Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].CC(C)([O-])C.[K+].[O:22]1[CH2:25][C:24](=O)[CH2:23]1>C1COCC1>[O:22]1[CH2:25][C:24](=[C:6]([CH3:7])[C:4]([O:3][CH2:2][CH3:1])=[O:5])[CH2:23]1
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Reactant: O=C1COC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C)=C1COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.2 %

Procedure:
To a solution of triethyl 2-phosphonopropionate (800 mg, 3.4 mmol) in anhydrous THF (3 mL) was added potassium tert-butoxide (340 mg, 3.1 mmol). The reaction was stirred for 1 h at RT then oxetan-3-one (CAS-RN 6704-31-0, available from commercial suppliers, 220 mg, 3.1 mmol) added in a single portion. The reaction was heated at reflux for 20 h then cooled to RT and adsorbed onto silica gel. Purification by automated column chromatography (Biotage SP4) on silica gel (12 g Grace cartridges) eluting with EtOAc: n-heptane (gradient elution, 0% (equil., 5 CV), 0% (5 CV) 0-100% (25 CV), 100% EtOAc (10 CV)) afforded (i) (151 mg, 31%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]3[C:17]([N:18]=[C:19]4[CH2:25]CCC[CH2:21][C:20]=24)=[CH:16][CH:15]=[N:14]3)=[CH:8][CH:7]=1.N1N2C(N=C3C(=C2C2C=CC([OH:45])=CC=2)CCCC3)=CC=1.BrCCCCl>>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]3[C:17](=[CH:16][CH:15]=[N:14]3)[N:18]=[C:19]3[C:20]=2[CH2:21][O:45][CH2:25]3)=[CH:8][CH:7]=1
Reactant: ClCCCOc1ccc(-c2c3c(nc4ccnn24)CCCCC3)cc1
Reactant: Oc1ccc(-c2c3c(nc4ccnn24)CCCC3)cc1
Agent: ClCCCBr
Product: ClCCCOc1ccc(-c2c3c(nc4ccnn24)COC3)cc1

Procedure:
Using the method described for the preparation of 10-[4-(3-Chloro-propoxy)-phenyl]-6,7,8,9-tetrahydro-5H-1,4,10a-triaza-cyclohepta[f]indene, the reaction of 4-(5,6,7,8-tetrahydro-pyrazolo[5,1-b]quinazolin-9-yl)-phenol and 1-bromo-3-chloropropane provided the title compound which was used without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6])=O.[CH2:13]([O:15][CH:16]([O:25][CH2:26][CH3:27])[C:17](=[O:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:14].C(O)(=O)C>C1C=CC=CC=1.N1CCCCC1=O>[CH3:8][O:7][C:5]([C:4]1[CH:9]=[CH:10][CH:11]=[CH:12][C:3]=1[CH:1]=[C:18]([C:17]([CH:16]([O:15][CH2:13][CH3:14])[O:25][CH2:26][CH3:27])=[O:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:6]
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Reactant: COC(=O)c1ccccc1C=O
Agent: O=C1CCCCN1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)C(=Cc1ccccc1C(=O)OC)C(=O)C(OCC)OCC
Yield: 116.3 %

Procedure:
2-(i) To a mixture of methyl 2-formylbenzoate (4.92 g), ethyl 4,4-diethoxyacetoacetate (7.2 g) and acetic acid (0.36 g) in benzene (15 ml) was added portionwise each one third portion of a solution of piperidone (306 mg) in benzene (5 ml) for each 20 minutes' interval, and the mixture was heated to reflux for 3 hours under removing off azeotropically the resulting water. After cooling, the reaction mixture was diluted with additional benzene (25 ml), washed three times with water and successively with diluted aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give reddish oil (12.7 g) of crude ethyl 2-(2-methoxycarbonylbenzyliden)-4,4-diethoxyacetoacetate which was used in the following reaction without any further purification.
Reaction SMILES: [C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)=[O:8].Cl[C:24]1[CH:33]=[C:32]([CH3:34])[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[N:25]=1>>[C:1]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([N:9]1[CH2:10][CH:11]2[CH2:12][N:13]([C:24]3[CH:33]=[C:32]([CH3:34])[C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]=3)[CH2:14][CH:15]2[CH2:16]1)=[O:8]
Reactant: O=C(c1ccccc1-c1ccccc1)N1CC2CNCC2C1
Reactant: Cc1cc(Cl)nc2ccccc12
Product: Cc1cc(N2CC3CN(C(=O)c4ccccc4-c4ccccc4)CC3C2)nc2ccccc12

