Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:35])[CH2:4][C:5]1[N:6]=[C:7]([NH:11][C:12](=[O:34])[C:13]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH3:14])[S:8][C:9]=1[Cl:10].C(O)C.O.[OH-].[Li+]>C1COCC1>[Cl:10][C:9]1[S:8][C:7]([NH:11][C:12](=[O:34])[C:13]([O:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:27]=2[F:33])([C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH3:14])=[N:6][C:5]=1[CH2:4][C:3]([OH:35])=[O:2]
Reactant: COC(=O)Cc1nc(NC(=O)C(C)(Oc2ccc(F)cc2F)c2ccc(S(C)(=O)=O)cc2)sc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC(Oc1ccc(F)cc1F)(C(=O)Nc1nc(CC(=O)O)c(Cl)s1)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 33.9 %

Procedure:
To a solution of {5-Chloro-2-[2-(2,4-difluoro-phenoxy)-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid methyl ester (0.03 g, 0.05 mmol) in THF:Ethanol:water (1 ml+0.3 ml+0.3 ml) was added lithium hydroxide (0.0046 g, 0.11 mmol). The resulting mixture was stirred for 5 hours at room temperature followed by removal of solvent under reduced pressure. The residue was suspended in water (15 ml), extracted with ethyl acetate to remove impurities. The aqueous layer was acidified with 1N HCl (0.5 ml) and extracted with ethyl acetate (2×10 ml), This ethyl acetate layer was washed with water (15 ml), brine (20 ml), dried over anhydrous sodium sulfate and solvent was removed under reduced pressure to give solid product {5-Chloro-2-[2-(2,4-difluoro-phenoxy)-2-(4-methanesulfonyl-phenyl)-propionylamino]-thiazol-4-yl}-acetic acid (9 mg). 1H NMR (400 MHz, CDCl3): δ 1.85 (s, 3H), 3.07 (s, 3H), 3.72 (s, 2H), 6.64-6.69 (m, 2H), 6.89-6.91 (m, 1H), 7.84 (d, J=8.4 Hz, 2H), 8.00 (d, J=8.8 Hz, 2H). MS (EI) m/z: 530.70 (M+1), mp: 109-111° C.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:9][N:8]([CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21](I)[CH:20]=3)[CH:15]([CH3:26])[C:14]2=[O:27])[CH2:7][CH2:6][C:3]21[CH2:5][CH2:4]2.[C:28]1(B(O)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+].CC(C)=O>CC([O-])=O.CC([O-])=O.[Pd+2].O>[C:21]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=[CH:23][CH:24]=[C:19]([N:16]2[CH2:17][CH2:18][N:13]([CH2:12][CH2:11][CH2:10][N:8]3[CH2:7][CH2:6][C:3]4([CH2:5][CH2:4]4)[C@H:2]([OH:1])[CH2:9]3)[C:14](=[O:27])[CH:15]2[CH3:26])[CH:20]=1
Reactant: OB(O)c1ccccc1
Reactant: CC1C(=O)N(CCCN2CCC3(CC3)[C@H](O)C2)CCN1c1cccc(I)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Product: CC1C(=O)N(CCCN2CCC3(CC3)[C@H](O)C2)CCN1c1cccc(-c2ccccc2)c1
Temperature: 65 °C
Yield: 98 %

Procedure:
A mixture of 1-[3-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-4-(3-iodo-phenyl)-3-methyl-piperazin-2-one (example 89; 60 mg, 0.12 mmol), phenylboronic acid (16 mg, 0.13 mmol), potassium carbonate (43 mg, 0.31 mmol), Pd(OAc)2 (0.6 mg, 2 μmol), acetone (0.5 mL), and water (0.6 mL) was heated at 65° C. for 30 min, then partitioned between CH2Cl2 and sat. aq. NaHCO3 solution. The organic layer was dried (MgSO4), filtered, and evaporated. Chromatography (SiO2; EtOAc/MeOH 19:1) afforded the title compound (51 mg, 95%). Colorless gum, MS: 434.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([C:7]2[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=2[C:9]([NH:11][C@H:12]2[CH2:16][CH2:15][CH2:14][C@@H:13]2[NH:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=2)=[O:10])ON=1.[N:32]1C=CC=N[C:33]=1C1C=CC=CC=1C(O)=O.Cl.FC(F)(F)C1C=CC(N[C@H]2CCC[C@@H]2N)=NC=1>>[N:6]1[CH:2]=[CH:1][CH:33]=[N:32][C:5]=1[C:7]1[CH:31]=[CH:30][CH:29]=[CH:28][C:8]=1[C:9]([NH:11][C@H:12]1[CH2:16][CH2:15][CH2:14][C@@H:13]1[NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][N:19]=1)=[O:10]
Reactant: Cc1noc(-c2ccccc2C(=O)N[C@H]2CCC[C@@H]2Nc2ccc(C(F)(F)F)cn2)n1
Reactant: O=C(O)c1ccccc1-c1ncccn1
Agent: Cl
Agent: N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ccc(C(F)(F)F)cn1)c1ccccc1-c1ncccn1

