Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:12]([O:14]C)[C:5]2[N:6]([CH:9]3[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1.B(Br)(Br)Br.N.CO>ClCCl>[Br:1][C:2]1[CH:13]=[C:12]([OH:14])[C:5]2[N:6]([CH:9]3[CH2:11][CH2:10]3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: COc1cc(Br)cc2ncn(C3CC3)c12
Agent: BrB(Br)Br
Agent: N
Solvent: CO
Solvent: ClCCl
Product: Oc1cc(Br)cc2ncn(C3CC3)c12
Temperature: 35 °C
Reaction time: 5 h

Procedure:
5-bromo-1-cyclopropyl-7-methoxy-1H-benzo[d]imidazole (0.54 g, 2.01 mmol) was dissolved in dichloromethane (12 mL) under N2. A 1M BBr3 solution in DCM (12 mL, 12 mmol) was added dropwise over 1 min. The resulting stirred suspension was heated to 35° C. After 5 h, the reaction mixture was cooled in an ice water bath. A 7M ammonia in MeOH solution (7.5 mL, 53 mmol) was then added over 2 min via syringe. The mixture was stirred 5 min and was removed from the ice bath. After an additional 10 min, the mixture was concentrated in vacuo, and the crude product was dissolved in MeOH (30 mL) and was concentrated in vacuo. The resulting crude solids were suspended in 20% MeOH in DCM (30 mL) and were filter through a short pad of silica, eluting with 20% MeOH in DCM. Filtrate was concentrated in vacuo, and the crude product was adsorbed onto silica gel. Purification by silica gel chromatography (0-20% MeOH in DCM) gave 5-bromo-1-cyclopropyl-1H-benzo[d]imidazol-7-ol (2.73). LCMS-ES r (m/z): [m+H]+ calcd for C10H10BrN2O: 253.00; found: 253.14.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[F:21][C:22]1[CH:23]=[C:24]([N:28]2[C:32]([N:33]([CH3:37])[C:34](=[O:36])[CH3:35])=[C:31]([C:38]([O:40]CC)=O)[CH:30]=[N:29]2)[CH:25]=[CH:26][CH:27]=1>C1COCC1>[F:21][C:22]1[CH:23]=[C:24]([N:28]2[C:32]3[N:33]([CH3:37])[C:34](=[O:36])[CH:35]=[C:38]([OH:40])[C:31]=3[CH:30]=[N:29]2)[CH:25]=[CH:26][CH:27]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(F)c2)c1N(C)C(C)=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cn1c(=O)cc(O)c2cnn(-c3cccc(F)c3)c21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of diisopropylamine (3.45 mL, 24.4 mmol) in 15 mL THF under argon at 0° C. was treated with n-butyllithium (14.7 mL of 1.6 M solution in hexanes, 23.5 mmol) and stirred at this temperature for 30 min. The freshly prepared LDA was added dropwise to a solution of ethyl 1-(3-fluorophenyl)-5-(N-methylacetamido)-1H-pyrazole-4-carboxylate (2.87 g, 9.40 mmol) in 5 mL of THF at −78° C. After the reaction mixture was gradually warmed to RT in 4 h, it was partitioned between 1N NaOH and 45 mL of ether. The ether layer was separated and discarded; the aqueous layer was acidified with 2 N HCl, and extracted three times with EtOAc. The combined EtOAc layers were washed with brine, dried over MgSO4, and concentrated to yield the title compound as a tan crystalline solid. MS (ESI, pos.ion) m/z: 260.1 (M+1). The crude material was used in the next step without further purification.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[BH4-].[Na+].[OH-].[Na+]>C(O)C>[CH2:16]([N:13]1[CH2:12][CH:11]=[C:10]([CH2:9][CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:15][CH2:14]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc(CCCc2ccncc2)cc1
Reactant: BrCc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C1=C(CCCc2ccccc2)CCN(Cc2ccccc2)C1
Temperature: 0 °C

