then added and the mixture allowed to warm to RT and stirred overnight. The reaction was poured into a mixture of sodium bicarbonate solution (20 mL) and water (80 mL). The aqueous phase was extracted with ether (3×100 mL). The combined organic solutions were washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The crude product was purified by silica gel chromatography eluting with 95:5 ethyl acetate:triethylamine. The fractions containing product were combined and evaporated to give the subtitled compound as a yellow oil. Yield 0.22 g.
Reaction SMILES: C(OC(=O)[C:5](=[C:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)[C:6]#[N:7])C.[C-:22]#[N:23].[K+]>CCO.O>[CH2:14]([N:11]1[CH2:10][CH2:9][C:8]([CH2:5][C:6]#[N:7])([C:22]#[N:23])[CH2:13][CH2:12]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(C#N)=C1CCN(Cc2ccccc2)CC1
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CCO
Product: N#CCC1(C#N)CCN(Cc2ccccc2)CC1
Reaction time: 24 h
Yield: 81.2 %

Procedure:
To a solution of (1-benzyl-piperidin-4-ylidene)-cyano-acetic acid ethyl ester (112.9 g, 0.40 mol) in EtOH (500 ml) and H2O (100 ml), potassium cyanide (64.6 g, 0.99 mol) is added at ambient temperature. The reaction mixture is stirred at 65 C.° for 24 h. After removal of EtOH, H2O is added to the residue. The waster phase is extracted with diethyl ether. The combined extracts are washed with H2O and brine, dried over sodium sulfate and evaporated down to give 77.7 g of 1-benzyl-4-cyanomethyl-piperidine-4-carbonitrile.
Reaction SMILES: [Na].C(O)C.[CH:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:10][CH2:11][C:12](OCC)=[O:13]>C(OCC)C>[Cl:10][CH:11]([CH:12]=[O:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CCl
Reactant: CCOC=O
Agent: [Na]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)C(Cl)C=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 14 %

Procedure:
To a flask was added sodium (4.45 g, 194 mmol) and ethanol (56.5 mL, 968 mmol) and the mixture was stirred at room temperature for 4 hours until all of the metal had dissolved. Diethyl ether (100 mL) was added, followed by the slow addition of ethyl formate (17.2 mL, 213 mmol) and ethyl chloroacetate (22.79 mL, 213 mmol) as a solution in diethyl ether (100 mL). The reaction solution was stirred at room temperature for 16 hours. The resulting precipitate that formed was filtered and washed with ether, and dissolved in water. The aqueous layer was acidified with HCl (1N) to pH 4, and the product was extracted with diethyl ether (3 times). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated to give 1B (4.5 g, 15.4% yield).
Reaction SMILES: [C:1]1([N:7]2[CH2:19][C:18]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[N:11]=[CH:10][C:9]=3[C:8]2=[O:20])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:29])C=1>C(Cl)Cl>[C:1]1([N:7]2[CH2:19][C:18]3[C:17]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[NH:11][C:10](=[O:29])[C:9]=3[C:8]2=[O:20])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=C1c2cnc3ccccc3c2CN1c1ccccc1
Solvent: ClCCl
Product: O=C1c2c(c3ccccc3[nH]c2=O)CN1c1ccccc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A mixture of 2-Phenyl-pyrrolo[3,4-c]quinolin-3(1H)-one (60 mg), and m-chloroperbenzoic acid (105 mg) in 3 mL of methylene chloride was kept at room temperature for 24 h. The mixture was diluted with methylene chloride and washed with sodium carbonate solution. The organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was heated at 50° C. for 3 h with 1 mL of acetic anhydride. The reaction was quenched with methanol and made basic with ammonium hydroxide. The reaction mixture was concentrated in vacuo, and the resulting aqueous solution was extracted with ethyl acetate, the organic layer was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was triturated with ether to afford 2-Phenyl-pyrrolo[3,4-c]quinoline-3(1H),4(5H)-dione (Compound 16) as a white solid.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[S:11][CH2:10][CH2:9][C:8]2([CH3:16])[CH3:15])[OH:4])#[CH:2].[OH:17][C:18]1[CH:27]=[C:26](I)[CH:25]=[CH:24][C:19]=1[C:20]([O:22][CH3:23])=[O:21].C(N(CC)CC)C>O.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)I>[CH3:23][O:22][C:20](=[O:21])[C:19]1[CH:24]=[CH:25][C:26]([C:2]#[C:1][CH:3]([OH:4])[C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][CH:14]=2)[S:11][CH2:10][CH2:9][C:8]3([CH3:16])[CH3:15])=[CH:27][C:18]=1[OH:17]
Reactant: COC(=O)c1ccc(I)cc1O
Reactant: C#CC(O)c1ccc2c(c1)C(C)(C)CCS2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: O
Solvent: CCOCC
Product: COC(=O)c1ccc(C#CC(O)c2ccc3c(c2)C(C)(C)CCS3)cc1O
Reaction time: 4 h