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 17 and 2-chloro-4-methyl-quinoline. MS (ESI) mass calcd. for C29H27N3O, 433.56; m/z found, 434.3 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[C:6]([C:14]([F:17])([F:16])[F:15])[CH:5]=1)=[O:3].[BH4-].[Na+].Cl>CO>[F:11][C:10]([F:12])([F:13])[C:8]1[CH:9]=[C:4]([CH:2]([OH:3])[CH3:1])[CH:5]=[C:6]([C:14]([F:15])([F:16])[F:17])[CH:7]=1
Reactant: CC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Yield: 99.2 %

Procedure:
A solution of 3,5-bis(trifluoromethyl)acetophenone (2.00 g, 7.81 mmol) in methanol (20 mL) was added with sodium borohydride (591 mg, 15.6 mmol) with stirring on an ice bath, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added with 1 M hydrochloric acid (pH<7) on an ice bath, and then concentrated under reduced pressure, the resulting residue was added with water (20 mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain 1-[3,5-bis(trifluoromethyl)phenyl]ethanol (2.00 g, 99%) as colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[B:11](OC(C)C)([O:16]C(C)C)[O:12]C(C)C.Cl>CCCCCC.C1COCC1.C1(C)C=CC=CC=1>[CH:8]1([C:5]2[CH:6]=[CH:7][C:2]([B:11]([OH:16])[OH:12])=[CH:3][CH:4]=2)[CH2:10][CH2:9]1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc(C2CC2)cc1
Agent: Cl
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: OB(O)c1ccc(C2CC2)cc1
Temperature: -70 °C

Procedure:
2.5 M nButyllithium in hexane (14.5 mL) is added dropwise to a solution of 1-bromo-4-cyclopropyl-benzene (5.92 g) in THF (14 mL) and toluene (50 mL) chilled to −70° C. The resultant solution is stirred at −70° C. for 30 min before triisopropyl borate (8.5 mL) is added. The solution is warmed to −20° C. and then treated with 4 M aqueous hydrochloric acid (15.5 mL). The reaction mixture is further warmed to room temperature and then the organic phase is separated. The aqueous phase is extracted with ethyl acetate and the combined organic phases are dried (sodium sulphate). The solvent is evaporated and the residue is triturated with a mixture of ether and cyclohexane to give the product as a colorless solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2].C(O[C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42]2[CH:47]=[CH:46][C:45]([C:48](O)=O)=[CH:44][CH:43]=2)[CH2:38][CH2:37]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:48][C:45]1[CH:44]=[CH:43][C:42]([CH:39]2[CH2:38][CH2:37][N:36]([CH3:34])[CH2:41][CH2:40]2)=[CH:47][CH:46]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=2[CH2:13]1)[CH3:2]
Reactant: CCNc1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Product: CCN(Cc1ccc(C2CCN(C)CC2)cc1)c1cc(OC)ccc1C1CCc2cc(O)ccc2C1
Yield: 29.1 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4-methoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (100 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (120 mg) according to an analogous synthetic method to Example 337 described below, the title compound (37 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[C:10]2[C:6]([C:7]([C:14]3[N:15]=[CH:16][NH:17][CH:18]=3)=[CH:8][CH2:9]2)=[CH:5][CH:4]=1>CO.[Pd]>[CH3:13][O:12][C:11]1[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[C:6]2[C:10]=1[CH2:9][CH2:8][CH:7]2[C:14]1[N:15]=[CH:16][NH:17][CH:18]=1
Reactant: COc1ccc2c(c1OC)CC=C2c1c[nH]cn1
Agent: [Pd]
Solvent: CO
Product: COc1ccc2c(c1OC)CCC2c1c[nH]cn1