Procedure:
A solution of 1.7 g (8.6 mmol) of 4-(3-phenylpropyl)pyridine and 1.5 mL of benzylbromide in 5 mL of ethanol was stirred at rt for 0.5 h. To the reaction mixture was added 10 mL of ethanol and the mixture was cooled to 0° C. To this mixture was added 0.5 g (13.2 mmol) of NaBH4 small portions over a period of 1 h. To the reaction mixture was then added 5 mL of a 1N NaOH solution and the mixture was partitioned between 200 mL of ether and 50 mL of H2O. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate, 9:1) to give the title compound.
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][C:6]1[O:10][N:9]=[C:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:14][C:13]=2[CH2:25][S:26][C:27]([CH3:30])([CH3:29])[CH3:28])[N:7]=1)C.[Li+].[OH-]>CO.O>[C:27]([S:26][CH2:25][C:13]1[CH:14]=[C:15]([NH:18][C:19](=[O:24])[C:20]([CH3:23])([CH3:22])[CH3:21])[CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[N:7]=[C:6]([CH2:5][C:4]([OH:31])=[O:3])[O:10][N:9]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CCOC(=O)Cc1nc(Cc2ccc(NC(=O)C(C)(C)C)cc2CSC(C)(C)C)no1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1Cc1noc(CC(=O)O)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
{3-[2-tert-Butylsulfanylmethyl-4-(2,2-dimethyl-propionylamino)-benzyl]-[1,2,4]oxadiazol-5-yl}-acetic acid ethyl ester (0.28 mmol) in MeOH (5 mL) was treated with 1N aqueous LiOH (0.5 mL), and the reaction was stirred for 6 hours at room temperature. The mixture was diluted with H2O and extracted with EtOAc. The combined organic layers were dried and concentrated to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])[CH3:2].[Cl:13]N1C(=O)CCC1=O>C(#N)C>[Cl:13][C:10]1[CH:11]=[CH:12][C:4]([O:3][CH2:1][CH3:2])=[C:5]([CH:9]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOc1ccccc1C(=O)O
Solvent: CC#N
Product: CCOc1ccc(Cl)cc1C(=O)O
Temperature: 25 °C
Reaction time: 70 h

Procedure:
To a solution of 2-ethoxybenzoic acid (4.4 g, 26.6 mmol) in 80 mL of acetonitrile at 0° C. was added N-chlorosuccinimide (3.7 g, 28 mmol) in 20 mL of acetonitrile dropwise over 30 minutes. The reaction mixture was warmed to ambient temperature and the mixture was allowed to stir for 70 hours. The mixture was quenched with 20 mL of H2O and the layers were separated. The aqueous layer was extracted with three 15 mL portions of CH2Cl2 and the combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via recrystallization with ether and hexanes afforded the title compound. MS (DCI/NH3) m/z 201 (M+H)+, 218 (M+NH4)+.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][CH:10]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:39][C:40]1[CH:45]=[C:44]([C:46]2[S:47][CH:48]=[CH:49][CH:50]=2)[CH:43]=[CH:42][C:41]=1[NH:51]C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>CN(C=O)C>[NH2:51][C:41]1[CH:42]=[CH:43][C:44]([C:46]2[S:47][CH:48]=[CH:49][CH:50]=2)=[CH:45][C:40]=1[NH:39][C:13]([C:12]1[CH:11]=[CH:10][C:9]([P:4](=[O:5])([O:3][CH2:1][CH3:2])[O:6][CH2:7][CH3:8])=[CH:17][CH:16]=1)=[O:15]
Reactant: CCOP(=O)(OCC)c1ccc(C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(OCC)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Reaction time: 16 h

