Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]([C:6]2[CH:7]=[C:8](Br)[CH:9]=[C:10]3[C:14]=2[N:13](COCC[Si](C)(C)C)[N:12]=[CH:11]3)=[CH:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]1=2.S1C(C2C=CC=C3C=2NN=C3[C:42]([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=2)=[O:43])=CC2C=CC=CC1=2>>[S:1]1[C:5]([C:6]2[CH:7]=[C:8]([C:42]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)=[O:43])[CH:9]=[C:10]3[C:14]=2[NH:13][N:12]=[CH:11]3)=[CH:4][C:3]2[CH:24]=[CH:25][CH:26]=[CH:27][C:2]1=2
Reactant: C[Si](C)(C)CCOCn1ncc2cc(Br)cc(-c3cc4ccccc4s3)c21
Reactant: O=C(c1ccccn1)c1n[nH]c2c(-c3cc4ccccc4s3)cccc12
Product: O=C(c1cc(-c2cc3ccccc3s2)c2[nH]ncc2c1)c1ccccn1
Yield: 11 %

Procedure:
Starting with 7-benzo[b]thiophen-2-yl-5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-indazole (Preparation #23, 0.2 g, 0.435 mmol) and using the procedure for the preparation of (7-benzo[b]thiophen-2-yl-1H-indazol-3-yl)-pyridin-2-yl-methanone (Preparation #52 above) provided (7-benzo[b]thiophen-2-yl-1H-indazol-5-yl)-pyridin-2-yl-methanone (17 mg, 11%); (DMSO-d6, 400 MHz) δ 8.79 (d, 1H), 8.65 (s, 1H), 8.54 (s, 1H), 8.27 (s, 1H), 8.24 (s, 1H), 8.11 (m, 1H), 8.05 (m, 2H), 7.95 (m, 1H), 7.72 (m, 1H), 7.45 (m, 2H); RP-HPLC (Table 1, Method e) Rt 2.28 min; m/z: (M−H)− 354.1.
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[N:13]1[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]1)[CH:8]=O.[F:19][C:20]1[CH:21]=[C:22]([C@H:27]2[N:31]3[C:32](=[O:45])[CH:33](P(=O)(OCC)OCC)[CH2:34][CH2:35][CH2:36][C@H:30]3[CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[F:26].C(O)C>O1CCCC1>[F:19][C:20]1[CH:21]=[C:22]([C@H:27]2[N:31]3[C:32](=[O:45])/[C:33](=[CH:8]/[C:7]4[CH:10]=[CH:11][C:12]([N:13]5[CH:17]=[C:16]([CH3:18])[N:15]=[CH:14]5)=[C:5]([O:4][CH3:3])[CH:6]=4)/[CH2:34][CH2:35][CH2:36][C@H:30]3[CH2:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[F:26]
Reactant: COc1cc(C=O)ccc1-n1cnc(C)c1
Reactant: CCOP(=O)(OCC)C1CCC[C@H]2CC[C@@H](c3ccc(F)c(F)c3)N2C1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(/C=C2\CCC[C@H]3CC[C@@H](c4ccc(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Lithium hydroxide (0.0668 g) was added to a mixed solution of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (0.20 g) and diethyl [(3S,9aS)-3-(3,4-difluorophenyl)-5-oxooctahydropyrrolo[1,2-a]azepin-6-yl]phosphonate obtained above (0.52 g) in tetrahydrofuran (1 mL)-ethanol (4 mL), and the reaction solution was stirred at room temperature for 12 hours. The reaction solution was added to ice-sodium bicarbonate water, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 0.223 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[N+:14]([O-])=O)[CH:7]=1>CCO.CCOC(C)=O.[Pd]>[NH2:14][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:8]=1[C:6]1[CH:5]=[C:4]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cc(-c2ccncc2[N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1cc(NC(=O)OC(C)(C)C)cc(-c2ccncc2N)c1
Reaction time: 8 h
Yield: 111.7 %

