Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11](=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=3)[CH:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32]>ClCCl>[F:29][C:30]([F:35])([F:34])[C:31]([OH:33])=[O:32].[F:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([CH:14]=[C:11]3[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]3)[CH:16]=2)=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=Cc2cccc(Oc3ccc(F)cn3)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Reaction time: 3 h

Procedure:
A solution of tert-butyl-4-(3-(5-fluoropyridin-2-yloxy)benzylidene)piperidine-1-carboxylate (0.274 g) in dichloromethane (2.5 mL, 0.28 M) was treated with trifluoroacetic acid (2.5 mL). The reaction was allowed to stir for 3 hours, then concentrated to an oil. The oil was used without purification. 0.466 g, quantitative yield.
Reaction SMILES: Br[C:2]1[S:22][C:5]2=[N:6][C:7]([CH3:21])=[CH:8][C:9]([NH:10][S:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)(=[O:13])=[O:12])=[C:4]2[C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=1.[C:31]1(B(O)O)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+].C(Cl)Cl>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:20][C:16]1[CH:15]=[C:14]([S:11]([NH:10][C:9]2[CH:8]=[C:7]([CH3:21])[N:6]=[C:5]3[S:22][C:2]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[CH:24]=4)[C:4]=23)(=[O:13])=[O:12])[CH:19]=[CH:18][CH:17]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(-c3ccccc3)sc3nc(C)cc(NS(=O)(=O)c4cccc(Cl)c4)c23)c1
Temperature: 25 °C
Yield: 56.6 %

Procedure:
A mixture of N-{2-bromo-6-methyl-3-[3-(methyloxy)phenyl]thieno[2,3-b]pyridin-4-yl}-3-chlorobenzenesulfonamide (50 mg, 0.095 mmol) (Example 33), phenylboronic acid (13.97 mg, 0.115 mmol), sodium carbonate (20.23 mg, 0.191 mmol) and PdCl2(dppf).DCM (3.90 mg, 4.77 μmol) in DMF (1 mL) and water (250 μl) was heated at 90° C. under nitrogen, for 3.5 h. The reaction mixture was then cooled to RT and concentrated. Purification by chromatography on silica gel, eluting with a gradient of 0-20% ethyl acetate in DCM, afforded the title compound (28 mg). LCMS (A) m/z: 521 [M+1]+, Rt 1.57 min (acidic), Rt 0.98 min (basic).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([CH3:10])[N:7]([C:11]3[N:16]=[CH:15][N:14]=[C:13]([NH2:17])[N:12]=3)[C:6]=2[CH:18]=1.[C:19]([C:21]1([OH:28])[CH2:26][CH:25]2[CH2:27][CH:22]1[CH2:23][CH2:24]2)#[CH:20].C1C=CC(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[Cu]I>[NH2:17][C:13]1[N:14]=[CH:15][N:16]=[C:11]([N:7]2[C:6]3[CH:18]=[C:2]([C:20]#[C:19][C:21]4([OH:28])[CH2:26][CH:25]5[CH2:27][CH:22]4[CH2:23][CH2:24]5)[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[CH3:10])[N:12]=1
Reactant: Cc1nc2ccc(Br)cc2n1-c1ncnc(N)n1
Reactant: C#CC1(O)CC2CCC1C2
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: Cc1nc2ccc(C#CC3(O)CC4CCC3C4)cc2n1-c1ncnc(N)n1
Temperature: 120 °C
Yield: 7.8 %

