Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](F)(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:8].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:21]([O-:23])=[O:22])=[C:6]([CH:20]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=C(Nc1ccc(S(=O)(=O)F)cc1)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(S(=O)(=O)N2CCOCC2)cc1)c1cc(Cl)ccc1[N+](=O)[O-]

Procedure:
120.00 g (0.33 mol) of 4-(5-chloro-2-nitro-benzoylamino)-benzenesulfonyl fluoride, 29.10 g (0.33 mol) of morpholine and 33.85 g (0.33 mol) of triethylamine were stirred in 1200 ml of toluene at 60° C. for 2 days. The precipitated solid was filtered off with suction and recrystallized from acetone/n-hexane. 102.10 g (71%) of the title compound having a melting point of 243-245° C. were obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]1=[O:13].[C:14](Cl)(=[O:16])[CH3:15]>C(Cl)Cl>[C:14]([O:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]1=[O:13])(=[O:16])[CH3:15]
Reactant: CCOC(=O)CN1CCC(O)C1=O
Reactant: CC(=O)Cl
Solvent: ClCCl
Product: CCOC(=O)CN1CCC(OC(C)=O)C1=O

Procedure:
1.70 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetate are boiled at reflux for 2.5 hours while stirring in 30 ml of methylene chloride and 0.53 ml of acetyl chloride. The mixture is then evaporated. The residue is distilled in a bulb-tube. There is obtained ethyl (R/S)-2-(3-acetoxy-2-oxo-1-pyrrolidinyl)acetate of boiling point 225°/0.01 mmHg.
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]1[N:8]=[CH:9][S:10][CH:11]=1.[CH2:12]([Sn:16](Cl)([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:13][CH2:14][CH3:15].O>O1CCCC1>[CH3:6][C:7]1[N:8]=[C:9]([Sn:16]([CH2:17][CH2:18][CH2:19][CH3:20])([CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][CH2:13][CH2:14][CH3:15])[S:10][CH:11]=1
Reactant: Cc1cscn1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1nc(C)cs1
Reaction time: 1 h
Yield: 45 %

Procedure:
A solution of n-butyl lithium (2.71 M hexane solution, 3.9 ml) in tetrahydrofuran (10 ml) was cooled to −78° C. under argon atmosphere, and thereto was added dropwise a solution of 4-methylthiazole (1.0 g) in tetrahydrofuran (10 ml). The mixture was stirred at same temperature for one hour and thereto was added dropwise a solution of tri-n-butyltin chloride (3.6 g) in tetrahydrofuran (10 ml). The mixture was stirred at same temperature for 30 minutes, warmed, and further stirred at room temperature overnight. Thereto was added water, and the mixture was extracted with diethyl ether. The extract was washed with brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by alumina column chromatography (hexane) to give the title compound (1.76 g) as oil. APCI-Mass m/z 386/388 (M+H)
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[CH:18]=[N:17][CH:16]=[CH:15][N:14]=2)=[CH:7][C:6]=1[CH3:19])=O.[NH2:20][C:21]([NH2:23])=[S:22]>CCO>[CH3:19][C:6]1[CH:7]=[C:8]([O:12][C:13]2[CH:18]=[N:17][CH:16]=[CH:15][N:14]=2)[CH:9]=[C:10]([CH3:11])[C:5]=1[C:3]1[N:20]=[C:21]([NH2:23])[S:22][CH:2]=1
Reactant: NC(N)=S
Reactant: Cc1cc(Oc2cnccn2)cc(C)c1C(=O)CBr
Solvent: CCO
Product: Cc1cc(Oc2cnccn2)cc(C)c1-c1csc(N)n1
Yield: 53.6 %

