Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C@@H:11]2[CH2:15][C@H:14]([N:16]3[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]3)[C@@H:13]([OH:23])[C@H:12]2[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[N:3]=1.FC(F)(F)C(O)=O.C1(C(C2C=CC=CC=2)CNC2N=C(NCCN3CCCCC3)N=C3C=2N=CN3[C@@H]2C[C@H](N3C=C(CO)C=N3)[C@@H](O)[C@H]2O)C=CC=CC=1.[C:94]([O:98][C:99](=[O:106])[NH:100][C@@H:101]1[CH2:105][CH2:104][NH:103][CH2:102]1)([CH3:97])([CH3:96])[CH3:95]>>[C:94]([O:98][C:99](=[O:106])[NH:100][C@@H:101]1[CH2:105][CH2:104][N:103]([C:2]2[N:10]=[C:9]3[C:5]([N:6]=[CH:7][N:8]3[C@@H:11]3[CH2:15][C@H:14]([N:16]4[CH:20]=[C:19]([CH2:21][CH3:22])[CH:18]=[N:17]4)[C@@H:13]([OH:23])[C@H:12]3[OH:24])=[C:4]([NH:25][CH2:26][CH:27]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:3]=2)[CH2:102]1)([CH3:97])([CH3:95])[CH3:96]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Reactant: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)[C@H](O)[C@@H]2O)c1
Agent: OCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NCCN5CCCCC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Product: CCc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(N5CC[C@@H](NC(=O)OC(C)(C)C)C5)nc43)[C@H](O)[C@@H]2O)c1

Procedure:
This compound is prepared from (1R,2S,3R,5S)-3-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-ethyl-pyrazol-1-yl)-cyclopentane-1,2-diol. (Intermediate BA8) using a procedure analogous to that of (1R,2S,3R,5S)-3-[6-(2,2-diphenyl-ethylamino)-2-(2-piperidin-1-yl-ethylamino)-purin-9-yl]-5-(4-hydroxymethyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 46) by replacing the trans-1,4-diaminocyclohexane with (R)-pyrrolidin-3-yl-carbamic acid tert-butyl ester.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[CH3:32])=[O:9])[CH:5]=[CH:4][N:3]=1.[CH3:33][N:34]([CH3:40])[CH2:35][CH2:36][CH2:37][NH:38][CH3:39]>>[CH3:33][N:34]([CH3:40])[CH2:35][CH2:36][CH2:37][N:38]([C:2]1[CH:7]=[C:6]([C:8]([NH:10][C:11]2[CH:16]=[C:15]([NH:17][C:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]([N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)[CH:21]=3)=[O:19])[CH:14]=[CH:13][C:12]=2[CH3:32])=[O:9])[CH:5]=[CH:4][N:3]=1)[CH3:39]
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccnc(Cl)c1
Reactant: CNCCCN(C)C
Product: Cc1ccc(NC(=O)c2ccnc(N3CCOCC3)c2)cc1NC(=O)c1ccnc(N(C)CCCN(C)C)c1
Yield: 56 %

Procedure:
Using an analogous procedure to that described in Example 21, 2-chloro-N-[2-methyl-5-(2-morpholinopyrid-4-ylcarbonylamino)phenyl]pyridine-4-carboxamide was reacted with N-(3-dimethylaminopropyl)-N-methylamine to give the title compound in 56% yield; Mass Spectrum: M+H+ 532.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[C:15]([CH2:18][NH2:19])[S:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.[F:20][C:21]([F:35])([F:34])[O:22][C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29](Cl)=[O:30])=[CH:25][CH:24]=1.N1C=CC=CC=1.[NH4+].[Cl-]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[C:15]([CH2:18][NH:19][C:29](=[O:30])[CH2:28][O:27][C:26]3[CH:32]=[CH:33][C:23]([O:22][C:21]([F:34])([F:20])[F:35])=[CH:24][CH:25]=3)[S:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)COc1ccc(OC(F)(F)F)cc1
Reactant: NCc1nc(C(=O)NCCc2cccc(Cl)c2)cs1
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(COc1ccc(OC(F)(F)F)cc1)NCc1nc(C(=O)NCCc2cccc(Cl)c2)cs1
Reaction time: 12 h

