Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].C(O)(=O)C.[C:23]([O:26][C@H:27]1[C@H:40]([O:41][Si:42]([C:45]([CH3:48])([CH3:47])[CH3:46])([CH3:44])[CH3:43])[C@@H:39]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[O:38][C@@H:29]([O:30][Si](C(C)(C)C)(C)C)[C@@H:28]1[N:54]=[N+:55]=[N-:56])(=[O:25])[CH3:24].[Cl:57][C:58]([Cl:62])([Cl:61])[C:59]#[N:60].C1CCN2C(=NCCC2)CC1>C1COCC1>[Cl:57][C:58]([Cl:62])([Cl:61])[C:59](=[NH:60])[O:30][C@H:29]1[O:38][C@H:39]([CH2:49][O:50][C:51](=[O:53])[CH3:52])[C@@H:40]([O:41][Si:42]([C:45]([CH3:46])([CH3:47])[CH3:48])([CH3:44])[CH3:43])[C@H:27]([O:26][C:23](=[O:25])[CH3:24])[C@H:28]1[N:54]=[N+:55]=[N-:56]
Reactant: CC(=O)OC[C@H]1O[C@@H](O[Si](C)(C)C(C)(C)C)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1O[Si](C)(C)C(C)(C)C
Reactant: N#CC(Cl)(Cl)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(=O)OC[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](N=[N+]=[N-])[C@@H](OC(C)=O)[C@@H]1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
TBAF (1.0 M in THF, 1.4 mL) and glacial acetic acid (80 μL, 5.9 mmol) were added dropwise to a solution of tert-butyldimethylsilyl 3,6-di-O-acetyl-2-azido-4-O-tert-butyldimethylsilyl-2-deoxy-β-D-glucopyranoside (590 mg, 1.14 mmol) in THF (12 mL) under nitrogen at 0° C. The reaction mixture was warmed to room temperature, stirred for 1.5 h and quenched with saturated NaHCO3 solution. After extraction with CH2Cl2 (3×), the combined organic phases were dried over MgSO4, filtered and the solvents were removed in vacuo. The crude material was dried by coevaporation with anhydrous toluene and vacuum for 1 h and dissolved in CH2Cl2 (25 mL). Trichloroacetonitrile (1.3 mL, 12.50 mmol) and freshly activated 4 Å powdered molecular sieves (300 mg) were added and the mixture was stirred for 30 minutes at room temperature. After cooling to 0° C., DBU (30 μl, 0.2 mmol) was added and the temperature was allowed to rise to room temperature. After 1 h, the mixture was filtered through Celite and the solvents were removed in vacuo. Flash chromatography on silica gel (Hexanes:EtOAc 85:15) afforded 13α (437 mg, 0.80 mmol, 70%) and 13β (94 mg, 0.17 mmol, 15%). 13α: 1H-NMR (500 MHz, CDCl3) δ 8.81 (s, 1H, NH), 6.44 (d, J=3.6 Hz, 1H, H-1), 5.43 (dd, J=8.8, 10.4 Hz, 1H, H-3), 4.41 (dd, J=1.9, 12.0 Hz, 1H, H-6a), 4.12-3.99 (m, 2H, H-6b, H-5), 3.87 (t, J=9.1 Hz, 1H, H-4), 3.58 (dd, J=3.6, 10.7 Hz, 1H, H-2), 2.17 (s, 3H, OCH3), 2.01 (s, 3H, OCH3), 0.86 (s, 9H, C(CH3)3), 0.08 (s, 3H, SiCH3), 0.06 (s, 3H, SiCH3); 13C-NMR (125 MHz, CDCl3) δ 170.5, 169.7, 160.8, 94.7, 72.77, 69.1, 62.5, 61.5, 25.9, 21.6, 21.0, 18.2, −3.8, −4.6. 13β: 1H-NMR (500 MHz, CDCl3) δ 8.81 (s, 1H, NH), 5.73 (d, J=8.2 Hz, 1H, H-1), 5.03 (dd, J=8.8 Hz, J=9.8 Hz, 1H, H-3), 4.40 (dd, J=2.1 Hz, J=11.9 Hz, 1H, H-6a), 4.13 (dd, J=4.2 Hz, J=11.9 Hz, 1H, H-6b), 3.87 (t, J=9.5 Hz, 1H, H-4), 3.58 (m, 2H, H-2, H-5), 2.17 (s, 3H, OCH3), 2.08 (s, 3H, OCH3),0.84 (s, 9H, C(CH3)3), 0.05 (s, 3H, SiCH3), 0.04 (s, 3H, SiCH3); 13C-NMR (125 MHz, CDCl3) δ 170.7, 169.9, 160.8, 96.6, 75.3, 68.8, 64.1, 62.4, 25.9, 25.8, 25.8, 21.5, 21.1, 18.1, −3.9, −4.8.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([O:26][CH2:27][CH3:28])C(N)=O)=[CH:17][CH:16]=1)[CH3:11].O.[NH2:30][NH2:31].CO[CH:34](OC)[N:35]([CH3:37])C>C(OCC)(=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[N:10]([CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][O:26][CH2:27][CH2:28][C:34]2[NH:31][N:30]=[CH:37][N:35]=2)=[CH:17][CH:16]=1)[CH3:11]
Reactant: NN
Reactant: COC(OC)N(C)C
Reactant: CCOC(Cc1ccc(OCCN(C)c2nc3ccccc3o2)cc1)C(N)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CN(CCOc1ccc(CCOCCc2ncn[nH]2)cc1)c1nc2ccccc2o1
Temperature: 100 °C

