Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH2:7])=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[NH:4][N:3]=1.C(N(CC)CC)C.[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[C:26](Cl)=[O:27]>C(Cl)Cl>[CH3:1][C:2]1[C:6]([NH:7][C:26]([C:22]2[O:21][CH:25]=[CH:24][CH:23]=2)=[O:27])=[C:5]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:4][N:3]=1
Reactant: O=C(Cl)c1ccco1
Reactant: Cc1n[nH]c(-c2ccccc2)c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1n[nH]c(-c2ccccc2)c1NC(=O)c1ccco1
Reaction time: 2 h

Procedure:
To a RT solution of 337.3 mg of 3-methyl-5-phenyl-1H-pyrazol-4-ylamine in 4 mL methylene chloride was added 407 μL of triethylamine and 201 μL of 2-furoyl chloride. After 2 h at RT, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in chloroform and washed with saturated aqueous sodium carbonate and brine. The organic portion was dried with sodium sulfate and concentrated under reduced pressure. The residue contained the title compound as a yellow, amorphous solid and was used without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][Br:8].[CH2:9]([OH:13])[CH2:10][CH:11]=[CH2:12].[OH-].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][O:13][CH2:9][CH2:10][CH:11]=[CH2:12]
Reactant: BrCCCCCCBr
Reactant: C=CCCO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Product: C=CCCOCCCCCCBr