Procedure:
2.5 g (10.8 mmol) of α-ethynyl-4,4-dimethyl-6-thiochromanmethanol, 3 g (10.8 mmol) of methyl 2-hydroxy-4-iodobenzoate and 50 ml of triethylamine were introduced into a three-necked flask. The reaction mixture was degassed with nitrogen for 30 min. and then 600 mg (0.86 mmol) of bis(triphenylphosphine)-palladium(II) chloride and 240 mg (1.3 mmol) of copper iodide were added successively. Stirring was carried out at room temperature for four hours, the reaction mixture was evaporated to dryness and the residue obtained was taken up in water and ethyl ether. The organic phase was separated by settling, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with dichloromethane. 3.2 g (80%) of methyl 2-hydroxy-4-[3-hydroxy-3-(4,4-dimethylthiochroman-6-yl)-1-propynyl]benzoate, with a melting point of 105°-106° C., were recovered.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1ccc(-c2ccccc2)cn1
Solvent: CN(C)C=O
Solvent: CO
Product: O=C(CCCCCCN(c1ccccn1)c1ccc(-c2ccccc2)cn1)NO
Reaction time: 72 h
Yield: 7 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added the crude batch of III (16 mg) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 72 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×3 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:8 then 100:10) to furnish IV as a colourless oil (1.36 mg, 7% over two steps).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:12](Cl)(=[O:14])=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[CH3:16][NH2:17]>O1CCOCC1.C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([S:12]([NH:17][CH3:16])(=[O:14])=[O:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: CN
Reactant: O=S(=O)(Cl)c1cc(Br)cc(C(F)(F)F)c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CNS(=O)(=O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)-benzene sulphonyl chloride (200 mg) in 1,4-dioxane (1 mL) was added methylamine (40% aqueous solution, 96 mg). The mixture was stirred at room temperature for three hours then diluted with ethyl acetate (20 mL) and washed with HCl (1M, 2×20 mL). Organics were separated, dried over sodium sulphate, filtered, and solvent was removed under reduced pressure to yield 3-bromo-N-methyl-5-trifluoromethyl-benzenesulphonamide (181 mg) as a yellow solid. 1H NMR (MeOD): δ 8.19 (s, 1H), 8.05 (s, 1H), 7.98 (s, 1H), 4.58 (m, 1H), 2.74 (d, 3H). MS m/z 319.8 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:16][C:15]([C:25]1[S:26][C:27]([C:31]([NH2:33])=[O:32])=[C:28]([CH3:30])[N:29]=1)=[CH:14][CH:13]=2)(C)(C)C.[ClH:40]>C(OCC)(=O)C>[ClH:40].[NH2:7][CH2:8][C:9]1[N:10]([CH2:35][CH:36]([CH3:38])[CH3:37])[C:11](=[O:34])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[CH:16][C:15]([C:25]1[S:26][C:27]([C:31]([NH2:33])=[O:32])=[C:28]([CH3:30])[N:29]=1)=[CH:14][CH:13]=2
Reactant: Cc1nc(-c2ccc3c(=O)n(CC(C)C)c(CNC(=O)OC(C)(C)C)c(-c4ccccc4)c3c2)sc1C(N)=O
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1nc(-c2ccc3c(=O)n(CC(C)C)c(CN)c(-c4ccccc4)c3c2)sc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.7 %