Procedure:
tert-butyl (3-(3-aminopyridin-4-yl)-5-methylphenyl) carbamate. A solution of tert-butyl (3-methyl-5-(3-nitropyridin-4-yl)phenyl)carbamate (198 mg, 0.60 mmol) in EtOH (5 mL) and EtOAc (5 mL) was degassed by bubbling N2 (g) through the solution for 10 min. Pd/C (10 wt %, 64 mg, 0.060 mmol) was added. A gas bag with a 3-way stopcock filled with H2 was attached to the flask. The flask was evacuated under vacuum and then back-filled with H2 (3×). The mixture was stiffed overnight at RT. The solution was degassed by bubbling N2 (g) through the solution for 10 min and was then filtered through celite. The solution was concentrated to afford tert-butyl (3-(3-aminopyridin-4-yl)-5-methylphenyl)carbamate (200 mg, 0.67 mmol, 111% yield) as an off-white foam. MS (ESI, pos. ion) m/z: 300.0 (M+1).
Reaction SMILES: [N+:1]([C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([C:24]([OH:33])([C:29]([F:32])([F:31])[F:30])[C:25]([F:28])([F:27])[F:26])=[CH:20][N:19]=3)[C@@H:14]([CH2:34][N:35]([CH2:40][CH:41]([CH3:43])[CH3:42])[S:36]([CH3:39])(=[O:38])=[O:37])[CH2:13]2)(=[O:11])=[O:10])=[CH:6][CH:5]=1)([O-])=O.C([O-])(O)=O.[Na+]>[Fe].C(O)(=O)C>[NH2:1][C:4]1[S:8][C:7]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[N:23]=[CH:22][C:21]([C:24]([OH:33])([C:25]([F:28])([F:26])[F:27])[C:29]([F:32])([F:31])[F:30])=[CH:20][N:19]=3)[C@@H:14]([CH2:34][N:35]([CH2:40][CH:41]([CH3:43])[CH3:42])[S:36]([CH3:39])(=[O:38])=[O:37])[CH2:13]2)(=[O:10])=[O:11])=[CH:6][CH:5]=1
Reactant: CC(C)CN(C[C@H]1CN(S(=O)(=O)c2ccc([N+](=O)[O-])s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)S(C)(=O)=O
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)CN(C[C@H]1CN(S(=O)(=O)c2ccc(N)s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1)S(C)(=O)=O
Temperature: 50 °C
Yield: 76.1 %

Procedure:
A 20-mL vial was charged with N-(((2S)-4-((5-nitro-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-(2-methylpropyl)methanesulfonamide (0.0916 g, 0.134 mmol), iron filings (0.0455 g, 0.815 mmol) and acetic acid (2 mL). The reaction mixture was heated at 50° C. for 20 min., then allowed to cool iii to room temperature. Saturated aqueous NaHCO3 (40 mL) was carefully added and the aqueous phase was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with water (2×40 mL) and saturated aqueous NaCl (40 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (10 g of silica gel, 30 to 100% EtOAc in hexanes) to afford N-(((2S)-4-((5-amino-2-thiophenyl)sulfonyl)-1-(5-(2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl)-2-pyrimidinyl)-2-piperazinyl)methyl)-N-(2-methylpropyl)methanesulfonamide (0.0668 g) as a yellow foam.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:14][CH2:15][CH2:16][O:17][CH3:18].O>CN1C(=O)N(C)CCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:14][CH2:15][CH2:16][O:17][CH3:18])=[CH:4][CH:3]=1
Reactant: COCCCCl
Reactant: Brc1ccc2cc[nH]c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN1CCCN(C)C1=O
Solvent: O
Product: COCCCn1ccc2ccc(Br)cc21
Reaction time: 1 h

Procedure:
The stirred solution of 25 g of 6-bromo-1H-indole [52415-29-9] in 250 ml of DMPU is admixed at 0° C. with 11.2 g of sodium hydride (60% in mineral oil) in portions. The mixture is stirred over 1 hour and then admixed with 60.9 g of 1-chloro-3-methoxypropane and 4.71 g of tetrabutylammonium iodide (exothermic reaction). The mixture is stirred at room temperature over a further 1 hour. The resulting reaction mixture is poured onto 2 l of water (cold) and extracted with tert-butyl methyl ether (2×). The combined organic phases are washed successively with water (3×) and brine, dried over sodium sulphate and filtered, and the filtrate is concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.31 (1:2 EtOAc-heptane). Rt=5.10 (gradient I).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[NH:7]1[CH2:12][CH2:11][CH:10]([N:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[CH:20]=3)[CH:15]=[CH:14]2)[CH2:9][CH2:8]1.Br[CH2:28][CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>CN(C)C=O>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([CH2:29][CH2:28][N:7]2[CH2:8][CH2:9][CH:10]([N:13]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([CH2:22][NH:23][C:24](=[O:26])[CH3:25])[CH:20]=4)[CH:15]=[CH:14]3)[CH2:11][CH2:12]2)[CH:31]=1
Reactant: CC(=O)NCc1ccc2ccn(C3CCNCC3)c2c1
Reactant: BrCCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc2ccn(C3CCN(CCc4cccnc4)CC3)c2c1
Yield: 43.2 %