Procedure:
A mixture of 1,6-dibromohexane (18.30 g), 3-butene-1-ol (2.15 ml), and tetrabutylammonium bromide (0.81 g) were stirred vigorously with 10N NaOH (25 ml) at room temperature under nitrogen for 18 h. The reaction mixture was partitioned between water and EtOAc. The organic phase was washed with brine, dried (MgSO4), and evaporated to dryness. The residual oil was purified on a silica SPE bond elut cartridge (100 g). The excess 1,6-dibromohexane was eluted with cyclohexane. Elution with 5% diethyl ether in cyclohexane and removal of the solvent under reduced pressure gave the title compound (4.52 g). Tlc-silica (5% diethyl ether in cyclohexane) Rf=0.44.
Reaction SMILES: C([Si](CC)(CC)O[C@@H](CCN1CCC2(CC2)[C@H](O[Si](CC)(CC)CC)C1)CN)C.COC(OC)CNC[C@@H](O[Si](CC)(CC)CC)CCN1CCC2(CC2)[C@H](O[Si](CC)(CC)CC)C1.ClC1C=C(N[C@@H](C)C(O)=O)C=CC=1Cl.[Cl:79][C:80]1[CH:81]=[C:82]([NH:87][C@@H:88]([CH3:126])[C:89]([N:91]([CH2:120][CH:121](OC)OC)[CH2:92][C@@H:93]([O:112][Si](CC)(CC)CC)[CH2:94][CH2:95][N:96]2[CH2:103][CH2:102][C:99]3([CH2:101][CH2:100]3)[C@H:98]([O:104][Si](CC)(CC)CC)[CH2:97]2)=[O:90])[CH:83]=[CH:84][C:85]=1[Cl:86]>>[Cl:79][C:80]1[CH:81]=[C:82]([N:87]2[CH2:121][CH2:120][N:91]([CH2:92][C@@H:93]([OH:112])[CH2:94][CH2:95][N:96]3[CH2:103][CH2:102][C:99]4([CH2:101][CH2:100]4)[C@H:98]([OH:104])[CH2:97]3)[C:89](=[O:90])[C@@H:88]2[CH3:126])[CH:83]=[CH:84][C:85]=1[Cl:86]
Reactant: CC[Si](CC)(CC)O[C@@H](CCN1CCC2(CC2)[C@H](O[Si](CC)(CC)CC)C1)CN(CC(OC)OC)C(=O)[C@H](C)Nc1ccc(Cl)c(Cl)c1
Agent: CC[Si](CC)(CC)O[C@@H](CCN1CCC2(CC2)[C@H](O[Si](CC)(CC)CC)C1)CNCC(OC)OC
Agent: CC[Si](CC)(CC)O[C@H](CN)CCN1CCC2(CC2)[C@H](O[Si](CC)(CC)CC)C1
Agent: C[C@H](Nc1ccc(Cl)c(Cl)c1)C(=O)O
Product: C[C@H]1C(=O)N(C[C@@H](O)CCN2CCC3(CC3)[C@H](O)C2)CCN1c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was produced in analogy with example 104, steps A-H. Thus, reaction of 2-allyl-oxirane with benzyl carbamate in the presence of (1R,2R)-(−)-N—N′-bis(3,5-di-tert-butylsalicylidene)-1,2-cyclohexanediaminocobalt(II) in step A led to ((S)-2-hydroxy-pent-4-enyl)-carbamic acid benzyl ester, which was converted to ((S)-2-hydroxy-4-oxo-butyl)-carbamic acid benzyl ester in step B. This underwent a reductive amination reaction with (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride in step C, leading to [(S)-2-hydroxy-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-carbamic acid benzyl ester. Silylation in step D gave [(S)-2-triethylsilanyloxy-4-((S)-4-triethylsilanyloxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-carbamic acid benzyl ester, which was hydrogenated to (S)-2-triethylsilanyloxy-4-((S)-4-triethylsilanyloxy-6-aza-spiro[2.5]oct-6-yl)-butylamine in step E. This was converted to (2,2-dimethoxy-ethyl)-[(S)-2-triethylsilanyloxy-4-((S)-4-triethylsilanyloxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-amine in step F, followed by coupling with (S)-2-(3,4-dichloro-phenylamino)-propionic acid (intermediate 24) in step G, leading to (S)-2-(3,4-dichloro-phenylamino)-N-(2,2-dimethoxy-ethyl)-N—[(S)-2-triethylsilanyloxy-4-((S)-4-triethylsilanyloxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-propionamide. Finally, reductive cyclization and concomitant desilylation in step H afforded (S)-4-(3,4-dichloro-phenyl)-1-[(S)-2-hydroxy-4-((S)-4-hydroxy-6-aza-spiro[2.5]oct-6-yl)-butyl]-3-methyl-piperazin-2-one. Colourless gum, MS: 456.3 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH3:15])[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:16][C:17]1[C:26]([CH3:27])=[CH:25][CH:24]=[C:23]2[C:18]=1[CH:19]=[CH:20][NH:21][C:22]2=[O:28].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1>[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1>[CH3:27][C:26]1[C:17]([NH:16][C:2]2[C:7]([C:8]3[CH:9]=[C:10]([NH:14][CH3:15])[N:11]=[CH:12][N:13]=3)=[CH:6][CH:5]=[CH:4][N:3]=2)=[C:18]2[C:23](=[CH:24][CH:25]=1)[C:22](=[O:28])[NH:21][CH:20]=[CH:19]2
Reactant: Cc1ccc2c(=O)[nH]ccc2c1N
Reactant: CNc1cc(-c2cccnc2Cl)ncn1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Product: CNc1cc(-c2cccnc2Nc2c(C)ccc3c(=O)[nH]ccc23)ncn1
Temperature: 150 °C
Yield: 25.9 %