Procedure:
3-[4-[2-[N-(2-Benzoxazolyl)-N-methylamino]ethoxy]phenyl]-2-ethoxypropanamide (0.562 g, 1.5 mmol) in dimethylformamide dimethyl acetal was heated to 120° C. for 11/2 h then cooled and concentrated. The residue was dissolved in acetic acid (4 ml) and hydrazine hydrate (1.1 eq) added. After 11/2 h at 100° C. the solution was cooled, diluted with ethyl acetate and washed with water (×2) and sodium bicarbonate solution. After the solution was dried and concentrated the residue was chromatographed (methanol/dichloromethane) to give the product as a white solid m.p.=127°-129° C.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH2:15])[CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](#[N:19])[CH:17]=[CH2:18]>C(O)C>[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][CH2:18][CH2:17][C:16]#[N:19])[CH2:10][CH2:9]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC#N
Reactant: NCC1CCN(Cc2ccccc2)CC1
Solvent: CCO
Product: N#CCCNCC1CCN(Cc2ccccc2)CC1
Yield: 102.2 %

Procedure:
A mixture of 1-(phenylmethyl)-4-piperidinemethanamine (0.076 mol) and acrylonitrile (0.076 mol) in ethanol (250 ml) was stirred and refluxed for 4 hours. The solvent was evaporated, yielding 20.0 g (102.4%, crude residue, used in next reaction step, without further purification) of 3-[[[1-(phenylmethyl)-4-piperidinyl]methyl]amino]-propanenitrile (interm. 14).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][O:13][C:14]3[CH:15]=[C:16]([CH:20]([S:27][CH2:28][CH2:29][C:30](O)=[O:31])[S:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])[CH:17]=[CH:18][CH:19]=3)=[N:9]2)=[CH:4][CH:3]=1.C([N:35](CC)CC)C.[I-].ClC1C=CC=C[N+]=1C.N>C(Cl)Cl.CC#N.O>[C:30]([CH2:29][CH2:28][S:27][CH:20]([C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([O:13][CH2:12][C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=2)[CH:15]=1)[S:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])(=[O:31])[NH2:35]
Reactant: CCN(CC)CC
Reactant: O=C(O)CCSC(SCCC(=O)O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Agent: C[n+]1ccccc1Cl
Agent: N
Agent: [I-]
Solvent: O
Solvent: ClCCl
Solvent: CC#N
Product: NC(=O)CCSC(SCCC(=O)O)c1cccc(OCc2ccc3ccc(Cl)cc3n2)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The diacid (Example 3) (3.954 g, 8.04 mmoles) was dissolved in 250 mL CH2Cl2 :CH3CN 4:1. Triethylamine (2.5 mL, 2.2 equiv.) was added followed, at 0° C., by 2-chloro-1-methylpyridinium iodide (2.257 g, 1.1 equiv.). After stirring 1 hour at 0° C., ammonia was added and the mixture stirred for another hour at 10° C. Water was then added and the aqueous layer acidified to pH 5. Extraction with CH2Cl2 (2×) and EtOAc (2×) and the flash chromatography of the residue on silica with acetone:CH2Cl2 :AcOH 40:60:1 and 50:50:1 afforded the title compound.
Reaction SMILES: [K].N1C=CN=C1.FC(F)(F)C(OCC)=O.[F:16][C:17]([N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)(F)[CH:18]([F:20])[F:19]>O1CCCC1>[F:16][C:17]([N:22]1[CH:26]=[CH:25][N:24]=[CH:23]1)=[C:18]([F:20])[F:19]
Reactant: FC(F)C(F)(F)n1ccnc1
Agent: CCOC(=O)C(F)(F)F
Agent: [K]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: FC(F)=C(F)n1ccnc1
Temperature: -78 °C
Yield: 13 %

