Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([CH:17]=1)=[CH:7][CH:8]=[C:9](/[CH:11]=[C:12](\[CH3:16])/[C:13]([OH:15])=[O:14])[CH:10]=2.[CH:18]1[C:23]([N+:24]([O-:26])=[O:25])=[CH:22][CH:21]=[C:20](O)[CH:19]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C1C=CC=CN=1)C.ClCCl>[N+:24]([C:23]1[CH:18]=[CH:19][C:20]([O:14][C:13](=[O:15])[C:12]([CH3:16])=[CH:11][C:9]2[CH:10]=[C:5]3[CH:4]=[CH:3][C:2]([NH2:1])=[CH:17][C:6]3=[CH:7][CH:8]=2)=[CH:21][CH:22]=1)([O-:26])=[O:25]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: C/C(=C\c1ccc2cc(N)ccc2c1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Product: CC(=Cc1ccc2cc(N)ccc2c1)C(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 79.2 %

Procedure:
Into 20 ml of dichloromethane, 0.57 g (2.5 mmol) of (E)3-(2-amino-benzo[d]phenyl)-2-methyl-2-propenoic acid and 0.52 g (3.8 mmol) of p-nitrophenol (manufactured by Wako Pure Chemical Industries, Ltd.) were dissolved; and 20 mg of dimethylaminopyridine (manufactured by Wako Pure Chemical Industries, Ltd.) were added thereto. Thereafter, while the mixture was stirred under cooling with ice, 0.71 g (3.8 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC-HCl) (manufactured by Wako Pure Chemical Industries, Ltd.) was added thereto in portions. The liquid was returned to room temperature and then was stirred for 20 hours. After the end point of this reaction was verified by TLC, the reaction liquid was concentrated under a reduced pressure and then was dissolved in 100 ml of ethyl acetate. This solution was washed several times with a 5% aqueous sodium hydrogencarbonate solution and then with a saturated aqueous sodium chloride solution, and was dried with magnesium sulfate anhydride. Thereafter, the solvent was evaporated, whereby a crude product was obtained. This product was recrystallized from ethanol, whereby 0.69 g of the aimed product was obtained as a crystal (yield: 80%).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([C:7]1[CH:16]=[CH:15][C:10]2[C:11](=[O:14])[O:12][CH2:13][C:9]=2[C:8]=1[Cl:17])[CH:5]=C.CSC>CO>[Cl:17][C:8]1[C:9]2[CH2:13][O:12][C:11](=[O:14])[C:10]=2[CH:15]=[CH:16][C:7]=1[CH2:4][CH:5]=[O:1]
Reactant: C=CCc1ccc2c(c1Cl)COC2=O
Reactant: O=[O+][O-]
Solvent: CSC
Solvent: CO
Product: O=CCc1ccc2c(c1Cl)COC2=O
Temperature: 25 °C