Procedure:
6-(2-chloropyridin-3-yl)-N-methylpyrimidin-4-amine (897 mg, 4.1 mmol), 5-amino-6-methylisoquinolin-1(2H)-one (779 mg, 4.5 mmol), 2-dicyclohexylphosphino-2′-(N,N-dimethylamino) biphenyl (128 mg, 0.33 mmol) and tris(dibenzylideneacetone) dipalladium (0) (149 mg, 0.16 mmol) were added to a microwave tube. The tube was capped and flushed with nitrogen, and then lithium bis(trimethylsilyl)amide (16.9 mL, 1.0 M solution in THF) was added. The mixture was heated in a microwave reactor at 150° C. for 15 min. The reaction mixture was quenched with saturated aqueous sodium bicarbonate then extracted with DCM. The DCM extracts were concentrated and purified by flash chromatography (0-10% 2 M ammonia in methanol) to give the title compound (380 mg, 26%). MS (M+H)+ 359.
Reaction SMILES: [CH2:1]([C:3]1[C:8]([CH:9]=O)=[CH:7][CH:6]=[C:5]([C:11]([F:14])([F:13])[F:12])[N:4]=1)[CH3:2].[CH3:15][O:16][C:17](=[O:38])[CH:18]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH3:15][O:16][C:17](=[O:38])[CH:18]=[CH:9][C:8]1[C:3]([CH2:1][CH3:2])=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[CH:6][CH:7]=1
Reactant: CCc1nc(C(F)(F)F)ccc1C=O
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: CCc1nc(C(F)(F)F)ccc1C=CC(=O)OC
Temperature: 110 °C
Yield: 80 %

Procedure:
To a solution of 2-ethyl-6-trifluoromethyl-pyridine-3-carbaldehyde in toluene (10 mL) was added methyl(triphenylphosphoranylidene)acetate (172 mg, 0.516 mmol). The mixture was heated at 110° C. for overnight cooled to room temperature, and diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by column chromatography (EtOAc/hexanes=1/4) to yield the 3-(2-ethyl-6-trifluoromethyl-pyridin-3-yl)-acrylic acid methyl ester (89 mg, 80%).
Reaction SMILES: C[Si](C)(C)CC[O:5][C:6](=[O:33])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[NH:14][C:15]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=[O:16].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1.Cl>CN(C=O)C>[C:24]1([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]([O:20][CH2:19][CH2:18][O:17][C:15]([NH:14][C:8]2[CH:9]=[CH:10][CH:11]=[C:12]([Cl:13])[C:7]=2[C:6]([OH:33])=[O:5])=[O:16])=[CH:26][CH:25]=1
Reactant: C[Si](C)(C)CCOC(=O)c1c(Cl)cccc1NC(=O)OCCOc1ccc(-c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(Nc1cccc(Cl)c1C(=O)O)OCCOc1ccc(-c2ccccc2)cc1
Yield: 44.2 %

Procedure:
To a solution of 2-[2-(biphenyl-4-yloxy)-ethoxycarbonylamino]-6-chloro-benzoic acid 2-trimethylsilanyl-ethyl ester (340 mg, 0.664 mmol) and 1.0M tetrabutyl ammonium fluoride in THF (0.66 mL, 0.6636 mmol) in DMF (6 mL) and the mixture was stirred for 2 h. 2N HCl was added to adjust the pH to 1-2 and the mixture was partitioned between water and ethyl acetate. The combined organics were washed with water, then brine dried over magnesium sulfate and concentrated to dryness. Purification by crystallization gave 0.121 g of 2-[2-(biphenyl-4-yloxy)-ethoxycarbonylamino]-6-chloro-benzoic acid as a white solid, 801, mp:157.5-158.9.
Reaction SMILES: CC(C)(C)C([NH:5][C:6]1[N:11]=[C:10](F)[C:9]([C:13](=[O:29])[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)=[CH:8][CH:7]=1)=O.C[C:33](C)([O-:35])C.[K+]>CO.O>[NH2:5][C:6]1[N:11]=[C:10]([O:35][CH3:33])[C:9]([C:13](=[O:29])[CH2:14][CH2:15][CH:16]2[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17]2)=[CH:8][CH:7]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(CCC(=O)c2ccc(NC(=O)C(C)(C)C)nc2F)CC1
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1nc(N)ccc1C(=O)CCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Yield: 99.8 %