Procedure:
A mixture of 2-bromo-1-(2,6-dimethyl-4-(pyrazin-2-yloxy)phenyl)ethanone (7-2, 6.16 g, 19.2 mmol) and thiourea (1.46 g, 19.2 mmol) in 95% EtOH (27.4 mL) was heated at reflux for 60 min. The solution was concentrated and added with water and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and recrystallized in toluene. The solids were filtered and dried under vacuum to give 4-(2,6-dimethyl-4-(pyrazin-2-yloxy)phenyl)thiazol-2-amine (7-3, 3.07 g) as brown solids in 54% yield: 1H NMR (500 MHz, CDCl3) δ 8.40 (s, 1 H), 8.25 (d, 1 H), 8.14 (s, 1 H), 6.86 (s, 2 H), 6.31 (s, 1 H), 5.09 (s, 2 H), 2.18 (s, 6 H).
Reaction SMILES: [CH:1](=[C:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC(S([NH:27][NH2:28])(=O)=O)=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[C:2]1([C:1]2[C:8]3[CH2:16][C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9]=3[NH:27][N:28]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: O=C1C(=Cc2ccccc2)Cc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reaction time: 18 h

Procedure:
A mixture of 2-benzylidene-indan-1-one (3.99 g), p-toluenesulphonyl hydrazine (4.0 g), p-toluenesulphonic acid hydrate (0.7 g) and ethanol (60 ml) was boiled under reflux for 1.5 hours and then left to stand for 18 hours at ambient temperature. The mixture was boiled under reflux for a further 74 hours and then left to stand at ambient temperature for 74 hours. The solvent was removed under reduced pressure and the residue was partitioned between dichloromethane (100 ml) and 2M sodium hydroxide solution (50 ml). The organic layer was separated, dried over magnesium sulfate and filtered. The magnesium sulfate was washed with ethyl acetate and filtered. The ethyl acetate filtrate was evaporated to dryness to give a solid which was recrystallized from ethanol to give 3-phenyl-1,4-dihydroindeno[1,2-c]pyrazole, m.p. 234-236° C.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][C:4]=1[CH3:12])#[N:2].[S:13]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH:17][CH2:16][CH2:15][CH2:14]1>>[C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:17]2[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[S:13][CH2:14][CH2:15][CH2:16]2)=[O:9])=[CH:5][C:4]=1[CH3:12])#[N:2]
Reactant: Cc1cc(C(=O)O)ccc1C#N
Reactant: c1ccc2c(c1)NCCCS2
Product: Cc1cc(C(=O)N2CCCSc3ccccc32)ccc1C#N

Procedure:
The carboxylic acid from Example C (0.27 g; 1.68 mmol) was reacted with 2,3,4,5-tetrahydro-1,5-benzothiazepine (0.28 g, 1.70 mmol) according to the procedure in Example 1A. The product was purified by flash chromatography on silica (eluant EtOAc:pet. ether 60:40); yield 0.43 g (84%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([CH3:17])=[C:14]([CH3:16])[N:15]=2)[CH:10]=[CH:11][CH:12]=1.N1C=CC=CC=1.Cl[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl>[CH3:16][C:14]1[N:15]=[C:8]2[C:7]([NH:6][CH2:5][C:4]3[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:3]=3[CH2:2][NH:1][C:30](=[O:31])[O:32][CH3:33])=[CH:12][CH:11]=[CH:10][N:9]2[C:13]=1[CH3:17]
Reactant: COC(=O)Cl
Reactant: Cc1cccc(CN)c1CNc1cccn2c(C)c(C)nc12
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)NCc1cccc(C)c1CNc1cccn2c(C)c(C)nc12
Temperature: 12 °C
Reaction time: 1.5 h
Yield: 25.4 %

Procedure:
To an ice cooled solution of 8-(2-aminomethyl-6-methylbenzylamino)-2,3-dimethylimidazo[1,2-a]pyridine (0.17 g, 0.58 mmol), pyridine (0.046 g, 0.58 mmol) in methylene chloride (8 ml) was added methyl chloroformate (0.055 g, 0.58 mmol) and the reaction mixture was stirred for 1.5 h. and the temperature was allowed to raise to 12° C. Methylene chloride was added and the solution was washed twice with water. The organic layer was separated, washed with saturated sodium bicarbonate, dried and evaporated under reduced pressure. The residue was purified by by column chromatography on silica gel using methylene chloride:methanol (100:5) as eluent. Recrystallization from diethyl ether gave 0.052 g (25%) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[CH:15]([NH2:17])[CH3:16].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.N1C=CC=CC=1>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[CH:15]([NH:17][S:26]([C:23]1[CH:22]=[CH:21][C:20]([O:19][CH3:18])=[CH:25][CH:24]=1)(=[O:28])=[O:27])[CH3:16]
Reactant: CC(N)c1cc(F)ccc1-c1ccccc1F
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)NC(C)c2cc(F)ccc2-c2ccccc2F)cc1
Temperature: 25 °C
Yield: 47.3 %