Procedure:
Prepared according to the procedure for 2-(3-methyl-1,2,4-oxadiazol-5-yl)-N-[(1S,2S)-2-{[5-(trifluoromethyl)pyridin-2-yl]amino}cyclopentyl]benzamide (Example 8) from 2-(pyrimidin-2-yl)benzoic acid (CAS number 400892-62-8; 56 mg, 0.28 mmol) and (1S,2S)-1-N-[5-(trifluoromethyl)pyridin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 1; 72 mg, 0.26 mmol) to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:26](=[O:31])N(OC)C)[C:10]3[N:14]=[C:13]([O:15][CH2:16][CH3:17])[N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]=3[CH:25]=2)=[C:5]([CH3:32])[O:4][N:3]=1.[C:33]1([Mg]Cl)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[C:26]([C:9]1[C:10]2[N:14]=[C:13]([O:15][CH2:16][CH3:17])[N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[C:11]=2[CH:25]=[C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[CH3:32])[CH:8]=1)(=[O:31])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CCOc1nc2c(C(=O)N(C)OC)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Reactant: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: CCOc1nc2c(C(=O)c3ccccc3)cc(-c3c(C)noc3C)cc2n1C(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
Tert-butyl 6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-4-(methoxy(methyl)carbamoyl)-1H-benzo[d]imidazole-1-carboxylate was dissolved in THF (3 mL). To the solution was added a solution of phenyl magnesium chloride (2M in THF, 0.508 mmol, 0.254 mmol) at −78° C. after the addition, the reaction was allowed to warm up to room temperature. The reaction was stirred for 17 hat the same temperature. The reaction mixture was quenched with water (30 mL). The whole was extracted with AcOEt (30 mL×3). Organic layer was washed with brine (30 mL) and dried over Na2SO4. The solvent was removed under a reduced pressure to give the crude product. The crude product was purified by a silica gel column chromatography (hexane:EtOAc, 7:1 to 3:1) to give tert-butyl 4-benzoyl-6-(3,5-dimethylisoxazol-4-yl)-2-ethoxy-1H-benzo[d]imidazole-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21]Cl)[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH2:27]([NH:30][CH2:31][CH2:32][CH3:33])[CH2:28][CH3:29]>O1CCCC1>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]3[S:17][CH:18]=[C:19]([CH2:21][N:30]([CH2:31][CH2:32][CH3:33])[CH2:27][CH2:28][CH3:29])[N:20]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(-c3nc(CCl)cs3)c2[C@@H]2CCCN12
Reactant: CCCNCCC
Solvent: C1CCOC1
Product: CCCN(CCC)Cc1csc(-c2ncn3c2[C@@H]2CCCN2C(=O)c2c(Cl)cccc2-3)n1
Reaction time: 96 h
Yield: 57 %

Procedure:
A solution of 1.0 g (0.0025 mol) of (S)-8-chloro-1-(4-chloromethyl-thiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in 20 ml of tetrahydrofuran was treated with 5 ml (0.037 mol) of dipropylamine and stirred at 50° for 96 hrs. All volatiles were removed in a waterjet vacuum and the residue was taken up with ethyl acetate and water. The organic phase was dried over magnesium sulphate, concentrated and the residue remaining was chromatographed over silica gel with methylene chloride/methanol 95:5 as the eluent. After recrystallization from ethyl acetate there was obtained 0.67 g (58%) of (S)-8-chloro-1-(4-dipropylaminomethyl-thiazol-2-yl)-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one in the form of white crystals; m.p. 213-214° and [α]D20 =-68.5° (MeOH, c=0.8%).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([O:13][CH3:14])=[O:12])[C:6]=1[O:15][CH3:16])=[O:4].[OH-].[Na+].Cl>O>[CH3:14][O:13][C:11]([NH:10][C:7]1[C:6]([O:15][CH3:16])=[C:5]([C:3]([OH:4])=[O:2])[O:9][N:8]=1)=[O:12]
Reactant: COC(=O)Nc1noc(C(=O)OC)c1OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)Nc1noc(C(=O)O)c1OC
Temperature: 90 °C
Reaction time: 1 h
Yield: 84537.9 %