Procedure:
A mixture of 1,1-dimethylethyl 4-(3-{6-[(2,2-dimethylpropanoyl)amino]-2-fluoro-3-pyridinyl}-3-oxopropyl)-1-piperidinecarboxylate (step 2, 360 mg, 0.827 mmol) and potassium tert-butoxide (278 mg, 2.48 mmol) in methanol (8 ml) was refluxed for 1 h. After cooling to room temperature, the mixture was diluted with water (20 ml) and extracted with diethyl ether (100 ml×2). The combined organic layer was washed with water (50 ml) and brine (50 ml), and dried over magnesium sulfate. Removal of the solvent gave 300 mg (100%) of the title compound as a colorless gum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:16][CH:17]=O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1)=[O:8].O.[NH2:20][NH2:21]>CO>[NH2:20][N:21]1[C:7]([OH:8])([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Br:1])[CH:15]=2)[N:16]=[CH:17]1
Reactant: O=CNc1ccc(Br)cc1C(=O)c1ccccn1
Reactant: NN
Solvent: O
Solvent: CO
Product: NN1C=Nc2ccc(Br)cc2C1(O)c1ccccn1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a solution of 11.2 g. of the 2-(5-bromo-2-formamidobenzoyl)pyridine prepared in the experiment (a) in 50 ml. of methanol is added 10 ml. of hydrazine hydrate (100 %). The resulting mixture is heated at 60° C for several minutes and thereafter left to stand at room temperature for 5 hours. The resulting precipitate is collected by filtration and washed with methanol and ether and dried to give 3-amino-6-bromo-4-hydroxy-4-(2-pyridyl)-3,4-dihydroquinazoline as colorless granules melting at 185° to 187° C. (decomposition).
Reaction SMILES: [OH:1][C@@H:2]([C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1)[CH2:3][CH2:4][CH3:5].Cl.[NH2:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:1][C@@H:2]([C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:16][CH2:17][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[O:12])=[CH:13][CH:14]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCOC(=O)CCN
Reactant: CCC[C@@H](O)c1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCC[C@@H](O)c1ccc(C(=O)NCCC(=O)OCC)cc1
Reaction time: 1 h
Yield: 100.2 %