Procedure:
2-Aminomethyl-thiazole-4-carboxylic acid [2-(3-chlorophenyl)ethyl]amide (0.54 g, 1.8 mmol) was dissolved in methylene chloride (15 mL). (4-Trifluoromethoxyphenoxy)-acetyl chloride (0.47 g, 1.8 mmol) was added followed by pyridine (0.3 mL, 4 mmol) and DMAP (0.02 g, 0.1 mmol). The mixture was stirred for 12 hours. Saturated, aqueous NH4Cl was added and the mixture was extracted with methylene chloride ×3. The combined organic extracts were washed with 1N HCl, saturated, aqueous NaHCO3, brine, dried over sodium sulfate, filtered and concentrated in vacuo. The material was purified by recrystallization from ethanol/diethyl ether to afford the title compound (0.65 g, 68% from the Boc protected amine): 1H NMR (400 MHz, d6-DMSO): 9.08 (t, 1H), 8.40 (t, 1H), 8.10 (s, 1H), 7.27 (m, 5H), 7.17 (d, 1H), 7.06 (d, 2H), 4.65 (s, 2H), 4.62 (d, 2H), 3.48 (m, 2H), 2.84 (t, 2H); MS (ESI-LCMS) for C22H20ClF3N3O4S: 514 (MH+).
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][CH:11]=[C:12]([C:15](Cl)=[O:16])[CH:13]=3)[C:8]([CH2:18][CH3:19])=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:22]=1[CH:23]=[CH:24][CH:25]=[N:26]2>>[N:26]1[C:27]2[C:22](=[C:21]([NH:20][C:15]([C:12]3[CH:13]=[C:14]4[C:9]([C:8]([CH2:18][CH3:19])=[N:7][N:6]4[CH:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:10][CH:11]=3)=[O:16])[CH:30]=[CH:29][CH:28]=2)[CH:23]=[CH:24][CH:25]=1
Reactant: Nc1cccc2ncccc12
Reactant: CCc1nn(C2CCCC2)c2cc(C(=O)Cl)ccc12
Product: CCc1nn(C2CCCC2)c2cc(C(=O)Nc3cccc4ncccc34)ccc12
Yield: 30 %

Procedure:
This compound was prepared according to the method of Example 15, using 91 mg (0.329 mmol, 1.0 equiv) 1-cyclopentyl-3-ethyl-1H-indazole-6-carbonyl chloride and 52 mg (0.362 mmol, 1.1 equiv) 5-amino-quinoline as starting materials, to give 38 mg (30%) of pale yellow powder: mp 176-178° C.; Anal. calcd for C24H24N4O: C, 74.96; H, 6.29; N, 14.57. Found: C, 74.33; H, 6.53; N, 14.31.
Reaction SMILES: [C:1]1([CH:7]=[C:8]([C:13](=[O:26])[C:14](=[CH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:15]([O:17][CH3:18])=[O:16])[C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H].C(Cl)Cl>CO.[Pd]>[CH3:18][O:17][C:15](=[O:16])[CH:14]([CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:13](=[O:26])[CH:8]([CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:9]([O:11][CH3:12])=[O:10]
Reactant: COC(=O)C(=Cc1ccccc1)C(=O)C(=Cc1ccccc1)C(=O)OC
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)C(Cc1ccccc1)C(=O)C(Cc1ccccc1)C(=O)OC
Yield: 58.6 %

Procedure:
Dimethyl 2,4-bis(phenylmethylene)-3-oxo-glutarate (630 mg, 1.8 mmol) (C. H. Chen, et al, J. Org. Chem., 1981, 46, 2752-2757) was dissolved in about 100 mL of methanol and 250 mg of 10% palladium on carbon was added. The reaction mixture was shaken at ambient temperature under 4 atmospheres of hydrogen for about 12 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure. The residue (750 mg) was taken up in ~15 mL of methylene chloride and applied to a 1.0×45 cm column of silica gel. The column was eluted @ 5 p.s.i. with 150 mL of methylene chloride to give 374 mg (58% yield) of the title compound. The 300 MHz 1H NMR was consistent with the assigned structure.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][CH2:16][CH:15]2[O:22][CH2:23][CH:24]=[CH2:25])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.O>O1CCCC1>[OH:8][CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]([CH2:20][CH3:21])[CH2:17][CH2:16][CH:15]2[O:22][CH2:23][CH:24]=[CH2:25]
Reactant: C=CCOC1CCN(CC)c2c(CO[Si](C)(C)C(C)(C)C)cccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: C=CCOC1CCN(CC)c2c(CO)cccc21
Reaction time: 1 h
Yield: 105 %