Procedure:
A mixture of 4-(diethoxyphosphoryl)benzoic acid (commercially available, 50 mg, 0.194 mmol), EDCI (44.6 mg, 0.233 mmol), HOBT (31.5 mg, 0.233 mmol) and tert-butyl [2-amino-4-(2-thienyl)phenyl]carbamate (67.7 mg, 0.233 mmol) were taken into DMF (0.58 mL) and stirred for 16 h. Approximately 5 mL of TFA was added to the mixture which was stirred for 1 h and concentrated. The product was purified by HPLC (30-90% MeCN in H2O with 0.025% TFA) to afford the requisite product. 1H NMR (DMSO-d6, 600 MHz) δ 9.87 (s, 1H), 8.11 (dd, J=7.9, 3.5 Hz, 2H), 7.83 (dd, J=21.1, 8.2 Hz, 2H), 7.45 (d, J=2.0 Hz, 1H), 7.33 (dd, J=5.0, 0.9 Hz, 1H), 7.29 (dd, J=8.2, 2.0 Hz, 1H), 7.22 (d, J=2.9 Hz, 1H), 7.03 (dd, J=5.0, 3.5 Hz, 1H), 6.79 (d, J=8.5 Hz, 1H), 5.39 (s, 2H), 3.97-4.16 (m, 4H), 1.33 (t, J=7.04 Hz, 6H). MS: cal'd 431 (MH+), exp 431 (MH+).
Reaction SMILES: S(Cl)(Cl)=O.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([CH:20]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:21]([OH:23])=[O:22])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([O-:7])=[O:6].[CH2:30](Cl)Cl>>[N+:5]([C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:19][CH2:18][CH:17]([CH:20]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:21]([O:23][CH3:30])=[O:22])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)([O-:7])=[O:6]
Reactant: ClCCl
Reactant: O=C(O)C(c1ccccc1)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Solvent: O=S(Cl)Cl
Product: COC(=O)C(c1ccccc1)C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 8 h

Procedure:
Thionyl chloride (0.01 mol) was added to a mixture of intermediate (16) (0.0029 mol) in DCM (10 ml). The mixture was stirred overnight and then the solvent was evaporated. The residue was dissolved in DCM (10 ml). Methanol (10 ml) was added. The mixture was allowed to stand for 4 hours, then poured out into a NaHCO3 solution and extracted with DCM. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was triturated in hexane/DIPE. The precipitate was filtered off and dried, yielding 0.9 g of (±)-methyl 1-(4-nitrophenyl)-α-phenyl-4-piperidineacetate (intermediate 17, mp. 124° C.).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[S:8][C:9]([C:11]([NH:13][C:14]3[CH:19]=[C:18]([NH:20][C:21](=[O:33])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([C:31]#[N:32])([CH3:30])[CH3:29])[CH:23]=4)[CH:17]=[CH:16][C:15]=3[CH3:34])=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:35][NH2:36].CO>CC(O)CC>[C:31]([C:28]([C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[C:21]([NH:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:34])=[C:14]([NH:13][C:11]([C:9]2[S:8][C:6]3=[N:7][C:2]([NH:36][CH3:35])=[CH:3][N:4]=[C:5]3[CH:10]=2)=[O:12])[CH:19]=1)=[O:33])([CH3:30])[CH3:29])#[N:32]
Reactant: CN
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NC(=O)c1cc2ncc(Cl)nc2s1
Solvent: CO
Solvent: CCC(C)O
Product: CNc1cnc2cc(C(=O)Nc3cc(NC(=O)c4cccc(C(C)(C)C#N)c4)ccc3C)sc2n1
Yield: 12 %