Procedure:
Ozone was bubbled through a solution of 5-allyl-4-chloro-2-benzofuran-1(3H)-one (80 mg, 0.38 mmol) in MeOH at −78° C. until it turned light blue. After excess ozone was removed by bubbling nitrogen through the solution, dimethyl sulfide (0.57 mL, 7.7 mmol) was added into the reaction. The solution was allowed to warm to RT. The crude material was purified by MPLC to provide (4-chloro-1-oxo-1,3-dihydro-2-benzofuran-5-yl)acetaldehyde. LC-MS (IE, m/z): 211 [M+1]+.
Reaction SMILES: Cl[C@H:2]([CH3:19])[C:3]([O:5][CH:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[OH:20]/[N:21]=[C:22](/[C:29]1[N:30]=[C:31]([NH:34][C:35]([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[S:32][CH:33]=1)\[C:23]([O:25]CC=C)=[O:24].C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:35]([NH:34][C:31]1[S:32][CH:33]=[C:29]([C:22](=[N:21][O:20][C@H:2]([C:3]([O:5][CH:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[O:4])[CH3:19])[C:23]([OH:25])=[O:24])[N:30]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: C=CCOC(=O)/C(=N\O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: C[C@@H](Cl)C(=O)OC(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@H](ON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In 11 ml of dimethylformamide was dissolved 2.16 g of benzhydryl L-lactate. After cooling the solution to -40° C., 0.8 ml of sulfuryl chloride was added thereto followed by stirring for an hour. Thereafter the reaction solution was extracted with ethyl acetate and a sodium bicarbonate aqueous solution. The organic phase was washed with water, dried and then concentrated to dryness to give 1.8 g of benzhydryl (2R)-2-chloropropionate. This ester was reacted with 3.1 g of allyl (Z)-2-hydroxyimino-2-(2-tritylaminothiazol-4-yl)acetate prepared in a manner similar to the description of Published Unexamined Japanese Patent Application No. 149289/80 in 16 ml of dimethylsulfoxide overnight at room temperature in the presence of 1.8 g of potassium carbonate. The reaction solution was partitioned with ice water and ethyl acetate. The organic phase was washed with water, dried and concentrated. The residue was dissolved in 30 ml of methylene chloride. To the solution were added 182 mg of triphenylphosphine and 34 mg of tetrakistriphenylphosphine palladium. The mixture was stirred at room temperature for 30 minutes. Then, a solution of 1.26 g of potassium 2-ethylhexanoate in ethyl acetate. After stirring at room temperature for 2 hours, 45 ml of isopropyl ether was added and the mixture was allowed to stand overnight at 0° C. The obtained precipitates were partitioned in ethyl acetate-acidic water (pH 2.8). The organic phase was washed with water, dried and concentrated to give 2.13 g of 2-(2-tritylamino-thiazol-4-yl)-2-{(1S)-1-diphenylmethoxycarbonylethoxyimino}acetic acid.
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[C:6]=1[Cl:7].[I:11][C:12](=[C:25]([I:27])[I:26])[CH2:13]OS(C1C=CC(C)=CC=1)(=O)=O.C(N(CC)CC)C.O>CN(C)C=O>[I:11][C:12](=[C:25]([I:27])[I:26])[CH2:13][N:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[C:6]([Cl:7])=[C:2]1[Cl:1]
Reactant: Cc1ccc(S(=O)(=O)OCC(I)=C(I)I)cc1
Reactant: O=[N+]([O-])c1c[nH]c(Cl)c1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cn(CC(I)=C(I)I)c(Cl)c1Cl
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 220 mg (1.2 mmoles) of 2,3-dichloro-4-nitropyrrole (pyrrolomycin A) in 10 ml of dry N,N-dimethylformamide were added 606 ml (1 mmole) of 2,3,3-triiodoallyl-p-toluenesulfonate and 0.14 ml (1 mmole) of triethylamine and the resulting mixture was heated at 60° C. for 30 minutes. After cooling, 20 ml of cold water were added dropwise with stirring to the reaction mixture and stirring was continued for a further one hour. The so separated crystalline substance, 1-(2',3',3'-triiodoallyl)-2,3-dichloro-4-nitropyrrole, was recovered by filtration, washed with water and then dried. Yield 567 mg (95%), mp 126°-127° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[C:12]([C:15]([OH:17])=[O:16])=[N:13][CH:14]=2)=[CH:4][CH:3]=1.[C:27](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O.C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]2[CH:10]=[C:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[C:12]([C:15]([O:17][CH3:27])=[O:16])=[N:13][CH:14]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(Nc2cc(Cc3ccc(F)cc3)cnc2C(=O)O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ncc(Cc2ccc(F)cc2)cc1Nc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64 %