Procedure:
Tert-butyl{6-[5-(aminocarbonyl)-4-methyl-1,3-thiazol-2-yl]-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-3-isoquinolinyl}methylcarbamate (0.14 g, 0.25 mmol) was dissolved in a solution of 4N hydrogen chloride in ethyl acetate (5 ml). The solution was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure, and the resulting crystals were recrystallized from methanol-ethyl acetate to give 2-[3-(aminomethyl)-2-isobutyl-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl]-4-methyl-1,3-thiazole-5-carboxamide hydrochloride (0.11 g, 91.7%) as crystals.
Reaction SMILES: [C:1]([O-:4])(=[O:3])[CH3:2].[Pb+4:5].[C:6]([O-:9])(=[O:8])[CH3:7].[C:10]([O-:13])(=[O:12])[CH3:11].C([O-])(=O)C.[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH:28]2[CH2:30][CH2:29]2)=[C:23](B(O)O)[CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)(Cl)Cl.C([O-])(=O)C.[Hg+2].C([O-])(=O)C>[C:1]([O-:4])(=[O:3])[CH3:2].[C:6]([O-:9])(=[O:8])[CH3:7].[C:10]([O-:13])(=[O:12])[CH3:11].[Br:18][C:19]1[CH:20]=[CH:21][C:22]([CH:28]2[CH2:30][CH2:29]2)=[C:23]([Pb+3:5])[CH:24]=1
Reactant: [Pb+4]
Reactant: OB(O)c1cc(Br)ccc1C1CC1
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Hg+2]
Solvent: ClC(Cl)Cl
Product: Brc1ccc(C2CC2)c([Pb+3])c1
Temperature: 25 °C
Reaction time: 0.03 h

Procedure:
To a solution of lead (IV) acetate (4.0 g, 0.0089 mol) and mercury (II) acetate (139 mg, 0.45 mmol) in chloroform (12 ml) at 50° C. is added 5-bromo-2-cyclopropylphenyl boronic acid (2.0 g, 0.0083 mol), and the solution is heated at this temperature for 5 hours. After cooling to room temperature the suspension is further cooled to 0° C. and anhydrous potassium carbonate (1.8 g) is added with rapid stirring for 2 minutes. The reaction mixture is then filtered (washing with additional chloroform), and the filtrate is concentrated to half its original volume and the crude product is precipitated with hexanes. Further concentration then filtration affords 5-bromo-2-cyclopropylphenyl lead triacetate as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][OH:15])[O:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.[OH:18]S(O)(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[F:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:12]=[C:11]([CH2:13][C:14]([OH:18])=[O:15])[O:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: O=C(c1ccc(F)cc1)c1cc(CCO)on1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Solvent: ClCCl
Product: O=C(O)Cc1cc(C(=O)c2ccc(F)cc2)no1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 13.5 g of 2-[3-(4-fluorobenzoyl)-isoxazol-5-yl]ethanol and a few crystals of tetrabutylammonium hydrogen sulfate in 1 liter of CH2Cl2 was added 150 ml of 9M H2SO4. To this was added 16.9 g of pulverized K2Cr2O7 and the mixture was stirred at room temperature for 1 hour. The organic phase was separated from the aqueous phase and washed with water. The acid product was extracted from the organic phase using 100 ml of 5% NaHCO3. The alkaline solution was washed with CH2Cl2 several times, until all of the neutral impurities were removed, and then acidified slowly with 5% HCl. The precipitated solid was collected, washed with water and dried to yield 6.7 g of a powder. Recrystallization from 180 ml of 50% toluene/hexane gave 5.9 g (41%) of crystals, m.p. 113°-115°.
Reaction SMILES: [C:1]1([S:7]([N:10](S(C2C=CC=CC=2)(=O)=O)[C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[CH:13][C:12]=2[I:21])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>O1CCOCC1>[C:1]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:18])=[O:19])=[CH:13][C:12]=2[I:21])(=[O:8])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CS(=O)(=O)c1ccc(N(S(=O)(=O)c2ccccc2)S(=O)(=O)c2ccccc2)c(I)c1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CS(=O)(=O)c1ccc(NS(=O)(=O)c2ccccc2)c(I)c1
Temperature: 100 °C
Reaction time: 1 h
Yield: 93.5 %

Procedure:
To a suspension of the compound obtained in Example 8 (4) (4.90 g) in 1,4-dioxane (85 ml), a 1N aqueous potassium hydroxide solution (21.2 ml) was added and the mixture was stirred at 100° C. for 1 hour. After completion of the reaction, the reaction solution was concentrated under reduced pressure, poured into a saturated aqueous NaCl solution, extracted with tetrahydrofuran, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (chloroform:methanol=10:1) to obtain 3.47 g of the desired product in a colorless amorphous form.