Procedure:
8-t-Butyldimethylsilyloxymethyl-4-allyloxy-1-ethyl-1,2,3,4-tetrahydroquinoline (1.81 g) was dissolved in tetrahydrofuran (20 ml), and to this solution was added dropwise 1M tetrabutylammonium fluoride-tetrahydrofuran solution (6 ml) under ice-cooling. The mixture was stirred for 1 hour at the same temperature. Water was added to the reaction mixture and after distilling off tetrahydrofuran, the residue was extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and distilled off then 8-hydroxymethyl-4-allyloxy-1-ethyl-1,2,3,4-tetrahydroquinoline (1.30 g) was obtained.
Reaction SMILES: Cl.C(OCC)(=O)C.[Cl:8][C:9]1[N:10]=[C:11]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27]C(C)(C)C)=O)[CH2:21][C@H:20]2[O:32][CH3:33])=[O:17])[NH:12][C:13]=1[CH2:14][CH3:15].ClC1O[C:37]2[C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=[CH:40][C:38]=2[N:39]=1.C(N(C(C)C)CC)(C)C>C(OCC)(=O)C.CO>[Cl:8][C:9]1[N:10]=[C:11]([C:16]([NH:18][C@H:19]2[CH2:24][CH2:23][N:22]([C:25]3[O:27][C:37]4[C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=[CH:40][C:38]=4[N:39]=3)[CH2:21][C@H:20]2[O:32][CH3:33])=[O:17])[NH:12][C:13]=1[CH2:14][CH3:15]
Reactant: COC(=O)c1cccc2nc(Cl)oc12
Reactant: CCc1[nH]c(C(=O)N[C@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2OC)nc1Cl
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3nc4cccc(C(=O)OC)c4o3)C[C@H]2OC)nc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.5 %

Procedure:
Methanol (2 ml) and a 4 N hydrochloric acid/ethyl acetate solution (2 mL) were added to tert-butyl cis(±)-4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidine-1-carboxylate obtained in Example (1g) (60 mg, 0.16 mmol), and the mixture was stirred at room temperature for two hours. Following concentration under reduced pressure, the residue was dissolved in DMF (4 mL). Methyl 2-chloro-1,3-benzooxazole-7-carboxylate (34 mg, 0.16 mmol) (reference: U.S. Pat. No. 6,166,011 A1) and diisopropylethylamine (1 ml) were added, and the mixture was stirred at 80° C. for six hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed with water and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was recrystallized from an ethyl acetate/hexane solvent to obtain 75 mg of the title compound as crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[CH:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[S:9][C:8]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:4][CH:3]=1.C[Si](C)(C)N[Si](C)(C)C.[Na].O1[CH2:39][CH2:38][N:37]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])S1(=O)=O>CN(C)C=O.O1CCCC1>[C:43]([O:42][C:40]([NH:37][CH2:38][CH2:39][CH:6]([C:7]1[CH:11]=[C:10]([N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)[S:9][C:8]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:24][CH:23]=1)=[O:41])([CH3:46])([CH3:45])[CH3:44].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:11]=[C:10]([N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[S:9][C:8]=2[C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCOS1(=O)=O
Agent: CCOC(=O)c1sc(N2CCOCC2)cc1Cc1ccc(Cl)cc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1sc(N2CCOCC2)cc1C(CCNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 64 %