Procedure:
A solution of 3-chloro-N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)thieno[2,3-b]pyrazine-6-carboxamide 95 (0.049 mmol, 24 mg) and methylamine 33% in MeOH (0.049 mmol, 500 μL, 4.61 mg) in butan-2-ol (500 μL) was stirred at 150° C. for 5 h. The reaction mixture was concentrated under reduced pressure and purified with HPLC to give the title compound N-(5-(3-(2-cyanopropan-2-yl)benzamido)-2-methylphenyl)-3-(methylamino)thieno[2,3-b]pyrazine-6-carboxamide (96a) (3 mg, 12%). NMR (400 MHz, DMSO-d6) 1.75 (s, 6H), 2.24 (s, 3H), 2.89 (d, J=4.7 Hz, 3H), 7.28 (d, J=8.2 Hz, 1H), 7.60 (t, J=7.8 Hz, 1H), 7.62 (dd, J=8.2 Hz and 2.0 Hz, 1H), 7.75 (d, J=7.8 Hz, 1H), 7.83 (m, 2H), 7.95 (d, J=7.8 Hz, 1H), 8.05 (s, 1H), 8.11 (s, 1H), 8.25 (s, 1H), 10.08 (s, 1H), 10.33 (s, 1H). (m/z)=485 (M+H)+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[NH3:31]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH2:31])=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Reactant: N
Product: CC(=O)N1c2ccc(C(N)=O)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Yield: 100 %

Procedure:
[Step 1] Reactions and treatments were carried out in the same manner as in Example 118, using 122.8 mg of (2S,4R)-1-acetyl-2-methyl-4-[(4-morpholinophenyl)amino]-1,2,3,4-tetrahydroquinoline-6-carboxylic acid instead of (2S,4R)-1-acetyl-2-methyl-4-(4-morpholinophenoxy)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid, and using aqueous ammonia instead of monomethylamine. Thus, 140.4 mg (100%) of (2S,4R)-1-acetyl-2-methyl-4-[(4-morpholinophenyl)amino]-1,2,3,4-tetrahydroquinoline-6-carboxamide was obtained as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=O)[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1.[S:13]1[CH2:17][C:16](=[O:18])[NH:15][C:14]1=[O:19]>>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]([CH:11]=[C:17]3[S:13][C:14](=[O:19])[NH:15][C:16]3=[O:18])[CH:9]=[CH:10][C:5]=2[O:4][CH:3]=1
Reactant: O=C1CSC(=O)N1
Reactant: Cc1coc2ccc(C=O)cc12
Product: Cc1coc2ccc(C=C3SC(=O)NC3=O)cc12

Procedure:
Following the general method as outlined in Example 1, starting from 3-Methyl-benzofuran-5-carbaldehyde (intermediate 57) and 1,3-thiazolidine-2,4-dione, the title compound was obtained.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:14]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17]>C(=S)=S>[CH2:14]([C:18]1[CH:23]=[CH:22][C:21]([C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:8])=[CH:20][CH:19]=1)[CH2:15][CH2:16][CH3:17]
Reactant: CCCCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCCCc1ccc(C(=O)c2ccccc2)cc1
Reaction time: 18 h
Yield: 96.5 %