Procedure:
2.3 g (0.0095 mole) of 4-(6,7-dimethoxy-1H-inden-3-yl)-1H-imidazole prepared in Example 2.5.a in 200 ml of methanol are hydrogenated under a hydrogen pressure of 2 kg at 40° C., in the presence of palladium on carbon (Pd 10%). At the end of the reaction, the catalyst is filtered off and the methanol distilled. The residue is crystallized from ethyl acetate and 4-(2,3-dihydro-4,5-dimethoxy-1H-inden-1-yl)-1H-imidazole is obtained.
Reaction SMILES: N#N.[O:3]1[CH:7]=[CH:6][N:5]=[C:4]1[CH:8]([OH:10])[CH3:9].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12].N1C=CN=C1.[NH4+].[Cl-]>C1COCC1.CC(=O)OCC>[C:14]([Si:11]([CH3:13])([CH3:12])[O:10][CH:8]([C:4]1[O:3][CH:7]=[CH:6][N:5]=1)[CH3:9])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(O)c1ncco1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncco1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), 1-oxazol-2-yl-ethanol (1.21 g, 10.71 mmol) was dissolved in dry THF (50 mL). tert-Butyldimethylsilyl chloride (3.23 g, 21.43 mmol) was added at rt followed by imidazole (1.46 g, 21.43 mmol). The reaction mixture was stirred at rt for 16 h. Sat. aq. NH4Cl (100 mL) and EA (100 mL) were added, the layers separated and the aq. layer extracted with EA (1×100 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvent removed under reduced pressure. Purification of the residue by FC (4:1 hexane-Et2O) gave the title compound as a colorless oil. TLC:rf (4:1 hexane-Et2O)=0.39. LC-MS-conditions 02: tR=1.08 min; [M+H]+=228.56.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21](S(C)(=O)=O)[N:20]=2)=[CH:10][CH:9]=1)=[O:6].[CH3:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[C:30]([N:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[CH:31]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][N:22]=[C:21]([N:42]3[CH2:43][CH2:44][N:39]([CH3:38])[CH2:40][CH2:41]3)[N:20]=2)=[CH:10][CH:9]=1)=[O:6]
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)c1nccc(Oc2ccc(NC(=O)c3cc(F)cc(N4CCCCC4)c3)c3ccccc23)n1
Product: CN1CCN(c2nccc(Oc3ccc(NC(=O)c4cc(F)cc(N5CCCCC5)c4)c4ccccc34)n2)CC1

Procedure:
Compound is prepared from 3-fluoro-N-[4-(2-methanesulfonyl-pyrimidin-4-yloxy)-naphthalen-1-yl]-5-piperidin-1-yl-benzamide and N-methylpiperazine according to conditions described in general procedure C. Mp: 182-184° C.; 1H NMR (400 MHz, DMSO-d6) δ 1.60 (s, 6 H), 2.13 (s, 2 H), 2.20 (s, 3 H), 2.49-2.54 (m, 2 H), 3.22 (s, 2 H), 3.30 (s, 4 H), 3.48 (s, 2 H), 6.22-6.24 (m, 1 H), 6.97 (d, J=12.8 Hz, 1 H), 7.15 (d, J=8.8 Hz, 1 H), 7.42 (d, J=8.0 Hz, 1 H), 7.48 (s, 1 H), 7.55-7.63 (m, 3 H), 7.84 (d, J=7.3 Hz, 1 H), 7.99 (d, J=8.4 Hz, 1 H), 8.26-8.28 (m, 1 H), 10.45 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>C1(C)C=CC=CC=1.[Pt]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CC(C)(C)OC(=O)NCCOCCNc1c([N+](=O)[O-])cnc2ccccc12
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCOCCNc1c(N)cnc2ccccc12
Reaction time: 24 h
Yield: 99.9 %

Procedure:
A solution of tert-butyl 2-{2-[(3-nitroquinolin-4-yl)amino]ethoxy}ethylcarbamate (7.52 g, 20.0 mmol) in toluene was treated with 1.5 g of 5% Pt on carbon and shaken under H2 (3 Kg/cm2) for 24 h. The solution was then filtered through a Celite pad and concentrated to give 6.92 g of crude tert-butyl 2-{2-[(3-aminoquinolin-4-yl)amino]ethoxy}ethylcarbamate as a yellow syrup.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([NH2:25])[CH2:21][CH2:20]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1.[CH3:26][CH:27]([CH2:31][CH3:32])[C:28](O)=[O:29]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][C@H:19]4[CH2:20][CH2:21][C@H:22]([NH:25][C:28](=[O:29])[CH:27]([CH3:26])[CH2:31][CH3:32])[CH2:23][CH2:24]4)[CH2:13][CH2:12]3)[C:5]=2[O:4][CH2:3]1
Reactant: N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1
Reactant: CCC(C)C(=O)O
Agent: Cl
Product: CCC(C)C(=O)N[C@H]1CC[C@H](CCN2CCC(c3cccc4c3OCO4)CC2)CC1