Procedure:
5-[(4-fluorophenyl)methyl]-3-{[4-(methyloxy)phenyl]amino}-2-pyridinecarboxylic acid (560 mg, 1.59 mmol) was dissolved in N,N-dimethylformamide (50 mL) and potassium carbonate (483 mg, 3.50 mmol) and iodomethane (0.15 mL, 2.39 mmol) were added. The reaction was stirred at ambient temperature for 3 hours, diluted with ethyl acetate and water, and extracted with ethyl acetate. The organics were dried over sodium sulfate and concentrated under reduced pressure. Purification by silica gel chromatography (20-100% ethyl acetate/hexanes gradient elution) gave methyl 5-[(4-fluorophenyl)methyl]-3-{[4-(methyloxy)phenyl]amino}-2-pyridinecarboxylate (373 mg, 64% yield) as a white solid. 1H NMR (CDCl3) δ 9.22 (s, 1 H), 7.89 (s, 1 H), 7.09-7.02 (m, 4 H), 6.96-6.86 (m, 4 H), 3.97 (s, 2 H), 3.82 (s, 3 H), 3.80 (s, 3 H); MS m/z 367 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:13](O)(=[O:22])[C@@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:15].C(=O)([O-])[O-].[K+].[K+].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>O.CN(C)C=O>[OH:15][C@H:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:13]([NH:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)=[O:22]
Reactant: O=C(O)[C@H](O)c1ccccc1
Reactant: NCCc1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCCc1ccc([N+](=O)[O-])cc1)[C@H](O)c1ccccc1
Reaction time: 2 h
Yield: 87.8 %

Procedure:
To a mixture of 9.77 g of 4-nitrophenylethylamine 1/2 sulfate, 6.00 g of (R)-mandelic acid, 4.70 g of potassium carbonate and 60 mL of N,N-dimethylformamide, 6.14 g of hydroxybenztriazole and 8.70 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (EDC) were added, and the mixture was stirred at around room temperature for 2 hours. 0.87 g of EDC was further added, and the mixture was stirred at around room temperature overnight. The reaction solution was diluted with water and extracted with ethyl acetate. The organic layer was washed successively with 1M hydrochloric acid aqueous solution, 20% potassium carbonate aqueous solution and water, and then concentrated in vacuo. The residue was recrystallized from toluene to obtain 10.4 g of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide as a pale yellow crystal.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:10]=[CH:9][N:8]=[N:7][CH:6]=1)[NH2:4].[N:11]1[CH:16]=[C:15]([C:17](O)=O)[CH:14]=[N:13][CH:12]=1.N>>[N:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:4]=[C:17]([C:15]3[CH:16]=[N:11][CH:12]=[N:13][CH:14]=3)[O:1][N:2]=2)=[CH:6][N:7]=1
Reactant: O=C(O)c1cncnc1
Reactant: NC(=NO)c1ccnnc1
Agent: N
Product: c1ncc(-c2nc(-c3ccnnc3)no2)cn1

Procedure:
The titled compound was prepared according to the procedure of Method C using the product of Example 83D and pyrimidine-5-carboxylic acid (Maybridge). 1H NMR (300 MHz, CD3OD) δ 8.41 (dd, J=5.4, 2.4 Hz, 1 H), 9.44 (s, 1 H), 9.47 (dd, J=5.4, 1.4 Hz, 1 H), 9.59 (s, 2 H), 9.90 (dd, J=2.2, 1.2 Hz, 1 H) ppm; MS (DCI/NH3) m/z=227 (M+H)+.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([N:13]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:14]([CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:28])[CH2:24][N:25]([CH3:27])[CH3:26])[C:15](O)=[O:16])(=[O:12])=[O:11])=[CH:6][CH:5]=1.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[C:55]([O:59][NH2:60])([CH3:58])([CH3:57])[CH3:56].Cl.CN(CCCN=C=NCC)C>C(Cl)Cl.CN(C)C=O>[C:55]([O:59][NH:60][C:15](=[O:16])[C@H:14]([N:13]([S:10]([C:7]1[CH:6]=[CH:5][C:4]([O:3][CH3:2])=[CH:9][CH:8]=1)(=[O:11])=[O:12])[CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23](=[O:28])[CH2:24][N:25]([CH3:27])[CH3:26])([CH3:58])([CH3:57])[CH3:56]
Reactant: CC(C)(C)ON
Reactant: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@H](CCCCNC(=O)CN(C)C)C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N(Cc2ccccc2)[C@H](CCCCNC(=O)CN(C)C)C(=O)NOC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-[(N,N-dimethylglycyl)amino] hexanoic acid hydrochloride (4.12 g, 7.82 mmol) in methylene chloride (78 mL) and dimethylformamide (5 mL) is added 1-hydroxybenzotriazole monohydrate (1.26 g, 8.21 mmol), N-methylmorpholine (2.58 ml, 23.45 mmol), and O-t-butylhydroxylamine hydrochloride (1.08 g, 8.60 mmol). The reaction is cooled to 0° C., and N-[dimethylaminopropyl]-N'-ethylcarbodiimide hydrochloride (3.0 g, 15.64 mmol) is added. The reaction mixture is warmed to room temperature and stirred overnight. The mixture is then diluted with methylene chloride and washed with saturated aqueous sodium bicarbonate, and then with brine. The organic layer is dried (Na2SO4), filtered, and and the solvent is evaporated. The crude product is purified by silica gel chromatography (10/0.5/0.5 ethyl acetate/methanol/ammonium hydroxide ) to provide N-(t-butyloxy)-2(R)-[[4-methoxybenzenesulfonyl](benzyl)amino]-6-[(N,N-dimethylglycyl)amino] hexanamide.
Reaction SMILES: ClCCl.[OH:4][C:5]([CH3:14])([CH3:13])[C:6]#[C:7][C:8]([O:10][CH2:11][CH3:12])=[O:9].ClS([N:19]=[C:20]=[O:21])(=O)=O>O>[C:20]([O:4][C:5]([CH3:13])([CH3:14])[C:6]#[C:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:21])[NH2:19]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CCOC(=O)C#CC(C)(C)O
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)C#CC(C)(C)OC(N)=O
Yield: 33.6 %