Procedure:
A stirred solution of 1-(2′,4-difluoro-1,1′-biphenyl-2-yl)ethylamine (0.26 g, 1.12 mmol) in dichloromethane (10 mL) was treated with 4-methoxybenzenesulfonyl chloride (0.23 g, 1.12 mmol), and pyridine (0.09 g, 1.12 mmol). The reaction was stirred at room temperature for twelve hours, diluted with dichloromethane, washed sequentially with a 1 N hydrochloric acid solution (2×) and a saturated, aqueous, sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate, filtered through a short column of silica gel, and evaporated to a residue which, after crystallization from ethyl acetate-hexane, afforded the title compound (0.22 g, 0.53 mmol, 48%) as a racemic, homogeneous, colorless, crystalline solid, m.p. 182-184° C.;
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=O)[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([O:20][CH2:21][CH2:22][N:23]4C(=O)C5=CC=CC=C5C4=O)[CH:18]=[CH:19][C:10]=3[S:9]2(=O)=O)=[CH:4][CH:3]=1.O.NN.Cl>CO>[NH2:23][CH2:22][CH2:21][O:20][C:17]1[CH:18]=[CH:19][C:10]2[S:9][N:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:13][N:12]([CH3:15])[C:11]=2[CH:16]=1
Reactant: CN1C(=O)N(c2ccc(Cl)cc2)S(=O)(=O)c2ccc(OCCN3C(=O)c4ccccc4C3=O)cc21
Agent: Cl
Agent: NN
Solvent: CO
Solvent: O
Product: CN1CN(c2ccc(Cl)cc2)Sc2ccc(OCCN)cc21

Procedure:
To a solution of 2-(4-chlorophenyl)-4-methyl-6-(2-phthalimidoethoxy)-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (0.153 g) in methanol (1.5 ml) was added hydrazine monohydrate (30 mg). After the mixture was refluxed for one hour, the reaction mixture was treated with conc. HCl and further refluxed for 30 minutes. The precipitate was removed by filtration and the filtrate was washed two times with ether. The aqueous layer was treated with aqueous 1N NaOH solution and extracted with ethyl acetate. The extract was washed with brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was triturated with IPE. The colorless crystals were collected by filtration and recrystallized from ethanol to give 6-(2-aminoethoxy)-2-(4-chlorophenyl)-4-methyl-2H-1,2,4-benzothiadiazine-(3-(4H)-one 1,1-dioxide (30 mg) as colorless prisms.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1>>[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH:22][C:8]2[CH:7]=[CH:6][C:5]3[C:4]([NH2:1])=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=2)=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3c(N)cccc3n2)o1

Procedure:
The title compound, MS: m/e=254.4 (M+H+), was prepared in accordance with the general method of example 1 from 5-nitro-2-chloroquinoline and 5-methyl-2-furanmethanamine.
Reaction SMILES: [CH2:1]([N:3]([S:11]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)(=[O:13])=[O:12])[C@@H:4]([CH2:9]O)[C:5]([O:7]C)=[O:6])[CH3:2].[OH-].[Na+]>O1CCOCC1>[CH2:1]([N:3]([S:11]([C:14]1[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=1)(=[O:13])=[O:12])[C:4](=[CH2:9])[C:5]([OH:7])=[O:6])[CH3:2]
Reactant: CCN([C@@H](CO)C(=O)OC)S(=O)(=O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C=C(C(=O)O)N(CC)S(=O)(=O)c1ccc(F)cc1
Temperature: 80 °C
Yield: 71.2 %