Procedure:
Into a 50 ml autoclave were poured 10.6 g (100 mmol) of potassium salt of imidazole and tetrahydrofuran (30 ml), and the inside of the autoclave was cooled to −78° C., and evacuation and replacement by nitrogen were carried out three times. After the inside of a system was evacuated, TFE was introduced until the inside pressure of the system reached 0.1 MPa·G. Then the temperature of the reaction system was increased to 100° C., and TFE was further introduced to maintain the inside pressure of the reaction system at 0.3 to 0.5 MPa·G. Supply of TFE was stopped when the amount of TFE reached 1.1 equivalents (11 g=110 mmol) to the potassium salt of imidazole, and stirring was continued at 100° C. Fifteen hours after starting of the stirring, the inside of the reaction system was brought to room temperature, followed by evacuation to terminate the reaction. To this crude reaction product was added 2.84 g (20 mmol) of ethyl trifluoroacetate, and it was confirmed by a 19F-NMR analysis based on ethyl trifluoroacetate that 1-(1,1,2,2-tetrafluoroethyl)imidazole had been produced at yield of 13% and 1-(1,2,2-trifluoroethenyl)imidazole had been produced at yield of 56%. Also according to gas chromatography analysis, it was confirmed that 14% of imidazole remained.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[CH:4]=[C:5]([C@@H:11]([NH3+:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[Cl:2][C:3]1[CH:4]=[C:5]([C@@H:11]([NH:13][C:43]([C:39]2[CH:38]=[C:37]3[C:42](=[CH:41][CH:40]=2)[N:34]([CH2:33][C:30]2[CH:29]=[CH:28][C:27]([C:22]4[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:32][CH:31]=2)[C:35]([CH3:47])=[C:36]3[CH3:46])=[O:44])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc([C@H](C)[NH3+])cc1Cl
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Agent: [Cl-]
Product: COc1ccc([C@H](C)NC(=O)c2ccc3c(c2)c(C)c(C)n3Cc2ccc(-c3ccccc3C(=O)O)cc2)cc1Cl

Procedure:
The title compound was prepared following the same general synthetic procedure as described in Steps 3-4, Example 2, starting with (S)-1-(3-chloro-4-methoxyphenyl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of (S)-1-(4-(tert-butyl)phenyl)ethanaminium chloride and 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 567 [M+1]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:9]=[C:8]([C:10]([OH:12])=O)[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19].[NH2:20][C:21](=[N:33][OH:34])[C:22]1[CH:31]=[CH:30][C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]([F:32])[CH:23]=1>>[F:32][C:24]1[CH:23]=[C:22]([C:21]2[N:20]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:12][N:33]=2)[CH:31]=[CH:30][C:25]=1[C:26]([O:28][CH3:29])=[O:27].[F:32][C:24]1[CH:23]=[C:22]([C:21]2[N:20]=[C:10]([C:8]3[CH:7]=[CH:6][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[CH3:19])=[C:4]([CH2:3][O:2][CH3:1])[CH:9]=3)[O:34][N:33]=2)[CH:31]=[CH:30][C:25]=1[C:26]([OH:28])=[O:27]
Reactant: COCc1cc(C(=O)O)ccc1-c1ccccc1C
Reactant: COC(=O)c1ccc(C(N)=NO)cc1F
Product: COCc1cc(-c2nc(-c3ccc(C(=O)O)c(F)c3)no2)ccc1-c1ccccc1C
Product: COCc1cc(-c2nc(-c3ccc(C(=O)OC)c(F)c3)no2)ccc1-c1ccccc1C