Procedure:
A mixture of 4-(6-bromo-2-methyl-1H-benzo[d]imidazol-1-yl)-1,3,5-triazin-2-amine (200 mg, 0.66 mmol) and 2-ethynylbicyclo[2.2.1]heptan-2-ol (85 mg, 1.3 mmol) in DMF (2.5 mL) was treated with palladium(II) acetate (16 mg, 0.07 mmol), DPPP (58 mg, 0.14 mmol), copper(I) iodide (5 mg, 0.04 mmol) and potassium carbonate (180 mg, 1.3 mmol), then the mixture was heated at 120° C. for 40 min under microwave irradiation. After cooling to RT, the reaction mixture was filtered and the filtrate concentrated in vacuo. Purification of the residue by silica gel column chromatography furnished the title compound (18.5 mg, yield 8%): 1H NMR: (400 MHz, MeOD) delta 1.30-1.47 (m, 4H), 1.56-1.67 (m, 1H), 1.92-2.48 (m, 5H), 2.97 (s, 3H), 7.36 (dd, J=1.6, 8.4 Hz, 1H), 7.53 (d, J=8.4 Hz, 1H), 8.50 (s, 1H), 8.60 (s, 1H); LC-MS: m/z=+361.0 (M+H)+.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]([CH2:16][CH2:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:20]=1[C:21]#[N:22])[CH3:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[CH2:7]([N:14]([CH2:16][CH2:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:20]=1[CH2:21][NH2:22])[CH3:15])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN(CCOc1cccc(Cl)c1C#N)Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(CCOc1cccc(Cl)c1CN)Cc1ccccc1
Reaction time: 1 h

Procedure:
A solution of lithium aluminium hydride in THF (790 ml of a 1M solution) was stirred under nitrogen at ambient temperature and diluted with dry THF (1 l) and then a solution of 2-[2-(N-benzyl-N-methylamino)ethoxy]-6-chlorobenzonitrile (237 g) in dry THF (200 ml) was added over 30 minutes. When approximately three-quarters of the solution had been added an exotherm was observed and this was checked by cooling the reaction mixture in an ice/water bath. The mixture was stirred for 1 hour after the addition and then quenched by the cautious addition of water (30 ml), 15% sodium hydroxide solution (30 ml) and water (90 ml). The mixture was diluted with ethyl acetate (1 l) and filtered through a filter aid. The filter aid was boiled with ethyl acetate (2×500 ml) and filtered through a filter aid. The combined filtrates were dried and evaporated to give 2-[2-(N-benzyl-N-methylamino)ethoxy]-6-chlorobenzylamine as an oil.
Reaction SMILES: Cl[C@H:2]1[C@H:8]2[C:9](=[O:10])[C@H:5]([CH:6]=[CH:7]2)[N:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]1=[O:19].Cl[C@@H:21]1[C@H:27]2[C:28](=O)[C@H](C=[CH:26]2)N(OCC2C=CC=CC=2)C1=O.ClC(Cl)C(NOCC1C=CC=CC=1)=O.O1C=CC=C1>CCOC(C)=O>[CH3:26][CH:27]([CH3:28])[CH2:21][C@H:2]1[C@@H:8]2[C:9](=[O:10])[C@H:5]([CH:6]=[CH:7]2)[N:4]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:3]1=[O:19]
Reactant: O=C1[C@H]2C=C[C@@H]1N(OCc1ccccc1)C(=O)[C@H]2Cl
Reactant: O=C1[C@H]2C=C[C@@H]1N(OCc1ccccc1)C(=O)[C@@H]2Cl
Agent: O=C(NOCc1ccccc1)C(Cl)Cl
Solvent: c1ccoc1
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H]1C(=O)N(OCc2ccccc2)[C@H]2C=C[C@H]1C2=O