Procedure:
N,N-dimethylformamide (16.9 mL) was added to a vial containing (R)-4-(1-hydroxybutyl)benzoic acid (2.6 g, 13.5 mmol), ethyl 3-aminopropanoate hydrochloride (4.16 g, 27.1 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (10.3 g, 27.1 mmol). Diisopropylethylamine (11.8 mL, 67.7 mmol) was then added. The reaction was stirred for 1 h, and was then concentrated. Purification by column chromatography (0-50% ethyl acetate in heptane) afforded (R)-ethyl 3-(4-(1-hydroxybutyl)benzamido)propanoate (3.97 g, 100% yield) as an oil. 1H NMR (400 MHz, CDCl3, δ): 7.75 (d, J=8.2 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 6.83 (br. s., 1H), 4.74 (t, J=8.2 Hz, 1H), 4.18 (q, J=7.1 Hz, 2H), 3.73 (q, J=5.9 Hz, 2H), 2.64 (t, J=6.4 Hz, 2H), 1.87 (br. s., 1H), 1.84-1.62 (m, 2H), 1.49-1.30 (m, 2H), 1.28 (t, J=7.1 Hz, 3H), 0.93 (t, J=7.3 Hz, 3H). MS (M+1): 294.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10]/[N:11]=[CH:12]/[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N+]([C:21]([CH2:48][CH2:49][CH2:50][CH3:51])=[CH:22][C:23]1[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:25][C:24]=1[C:36]([N:38]1[CH2:47][CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1)=[O:37])([O-])=O>>[C:30]([O:29][C:27]([C:26]1[CH:34]=[CH:35][C:23]([C:22]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=3)[C:21]=2[CH2:48][CH2:49][CH2:50][CH3:51])=[C:24]([C:36]([N:38]2[CH2:47][CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39]2)=[O:37])[CH:25]=1)=[O:28])([CH3:31])([CH3:32])[CH3:33]
Reactant: CCCCC(=Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)N1CCc2ccccc2C1)[N+](=O)[O-]
Reactant: CCOC(=O)/C=N/Nc1ccc(C(C)C)cc1
Product: CCCCc1c(-c2ccc(C(=O)OC(C)(C)C)cc2C(=O)N2CCc3ccccc3C2)c(C(=O)OCC)nn1-c1ccc(C(C)C)cc1
Yield: 51.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 223E, (E)-ethyl 2-(2-(4-isopropylphenyl)hydrazono)acetate (25.2 mg, 0.108 mmol) and tert-butyl 4-(2-nitrohex-1-enyl)-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (50 mg, 0.108 mmol) were converted to the title compound (36 mg, 52%) as a pale yellow oil. 1H NMR (CDCl3, 1:1 mixture of amide rotamers) δ 8.08 (dd, J=8, 2 Hz, 1H), 8.04-8.03 (m, 1H), 7.43-6.81 (m, 9H), 5.02-4.98 (m, 1H), 4.46-4.38 (m, 1H), 4.30-4.27 (m, 2H), 4.15-3.98 (m, 1H), 3.54-3.33 (m, 1H), 2.98-2.50 (m, 5H), 1.61 (s, 9H), 1.29-1.24 (m, 7.5H), 1.22 (t, J=8 Hz, 1.5H), 1.18-0.95 (m, 4H), 0.60-0.56 (m, 3H); MS (ESI+) m/z 650.4 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3](=[O:23])[N:4]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5](=[O:16])[C:6]=1[C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1.[CH:24]1[C:34]2=[C:35]3[C:30](=[CH:31][CH:32]=[CH:33]2)[CH2:29][CH2:28][CH2:27][N:26]3[CH:25]=1.C[Si](C)(C)[Si](C)(C)C.[Li]>C1(C)C=CC=CC=1.C1(B(O)O)C2=C3C(=CC=C2)CCCN3C=1>[C:24]1([C:2]2[C:3](=[O:23])[N:4]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:5](=[O:16])[C:6]=2[C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[C:34]2=[C:35]3[C:30](=[CH:31][CH:32]=[CH:33]2)[CH2:29][CH2:28][CH2:27][N:26]3[CH:25]=1
Reactant: c1cc2c3c(c1)ccn3CCC2
Reactant: O=C1C(Br)=C(c2c[nH]c3ccccc23)C(=O)N1c1ccccc1
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: OB(O)c1cn2c3c(cccc13)CCC2
Agent: [Li]
Solvent: Cc1ccccc1
Product: O=C1C(c2c[nH]c3ccccc23)=C(c2cn3c4c(cccc24)CCC3)C(=O)N1c1ccccc1

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione may be prepared by reacting 1H-indole and 3,4-dibromo-1-phenyl-pyrrole-2,5-dione in the presence of methyl magnesium bromide to yield 3-bromo-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione. The 3-bromo-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione is subsequently reacted with 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline and LiHMDS (lithium hexamethyldisilane) in toluene or (5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-boranediol and Pd(PPh3)4(tetrakis(triphenylphosphine)palladium) to yield 3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4-(1H-indol-3-yl)-1-phenyl-pyrrole-2,5-dione, which is reduced and deprotected by treatment with Mg in methanol, as in Example 2 procedure C, followed by catalytic hydrogenation over palladium on carbon to yield (±)-trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)-4(1H-indol-3-yl)pyrrolidine-2,5-dione. Bnz is benzyl.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:25][CH3:26])[CH:23]=3)[NH:18][C:17]=2[CH3:27])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[Na].[F:31][C:32]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:33]=1[C:34](Cl)=[O:35]>CN(C=O)C>[F:31][C:32]1[CH:40]=[C:39]([F:41])[CH:38]=[CH:37][C:33]=1[C:34]([N:18]1[C:19]2[C:24](=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][N:9]2[CH2:10][CH2:11][CH2:12][CH2:13][CH:8]2[CH2:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:17]1[CH3:27])=[O:35]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: COc1ccc2[nH]c(C)c(CCN3CCCCC3CC3CCCCC3)c2c1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CCN1CCCCC1CC1CCCCC1)c(C)n2C(=O)c1ccc(F)cc1F