Procedure:
A 2.8 g (0.02 mole) of benzoic acid chloride was dissolved in 30 ml of carbon disulfide and then, 4.0 g (0.03 mole) of anhydrous aluminum chloride was added to the solution. A 2.68 g (0.02 mole) of n-butyl benzene was further added to the mixture with stirring, and the reaction was carried out at room temperature for 18 hours. Carbon disulfide was distilled off from the reaction mixture and water was added and the reaction product was extracted with benzene. The benzene phase was separated and washed with 1N-NaOH and with water and was dried with anhydrous sodium sulfate. The solvent was distilled off to obtain a pale yellow oily product. The oily product was distilled under a reduced pressure to obtain 4.6 g of 4-n-butyl benzophenone having a boiling point of 184° to 188° C./6 mmHg. (yield of 96.8%).
Reaction SMILES: [Cl:1][CH:2]([C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[O:7])[CH2:3][CH2:4]Cl>C(O)(C)(C)C>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:2]2([Cl:1])[CH2:4][CH2:3]2)=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(c1ccc(F)cc1)C(Cl)CCCl
Solvent: CC(C)(C)O
Product: O=C(c1ccc(F)cc1)C1(Cl)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
233 g (0.99 mol) of 4-fluorophenyl 1,3-dichloropropyl ketone are dissolved in 300 ml of tert.-butanol and 135 g of potassium tert.-butylate are added in portions. The mixture is substantially stirred at 40° C. for 2 hours and concentrated in vacuo. The residue is taken up in methylene chloride and water. The organic phase is seperated off, dried over sodium sulphate and concentrated in vacuo. The residue is distilled under a high vacuum. 145 g (74% of theory) of 1-(4-fluorobenzoyl)-1-chloro-cyclopropane of boiling point 73° C./0.1 mbar are obtained.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[C:9]([C:11]3[CH:12]=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[C:18]([O:21][C@@H:22]3[CH2:27][CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]3)[CH:17]=[CH:16]4)[NH:10][C:6]=2[CH2:5][CH2:4][NH:3]1.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH:24]1[CH2:25][CH2:26][CH2:27][C@@H:22]([O:21][C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[C:11]([C:9]4[NH:10][C:6]5[CH2:5][CH2:4][NH:3][C:2](=[O:1])[C:7]=5[CH:8]=4)[CH:12]=[CH:13][CH:14]=3)[N:19]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](Oc2ccc3cccc(-c4cc5c([nH]4)CCNC5=O)c3n2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1NCCc2[nH]c(-c3cccc4ccc(O[C@@H]5CCCNC5)nc34)cc21
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 13.2 %

Procedure:
To a solution of (R)-tert-butyl 3-((8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinolin-2-yl)oxy)piperidine-1-carboxylate (117 mg, 0.25 mmol) in DCM (3.0 mL) at 0° C. was added TFA (0.5 mL, 6.73 mmol). The reaction was stirred at RT for 20 min. The solution was concentrated, the residue was dissolved in DCM and washed with a saturated aq. solution of NaHCO3. The aq. layer was extracted with DCM (2×). The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was dissolved in DMSO (3.0 mL). Purification by rpHPLC (Silicycle Silichrome XT C18 column; 30×150 mm, 5 μm, 5-95% 0.1% TFA/ACN in 0.1% TFA/water by volume over 10 min.), followed by drying in a Genevac Series II Evaporator afforded (R)-2-(2-(piperidin-3-yloxy)quinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one 2,2,2-trifluoroacetate (15.7 mg, 0.033 mmol, 13.0% yield) as an amorphous yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.63 (br. s., 1H), 8.76 (s, 1H), 8.80 (s, 1H), 8.34 (d, J=8.8 Hz, 1H), 7.96 (d, J=7.2 Hz, 1H), 7.79 (d, J=8.0 Hz, 1H), 7.50 (t, J=7.6 Hz, 1H), 7.17 (d, J=2.0 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 7.03 (br. s., 1H), 5.52 (br. s., 1H), 3.39-3.55 (m, 4H), 3.15 (br. s., 2H), 2.89 (t, J=6.7 Hz, 2H), 2.13-2.24 (m, 1H), 1.93-2.07 (m, 2H), 1.82-1.92 (m, 1 H). 19F NMR (376 MHz, DMSO-d6) δ ppm −74.47 (s, 3F). m/z (ESI, +ve ion) 363.0 (M+H)+.
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.[F:15][C:16]([F:38])([F:37])[C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Si:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=2)[CH:20]=[CH:21][CH:22]=1>>[F:38][C:16]([F:15])([F:37])[C:17]1[CH:18]=[C:19]([CH2:23][CH2:24][N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Si:33]([CH3:35])([CH3:34])[CH3:36])=[CH:29][CH:28]=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:20]=[CH:21][CH:22]=1
Reactant: C[Si](C)(C)c1ccc(CNCCc2cccc(C(F)(F)F)c2)cc1
Reactant: O=C(O)c1c(F)c(Cl)cc2cc[nH]c12
Product: C[Si](C)(C)c1ccc(CN(CCc2cccc(C(F)(F)F)c2)C(=O)c2c(F)c(Cl)cc3cc[nH]c23)cc1