Procedure:
To 100 ml of a dichloromethane solution containing 4.9 g (31.4 millimoles) of ethyl 4-hydroxy-4-methyl-2-pentynoate, 3 ml (34.5 millimoles) of chlorosulfonyl isocyanate was added at a temperature of -10° C. The mixture was reacted for 30 minutes at -10° C. under stirring. The reaction mixture was returned to room temperature, and 20 ml of water was added thereto. The mixture was stirred for 15 minutes for hydrolysis treatment. The dichloromethane phase was separated by phase separation, washed with a 10% barium chloride solution and water successively, dried over sodium sulfate and then concentrated under reduced pressure, whereby 2.1 g (yield: 33%) of ethyl 4-carbamoyloxy-4-methyl-2-pentynoate in crystal form was obtained.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[NH:16][CH:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:2]1.[CH3:23][O:24][C:25]1[CH:50]=[CH:49][C:48]([N:51]2[CH:55]=[N:54][N:53]=[N:52]2)=[CH:47][C:26]=1[C:27]([N:29]1[CH2:33][CH2:32][C:31]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)([CH2:34][CH2:35]OS(C)(=O)=O)[CH2:30]1)=[O:28]>>[CH3:23][O:24][C:25]1[CH:50]=[CH:49][C:48]([N:51]2[CH:55]=[N:54][N:53]=[N:52]2)=[CH:47][C:26]=1[C:27]([N:29]1[CH2:33][CH2:32][C:31]([CH2:34][CH2:35][N:20]2[CH2:19][CH2:18][CH:17]([NH:16][C:8]3[N:7]([CH2:6][C:3]4[CH:4]=[CH:5][O:1][CH:2]=4)[C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=4[N:9]=3)[CH2:22][CH2:21]2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[CH2:30]1)=[O:28]
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: c1ccc2c(c1)nc(NC1CCNCC1)n2Cc1ccoc1
Product: COc1ccc(-n2cnnn2)cc1C(=O)N1CCC(CCN2CCC(Nc3nc4ccccc4n3Cc3ccoc3)CC2)(c2ccccc2)C1