Procedure:
The title compound, white solid (17.7 mg, 62.7%), MS (ISP) m/z=415.3 [(M+H)+], was prepared in accordance with the general method of example 1 from Trans-4-[2-(4-Benzo[1,3]dioxol-4-yl-piperidin-1-yl)-ethyl]-cyclohexylamine hydrochloride (intermediate A) (25 mg, 0.0681 mmol) and 2-methylbutanoic acid.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH3:8])(=[O:6])[CH2:4][SH:5].[Br:9][C:10]1[CH:17]=[CH:16][CH:15]=[C:14](F)[C:11]=1[CH:12]=O.O>CS(C)=O>[CH3:8][O:7][C:3]([C:4]1[S:5][C:14]2[CH:15]=[CH:16][CH:17]=[C:10]([Br:9])[C:11]=2[CH:12]=1)=[O:6]
Reactant: COC(=O)CS
Reactant: O=Cc1c(F)cccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cc2c(Br)cccc2s1
Reaction time: 0.25 h

Procedure:
To a suspension of sodium hydride (55%, 1.11 g) in dimethyl sulfoxide (20 mL) was added methyl thioglycolate (1.53 mL) at room temperature, and the mixture was stirred for 15 minutes. A solution of 2-bromo-6-fluorobenzaldehyde (3.43 g) in dimethyl sulfoxide (4 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 5 minutes. The reaction mixture was poured into water with ice and precipitated crystalline solid was collected by filtration, washed with water and dried under reduced pressure to give 2-methoxycarbonyl-4-bromobenzo-[b]thiophene (1.52 g). This material was suspended in a mixed solvent of methanol (20 mL) and water (10 mL) and sodium hydroxide (0.91 g) was added to the suspension. The mixture was stirred for at 50° C. for 5 hours. The reaction mixture was cooled with ice bath, and the reaction mixture was acidified by adding 2 mol/L hydrochloric acid. The precipitated crystalline solid was collected by filtration, washed with water and dried under reduced pressure to give 2-carboxybenzo[b]thiophene (1.27 g). To this material were added copper powder (0.42 g) and quinoline (10 mL), and the mixture was stirred at 190° C. for 1 hour. After the reaction mixture was cooled to room temperature, 2 mol/L hydrochloric acid (40 mL) and ethyl acetate (20 mL) were added to the reaction mixture, and the mixture was stirred for 15 minutes. Insoluble material in the mixture was removed by filtration, and the organic layer of the filtrate was separated. The aqueous layer of filtrate was extracted with ethyl acetate. The organic layers were combined, and the combined organic layer washed with 2 mol/L hydrochloric acid, water and brine and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane) to give the title compound (0.55 g).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])=[CH:6][CH:5]=1)[CH3:2].O1CCCC1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:30]([N:37]1[CH2:42][CH2:41][C:40](=[O:43])[CH2:39][CH2:38]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O>[CH2:1]([O:3][C:4]1[CH:14]=[CH:13][C:7]([N:8]([CH3:12])[C:9](=[O:11])[CH2:10][C:40]2([OH:43])[CH2:41][CH2:42][N:37]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:38][CH2:39]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc(N(C)C(C)=O)cc1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(N(C)C(=O)CC2(O)CCN(Cc3ccccc3)CC2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 56.3 %