Procedure:
5-Chloro-6-fluoro-1H-indole-7-carboxylic acid [2-(3-trifluoromethyl-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amide was prepared in analogy to example 1 from 5-chloro-6-fluoro-1H-indole-7-carboxylic acid and [2-(3-trifluoromethyl-phenyl)-ethyl]-(4-trimethylsilanyl-benzyl)-amine. MS (ISP) 547.3/549.4 (100/33) (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([NH2:11])[C:3]=1[NH2:12].[CH:13]1([C:16](O)=O)[CH2:15][CH2:14]1.Cl.[OH-].[Na+]>>[Br:1][C:2]1[C:3]2[N:12]=[C:16]([CH:13]3[CH2:15][CH2:14]3)[NH:11][C:4]=2[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: Nc1cc([N+](=O)[O-])cc(Br)c1N
Reactant: O=C(O)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=[N+]([O-])c1cc(Br)c2nc(C3CC3)[nH]c2c1
Temperature: 105 °C
Yield: 88.4 %

Procedure:
In a 250 mL round-bottom flask a mixture of 3-bromo-5-nitrobenzene-1,2-diamine (4 g, 17.24 mmol) and cyclopropanecarboxylic acid (14.06 ml, 155 mmol) in 3M HCl (40 ml, 120 mmol) was heated to 105° C. for 5 days. The mixture was allowed to cool to room temperature and was poured into chilled 5M NaOH (25 ml, 125 mmol) solution. The resulting mixture was allowed to stand in an icebath and the brown solid that precipitated was collected by filtration. The solid was washed several times with H2O and then dried in a vacuum oven at 50° C. The resulting dark solid 4-bromo-2-cyclopropyl-6-nitro-1H-benzo[d]imidazole (4.3 g, 15.24 mmol, 88% yield) will be used as is in the next step. MS (ES+) m/e: 280.9, 281.8 [M+H]+
Reaction SMILES: [C:1]([O:5][CH2:6][C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].O>CO>[C:1]([O:5][CH2:6][CH:7]([OH:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)CC(=O)COC(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CC(O)COC(C)(C)C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
Ethyl 4-t-butoxyacetoacetate (20.0 g) synthesized according to the method described in Heterocycles 26, 2841 (1987) was dissolved in methanol (150 mL) and sodium borohydride (1.68 g) was added at a temperature of from 5° C. to 15° C. The mixture was stirred for 1 hr and water (100 mL) was added. The solvent was mostly evaporated, and the organic layer extracted twice with MTBE (150 mL) was washed well with water. MTBE was evaporated to give ethyl (±)-4-t-butoxy-3-hydroxybutanoate (16.9 g). To a solution of lithium diisopropylamide 1.5 M cyclohexane solution (73 mL) in THF (100 mL) was added a solution of ethyl (±)-4-t-butoxy-3-hydroxybutanoate (10.66 g) in THF (30 mL) at a temperature of from −58° C. to −48° C. and the temperature was raised to −20° C. Separately, 2-iodoethanol (21.5 g) and ethyl vinyl ether (11.4 g) were mixed in the presence of p-toluenesulfonic acid monohydrate (10 mg) to give 2-(1-ethoxyethoxy)ethyl iodide (19.1 g) and 15.3 g thereof was added dropwise at a temperature near −20° C. to 0° C. The mixture was stirred overnight at room temperature. The reaction mixture was poured into a 1N aqueous hydrochloric acid (100 mL), MTBE (100 mL) was added and the mixture was extracted and washed with saturated aqueous sodium hydrogen carbonate solution. The solvent was evaporated and ethanol (150 mL) and p-toluenesulfonic acid monohydrate (1.3 g) were added to the residue. The mixture was stirred at room temperature for 6 hr. Saturated aqueous sodium hydrogen carbonate solution (20 mL) was added to the reaction mixture and the solvent was mostly evaporated. The residue was extracted with MTBE (100 mL). The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution (50 mL) and dried over anhydrous magnesium sulfate. The solvent was evaporated and the residue was subjected to flash chromatography using heptane/ethyl acetate (3:1) as an eluent to give the title compound (2.0 g) as pale yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[Se:5][C:6]=1[C:7]([NH2:9])=[O:8].[N:14]([O-])=O.[Na+]>S(=O)(=O)(O)O>[N:1]1[C:2]2[C:3]3[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=3[Se:5][C:6]=2[C:7](=[O:8])[NH:9][N:14]=1
Reactant: O=N[O-]
Reactant: NC(=O)c1[se]c2ccccc2c1N
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=c1[nH]nnc2c1[se]c1ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 19.2 %