Procedure:
A mixture of 2.50 g (0.011 mmol) of methyl-3-(methoxycarbonyl)amino-4-methoxy-isoxazole-5-carboxylate (prepared according to the method described in W. Kloetzer, J. Schantz, Monatsh. Chem., 1965, 102–115) and 1.30 g of powdered sodium hydroxide dissolved in 9 ml of water is heated at 90° C. for 3 hours. After cooling, the mixture is acidified to pH=2 with concentrated hydrochloric acid, controlling the temperature so as not to exceed 5° C. After 1 hour of stirring at 0° C., the precipitate obtained is filtered off and washed with cold water. There is obtained 2.01 g (86% yield) of a white solid (M+1=217).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:27]([F:30])([F:29])[F:28])=[CH:4][C:5]2[N:9]=[C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:12][CH2:11]3)[NH:7][C:6]=2[CH:26]=1.C(N(CC)C(C)C)(C)C.[CH3:40][Si:41]([CH3:48])([CH3:47])[CH2:42][CH2:43][O:44][CH2:45]Cl>ClCCl>[Br:1][C:2]1[C:3]([C:27]([F:30])([F:28])[F:29])=[CH:4][C:5]2[N:9]([CH2:45][O:44][CH2:43][CH2:42][Si:41]([CH3:48])([CH3:47])[CH3:40])[C:8]([N:10]3[CH2:11][CH2:12][N:13]([C:16]4[C:21]([C:22]([F:23])([F:24])[F:25])=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:14][CH2:15]3)=[N:7][C:6]=2[CH:26]=1
Reactant: FC(F)(F)c1cc2nc(N3CCN(c4ncccc4C(F)(F)F)CC3)[nH]c2cc1Br
Reactant: C[Si](C)(C)CCOCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCn1c(N2CCN(c3ncccc3C(F)(F)F)CC2)nc2cc(Br)c(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-bromo-5-trifluoromethyl-2-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-1H-benzoimidazole (203 mg, 0.41 mmol, Example 89 g) in dichloromethane (6 mL) was added N,N-diisopropylethylamine (148 mg, 1.15 mmol) followed by 2-(trimethylsilyl)ethoxymethyl chloride (94 mg, 0.57 mmol, Aldrich). The reaction mixture was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel column chromatography, eluting with EtOAc/hexane (1:3) to afford the title compound as an amorphous solid. MS (ESI, pos. ion) m/z: 624 (M+1).
Reaction SMILES: O.Cl.Cl.[CH3:4][N:5]([CH3:20])[CH:6]1[CH2:19][CH2:18][C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=3[C:8]=2[CH2:7]1.CN(C)C1CCC2[O:27][C:28]3[CH:33]=[CH:32][C:31](N)=CC=3C=2C1.Cl.Cl.C1(C(Cl)=O)CC1>>[CH3:4][N:5]([CH3:20])[CH:6]1[CH2:19][CH2:18][C:9]2[O:10][C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:28]([CH:33]4[CH2:31][CH2:32]4)=[O:27])=[CH:13][C:12]=3[C:8]=2[CH2:7]1
Reactant: CN(C)C1CCc2oc3ccc(N)cc3c2C1
Agent: Cl
Agent: O=C(Cl)C1CC1
Solvent: O
Product: CN(C)C1CCc2oc3ccc(NC(=O)C4CC4)cc3c2C1

Procedure:
Beginning with 9.0 mg (0.029 mMol) of N,N-dimethyl-8-amino-1,2,3,4-tetrahydro-2-dibenzofuranamine dihydrochloride hemihydrate and 4.3 mg (0.036 mMol) of cyclopropanecarbonyl chloride, the title compound was recovered by the procedure described in Example 2.
Reaction SMILES: [OH:1][CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][NH:8][CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12].[CH:27]1([S:32][CH2:33][CH2:34]Cl)[CH2:31][CH2:30][CH2:29][CH2:28]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C.CO>[OH:1][CH:2]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=2)[N:18]=[CH:17][CH:16]=1)[CH2:3][CH2:4][C@@H:5]1[CH2:10][CH2:9][N:8]([CH2:34][CH2:33][S:32][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[CH2:7][C@@H:6]1[C:11]([O:13][CH3:14])=[O:12]
Reactant: ClCCSC1CCCC1
Reactant: COC(=O)[C@H]1CNCC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Product: COC(=O)[C@H]1CN(CCSC2CCCC2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Temperature: 20 °C
Yield: 49.3 %