Procedure:
(±)-(4S,5R,1S) 4-chloro-8-oxo-2-(phenyl methoxy)-2-azabicyclo[3.2.1]oct-6-en-3-one (endo-5e) and (±)-(4R,5R,1S) 4-chloro-8-oxo-2-(phenylmethoxy)-2-azabicyclo[3.2.1]oct-6-en-3-one (exo-5e):Prepared in 73% yield (72 mg, 0.31 mmol) from the reaction of 2,2-dichloro-N-(phenylmethoxy)acetamide (100.2 mg, 0.43 mmol) with furan via general procedure B. Rf=0.50 (3:1, hexanes:EtOAc) 1H NMR (400 MHz, CDCl3) δ 7.51-7.30 (m, 3H), 6.54 (dd, J=6.0, 1.1 Hz, 1H), 6.51 (dd, J=6.0, 1.7 Hz, 1H), 5.27 (d, J=1.1 Hz, 1H), 5.09 (dd, J=5.1, 1.6 Hz, 1H), 5.00 (d, J=11.0 Hz, 1H), 4.89 (d, J=11.0 Hz, 1H), and 4.76 (d, J=5.2 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 165.9, 136.8, 135.3, 133.1, 129.8, 129.2, 128.2, 92.1, 82.1, 78.3, and 56.9; IR (film) 3032, 2950, 2922, 2852, 1712 (s), 1455, 1369, 1213, 1189, 1059, 1023 cm-1. HR-ESIMS calculated for C13H12ClNNaO3 (M+Na)+288.0398, found 288.0391. exo-diastereoisomer: Rf=0.3 (3:1, hexanes:EtOAc); 1H NMR (400 MHz, CDCl3): δ 7.48-7.35 (m, 2H), 6.68 (d, J=5.9 Hz, 1H), 6.34 (dd, J=6.0, 1.1 Hz, 1H), 5.28 (s, 1H), 5.02 (d, J=10.9 Hz, 2H), 4.98 (s, 1H), 4.92 (d, J=10.9 Hz, 2H), and 4.09 (s, 1H); 13C NMR (101 MHz, CDCl3) δ 165.5, 138.2, 135.0, 131.4, 129.9, 129.2, 128.8, 91.3, 84.2, 78.4, and 56.1; IR (neat) 3067, 3034, 2946, 2885, 1694, 1046 cm-1; HRMS calculated for C13H12ClNNaO3 (M+Na)+288.0398, observed 288.0399.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14](S(C)=O)=[N:15]3)=[CH:10][CH:9]=2)[CH:7]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[NH2:27]>COCCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:20][CH3:21])=[C:6]([C:8]2[N:16]3[C:11]([CH:12]=[N:13][C:14]([NH:27][C:26]4[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:24]([O:23][CH3:22])[CH:25]=4)=[N:15]3)=[CH:10][CH:9]=2)[CH:7]=1
Reactant: COc1ccc(Cl)cc1-c1ccc2cnc(S(C)=O)nn12
Reactant: COc1ccc(N)cc1OC
Solvent: COCCO
Product: COc1ccc(Nc2ncc3ccc(-c4cc(Cl)ccc4OC)n3n2)cc1OC
Temperature: 180 °C
Yield: 34.1 %

Procedure:
[7-(5-Chloro-2-methoxy-phenyl)-2-methanesulfinyl-pyrrolo[2,1-f][1,2,4]triazine (75.0 mg, 0.000233 mol) and 3,4-dimethoxyaniline (71.4 mg, 0.000466 mol) were dissolved in 2-Methoxyethanol (1.64 mL) and the reaction was heated at 180° C. until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 32.66 mg of [7-(5-Chloro-2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(3,4-dimethoxy-phenyl)-amine as a lyophilized powder. (M+H)=411.12. 1H NMR (400 MHz, DMSO, d6) δ 9.24 (s, 1H), 8.95 (s, 1H), 7.93 (s, 1H), 7.48 (m, 1H), 7.31 (m, 2H), 6.97 (d, 1H, J=4.80 Hz), 6.82 (d, 1H, J=8.34 Hz), 6.26 (m, 1H), 6.05 (dd, 1H, J=2.52, 6.07 Hz), 3.79 (s, 3H), 3.69 (s, 3H), 3.65 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C@@H:14]([O:15][CH2:16][C:17]3[CH:18]=[CH:19][C:20]4[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=4[CH:31]=3)[CH2:13][N:12]([S:32]([C:35]3[CH:40]=[CH:39][C:38]([CH3:41])=[CH:37][CH:36]=3)(=[O:34])=[O:33])[C@@H:11]([CH2:42][CH2:43][C:44]([OH:46])=O)[CH2:10]2)=[CH:5][CH:4]=1.Cl.[CH3:48][NH:49][O:50][CH3:51]>>[CH3:51][O:50][N:49]([CH3:48])[C:44](=[O:46])[CH2:43][CH2:42][C@H:11]1[CH2:10][C@H:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C@@H:14]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]3[O:25][CH2:24][CH2:23][N:22]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:21]=3[CH:31]=2)[CH2:13][N:12]1[S:32]([C:35]1[CH:36]=[CH:37][C:38]([CH3:41])=[CH:39][CH:40]=1)(=[O:34])=[O:33]
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCC(=O)O)C[C@@H]3c3ccc(OC)cc3)cc21
Reactant: CNOC
Agent: Cl
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@@H](CCC(=O)N(C)OC)C[C@@H]3c3ccc(OC)cc3)cc21