Procedure:
To an ice cold (0° C.) solution of 3-aminobenzo[b]selenophene-2-carboxamide (1.0 g, 4.16 mmol) in concentrated sulfuric acid (25 mL) was added a cold (0° C.) solution of sodium nitrite (0.316 g, 4.58 mmol) in concentrated sulfuric acid (10 mL) for 10 min (while adding, the temperature should keep between −5-0° C.). After addition, the mixture was stirred at 0° C. for 1 h and at rt for 2 h. The reaction mixture was cooled, poured into crushed ice slowly with stirring for 15 min and stirred at the same temperature for 15 min. The solution was extracted with ethyl acetate (3×200 mL) and the combined EtOAc layer was washed with water, brine and dried over sodium sulfate. The solution was filtered, evaporated the solvent to give the product as a yellow color solid (200 mg, 19%), mp 176-178° C. 1H NMR (400 MHz, DMSO-d6): δ 15.48 (1H, s, —NH), 8.53-8.58 (1H, m, H-9), 8.41-8.46 (1H, m, H-6), 7.74-7.80 (2H, m, H-7,8).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[S:26][C:8]2[S:9][CH2:10][CH2:11][C:12]3[C:13](=[N:14][N:15]([C:19]4[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=4)[C:16](=[O:18])[CH:17]=3)[C:7]=2[CH:6]=1)=[O:4].[C:27]([O-:30])(=[O:29])[CH3:28].[K+].O>C(O)(=O)C>[C:27]([O:30][CH2:2][C:3]([C:5]1[S:26][C:8]2[S:9][CH2:10][CH2:11][C:12]3[C:13](=[N:14][N:15]([C:19]4[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=4)[C:16](=[O:18])[CH:17]=3)[C:7]=2[CH:6]=1)=[O:4])(=[O:29])[CH3:28]
Reactant: CC(=O)[O-]
Reactant: O=C(CCl)c1cc2c(s1)SCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)OCC(=O)c1cc2c(s1)SCCc1cc(=O)n(-c3ccc(Cl)cc3)nc1-2

Procedure:
To a suspension of 3.2 g of 9-chloroacetyl-2-(4-chlorophenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one obtained in Example 47 in 40 ml of acetic acid is added 6.0 g of potassium acetate and the mixture is refluxed under heating for 3 hours with stirring. After cooling, to the mixture is added water and the solution is extracted with chloroform. The extract is washed with water, dried and concentrated under reduced pressure. The resulting residue is subjected to column chromatography on silica gel and eluted with a mixed solvent of choloroform and methanol (99:1). The crystals obtained from the fraction are recrystallized from a mixed solvent of chloroform and ethanol to give 9-acetyloxyacetyl-2-(4-chlorophenyl)-5,6-dihydrothieno[2',3':2,3]thiepino[4,5-c]pyridazin-3(2H)-one as white crystals, melting at 172°-174° C.