Procedure:
0.717 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-carboxylate in 15 cm3 of acetonitrile and 15 cm3 of methanol was heated for 3½ h at a temperature in the region of the reflux temperature, with stirring and under an inert atmosphere, with 0.439 g of 90% 2-chloroethyl cyclopentyl sulfide in the presence of 0.332 g of potassium carbonate and 0.4 g of potassium iodide. After cooling the reaction mixture to a temperature in the region of 20° C., the insoluble material was filtered off and then washed with acetonitrile. The filtrate was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. The residue obtained was purified by chromatography under a nitrogen pressure of 100 kPa on a column of silica gel (particle size 40-63 μm; diameter 3.5 cm; height 45 cm), elution was carried out with a dichloromethane/methanol (95/5 by volume) mixture, and 35-cm3 fractions were collected. Fractions 25 to 45 were combined and then evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. 0.48 g of methyl (3R,4R)-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]-1-[2-(cyclopentylthio)-ethyl]piperidine-3-carboxylate was obtained in the form of a lacquer with a dark-green color.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])[C:3]1=[O:27].[CH3:28][O:29][C:30]1[CH:31]=[C:32]([N:36]=[C:37]=[O:38])[CH:33]=[CH:34][CH:35]=1>O1CCCC1>[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:36][C:37]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[N:4]([CH2:19][C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])[C:3]2=[O:27])=[O:38])[CH:33]=[CH:34][CH:35]=1
Reactant: CCN(CC)C(=O)CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: COc1cccc(N=C=O)c1
Solvent: C1CCOC1
Product: CCN(CC)C(=O)CN1C(=O)C(NC(=O)Nc2cccc(OC)c2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3-amino-N,N-diethyl-2,3-dihydro-2-oxo-5-phenyl-1H-1,4-benzodiazepine-1-acetamide and 3-methoxyphenylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 222°-224° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:14])([F:13])[CH2:7][S:8][CH2:9][C:10](O)=[O:11]>>[F:5][C:6]([F:14])([F:13])[CH2:7][S:8][CH2:9][C:10]([Cl:3])=[O:11]
Reactant: O=C(O)CSCC(F)(F)F
Reactant: O=S(Cl)Cl
Product: O=C(Cl)CSCC(F)(F)F

Procedure:
Thionyl chloride (21.9 g, 184 mmol) and trifluoroethylmercaptoacetic acid (15.9 g, 91 mmol) were stirred together overnight. The excess reagent was removed in vacuo and the product was distilled; bp 62°-68°/20 mm.
Reaction SMILES: O.[NH2:2][CH2:3][CH:4]1[C:10]2=[CH:11][NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[C:8]([C:9]=32)[C:7](=[O:17])[NH:6][CH2:5]1.[CH3:18][N:19]([CH3:22])[CH:20]=O>>[CH3:18][N:19]([CH:22]=[N:2][CH2:3][CH:4]1[C:10]2=[CH:11][NH:12][C:13]3[CH:14]=[CH:15][CH:16]=[C:8]([C:9]=32)[C:7](=[O:17])[NH:6][CH2:5]1)[CH3:20]
Reactant: NCC1CNC(=O)c2cccc3[nH]cc1c23
Reactant: CN(C)C=O
Solvent: O
Product: CN(C)C=NCC1CNC(=O)c2cccc3[nH]cc1c23
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1 g of 3-aminomethyl-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole hydrate (see Example 1C for preparation) was dissolved in 10 ml of dimethylformamide at room temperature. 1 g of N-chloromethylene-N,N-dimethyliminium chloride was added to this solution. The reaction mixture was subsequently stirred at room temperature for 2 hours. To work up the reaction mixture it was evaporated under reduced pressure (water pump vacuum) and the residue was taken up in a mixture of equal parts of water and ethyl acetate. The aqueous phase was adjusted to a pH of 8.5 by adding saturated sodium bicarbonate solution, then the organic phase was separated and the aqueous phase was extracted three times more with 50 ml portions of ethyl acetate. The combined organic extracts were concentrated to 25 ml. The solution of the title compound obtained in this way was further worked up as described in Example 15. 0.5 g of 3-(dimethylaminomethylideneamino-methyl)-3,4,5,6-tetrahydro-6-oxo-1H-azepino[5,4,3-cd]indole hydrochloride was obtained with a melting point of 178° to 179° C.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([CH2:6][NH:7][C:8]2[C:13]([C:14]([OH:16])=O)=[CH:12][C:11]([S:17]([NH2:20])(=[O:19])=[O:18])=[C:10]([Cl:21])[CH:9]=2)[O:4][CH:5]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH2:36]([NH:38][CH2:39][CH3:40])[CH3:37]>CN(C=O)C>[CH2:36]([N:38]([CH2:39][CH3:40])[C:14](=[O:16])[C:13]1[CH:12]=[C:11]([S:17]([NH2:20])(=[O:19])=[O:18])[C:10]([Cl:21])=[CH:9][C:8]=1[NH:7][CH2:6][C:3]1[O:4][CH:5]=[CH:1][CH:2]=1)[CH3:37]
Reactant: CCNCC
Reactant: NS(=O)(=O)c1cc(C(=O)O)c(NCc2ccco2)cc1Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CCN(CC)C(=O)c1cc(S(N)(=O)=O)c(Cl)cc1NCc1ccco1