Procedure:
Methyl 2-fluoro-4-{5-[2-(methoxymethyl)-2′-methylbiphenyl-4-yl]-1,2,4-oxadiazol-3-yl}benzoate was prepared following the general procedure 7 starting from Intermediate 3 and Intermediate 35. It was then hydrolysed following procedure 9, affording the title compound as as a beige solid. 1H NMR (DMSO, 300 MHz) δ 13.64 (br s, 1H), 8.33 (d, J=1.4 Hz, 1H), 8.17 (dd, J=7.9, 1.4 Hz, 1H), 8.13-8.03 (m, 2H), 7.96 (dd, J=11.1, 1.2 Hz, 1H), 7.43 (d, J=7.9 Hz, 1H), 7.37-7.27 (m, 3H), 7.15 (d, J=7.0 Hz, 1H), 4.25-4.14 (m, 2H), 3.25 (s, 3H), 2.04 (s, 3H). LC/MS (Method B): 419.1 (M+H)+; 417.2 (M−H)−. HPLC: Rt 5.19 min (Purity: 99.2%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[C@H:12]2[C@H:16]([OH:17])[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13]2)=[C:5]([NH:21][CH2:22][C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[N:4]=1.C(N(CC)CC)C.[C:40]1([S:46](Cl)(=[O:48])=[O:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>O1CCOCC1>[NH3:1].[OH:17][C@@H:16]1[C@H:15]([OH:18])[C@@H:14]([CH2:19][OH:20])[O:13][C@H:12]1[N:9]1[CH:8]=[N:7][C:6]2[C:10]1=[N:11][C:3]([CH2:2][NH:1][S:46]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:48])=[O:47])=[N:4][C:5]=2[NH:21][CH2:22][C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: NCc1nc(NCc2cccc3ccccc23)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: N
Product: O=S(=O)(NCc1nc(NCc2cccc3ccccc23)c2ncn([C@@H]3O[C@H](CO)[C@@H](O)[C@H]3O)c2n1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 140.6 %

Procedure:
A suspension of (2R,3R,4S,5R)-2-{2-(aminomethyl)-6-[(1-naphthylmethyl)amino]-9H-purin-9-yl}-5-(hydroxymethyl)tetrahydro-3,4-furandiol (0.16 g, 0.37 mmol) (Preparation 15) in dioxan (28 ml) was heated gently until a solution was achieved. The solution was cooled to room temperature and treated with triethylamine (0.12 g, 1.19 mmol) followed by addition of a solution of benzenesulphonyl chloride (0.060 g, 0.34 mmol) in dioxan (2 ml) over 10 minutes. The mixture was then stirred at room temperature for 30 minutes. The solvent was removed under reduced pressure and the residue azeotroped with dichloromethane. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:0.88 ammonia (92:8:0.4 by volume) to afford the title compound as a white solid (150 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.O[CH2:10][C:11]1[S:12][CH:13]=[CH:14][CH:15]=1.C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5](=[O:8])[N:6]([CH2:10][C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:7]=1
Reactant: O=c1ncc(Br)c[nH]1
Reactant: OCc1cccs1
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Solvent: CN(C)C=O
Product: O=c1ncc(Br)cn1Cc1cccs1
Yield: 48 %

Procedure:
5-Bromopyrimidin-2-one (10 mmol), 2-hydroxymethylthiophene (36 mmol) and N,N-dimethylformamide dineopentyl acetal (15 mmol) in DMF (40 ml) were heated together at 80° C. for 150 min. The coloured solution was evaporated to dryness at reduced pressure (1 mmHg), the residual viscous material triturated with pet, ether (2×25 ml) and with ether (50 ml) when it solidified. This material was dissolved in chloroform and chromatographed on alumina (20 g, activity III). The title compound was eluted with chloroform; yield 48%, m.p. 188°-190° C. (EtOAc). 1H NMR (TFA) δ 5.68 (CH2); 7.18, 7.41, 7.58 (H3', H4', H5'), 8.95 (H4, H6).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1>[Pd].C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[CH:21]=[CH:22]\[CH2:23][OH:24])[CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[CH:25][CH:26]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16](/[CH:21]=[CH:22]/[CH2:23][OH:24])[CH:17]=3)[NH:12][CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: O=C(NCc1ccc(Cl)cc1)c1c[nH]c2ccc(/C=C/CO)cc2c1=O
Product: O=C(NCc1ccc(Cl)cc1)c1c[nH]c2ccc(/C=C\CO)cc2c1=O
Reaction time: 4 h