Procedure:
Potassium carbonate (0.5 g) was added to a solution of 1-(piperidin-4-yl)-6-acetamidomethylindole (0.10 g) obtained in Example 386-1) and 3-(2-bromoethyl)pyridine (0.07 g) obtained in Production Example 26-2 in N,N-dimethylformamide (5 ml) and the resultant mixture was stirred at 70° C. for 6 hr. Then the reaction mixtures were concentrated under reduced pressure and the residue was partitioned between ethyl acetate (40 ml) and water (15 ml) followed by extraction with ethyl acetate. The ethyl acetate layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol system) to give the title compound (0.06 g) as a pale yellow wax (yield: 75.5%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19](Cl)[N:18]=[C:17]([CH3:31])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:32][CH2:33][CH2:34][OH:35]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:35][CH2:34][CH2:33][NH2:32])[N:18]=[C:17]([CH3:31])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NCCO
Reactant: COc1ccccc1Oc1c(Cl)nc(C)nc1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C)nc1OCCN

Procedure:
According to a procedure described in Example 4b) 0.5 g 4-tert.-butyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzene sulfonamide was reacted with 2-aminoethanol to give 560 mg 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzene sulfonamide. LC-MS: tR=3.84 min, [M+1]+=487.51, [M−1]−=485.54.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:10][N:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[N:20][N:21]=4)[N:18]=3)[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[CH:29]1([C:32](Cl)=[O:33])[CH2:31][CH2:30]1>>[CH:29]1([C:32]([NH:1][C:2]2[CH:7]=[C:6]([C:8]3[C:9]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[N:10][N:11]([C:13]4[CH:14]=[CH:15][C:16]5[N:17]([CH:19]=[N:20][N:21]=5)[N:18]=4)[CH:12]=3)[CH:5]=[CH:4][N:3]=2)=[O:33])[CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CC1
Reactant: Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)cc2)ccn1
Product: O=C(Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(F)cc2)ccn1)C1CC1
Yield: 37.3 %

Procedure:
The reaction was carried out in the same manner as in Example 9 except for using 200 mg (0.54 mmol) of 4-(2-aminopyridin-4-yl)-3-(4-fluorophenyl)-1-([1,2,4]triazolo-[4,3-b]pyridazin-6-yl)-1H-pyrazole obtained by the same reaction as in Example 8-2), and using 59.0 mg (0.56 mmol) of cyclopropylcarbonyl chloride in place of acetic anhydride to obtain 88.6 mg of the title compound as a white powder. (Yield: 37%)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[C:9](=[O:18])[CH:8]([NH:19][C:20](=[O:40])[C@H:21]([NH:26][C:27](=[O:39])[C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:30])[CH3:29])[CH2:22][CH:23]([CH3:25])[CH3:24])[CH2:7]2.[C:41]1(=O)[O:46][C:44](=[O:45])[CH2:43][CH2:42]1.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>O.C1(C)C=CC=CC=1>[O:45]=[C:44]1[CH2:43][CH2:42][C:41](=[O:46])[N:1]1[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][C:13]1[CH:17]=[CH:16][S:15][CH:14]=1)[C:9](=[O:18])[CH:8]([NH:19][C:20](=[O:40])[C@H:21]([NH:26][C:27](=[O:39])[C:28]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:29])[CH3:30])[CH2:22][CH:23]([CH3:24])[CH3:25])[CH2:7]2
Reactant: CC(C)C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N)c2N(Cc2ccsc2)C1=O
Reactant: O=C1CCC(=O)O1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(C)C[C@@H](NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(=O)NC1Cc2cccc(N3C(=O)CCC3=O)c2N(Cc2ccsc2)C1=O
Temperature: 25 °C