Procedure:
Glasswares were flame-dried before use. A solution of ethyl 3-(4-chlorobenzyl)-5-morpholin-4-ylthiophene-2-carboxylate (0.872 g, 2.38 mmol) in N,N-dimethylformamide (16.0 mL) and tetrahydrofuran (4.00 mL) was cooled to −78° C. with vigorous stirring. The solution was evacuated under highvac and purged with argon (×4). 1.00 M Sodium hexamethyldisilazane in tetrahydrofuran (2.62 mL, 2.62 mmol) was added; the solution turned deep purple. The mixture was stirred at −78° C. under argon for 10 min. A solution of tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.06 g, 4.77 mmol) in N,N-dimethylformamide (4.00 mL) was added dropwise over −1 min. The solution turned light red, and then slightly dark green in −1 min. In 15 min, the reaction was warmed to 0° C., and then in 1 h, it was warmed to rt. After 15 min of stirring at rt, the reaction was quenched and distributed between NH4Cl saturated solution and EtOAc. The aqueous layer was extracted with EtOAc (×2). The combined organic layer was washed with 10% LiCl aqueous solution (×2) and brine, dried, and concentrated. Purification on a silica gel column (continuous gradient from 5% EtOAc/hexanes to 25% EtOAc/hexanes over 30 min) provided 776 mg of ethyl 3-{3-[(tert-butoxycarbonyl)amino]-1-(4-chlorophenyl)propyl}-5-(morpholin-4-yl)thiophene-2-carboxylate (64% yield) and 303 mg of unreacted ethyl 3-(4-chlorobenzyl)-5-morpholin-4-ylthiophene-2-carboxylate (35% yield). LCMS: (AA) ES+ 510, 512; 1H NMR (400 MHz, CDCl3) δ 7.24-7.21 (s, 4H), 5.88-5.82 (s, 1H), 5.21-5.11 (t, J=7.8 Hz, 1H), 5.06-4.94 (s, 1H), 4.34-4.22 (qd, J=7.1, 2.8 Hz, 2H), 3.83-3.73 (t, J=4.9 Hz, 4H), 3.29-3.19 (s, 1H), 3.22-3.12 (t, J=4.9 Hz, 4H), 2.99-2.85 (m, 1H), 2.25-2.12 (d, J=6.6 Hz, 1H), 2.12-2.06 (s, 1H), 1.47-1.41 (s, 9H), 1.36-1.31 (m, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([NH:20][C:21]2[S:22][C:23]([CH:26]=O)=[CH:24][N:25]=2)[CH:11]=[CH:12][C:13]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1.O1CCCC1>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:26][C:23]1[S:22][C:21]([NH:20][C:10]2[CH:11]=[CH:12][C:13]([N:14]3[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]3)=[C:8]([O:7][CH3:6])[CH:9]=2)=[N:25][CH:24]=1
Reactant: COCCN
Reactant: COc1cc(Nc2ncc(C=O)s2)ccc1-n1cnc(C)c1
Solvent: ClCCl
Solvent: C1CCOC1
Product: COCCNCc1cnc(Nc2ccc(-n3cnc(C)c3)c(OC)c2)s1

Procedure:
The title compound was prepared in analogy to example 57 from 14 mg (0.19 mmol) 2-methoxyethylamine and 65 mg (0.21 mmol) 2-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenylamino]-thiazole-5-carbaldehyde using a solvent mixture of tetrahydrofurane (2 ml), and methylene chloride (1 ml). The reaction was not complete and the same amount of reagent was added like in example 57. The crude product was purified on silica gel with methylene chloride/methanol 9/1 yielding 47 mg (54%) {5-[(2-methoxy-ethylamino)-methyl]-thiazol-2-yl}-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine as a yellow oil. MS ISP (m/e): 374.2 (100) (M+H)+. 1H NMR (CDCl3, 250 MHz): δ (ppm)=7.64 (s, 1H), 7.26 (s, 1H), 7.18 (d, 1H), 7.12 (s, 1H), 6.95 (d, 1H), 6.87 (s, 1H), 3.93 (s, 2H), 3.85 (s, 3H), 3.51 (t, 2H), 3.36 (s, 3H), 2.83 (t, 2H), 2.30 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([NH2:21])[C:17]([NH2:20])=[N:18][CH:19]=2)=[N:6]1.[C:26](=O)(OC(Cl)(Cl)Cl)[O:27]C(Cl)(Cl)Cl>N1C=CC=CC=1>[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]3[NH:21][C:26](=[O:27])[NH:20][C:17]3=[N:18][CH:19]=2)=[N:6]1
Reactant: Nc1ncc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: O=c1[nH]c2ncc(-c3nn(Cc4ccccc4F)c4ncccc34)nc2[nH]1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
40 mg (0.12 mmol) of the compound from example 52A were initially charged in pyridine (5.0 ml), then 39 mg (0.13 mmol) of bis(trichloromethyl) carbonate were added and the mixture was stirred at 100° C. for 1 h. The reaction mixture was concentrated, admixed with saturated aqueous sodium hydrogencarbonate solution and extracted twice with ethyl acetate. The collected organic phases were dried over sodium sulfate, filtered and concentrated by rotary evaporation. The residue was separated by means of preparative HPLC (eluent: acetonitrile-water with 0.1% formic acid gradient) and the product fractions were concentrated. This gave 9 mg (20% of theory) of the title compound in solid form.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Cl:9][CH2:10][C:11](Cl)=[O:12]>ClCCCl>[Cl:9][CH2:10][C:11]([NH:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][N:3]=1)=[O:12]
Reactant: Nc1ncccc1F
Reactant: O=C(Cl)CCl
Solvent: ClCCCl
Product: O=C(CCl)Nc1ncccc1F
Temperature: 80 °C