Procedure:
A mixture of N-(4-chlorobenzyl)-4-hydroxy -6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (5.48 g) and Pd/C (10%, 0.55 g) in 3:1 CH2Cl2/MeOH (150 mL) are placed on a Parr hydrogenator under 50 psi of H2 and shaken for 4 h. Another 0.30 g of Pd/C was added, and the resulting mixture was shaken for 2 h. The reaction mixture is then filtered through Celite, 0.55 g of fresh catalyst is added, and the resulting mixture is shaken under H2 for 3 h. The reaction mixture is then filtered through Celite and concentrated in vacuo. Trituration from CHCl3/MeOH affords a solid which is purified by HPLC chromatography on a 0.46×25 cm Chiralcel OD-H column eluting with EtOH at a rate of 0.3 mL/min to give 0.383 g of N-(4-chlorobenzyl)-1,4-dihydro-6-[(1Z)-3-hydroxy-1-propenyl]-4-oxo-3-quinolinecarboxamide (cis title compound), and 0.492 g of N-(4-chlorobenzyl)-1,4-dihydro-6-[(1E)-3-hydroxy-1-propenyl]-4-oxo-3-quinolinecarboxamide (trans title compound). Crystallization of the cis isomer from ethyl acetate gave 0.29 g of the title cis compound as a solid. Crystallization of the trans isomer from CH2Cl2/MeOH gave 0.289 g of the title trans compound as a solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([Cl:9])[N:3]=1.[CH2:10]([NH:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13]>C(#N)C.O>[CH2:10]([NH:14][CH2:15][CH2:16][C:6]1[CH:5]=[C:4]([Cl:9])[N:3]=[C:2]([CH3:1])[N:7]=1)[CH2:11][CH2:12][CH3:13]
Reactant: Cc1nc(Cl)cc(Cl)n1
Reactant: CCCCNCC
Solvent: O
Solvent: CC#N
Product: CCCCNCCc1cc(Cl)nc(C)n1
Yield: 99.7 %

Procedure:
A mixture of 2-methyl-4,6-dichloro-pyrimidine (1.63 g, 10 mmol) in 5 ml of acetonitrile was treated with N-butyl-ethyl-amine (2.000 g, 20 mmol) and heated at reflux for 0.5 hours. The mixture was cooled, diluted with water and extracted with ethyl acetate. The organic layer was washed with brine, dried and concentrated to give 2.271 g (100%) of title compound as a light-brown oil. 1H NMR (CDCl3) δ 0.93 (t, 3H), 1.13 (t, 3H), 1.22-1.36 (m, 2H), 1.45-1.6 (m, 2H), 2.43 (s, 3H), 3.25-3.60 (m, 4H), 6.15 (s, 1H) ppm.
Reaction SMILES: CS(O[CH2:6][CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1)(=O)=O.[F-:18].C([N+](CCCC)(CCCC)CCCC)CCC>>[F:18][CH2:6][CH:7]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CC(COS(C)(=O)=O)C1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CC(C)(C)OC(=O)N1CC(CF)C1
Temperature: 25 °C

Procedure:
A mixture of tert-butyl 3-(((methylsulfonyl)oxy)methyl)azetidine-1-carboxylate (12.5 g, 47 mmol) and 235 mL tetrabutylammonium fluoride (1M solution in THF, 5 equiv.) was heated at reflux for 18 h. The reaction mixture was cooled to room temperature and excess THF was removed on a rotary evaporator. The residue was dissolved in ethyl acetate. The organic phase was washed with sat'd aqueous NaHCO3, washed with water, washed with brine, dried over Na2SO4, filtered and concentrated on a rotary evaporator to give the crude product. This crude product was purified by silica gel chromatography to afford tert-butyl 3-(fluoromethyl)azetidine-1-carboxylate as clear oil (7.5 g). 1H NMR (DMSO-d6): δ 4.52 (dd, 2H), 3.89 (br, 2H), 3.61 (br, 2H), 2.92-2.77 (m, 1H), 1.36 (s, 9H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH2:10])=[NH:9].[CH2:11]([CH:19]1[CH2:21][CH:20]1[C:22](Cl)=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>N1C=CC=CC=1>[CH2:11]([CH:19]1[CH2:21][CH:20]1[C:22]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([NH2:10])=[NH:9])=[O:23])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCC1CC1C(=O)Cl
Reactant: N=C(N)NCCCCCN
Solvent: c1ccncc1
Product: CCCCCCCCC1CC1C(=O)NCCCCCNC(=N)N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To 350 mg. of 1-amino-5-guanidinopentane suspended in 70 ml. of dry pyridine was added 700 mg. of 2-(n-octyl)cyclopropanecarbonyl chloride. This mixture was stirred at room temperature for 2 days, after which the solid was filtered and the filtrate concentrated to a brown oil (1.19 g.). The entire bulk of this oil was chromatographed on silica gel eluting with MeOH:CHCl3 (2:3) and collecting 10 ml. fractions. Fractions 20-40 gave 28.8 mg. of desired products. Mass spectrometry (EI): M+ m/e 324 for C18H36N4O.
Reaction SMILES: C([N:5]([C:15]1[N:16]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:17]=[C:18]2[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]2)C(NC1CCCCC1)=O)CCC.[CH2:31]([O:33][C:34]1[CH:35]=[C:36](N)[CH:37]=[CH:38][CH:39]=1)[CH3:32]>CN1CCCC1=O>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([N:16]2[C:15]([NH:5][C:38]3[CH:37]=[CH:36][CH:35]=[C:34]([O:33][CH2:31][CH3:32])[CH:39]=3)=[C:23]3[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]3)=[N:17]2)=[CH:25][CH:26]=1
Reactant: CCCCN(C(=O)NC1CCCCC1)c1c2ccccc2nn1-c1ccc(Cl)cc1
Reactant: CCOc1cccc(N)c1
Solvent: CN1CCCC1=O
Product: CCOc1cccc(Nc2c3ccccc3nn2-c2ccc(Cl)cc2)c1