Procedure:
tert-Butyl 1-((2R)-1-(8-amino-2-oxo-1-(thiophen-3-ylmethyl)-1,2,3,4-tetrahydroquinolin-3-ylamino)-4-methyl-1-oxopentan-2-ylamino)-2-methyl-1-oxopropan-2-ylcarbamate (100 mg) and succinic anhydride (21 mg) were added to toluene (1 mL), and the mixture was refluxed for two hours while being stirred. The reaction mixture was concentrated under reduced pressure, and the thus-recovered residue was purified through silica gel column chromatography (ethyl acetate, chloroform:methanol (5:1)), whereby the Compound A (114 mg) was yielded. The Compound A (110 mg), sodium acetate (75 mg), and acetic anhydride (1 mL) were added to toluene (1 mL), and the mixture was stirred at 80° C. for 20 minutes. The mixture was cooled to room temperature, and water was added thereto. The mixture was extracted with ethyl acetate twice, and the organic layers were combined. The combined organic layer was dried over sodium sulfate, and the solvent was evaporated under reduced pressure, whereby the title compound (100 mg) was yielded.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][C:14]([O:16]CC)=[O:15])=[CH:9][CH:8]=2)=[CH:3][N:2]=1.[OH-].[Na+].O.Cl>O1CCOCC1>[N:1]1[CH:6]=[CH:5][C:4]([C:7]2[CH:8]=[CH:9][C:10]([CH2:13][C:14]([OH:16])=[O:15])=[CH:11][CH:12]=2)=[CH:3][N:2]=1
Reactant: CCOC(=O)Cc1ccc(-c2ccnnc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)Cc1ccc(-c2ccnnc2)cc1
Temperature: 0 °C

Procedure:
Ethyl 2-(4-(pyridazin-4-yl)phenyl)acetate 37-3 (150 mg, 0.62 mmol) and NaOH (120 mg, 3 mmol) was mixed in dioxane (1.5 mL) and H2O (1.5 mL) and stirred at 80° C. for 1 hour. After cooled down to 0° C., the mixture was treated with 1 N HCl aqueous solution to pH 1, and taken to dryness by rotary evaporation. The crude product was extracted with ethyl acetate (100 mL×3). The combined organic phases were concentrated to give 2-(4-(pyridazin-4-yl)phenyl)acetic acid 37-4 as pale yellow solid. MS m/z 215.1 (M+1)
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C@H:5]([C:14]([OH:16])=O)[CH2:4][CH2:3]1.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl:39][C:40]1[C:45]([C:46]([F:49])([F:48])[F:47])=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:50][NH2:51]>ClCCl>[Cl:39][C:40]1[C:45]([C:46]([F:48])([F:49])[F:47])=[CH:44][CH:43]=[CH:42][C:41]=1[CH2:50][NH:51][C:14](=[O:16])[C@@H:5]1[CH2:4][CH2:3][C:2](=[O:1])[N:6]1[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C(O)[C@@H]1CCC(=O)N1Cc1cccnc1
Reactant: NCc1cccc(C(F)(F)F)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NCc1cccc(C(F)(F)F)c1Cl)[C@@H]1CCC(=O)N1Cc1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 7.5 %

Procedure:
5-oxo-1-(3-pyridinylmethyl)proline (0.210 g, 1 mmol, prepared as described below), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.383 g, 2 mmol), and 1-hydroxybenzotriazole (0.306 g, 2 mmol) were stirred together in dichloromethane (10 ml) at room temperature for 30 minutes. The mixture was then treated with {[2-chloro-3-(trifluoromethyl)phenyl]methyl}amine (0.314 g, 1.5 mmol) and the mixture was stirred overnight at room temperature. The mixture was concentrated and partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate. The aqueous layer was separated and extracted with more ethyl acetate and then the combined ethyl acetate fractions were washed sequentially with 3 portions of water and then with saturated aqueous sodium chloride solution. Drying over magnesium sulphate and concentration gave a solid residue which was purified by mass-directed automated HPLC to give pure N-{[2-chloro-3-(trifluoromethyl)phenyl]methyl}-5-oxo-1-(3-pyridinylmethyl)prolinamide (0.031 g).
Reaction SMILES: Cl[SiH:2]1[N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]1[C:11]([CH3:14])([CH3:13])[CH3:12].O1CCCC1.[CH3:20][C:21]([CH3:25])=[CH:22][Mg]Br>CCCCCC>[C:11]([N:3]1[CH:4]=[CH:5][N:6]([C:7]([CH3:10])([CH3:9])[CH3:8])[SiH:2]1[CH:20]=[C:21]([CH3:25])[CH3:22])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)N1C=CN(C(C)(C)C)[SiH]1Cl
Reactant: CC(C)=C[Mg]Br
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)=C[SiH]1N(C(C)(C)C)C=CN1C(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 69 %