Procedure:
Prepare by the method of Example 102.1 using (1-(fur-3-ylmethyl)-1H-benzimidazol-2-yl)(piperidin-4-yl)amine and 1-(2-methoxy-5-(1H-tetrazol-1-yl)benzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: C1(C)C=CC=CC=1.[CH2:8]1[C:11]2([O:16][CH2:15][CH:14]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][S:25][C:26]4[NH:30][C:29]5[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=5[N:27]=4)[C:19]=3[CH3:35])[CH2:13][O:12]2)[CH2:10][CH2:9]1.ClC1C=CC=C(C(OO)=[O:44])C=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CO.CO>[CH2:10]1[C:11]2([O:16][CH2:15][CH:14]([O:17][C:18]3[CH:23]=[CH:22][N:21]=[C:20]([CH2:24][S:25]([C:26]4[NH:27][C:28]5[CH:34]=[CH:33][CH:32]=[CH:31][C:29]=5[N:30]=4)=[O:44])[C:19]=3[CH3:35])[CH2:13][O:12]2)[CH2:8][CH2:9]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OC2COC3(CCC3)OC2)ccnc1CSc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1c(OC2COC3(CCC3)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Temperature: -50 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a toluene (30 ml)/methanol (3 ml) solution of the 2-(((4-(5,9-dioxaspiro[3.5]non-7-yloxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (290 mg, 0.73 mmol) obtained in the step (9h), a toluene/methanol (10:1) solution of 3-chloroperbenzoic acid (174 mg, 0.65 mmol as the content was regarded as 65%) was added at −70° C. in a nitrogen atmosphere. After the mixture was stirred at −50° C. for one hour, a saturated aqueous solution of sodium hydrogen carbonate was added. After the mixture was warmed to room temperature, the mixture was extracted with ethyl acetate twice. Organic layers were combined and dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate, ethyl acetate/methanol=9/1). Fractions containing the title compound was collected by use of ethyl acetate and concentrated. After diethyl ether was added to the residue, the solvent was distilled off to obtain the title compound (230 mg, yield: 76.2%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:12]([OH:14])=O)[C:10]=1[F:11])[NH:7][CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)C(C)C)(C)C.[C:46]([C:50]1[CH:69]=[CH:68][C:53]([CH2:54][NH:55][CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([O:64][CH:65]([F:67])[F:66])[CH:59]=2)=[CH:52][CH:51]=1)([CH3:49])([CH3:48])[CH3:47]>CN(C=O)C.O>[C:46]([C:50]1[CH:69]=[CH:68][C:53]([CH2:54][N:55]([CH2:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[C:60]([O:64][CH:65]([F:67])[F:66])[CH:59]=2)[C:12]([C:9]2[C:10]([F:11])=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:14])=[CH:52][CH:51]=1)([CH3:49])([CH3:47])[CH3:48]
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Reactant: CC(C)(C)c1ccc(CNCCc2cccc(OC(F)F)c2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1ccc(CN(CCc2cccc(OC(F)F)c2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 36.6 %

Procedure:
To a solution of 100 mg (0.47 mmol) of 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and 150 mg of TBTU (0.47 mmol) in 10 ml DMF, were added 0.4 ml (2.34 mmol) of N,N-diisopropylethyl amine. After stirring for 5 min at rt, 156 mg (0.47 mmol) of (4-tert-butyl-benzyl)-[2-(3-difluoromethoxy-phenyl)-ethyl]-amine were added. After stirring for 22 h at rt, the reaction mixture was diluted with 10 ml water and extracted with EtOAc (2×). The combined organic phases were washed with water and brine, dried with magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by two successive column chromatographies (8 g silica gel; EtOAc/heptane 1:3; then again 8 g silica gel; and DCM/heptane 70:30 to 90:10) to give 91 mg white solid (27%). MS(ISP) 528.3 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][CH:16]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)=[CH:23][CH:22]=3)[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:41](Cl)(=[O:50])[CH2:42][CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[C:44]1([CH2:43][CH2:42][C:41]([N:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:14][CH:13]=2)[CH:16]([C:21]2[CH:22]=[CH:23][C:24]([O:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][O:29]3)=[CH:25][CH:26]=2)[CH2:17][CH2:18][CH2:19][CH3:20])=[O:50])[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Cl)CCc1ccccc1
Reactant: CCCCC(Nc1ccc(OCCN2CCCC2)cc1)c1ccc(OC2CCCCO2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(c1ccc(OC2CCCCO2)cc1)N(C(=O)CCc1ccccc1)c1ccc(OCCN2CCCC2)cc1
Reaction time: 1 h