Procedure:
In a similar manner to Example 7, furosemide can be reacted with EDC, HOBt and diethylamine in DMF to yield N,N-diethyl 5-aminosulfonyl-4-chloro-2-[(2-furanylmethyl)-amino]benzamide.
Reaction SMILES: [Mg].Br[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[CH3:16][Si:17]([CH3:20])([CH3:19])Cl.S(=O)(=O)(O)O>BrCCCCCCC1C=CC(Cl)=CC=1.O1CCCC1.COC(C)(C)C.[Li+].[Li+].[Cl-].[Cl-].[Cl-].[Cl-].[Cu+2]>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([CH:8]([Si:17]([CH3:20])([CH3:19])[CH3:16])[CH2:7][CH2:6][CH2:5][CH2:4][CH3:3])=[CH:10][CH:11]=1
Reactant: C[Si](C)(C)Cl
Reactant: Clc1ccc(CCCCCCBr)cc1
Agent: [Cu+2]
Agent: O=S(=O)(O)O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCCCCC(c1ccc(Cl)cc1)[Si](C)(C)C
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 39 %

Procedure:
Approximately 2 g (82 mMol) of magnesium in a flask were moistened with tetrahydrofuran. A Grignard reaction was initiated using 5 drops of 1-(6-bromohexyl)-4-chlorobenzene. The remainder of a total of 17 g of the halogen compound (61 mMol), dissolved in 50 ml of tetrahydrofuran, was added dropwise at 50° to 60° C. When the addition was complete, the mixture was kept at this temperature for an additional 2.5 hours, and a solution of 12 g (110 mMol) of trimethylchlorosilane and a catalytic amount of dilithium tetrachlorocuprate in 40 ml of tetrahydrofuran was then added dropwise at 20° to 40° C. The mixture was stirred at 60° C. for 1 hour, then allowed to stand overnight and diluted with 200 ml of tert-butyl methyl ether. The mixture was then acidified using 2N sulfuric acid, the phases were separated, and the organic phase was washed and dried. The evaporated residue was fractionated. About 6.4 g of 1-chloro-4-(1-trimethylsilylhexyl)benzene (38.6 percent yield) were obtained at a pressure of 0.2 hPa and at 88° to 90° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=1.CN(C(SC1[N+]([O-])=CC=CC=1)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:47][C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[N:53]([NH2:57])[CH:52]=[C:51]2[CH3:58]>CN(C=O)C.O.CCOC(C)=O>[F:47][C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[N:53]([NH:57][C:13]([C:10]1[CH:11]=[N:12][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][CH:9]=1)=[O:15])[CH:52]=[C:51]2[CH3:58]
Reactant: Cc1cn(N)c2ccc(F)cc12
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1
Agent: CN(C)C(Sc1cccc[n+]1[O-])=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cn(NC(=O)c2cnc(-c3ccccn3)nc2)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
A solution of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (209 mg, 0.88 mmol), HOTT (435 mg, 1.17 mmol), and DIPEA (400 μL, 2.29 mmol) in DMF (10 mL) is stirred at rt under N2 for 20 min. 5-Fluoro-3-methyl-indol-1-ylamine (125 mg, 0.76 mmol) is added. The resulting mixture is stirred at rt overnight. The mixture is portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 70% EtOAc in heptane to afford 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-3-methyl-indol-1-yl)-amide (180 mg, 68%) as a solid. MS: 348 (M+H). 1H NMR (300 MHz, DMSO-d6): δ 12.12 (s, 1H), 9.47 (s, 2H), 8.82 (d, 1H), 8.51 (d, 1H), 8.05 (td, 1H), 7.62 (dd, 1H), 7.42 (dd, 1H), 7.35 (dd, 1H), 7.33 (s, 1H), 7.03 (td, 1H), 2.27 (s, 3H).
Reaction SMILES: [CH2:1]([CH:8]1[CH2:14][N:13]([CH2:15][C:16]([NH:18]C2C=CC=CC=2)=[O:17])[C:12](=[O:25])[CH2:11][N:10]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:9]1=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.NC1C=CC=CC=1.[CH2:44](N)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[CH2:44]([NH:18][C:16](=[O:17])[CH2:15][N:13]1[CH2:14][CH:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[C:9](=[O:36])[N:10]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[CH2:11][C:12]1=[O:25])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: O=C(CN1CC(Cc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(Cl)cc2)CC1=O)Nc1ccccc1
Reactant: NCc1ccccc1
Solvent: Nc1ccccc1
Product: O=C(CN1CC(Cc2ccccc2)C(=O)N(S(=O)(=O)c2ccc(Cl)cc2)CC1=O)NCc1ccccc1