Procedure:
In an argon atmosphere, 8.44 g (36.2 mmol) of Si(tBuNCHCHNtBu)(H)Cl was dissolved in 17 mL of hexane and after adding a (2-methylprop-1-en-1-yl)magnesium bromide tetrahydrofuran solution (0.56 mol/L, 68.0 mL, 38.1 mmol), the resulting solution was stirred at room temperature for 18 hours. Insoluble matters produced were separated by filtration, and the solvent was removed by distillation from the filtrate under atmospheric pressure. The obtained residue was distilled under reduced pressure (distillation temperature: 90° C./3.5×102 Pa) to obtain 1,3-di-tert-butyl-2-(2-methylprop-1-en-1-yl)-1,3-diaza-2-silacyclopent-4-ene (Si(tBuNCHCHNtBu)(H)CHC(CH3)2) as a yellow liquid (yielded amount: 6.30 g, yield: 69%).
Reaction SMILES: ClC(N(C)C)=C(C)C.[NH:9]([C:25]([O:27][CH2:28][CH:29]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:35]2[C:30]1=[CH:31][CH:32]=[CH:33][CH:34]=2)=[O:26])[C@H:10]([C:15]([O:17]CC1C=CC=CC=1)=[O:16])[CH2:11][C:12](=[O:14])O.[C:42]([NH2:61])([C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCCl.C(OCC)(=O)C>[NH:9]([C:25]([O:27][CH2:28][CH:29]1[C:30]2[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:36]2[C:41]1=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:26])[C@H:10]([C:15]([OH:17])=[O:16])[CH2:11][C:12](=[O:14])[NH:61][C:42]([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:55]1[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=1)[C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(O)C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCc1ccccc1
Agent: CC(C)=C(Cl)N(C)C
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h