Procedure:
In analogy to the procedure described in example 4.1, 3-chloro-2-(4-chloro-phenyl)-2H-indazole (Ardakani, Manouchehr; Smalley, Robert K.; Smith, Richard H., Synthesis (1979), (4), 308-9) was reacted with 3-ethoxy-phenylamine ([621-33-0]) in N-methyl 2-pyrrolidone for 4 d at 175° C. in a sealed tube to give the title compound as yellow solid. MS: m/e=364.3 [M+H+].
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1/[CH:31]=[CH:32]/[CH:33]=O.C([BH3-])#N.[Na+]>ClCCl.CO>[F:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1/[CH:31]=[CH:32]/[CH2:33][NH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1
Reactant: N#Cc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Reactant: O=C/C=C/c1cc(F)ccc1F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)N(CCN1CCC(NC/C=C/c3cc(F)ccc3F)CC1)C(=O)CO2
Yield: 30.9 %

Procedure:
4-[2-(4-Aminopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 58) (1.5 mmol), (2E)-3-(2,5-difluorophenyl)acrylaldehyde (202 mg, 1.2 mmol) (FR 2872164) (200 mg, 1.1 mmol) and sodium cyanoborohydride were reacted as described under Example 21. Chromatography on silica gel with dichloromethane/methanol gave 168 mg (25%) product
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][C:6](=[O:13])[N:7]2[CH3:12].CO.[Br:16]N1C(=O)CCC1=O>C(Cl)(Cl)Cl.ClCCl.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>[Br:16][C:11]1[C:3]([O:2][CH3:1])=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH3:12])[C:6](=[O:13])[CH2:5]2
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cccc2c1CC(=O)N2C
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1c(Br)ccc2c1CC(=O)N2C
Reaction time: 0.17 h

Procedure:
To a solution of 4-methoxy-1-methyl-1,3-dihydro-indol-2-one (440 mg, 2.483 mmol) in chloroform (25 ml) was added methanol (25.00 ml). The reaction was put at −10° C. and N-bromosuccinimide (442 mg, 2.483 mmol) was added in three portions over a 30 min interval and the reaction was then stirred for 10 minutes. The reaction was then diluted with dichloromethane, saturated aqueous sodium bicarbonate, and saturated aqueous sodium thiosulfate and the layers were separated. The aqueous layer was extracted two additional times with dichloromethane and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting residue was purified by silica gel flash chromatography (ethyl acetate-heptane, 0 to 60%) to afford 5-bromo-4-methoxy-1-methyl-1,3-dihydro-indol-2-one; MS: (ES+) m/z 255.8 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:12][C:13](=O)[CH3:14])[C:9](=O)C)=[C:4]([O:16][CH3:17])[CH:3]=1.C([O-])(=O)C.[NH4+:22].[OH-].[Na+]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:13]([CH3:14])[N:22]=[CH:9]2)=[C:4]([O:16][CH3:17])[CH:3]=1
Reactant: COc1cc(Br)ccc1N(CC(C)=O)C(C)=O
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1cc(Br)ccc1-n1cnc(C)c1
Temperature: 120 °C
Yield: 93.2 %

Procedure:
A mixture of N-(4-bromo-2-methoxyphenyl)-N-(2-oxopropyl)acetamide (23.4 g), ammonium acetate-(31.5 g), and acetic acid (49 g) was agitated under heating at 120° C. for 30 minutes. After the reaction solution was neutralized with sodium hydroxide under ice-cooling, the reaction solution was extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:hexane-ethyl acetate system), and 19.4 g of the title compound was obtained.