Procedure:
Instead of the starting material compound of Example 270, that is, aniline, benzylamine was used for the similar procedure as in Example 270 to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=3)[C:17]([CH3:28])([CH3:27])[CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=3)[C:17]([CH3:28])([CH3:27])[CH2:16]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CC(C)(C)c3ccc([N+](=O)[O-])cc32)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(CN2CC(C)(C)c3ccc(N)cc32)CC1
Reaction time: 3 h

Procedure:
A mixture of 240 mg 4-(3,3-dimethyl-6-nitro-2,3-dihydro-indol-1-ylmethyl)-piperidine-1-carboxylic acid tert-butyl ester, 20 mg of 10% palladium on carbon and 5 ml ethanol was stirred for 3 hours under hydrogen atmosphere. The mixture was filtered through a chem elut cartridge and the compound was eluted with ethanol. After concentration under reduced pressure the residue was directly subjected to the subsequent reaction without further purification.
Reaction SMILES: C(OC(=O)NC1(C2C=CC(C3C(=O)C4C(=CC=C(F)C=4)OC=3C3C=CC=CC=3)=CC=2)CCC1)(C)(C)C.[Br:37][C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:47]=1[O:46][C:45]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[C:44](I)[C:43]2=[O:55].CC1(C)C(C)(C)OB([C:64]2[CH:69]=[CH:68][C:67]([C:70]3([NH:74][S:75]([C:77]([CH3:80])([CH3:79])[CH3:78])=[O:76])[CH2:73][O:72][CH2:71]3)=[CH:66][CH:65]=2)O1>>[Br:37][C:38]1[CH:39]=[CH:40][CH:41]=[C:42]2[C:47]=1[O:46][C:45]([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[C:44]([C:64]1[CH:65]=[CH:66][C:67]([C:70]3([NH:74][S:75]([C:77]([CH3:80])([CH3:79])[CH3:78])=[O:76])[CH2:73][O:72][CH2:71]3)=[CH:68][CH:69]=1)[C:43]2=[O:55]
Reactant: CC(C)(C)S(=O)NC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)COC1
Reactant: O=c1c(I)c(-c2ccccc2)oc2c(Br)cccc12
Agent: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CC(C)(C)S(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4c(Br)cccc4c3=O)cc2)COC1
Yield: 55 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 8-bromo-3-iodo-2-phenyl-chromen-4-one and 2-methyl-propane-2-sulfinic acid {3-[4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-phenyl]-oxetan-3-yl}-amide were reacted to give the title compound as a tan solid (59 mg, 55%). LCMS (Method B): RT=5.02 min, [M+H]+=552/554.