Procedure:
2-Amino-3-fluoropyridine (1.5 g) was dissolved in DCE (15 mL) and chloroacetylchloride (1.1 mL) was added dropwise. The reaction was heated in a microwave at 80° C. for 5 mins. The reaction mixture was cooled and the resulting solid was filtered off, washed with DCE, MeCN and pentane then suspended in dichloromethane and aqueous NaHCO3 (sat) was added. The organic phase was separated and the aqueous layer was extracted with dichloromethane (×2). The combined organic layers were dried over sodium sulphate and concentrated. The crude product was purified by silica gel chromatography eluting with 0-100% EtOAc/cyclohexane to give the title compound as a white solid (800 mg).
Reaction SMILES: [CH2:1]([N:10]1[C:15](=[O:16])[C:14]([CH2:17]OS(C)(=O)=O)=[CH:13][C:12]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH3:30])[CH:24]=2)=[N:11]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:31][NH:32][CH3:33]>>[CH2:1]([N:10]1[C:15](=[O:16])[C:14]([CH2:17][N:32]([CH3:33])[CH3:31])=[CH:13][C:12]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([CH3:30])[CH:24]=2)=[N:11]1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: Cc1cc(-c2cc(COS(C)(=O)=O)c(=O)n(CC=Cc3ccccc3)n2)ccc1F
Reactant: CNC
Product: Cc1cc(-c2cc(CN(C)C)c(=O)n(CC=Cc3ccccc3)n2)ccc1F
Yield: 90.9 %

Procedure:
Following the procedure of Example 7, 2-cinnamyl-6-(4-fluoro-3-methylphenyl)-4-methanesulfonyloxymethyl-2H-pyridazin-3-one and dimethylamine were reacted to yield the title compound as a yellow oil (yield: 90.9%).
Reaction SMILES: [O:1]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][C:16]=1[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:20])[CH3:19])[CH:12]=[O:13])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[N+:25]([CH3:28])([O-:27])=[O:26]>C1COCC1>[O:1]([C:9]1[CH:10]=[C:11]([C@@H:12]([OH:13])[CH2:28][N+:25]([O-:27])=[O:26])[CH:14]=[CH:15][C:16]=1[O:17][Si:18]([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:19])[CH3:20])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: C[N+](=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)cc1O[Si](C)(C)C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc([C@@H](O)C[N+](=O)[O-])cc1O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 74 %

Procedure:
110 mg (0.2.9 mmol) of 3,4-di(t-butyldimethylsiloxy)benzaldehyde was dissolved in 10 ml of THF under the atmosphere of argon at −40° C., and 0.32 ml of rare earth metal complex solution A0 was mixed into the solution. After stirring for 30 minutes, 88.5 mg (1.45 mmol) of nitromethane was added dropwise to the mixture. After 67-hour reaction: time, (R)-1-(3,4-di(t-butyldimethylsiloxy)phenyl)-2-nitroethanol with an optical purity of 92% e.e. was obtained in a yield of 74%.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH2:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[CH3:10].[CH2:17]1[O:19][CH2:18]1>O>[N:14]1[CH:15]=[CH:16][C:11]([CH:9]([CH3:10])[CH2:18][CH2:17][OH:19])=[CH:12][CH:13]=1
Reactant: C1CO1
Reactant: CCc1ccncc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Product: CC(CCO)c1ccncc1
Temperature: 25 °C