Procedure:
A solution of 3B (1.1 g, 3.6 mmol) in dioxane (25 mL) was added with 20% NaOH aq. solution (20 mL) and the mixture heated at 80° C. for 4 h. The organic solvent was removed under reduced pressure and the aqueous phase acidified with 10% HCl and extracted with CH2Cl2 (3×30 mL). The combined organic phases were dried using Na2SO4, evaporated under reduced pressure and then the resulting residue purified by flash chromatography (100% EtOAc) to obtain 4B as white solid (0.7 g, 66% yield). 1HNMR (DMSO, 200 MHz) δ 1.12 (t, 3H), 3.29 (q, 2H), 5.69 (s, 1H), 6.32 (s, 1H), 7.39 (m, 2H), 7.89 (m, 2H), 12.9 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.ClC1C=C(Cl)C=CC=1C[N:23](CC)CCN>>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([NH2:23])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CCN(CCN)Cc1ccc(Cl)cc1Cl
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(N)=O

Procedure:
By following general method B using 1.0 g. of 4-amino-5-chloro-2-methoxybenzoic acid and 1.2 g. of N-(2',4'-dichlorophenylmethyl)-N-ethylethylenediamine, 1.6 g. of N-[2-(N'-2',4'-dichlorophenylmethyl)-N'-ethylamino)ethyl]-4-amino-5-chloro-2-methoxybenzamide was obtained.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH:12]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2].C=O.[C:25]([BH3-])#N.[Na+]>C(O)(=O)C>[C:1]([NH:4][C:5]1[C:14]2[CH2:13][CH:12]([NH:15][CH2:16][CH2:17][C:22]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:25]=3)[CH2:11][CH2:10][C:9]=2[CH:8]=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1CC(NCc1ccccc1)CC2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)Nc1cccc2c1CC(NCCc1ccccc1)CC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 103.8 %

Procedure:
A mixture of 1-acetamido-7-benzylamino-5,6,7,8-tetrahydronaphthalene (14.3 g, 50 mmol), paraformaldehyde (15 g, 0.5 mol) and sodium cyanoborohydride (15.7 g, 0.25 mol) in acetic acid (250 mL) was stirred at room temperature for 48 h. The solvent was removed and the residue taken up in water:diethyl ether. The aqueous phase was basified with 12.5% NaOH and back extracted with ether. The combined ether layers were washed with saturated NaCl, dried over magnesium sulfate, filtered and evaporated to give a viscous syrup (16 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[C:11](Cl)(=[O:14])[CH:12]=[CH2:13].O>O1CCCC1>[C:11]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:14])[CH:12]=[CH2:13]
Reactant: Oc1ccc(Br)cc1
Reactant: C=CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CC(=O)Oc1ccc(Br)cc1
Reaction time: 0.25 h
Yield: 91.3 %

Procedure:
To a solution of 4-bromophenol (15.1 g, 87.3 mmol) in tetrahydrofuran (170 mL) was added 60% sodium hydride (3.68 g, 91.6 mmol) under ice-cooling and the mixture was stirred for 15 min. A solution of acryloyl chloride (8.3 g, 91.6 mmol) in tetrahydrofuran (50 mL) was added, and the mixture was stirred for 15 min under ice-cooling. Water was added, and the solvent was evaporated under reduced pressure. The residue was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=20/80) to give the title compound (18.1 g, yield 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1.C[N:16]([CH:18]=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([NH:16][CH2:18][CH:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(F)c([N+](=O)[O-])c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COC(=O)c1ccc(NCC2CCCCC2)c([N+](=O)[O-])c1
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 25.0 g of 4-fluoro-3-nitro-benzoic acid methyl ester in 100 ml of abs. DMF was added 26.0 g of potassium carbonate, followed by 14.2 g of (cycloheylmethyl)amine. After 16 h at rt, the mixture was poured into water, and extracted with ethyl acetate three times. The combined organic phases were washed with water, dried over sodium sulphate and concentrated to yield 36.7 g (100%) of 4-(Cyclohexylmethyl-amino)-3-nitro-benzoic acid methyl ester as an orange solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([NH:11][S:12]([C:15]2[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=2[O:22][CH3:23])(=[O:14])=[O:13])[CH:5]=1.Br[CH2:26][CH2:27]Br>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[CH:8][C:7]2[O:10][CH2:27][CH2:26][N:11]([S:12]([C:15]3[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=3[O:22][CH3:23])(=[O:13])=[O:14])[C:6]=2[CH:5]=1)=[O:24]
Reactant: BrCCBr
Reactant: COC(=O)c1ccc(O)c(NS(=O)(=O)c2cc(Cl)ccc2OC)c1
Product: COC(=O)c1ccc2c(c1)N(S(=O)(=O)c1cc(Cl)ccc1OC)CCO2