Procedure:
A solution of 4′-ethoxy-N-methylacetanilide (0.97 g) in an anhydrous tetrahydrofuran (30 mL) was cooled to −78° C. under an argon atmosphere, and lithium hexamethyldisilazide (1M tetrahydrofuran solution; 6 mL) was added to the solution at below −65° C., followed by stirring at −78° C. for 15 minutes. Subsequently, 1-benzylpiperidin-4-one (1.1 g) was added to the reaction mixture at below −65° C., and the mixed solution was stirred at −78° C. for 10 minutes. After increasing the temperature to room temperature, water was added to the mixture and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The titled compound (1.08 g) was obtained by recrystallization of the obtained residue from hexane.
Reaction SMILES: C[Al](C)C.CCCCCCC.[NH2:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=1.C[O:26][C:27]([C:29]1[CH:37]=[C:36]2[C:32]([CH:33]=[CH:34][NH:35]2)=[CH:31][CH:30]=1)=O.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>O1CCOCC1.ClCCl>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([NH:12][C:27]([C:29]2[CH:37]=[C:36]3[C:32]([CH:33]=[CH:34][NH:35]3)=[CH:31][CH:30]=2)=[O:26])=[CH:14][C:15]=1[C:21]([F:22])([F:23])[F:24])#[N:18]
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCCCCCC
Solvent: ClCCl
Product: N#Cc1ccc(NC(=O)c2ccc3cc[nH]c3c2)cc1C(F)(F)F
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A 2 N trimethylaluminium solution in heptane (30.8 mmol, 15.41 mL, 3 equiv.) was added dropwise over 10 minutes to a solution of 4-amino-2-trifluoromethylbenzonitrile (30.8 mmol, 5.7 g, 3 equiv.) in dry dioxane (20 mL). The reaction mixture was stirred for a further 30 minutes then a solution of 1H-indole-6-carboxylic acid methyl ester (10.3 mmol, 1.8 g, 1 equiv.) in dioxane was added portionwise over 5 minutes and the reaction mixture was stirred at 106° C. for 16 hours. The solution was poured onto a 1M aqueous sodium tartrate solution (100 mL) and diluted with dichloromethane (50 mL). The organic layer was separated, dried over Na2SO4 and the solvent was removed under vacuum. The residue was dissolved in dichloromethane (10 mL) and sonicated for 5 minutes. The resultant solid was filtered to afford 1H-indole-6-carboxylic acid (4-cyano-3-trifluoromethyl-phenyl)-amide, 2.4 g (71% yield). LC @215 nm; Rt 1.50: 97%, m/z (ES+): 330 (M+H+.); δH (250 MHz; d6-DMSO) 10.89 (1H, s), 8.54 (1H, s), 8.32 (2H, m), 8.17 (1H, s), 8.13 (1H, s), 7.70 (2H, m), 7.62 (1H, t), 6.57 (1H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:20]=[CH:19][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]([NH2:18])=[O:17])[S:15][C:8]=23)=[CH:4][CH:3]=1.Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:24][N:23]=1>C(O)(C)(C)C>[C:32]1([C:25]2[C:26]3[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:22]([NH:1][C:2]3[CH:20]=[CH:19][C:5]([O:6][C:7]4[CH:12]=[CH:11][N:10]=[C:9]5[CH:13]=[C:14]([C:16]([NH2:18])=[O:17])[S:15][C:8]=45)=[CH:4][CH:3]=3)=[N:23][N:24]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: NC(=O)c1cc2nccc(Oc3ccc(N)cc3)c2s1
Reactant: Clc1nnc(-c2ccccc2)c2ccccc12
Solvent: CC(C)(C)O
Product: NC(=O)c1cc2nccc(Oc3ccc(Nc4nnc(-c5ccccc5)c5ccccc45)cc3)c2s1

Procedure:
A 5 ml microwave tube was charged with 7-(4-aminophenoxy)thieno[3,2-b]pyridine-2-carboxamide (85 mg, 0.300 mmol) and 1-chloro-4-phenylphthalazine (60 mg, 0.250 mmol) in 2.0 ml of tert-butanol. The vessel was capped and irradiated at 140° C. for 15 minutes in the microwave. Analysis of an aliquot of the crude mixture by LCMS showed remaining starting material and approximately 20% conversion to desired product. Irradiated at 150° C. for an additional 20 minutes, at which time reaction was deemed complete by LCMS analysis. Cooled to ambient temperature and diluted reaction mixture with methanol. Filtered solids, washed with additional methanol and concentrated in vacuo to afford 7-(4-(4-phenylphthalazin-1-ylamino)phenoxy)thieno[3,2-b]pyridine-2-carboxamide. MS m/z=490 [M+H]+. Calc'd for C28H19N5O2S: 489.55.
Reaction SMILES: C1([Si](C2C=CC=CC=2)(C2C=CC=CC=2)[C:8]#[C:9][C:10]2[C:15]([Cl:16])=[CH:14][C:13]([Cl:17])=[CH:12][C:11]=2[Cl:18])C=CC=CC=1.[C:31](=[O:33])=[O:32]>ClCCl.CO.C(O)(=O)C>[Cl:16][C:15]1[CH:14]=[C:13]([Cl:17])[CH:12]=[C:11]([Cl:18])[C:10]=1[C:9]#[C:8][C:31]([OH:33])=[O:32]
Reactant: Clc1cc(Cl)c(C#C[Si](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1
Reactant: O=C=O
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C(O)C#Cc1c(Cl)cc(Cl)cc1Cl