Procedure:
1-(2,4-Difluorobenzoyl)-3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole is prepared by reaction of 3-[2-(2-cyclohexylmethylpiperidino)ethyl]-5-methoxy-2-methylindole with sodium hydride in DMF and reaction of the resulting sodium salt with 2,4-difluorobenzoyl chloride following the procedure described above in Example 1.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[NH:11]1[CH2:18][CH2:17][CH2:16][C@H:12]1[C:13]([OH:15])=O>CS(C)=O.C(O)C.[Pd]>[O:15]=[C:13]1[NH:8][C:3]2[C:2](=[CH:7][CH:6]=[CH:5][CH:4]=2)[N:11]2[CH2:18][CH2:17][CH2:16][CH:12]12
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: O=C(O)[C@@H]1CCCN1
Agent: [Pd]
Solvent: CS(C)=O
Solvent: CCO
Product: O=C1Nc2ccccc2N2CCCC12

Procedure:
1.5 ml of o-fluoro-nitrobenzene and 8.2 g of L-proline were stirred at 60° C. for 3 hours in 50 ml DMSO. The mixture was then evaporated in vacuo to give a yellow oil. This oil was dissolved in 250 ml 96% ethanol and was hydrogenated at normal pressure at room temperature using 2 g 5% Pd/C as catalyst. After completion of hydrogen uptake, the mixture was filtered and evaporated in vacuo to give the title compound. M.p. 169°-172° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH:10]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9][NH:8][CH:7]=1)=[O:5])[CH3:2].[F:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:12]2[NH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:19]=3[C:11]=2[CH:10]([CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:9][N:8]([C:32](=[O:33])[C:31]2[CH:35]=[CH:36][C:28]([F:27])=[CH:29][CH:30]=2)[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CCOC(=O)C1=CNCC(Cc2ccccc2)c2c1[nH]c1ccccc21
Product: CCOC(=O)C1=CN(C(=O)c2ccc(F)cc2)CC(Cc2ccccc2)c2c1[nH]c1ccccc21

Procedure:
The title compound was prepared in a manner similar to that described in Example 2A by using 1-benzyl-1,2,3,6-tetrahydroazepino[4,5-b]indole-5-carboxylic acid ethyl ester and 4-fluorobenzoyl chloride; 1H NMR (CDCl3) δ 10.58 (1H, s), 8.07 (1H, s), 7.62-7.66 (2H, m), 7.36 (1H, d), 7.13-7.23 (9H, m), 6.99 (1H, t), 5.25 (1H, dd), 4.26 (2H, m), 3.94 (1H, d), 2.99 (1H, dd), 2.83 (1H, dd), 1.22 (3H, t); MS (ESI): 469 (MH+)
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15]Cl)[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[O-].[Na+].C1(C)C=CC=CC=1.O>CN(C)C=O>[C:1]([N:9]1[CH2:14][CH2:13][C:12](=[CH2:15])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)N1CCC(CCl)CC1
Agent: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CN(C)C=O
Product: C=C1CCN(C(=O)c2ccccc2)CC1
Temperature: 5 °C
Reaction time: 4 h
Yield: 78.6 %