Procedure:
To a solution of [4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-{1-[4-(tetrahydro-pyran-2-yloxy)-phenyl]-pentyl}-amine (0.100 g, 0.22 mmol) and triethylamine (0.092 mL, 0.66 mmol) in 2 mL methylene chloride was added hydrocinnamoyl chloride (0.082 mL, 0.55 mmol), dropwise. The reaction mixture was stirred for 1 hr. at room temperature. Saturated aqueous sodium bicarbonate was added and the layers were separated. The aqueous layer was extracted with an additional 2 mL of methylene chloride. The combined organic layers were concentrated to give the title compound of Step A. MS 585.1 (M+1)+
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[S:5].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=[O:20])=[CH:14][CH:13]=1>C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:6][C:19]([NH:18][C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1)=[O:20])=[S:5]
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: Cc1ccccc1C(N)=S
Solvent: Cc1ccccc1C
Product: Cc1ccccc1C(=S)NC(=O)Nc1ccc(Cl)cc1

Procedure:
2-Methylthiobenzamide in an amount of 1.67 g is suspended in 25 ml of dry xylene. After addition of 1.54 g of 4-chlorophenylisocyanate, the reaction mixture is refluxed over night. After cooling to room temperature the desired product crystallizes in a yield of 2.8 g, m.p. 211° C. The same result is obtained when 2-methylthiobenzoyl isocyanate is reacted with 4-chloroaniline.
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]2[CH2:6][CH2:7][O:8][C:9](=[O:13])[N:10]([CH2:11][CH3:12])[C:4]=2[CH:3]=1.Cl[C:17]1[N:22]=[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])[C:20]([Cl:35])=[CH:19][N:18]=1>>[Cl:35][C:20]1[C:21]([NH:23][C:24]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:25]=2[C:26]([NH:28][CH3:29])=[O:27])=[N:22][C:17]([NH:1][C:2]2[CH:15]=[CH:14][C:5]3[CH2:6][CH2:7][O:8][C:9](=[O:13])[N:10]([CH2:11][CH3:12])[C:4]=3[CH:3]=2)=[N:18][CH:19]=1
Reactant: CNC(=O)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Reactant: CCN1C(=O)OCCc2ccc(N)cc21
Product: CCN1C(=O)OCCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NC)n3)cc21

Procedure:
Following a procedure analogous to Example 1741e, 3-amino-5-ethyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one and 2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-N-methyl-benzamide were converted to 2-[5-chloro-2-(5-ethyl-6-oxo-5,6,8,9-tetrahydro-7-oxa-5-aza-benzocyclohepten-3-ylamino)-pyrimidin-4-ylamino]-3-fluoro-N-methyl-benzamide. HCl salt: 1H NMR (400 MHz, CD3OD) δ 8.24 (s, 1H), 7.45 (dd, 2H), 7.30 (dd, 2H), 7.21 (d, 1H), 7.09 (dd, 1H), 4.39 (t, 2H), 3.67 (q, 2H), 2.94 (t, 2H), 2.84 (s, 3H), 1.05 (t, 3H); MS (m/e) 485 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([Cl:10])[CH2:5][C:6]([Cl:9])(O)[CH:7]=1.BrC1C=C[C:15]([OH:18])=[C:14](CC)C=1>>[CH2:15]([O:18][C:5]1[C:4]([Cl:10])=[CH:3][C:2]([Br:1])=[CH:7][C:6]=1[Cl:9])[CH3:14]
Reactant: OC1(Cl)C=C(Br)C=C(Cl)C1
Reactant: CCc1cc(Br)ccc1O
Product: CCOc1c(Cl)cc(Br)cc1Cl

Procedure:
The title compound was prepared analogously to step 2 in Example A(125), where 5-Bromo-1,3-dichloro-phenol was substituted in place of 4-bromo-2-ethyl-phenol in that example.
Reaction SMILES: [N:1]1([C:7]2[S:8][C:9]3[C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[N:1]1([C:7]2[S:8][C:9]3[C:15]([CH2:16][OH:17])=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc2nc(N3CCCCC3)sc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OCc1cccc2nc(N3CCCCC3)sc12
Yield: 92.1 %

Procedure:
Ethyl ester of 2-piperidinobenzothiazole-7-carboxylic acid (475 mg, 1.64 mmol) was reduced by using lithium aluminium hydride as in Preparation 2-3) to give 2-piperidinobenzothiazole-7-methanol (375 mg, 91%) as pale yellow crystals.