Procedure:
0.8 ml of 1-chloro-N,N,2-trimethyl-prop-1-enylamine (A. Devos et al., J. Chem. Soc., Chem. Commun., Vol. 1979, p. 1180) is added to a stirred solution of 2.09 g of Fmoc-Asp-OBzl in 20 ml of 1,2-dichloroethane at 0° under an argon atmosphere. After 10 minutes, a solution of 1.2 g of tritylamine in 4 ml of 1,2-dichloroethane is added, and then the mixture is stirred for 2 hours, diluted with ethyl acetate and washed with water. The organic phase is dried and evaporated. The residue is taken up in chloroform and chromatographed on 250 g of silica gel. The fractions containing the Fmoc-Asn(Trt)-OBzl are combined and evaporated; the product is obtained as an amorphous foam.
Reaction SMILES: CI.[C:3](O)(=O)C(O)=O.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1([CH:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=3)[CH2:23][CH2:22][NH:21]2)[CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1([CH:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=3)[CH2:23][CH2:22][N:21]2[CH3:3])[CH2:19][CH2:18][CH2:17]1
Reactant: O=C(O)C(=O)O
Reactant: COc1ccc2c(c1)C(C1(c3ccccc3Cl)CCC1)NCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1ccc2c(c1)C(C1(c3ccccc3Cl)CCC1)N(C)CC2
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
A solution of methyl iodide (0.5 g) in acetone (10 ml) was added dropwise to a stirred suspension of 1-[1-(2-chlorophenyl)cyclobutyl]-7-methoxy-1,2,3,4-tetrahydroisoquinoline oxalate (1.4 g prepared as described in Example RC11) and anhydrous potassium carbonate (3 g) in acetone (80 ml). The mixture was stirred at ambient temperature for 3.5 hours and the solvent removed by evaporation. Water was added and the mixture extracted with ether. The ether layer yielded 1-[1-(2-chloro-phenyl)cyclobutyl]-7-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline as an oil.
Reaction SMILES: [C:1]([CH2:3]P(=O)(OCC)OCC)#[N:2].[H-].[Na+].[CH2:14]1[CH2:18][O:17][C:16]2[CH:19]=[CH:20][C:21]3[C:22]4[C:27]([C:28](=O)[C:29]=3[C:15]1=2)=[CH:26][CH:25]=[CH:24][CH:23]=4.CCOCC>C1COCC1.[Cl-].[Na+].O>[CH2:14]1[CH2:18][O:17][C:16]2[CH:19]=[CH:20][C:21]3[C:22]4[C:27]([C:28](=[CH:3][C:1]#[N:2])[C:29]=3[C:15]1=2)=[CH:26][CH:25]=[CH:24][CH:23]=4
Reactant: O=C1c2ccccc2-c2ccc3c(c21)CCO3
Reactant: CCOP(=O)(CC#N)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: N#CC=C1c2ccccc2-c2ccc3c(c21)CCO3
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A magnetically stirred solution of diethyl cyanomethylphosphonate (0.502 g, 2.83 mmol) in anhydrous THF (150 mL) was treated with sodium hydride (60% in mineral oil, 0.113 g, 2.82 mmol) in portions. The resultant suspension was treated dropwise with 2,10-dihydro-1H-fluoreno[2,1-b]furan-10-one (0.525 g, 2.36 mmol) in THF (100 mL), stirred 12 h, poured over ice (100 g), and treated with brine (100 mL), and Et2O (150 mL). The layers were separated and the aqueous layer further extracted with fresh Et2O (2×150 mL). The combined organic extracts were washed with brine (200 mL), dried (K2CO3), filtered, and concentrated in vacuo.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[CH:4]=1.Cl[C:13]1[C:22]([CH3:23])=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=2)[N:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd]>[CH3:9][C:5]1[CH:4]=[C:3]([C:13]2[C:22]([CH3:23])=[CH:21][C:20]3[C:15](=[CH:16][CH:17]=[C:18]([CH3:24])[CH:19]=3)[N:14]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: Cc1ccc2nc(Cl)c(C)cc2c1
Reactant: Cc1cccc(OB([O-])[O-])c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cccc(-c2nc3ccc(C)cc3cc2C)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
3-Methylphenyl borate (1.3 mmol), 2-chloro-3,6-dimethylquinoline (1 mmol), tetrakis(triphenylphosphine)palladium(O) (0.05 mmol) and potassium carbonate (3 mmol) were dissolved in THF (30 mL) and H2O (10 mL). The resulting solution was stirred in a bath at 100° C. for 24 hours. After completion of the reaction, the THF and the toluene were removed. The reaction solution was extracted with dichloromethane and water, and distilled under reduced pressure. The resulting residue was purified by silica gel column chromatography. The eluate was distilled under reduced pressure. The residue was recrystallized from dichloromethane and petroleum ether and filtered to yield 2-(3-methylphenyl)-3,6-dimethylquinoline as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:5].Cl>B#[Ni].CO>[CH3:1][C:2]1[CH:25]=[C:24]([CH3:26])[CH:23]=[CH:22][C:3]=1[C:4]([C:6]1[N:10]([CH3:11])[C:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[CH:8][CH:7]=1)=[O:5]
Reactant: Cc1ccc(C(=O)c2ccc(Cc3ccc([N+](=O)[O-])cc3)n2C)c(C)c1
Agent: B#[Ni]
Agent: Cl
Solvent: CO
Product: Cc1ccc(C(=O)c2ccc(Cc3ccc(N)cc3)n2C)c(C)c1
Yield: 103.8 %

Procedure:
A mixture of 4-{5-(2,4-dimethylbenzoyl)-1-methyl-1H-pyrrol-2-ylmethyl}nitrobenzene (0.81 g, 2.3 mmol), [prepared as in Example 7, Step (c)], nickel boride (1.6 g), 1 M HCl (30 ml), and methanol (30 ml) was refluxed for 30 min. The reaction mixture was filtered through a pad of Celite® and the filter cake was washed with ethyl acetate. The filtrate was cooled, made basic with concentrated ammonium hydroxide, and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and concentrated to give 4-{5-(2,4-dimethylbenzoyl)-1-methyl-1H-pyrrol-2-ylmethyl}aniline (760 mg, 100%) as an oil.