Procedure:
In 10 ml of N,N-dimethylformamide was dissolved 1.50 g (6.32 mmol) of N-benzoyl-4-chloromethylpiperidine (D). The resulting solution was cooled to 5° C. and thereto was added 1.36 g (25.28 mmol) of sodium methoxide. After stirring at 60° C. for 4 hours, the reaction mixture was cooled down to room temperature and then poured into a mixed liquid of 40 ml of toluene and 40 ml of iced water. An organic layer was separated and dried over 2 g of anhydrous magnesium sulfate and, thereafter, the solvent was removed by distillation. The residual liquid was subjected to silicagel column chromatography (stationary phase: 50 g of Silicagel 60 available from Merck KGaA). The fraction eluted with a hexane/ethyl acetate mixture (2:1 (v/v)) was collected. The solvent was removed by distillation from the obtained fraction to obtain 1.00 g of N-benzoyl-4-methylenepiperidine (E) as a colorless crystal. The NMR spectrum of this compound coincided with that of the product in Example 4.
Reaction SMILES: [Si:1](Cl)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:9]([OH:13])[C@H:10]([OH:12])[CH3:11].C(N(C(C)C)CC)(C)C>C(Cl)Cl.C(OCC)C.O>[CH3:5][C:4]([Si:1]([CH3:3])([CH3:2])[O:13][CH2:9][C@H:10]([OH:12])[CH3:11])([CH3:7])[CH3:6]
Reactant: C[C@@H](O)CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: C[C@@H](O)CO[Si](C)(C)C(C)(C)C
Reaction time: 72 h
Yield: 79.8 %

Procedure:
tert-Butyl(dimethyl)silyl chloride (5.90 g, 39.5 mmol) was added to a solution of (2R)-propane-1,2-diol (3.00 g, 39.5 mmol) in DCM (100 mL) followed by diisopropylethylamine (7.10 g, 55.3 mmol) and the reaction was stirred under argon for 72 h. The reaction was diluted with diethyl ether (500 mL) and water (140 mL) and the organic layer was separated then dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 1:15 to 1:10 ethyl acetate:hexane, afforded the title compound as a colourless oil (6.00 g, 80%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[Br:16])[C:12]([F:18])([F:17])[O:11][C:10]3([F:20])[F:19])[N:5]=[C:4]([C:21]#[N:22])[CH:3]=1.[F:23][C:24]([F:29])([F:28])[S:25]([O-])=[O:26].[Na+].S(C1C=CC(C)=CC=1)(O)(=O)=O.CNC.S(Cl)(Cl)=O>C1(C)C=CC=CC=1.O>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][C:15]=2[Br:16])[C:12]([F:18])([F:17])[O:11][C:10]3([F:20])[F:19])[N:5]=[C:4]([C:21]#[N:22])[C:3]=1[S:25]([C:24]([F:29])([F:28])[F:23])=[O:26]
Reactant: O=S([O-])C(F)(F)F
Reactant: N#Cc1cc(N)n(-c2cc3c(cc2Br)C(F)(F)OC3(F)F)n1
Agent: CNC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: N#Cc1nn(-c2cc3c(cc2Br)C(F)(F)OC3(F)F)c(N)c1S(=O)C(F)(F)F
Temperature: 55 °C
Yield: 20.3 %

Procedure:
To a suspension wherein 5-amino-1-(6-bromo-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)-3-cyanopyrazole (754 mg, 2.00 ml), sodium trifluoromethane-sulfinate (406 mg, 2.60 mmol) and dimethylamine tosylate (652 mg, 3.00 mmol) are in toluene (5 ml), thionyl chloride (309, mg, 2.60 mmol) was added dropwise under ice cooling over a period of about 10 minutes and then stirred under heating at 50 to 60° C. for 10 hours. After allowing time to cool, the reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the residue was subjected to silica gel column chromatography to give 200 mg of 5-amino-1-(6-bromo-1,1,3,3-tetrafluoro-1,3-dihydroisobenzofuran-5-yl)-3-cyano-4-trifluoromethylsulfinylpyrazole.