Procedure:
The title compound, MS (ISP)=522.2 (M−H)−, was produced in analogy with example 36, steps 1-4. Step 1 was performed using 3-(5-chloro-2-methoxy-benzenesulfonylamino)-4-hydroxy-benzoic acid methyl ester (example 30, step 1) and 1,2-dibromoethane, yielding 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid methyl ester, which was hydrolyzed in step 2 to afford 4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carboxylic acid. This was reacted with ethyl 2-amino-4-thiazoleacetate in step 3 to produce (2-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-thiazol-4-yl)-acetic acid ethyl ester, which was hydrolyzed in step 4.
Reaction SMILES: C[C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]([C@@H:11]1[CH2:13][C@H:12]1[C:14]([OH:16])=O)=[O:10].B(OC)(OC)O[CH3:19].C1COCC1.Cl>>[CH3:19][C@H:6]1[CH2:7][CH2:2][C@H:3]([NH:8][C:9]([C@@H:11]2[CH2:13][C@H:12]2[CH2:14][OH:16])=[O:10])[CH2:4][CH2:5]1
Reactant: COB(OC)OC
Reactant: C[C@@H]1CCCC[C@H]1NC(=O)[C@@H]1C[C@H]1C(=O)O
Agent: Cl
Solvent: C1CCOC1
Product: C[C@H]1CC[C@H](NC(=O)[C@@H]2C[C@H]2CO)CC1
Reaction time: 2 h

Procedure:
Stir a solution, under argon, at 0° C., of trans-2-(trans-2-methylcyclohexylcarbamoyl)-cyclopropanecarboxylic acid (Example 11b) (3.69 g, 16.4 mmol), trimethyl borate (5.6 mL, 50 mmol), and add slowly 2N borane dimethylsulfide complex in THF (16.4 mL, 32.8 mmol). Continue to stir the reaction at 0° C. for 1 h, and then at ambient temperature for 2 h. Carefully pour the reaction mixture into ice-H2O and acidify with 2N HCl. Extract the mixture with EtOAc (3 times), wash with brine, dry over MgSO4 and concentrate to obtain 2.85 g (83%) of product as a solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([CH3:11])[C:3]=1[C:12](O)=[O:13].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>C(OCC)C>[CH3:11][C:4]1[C:5]([F:10])=[C:6]([F:9])[C:7]([F:8])=[C:2]([F:1])[C:3]=1[CH2:12][OH:13]
Reactant: Cc1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Product: Cc1c(F)c(F)c(F)c(F)c1CO
Yield: 42.9 %