Procedure:
A solution of lithium diisopropylamide [made from n-BuLi (13.3 cm3) and diisopropylamine (2.8 cm3) in T.H.F. (10 cm3)] was added at -70° to a stirred solution of 4-ethylpyridine (2.0 g) in T.H.F. (10 cm3) under nitrogen. After 10 minutes the red solution was treated with ethylene oxide (1 cm3) giving an immediate suspension. After warming to room temperature, water (10 cm3) was added and the phases were separated. The aqueous phase was extracted with chloroform (2×20 cm3) and the combined organic extracts were dried (MgSO4) and evaporated in vacuo. Chromatography on silica (Merck 60.9385) eluting with methanol: ethyl acetate, 3:20, gave 3-(4-pyridyl)-butan-1-ol as an oil.
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[NH2:6][C@H:7]([C:12]([OH:14])=[O:13])[C:8]([CH3:11])([CH3:10])[CH3:9].[OH-].[Na+]>O1CCOCC1>[CH3:5][O:4][C:2]([NH:6][C@H:7]([C:12]([OH:14])=[O:13])[C:8]([CH3:11])([CH3:10])[CH3:9])=[O:3]
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Temperature: 60 °C

Procedure:
23.5 ml (305 mmol) of methyl chloroformate are added over a period of 20 min to a solution of 20 g (152 mmol) of (L)-tert-leucine (=2(S)-amino-3,3-dimethyl-butyric acid=(L)-α-tert-butylglycine; Fluka, Buchs/Switzerland) in a mixture of 252 ml (504 mmol) of 2N aqueous sodium hydroxide solution and 80 ml of dioxane, and the reaction solution is heated at 60° C. for 14 h. After cooling to room temperature, the reaction solution is washed 2× with methylene chloride. The aqueous phase is acidified to pH 2 with 4N aqueous hydrochloric acid and extracted three times with ethyl acetate. The organic extracts are combined, dried (Na2SO4) and concentrated by evaporation, the product beginning to solidify. Digestion of the solidified solid with hexane yields the title compound in the form of a white powder. M.p. 106-108° C.
Reaction SMILES: C([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]2([C:25]3[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=3)[NH:19][C:18]2=[O:27])[CH:9]1[C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Br:34])[C:29]=1[F:35])=[O:7])(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>ClCCl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Br:34][C:30]1[C:29]([F:35])=[C:28]([CH:9]2[CH:8]([C:6]([OH:7])=[O:5])[NH:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]32[C:25]2[C:20](=[CH:21][C:22]([Cl:26])=[CH:23][CH:24]=2)[NH:19][C:18]3=[O:27])[CH:33]=[CH:32][CH:31]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Br)c2F)C12C(=O)Nc1cc(Cl)ccc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Br)c2F)C12C(=O)Nc1cc(Cl)ccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 99.2 %

Procedure:
A solution of rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (1.2 g, 2.1 mmol) in dichloromethane (15 mL) was added trifluoroacetic acid (5 g). The reaction mixture was stirred at room temperature for 20 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give rac-(2′S,3′R,4′S,5′R)-4′-(3-bromo-2-fluoro-phenyl)-6-chloro-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a light yellow solid (1.3 g, 98%).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7](I)[CH2:8][CH3:9].Cl.[CH3:12][N:13]1[C:21]2[C:16](=[C:17]([C:22]3([OH:28])[CH2:27][CH2:26][CH2:25][NH:24][CH2:23]3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14]1>CN(C)C=O.O>[CH2:7]([N:24]1[CH2:25][CH2:26][CH2:27][C:22]([C:17]2[CH:18]=[CH:19][CH:20]=[C:21]3[C:16]=2[CH:15]=[CH:14][N:13]3[CH3:12])([OH:28])[CH2:23]1)[CH2:8][CH3:9]
Reactant: Cn1ccc2c(C3(O)CCCNC3)cccc21
Reactant: CCCI
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN1CCCC(O)(c2cccc3c2ccn3C)C1
Reaction time: 20 h

Procedure:
14.5 g of sodium carbonate and 6 ml of propyl iodide were added to a mixture of 12 g of 3-(1-methyl-1H-indol-4-yl)-3-piperidinol hydrochloride in 240 ml of dimethylformamide and the mixture was stirred for 20 hours and then was diluted with water. The mixture was extracted with ethyl acetate and the organic phase was washed with aqueous sodium chloride solution, dried and evaporated to dryness under reduced pressure. The 11 g of residue were chromtographed over silica gel and eluted with a 9-1 cyclohexane-triethylamine mixture to obtain 8.2 g of 1-propyl-3-(1-methyl-1H-indol-4-yl)-3-piperidinol) with an Rf=0.2.