Procedure:
Prepared analogously to Example 4.3.a. from triphenyl-(2,4,6-trichlorophenylethynyl)silane and dry ice. Yield: 3.3 g (77.7% of theory); melting point: 170° C.-175° C.; C9H3Cl3O2 (M=249.48); calc.: molecular ion peak (M+H)+: 249/251/253; found: molecular ion peak (M+H)+: 249/251/253; Rf value: 0.4 (silica gel, dichloromethane/methanol/acetic acid (50:10:1)).
Reaction SMILES: [NH2:1][C@H:2]1[C@@H:7]([NH:8][C:9]([C:11]2[NH:12][C:13]([CH2:17][CH3:18])=[C:14]([Cl:16])[N:15]=2)=[O:10])[CH2:6][CH2:5][N:4]([C:19]2[S:20][C:21]3[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:3]1.[C:33]1(=O)[CH2:36][CH2:35][CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[Cl:16][C:14]1[N:15]=[C:11]([C:9]([NH:8][C@H:7]2[CH2:6][CH2:5][N:4]([C:19]3[S:20][C:21]4[C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)[CH2:3][C@H:2]2[NH:1][CH:33]2[CH2:36][CH2:35][CH2:34]2)=[O:10])[NH:12][C:13]=1[CH2:17][CH3:18]
Reactant: O=C1CCC1
Reactant: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](N)C3)sc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCOC(=O)c1cccc2nc(N3CC[C@H](NC(=O)c4nc(Cl)c(CC)[nH]4)[C@H](NC4CCC4)C3)sc12
Yield: 53 %

Procedure:
The same operation as in Example (77d) was performed using ethyl cis(±)-2-(3-amino-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}piperidin-1-yl)-1,3-benzothiazole-7-carboxylate obtained by the method described in Example (81e) (30 mg, 0.063 mmol), cyclobutanone (95 μL, 1.27 mmol) and sodium (triacetoxy)borohydride (245 mg, 1.16 mmol), to obtain 17.6 mg of the title compound as a white solid (53%).
Reaction SMILES: [Si:1]([O:8][CH2:9][C@@H:10]([NH:14][C:15]([C:17]1[N:18]=[C:19]([N:22]2[CH2:25][CH:24](OS(C)(=O)=O)[CH2:23]2)[S:20][CH:21]=1)=[O:16])[CH:11]([CH3:13])[CH3:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:31]([O-:34])(=[S:33])[CH3:32].[K+]>CN(C)C=O>[C:31]([S:33][CH:24]1[CH2:25][N:22]([C:19]2[S:20][CH:21]=[C:17]([C:15](=[O:16])[NH:14][C@H:10]([CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3])[CH:11]([CH3:13])[CH3:12])[N:18]=2)[CH2:23]1)(=[O:34])[CH3:32]
Reactant: CC([O-])=S
Reactant: CC(C)[C@@H](CO[Si](C)(C)C(C)(C)C)NC(=O)c1csc(N2CC(OS(C)(=O)=O)C2)n1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)SC1CN(c2nc(C(=O)N[C@H](CO[Si](C)(C)C(C)(C)C)C(C)C)cs2)C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 62.7 %

Procedure:
To a solution of 1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-2-methylpropylcarbamoyl]-1,3-thiazol-2-yl}-3-methanesulfonyloxyazetidine (890 mg, 1.75 mmol) (obtained as described in Reference Example 36(5)) in dimethylformamide (45 ml) was added potassium thioacetate (1.20 g, 10.5 mmol) at room temperature. The mixture was stirred in an oil bath (80° C.) overnight. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (3:1→1:1) as the eluant to afford 3-acetylthio-1-{4-[(1S)-1-(t-butyldimethylsilyloxymethyl)-2-methylpropylcarbamoyl]-1,3-thiazol-2-yl}azetidine (502 mg, yield 63%) as a pale brown oil.