Procedure:
3,4,5,6-tetrafluoro-2-toluic acid (500 mg) was dissolved in dry diethyl ether (5.0 ml) added dropwise to a suspension of lithium aluminium hydride (100 mg) in dry ether (10 ml) under an argon atmosphere at the ambient temperature. When the addition was complete and the effervescence had subsided the mixture was heated at the reflux temperature for a period of 1 hour. After allowing the mixture to cool to the ambient temperature water (10 ml) was cautiously added and the resultant mixture extracted with diethyl ether (2×20 ml), the extracts washed with water and dried over anhydrous magnesium sulphate. After filtration the filtrate was concentrated by evaporation of the solvent. The residual low melting solid was recrystallised from petroleum ether (boiling range 40°-60° C.) to yield 2-methyl-3,4,5,6-tetrafluorobenzyl alcohol (200 mg). N.m.r. (1H(ppm)CDCl3): 2.18(s,1H); 2.32(t,3H); 4.86(s,2H).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([CH2:15][NH:16][C:17](=[O:32])[CH2:18][CH2:19][C:20]#[C:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[CH:13]=2)[CH:8]=[CH:7]1)C.[CH3:34]I.[H-].[Na+]>>[CH3:34][N:16]([CH2:15][C:12]1[CH:13]=[C:14]2[C:9]([CH:8]=[CH:7][N:6]2[CH2:5][C:4]([OH:3])=[O:33])=[CH:10][CH:11]=1)[C:17](=[O:32])[CH2:18][CH2:19][C:20]#[C:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:29])([F:31])[F:30])=[CH:24][CH:23]=1
Reactant: CI
Reactant: CCOC(=O)Cn1ccc2ccc(CNC(=O)CCC#Cc3ccc(C(F)(F)F)cc3)cc21
Agent: [H-]
Agent: [Na+]
Product: CN(Cc1ccc2ccn(CC(=O)O)c2c1)C(=O)CCC#Cc1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 8 d], (6-{[5-(4-trifluoromethyl-phenyl)-pent-4-ynoylamino]-methyl}-indol-1-yl)-acetic acid ethyl ester was reacted with methyl iodide in the presence of sodium hydride to give the title compound as yellow foam.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:29]=[CH:28][C:14]3[NH:15][C:16]([C:18]4[CH:23]=[CH:22][C:21]([NH2:24])=[C:20]([N+:25]([O-])=O)[CH:19]=4)=[N:17][C:13]=3[CH:12]=2)[CH2:7][CH2:6]1>[Pd].C(OCC)(=O)C.CO>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:11]2[CH:29]=[CH:28][C:14]3[NH:15][C:16]([C:18]4[CH:19]=[C:20]([NH2:25])[C:21]([NH2:24])=[CH:22][CH:23]=4)=[N:17][C:13]=3[CH:12]=2)[CH2:9][CH2:10]1
Reactant: COCCN1CCN(c2ccc3[nH]c(-c4ccc(N)c([N+](=O)[O-])c4)nc3c2)CC1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: COCCN1CCN(c2ccc3[nH]c(-c4ccc(N)c(N)c4)nc3c2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-{5-[4-(2-methoxy-ethyl)-piperazin-1-yl]-1H-benzoimidazol-2-yl}-2-nitro-phenylamine (0.5 g, 1.2 mmol) in 4:1 ethyl acetate/methanol (60 ml) under nitrogen, was added 5% palladium on carbon (100 mg) and the mixture was first evacuated and then stirred at room temperature under an atmosphere of hydrogen for 1 day. The reaction mixture was then filtered through Celite, washed with 1:1 ethyl acetate/methanol (10 mL) and the combined filtrate and washings were concentrated to give the crude 4-{5-[4-(2-methoxy-ethyl)-piperazin-1-yl]-1H-benzoimidazol-2-yl}-benzene-1,2-diamine as a thick oil that was used in the next step without any purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[C:19]([O:21][CH2:22][CH3:23])[CH:18]=[C:17]([CH:24]([NH:30][C:31]3[CH:36]=[CH:35][C:34]([C:37]#[N:38])=[CH:33][CH:32]=3)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:16]=2[F:39])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O.C([O-])([O-])=O.[Na+].[Na+]>ClCCl>[CH2:28]([O:27][C:25](=[O:26])[CH:24]([NH:30][C:31]1[CH:32]=[CH:33][C:34]([C:37]#[N:38])=[CH:35][CH:36]=1)[C:17]1[CH:18]=[C:19]([O:21][CH2:22][CH3:23])[CH:20]=[C:15]([O:14][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:16]=1[F:39])[CH3:29]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OC2CCNCC2)c1F
Temperature: 25 °C
Yield: 82.7 %

Procedure:
A solution of 2.30 g (RS)-4-{3-[(4-cyano-phenylamino)-ethoxycarbonyl-methyl]-5-ethoxy-2-fluoro-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester in 40 ml dichloromethane was cooled to 0° C. and treated dropwise with 3.25 ml trifluoroacetic acid. The reaction mixture was warmed to r.t. within 3 hrs, then again cooled to 0° C. and treated with 20 ml of 10% Na2CO3 solution. The product was extracted with dichloromethane. The organic layer was dried over MgSO4, filtrated and evaporated to give 1.55 g (RS)-(4-cyano-phenylamino)-[5-ethoxy-2-fluoro-3-(piperidin-4-yloxy)-phenyl]-acetic acid ethyl ester as an off-white solid foam which was used for the next step without further purification. MS: 442.3 ([M+H]+).