Procedure:
According to general procedure D, 1.65 g of 3-[(2S,4R,5R)-4-(4-methoxy-phenyl)-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-propionic acid and 271 mg of N,O-dimethylhydroxylamine hydrochloride are used to afford the title compound as a beige oil. Rf=0.18 (EtOAc-heptane 2:1); Rt=5.09.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH2:11]([O:13][CH2:14][CH2:15][NH2:16])[CH3:12].ClCCl>C(OCC)(=O)C>[CH2:11]([O:13][CH2:14][CH2:15][NH:16][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH3:12]
Reactant: CCOCCN
Reactant: O=[N+]([O-])c1ccccc1Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOCCNc1ccccc1[N+](=O)[O-]
Reaction time: 18 h

Procedure:
According to the method of R. Iemura et al., J. Med. Chem., 29 1178-1183 (1986), combine 1-chloro-2-nitrobenzene (69.0 g, 440 mmol) and 2-aminoethyl ethyl ether (102.5 g, 1.15 mol) and heat to reflux. After 18 hours, cool and dilute the reaction mixture with ethyl acetate (400 mL). Extract with brine. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with dichloromethane to give N-(2-ethoxyethyl)-2-nitroaniline.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:27]=[C:28]([CH3:30])[N:29]=1)[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[CH:10][CH:9]=1)=[O:6].[CH3:31][CH:32]1[CH2:37][CH2:36][CH2:35][NH:34][CH2:33]1>>[N:21]1([CH2:20][CH2:19][O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5]([C:4]3[CH:27]=[C:28]([CH3:30])[N:29]=[C:2]([N:34]4[CH2:35][CH2:36][CH2:37][CH:32]([CH3:31])[CH2:33]4)[CH:3]=3)=[O:6])=[CH:9][CH:10]=2)[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1
Reactant: CC1CCCNC1
Reactant: Cc1cc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc(Cl)n1
Product: Cc1cc(C(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc(N2CCCC(C)C2)n1

Procedure:
Compound is formed by reacting 2-chloro-6-methyl-N-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-isonicotinamide with 3-methylpiperidine under conditions described in general procedure A. 1H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 8.22 (d, 1H), 7.85 (m, 1H), 7.57 (m, 2H), 7.43 (d, 1H), 7.17 (s, 1H), 7.04 (d, 1H), 6.99 (s, 1H), 4.31 (m, 2H), 3.60 (t, 4H), 2.88 (t, 2H), 2.79 (t, 2H), 2.56 (t, 4H), 2.39 (s, 3H), 1.85-1.20 (m, 6H), 1.15 (m, 1H), 0.94 (d, 3H). MS: 489.2 (M+1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[C:11]([C:23]([C:25]2C=CC=CN=2)=S)[CH:10]=1.C[Mg+].[Br-].C1C[O:37]CC1>>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][C:9]1[C:21]2[C:20](=[O:22])[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:13]=2[CH:12]=[C:11]([C:23]([CH3:25])=[O:37])[CH:10]=1
Reactant: O=C1c2ccccc2-c2cc(C(=S)c3ccccn3)cc(COC3CCCCO3)c21
Reactant: C1CCOC1
Agent: C[Mg+]
Agent: [Br-]
Product: CC(=O)c1cc(COC2CCCCO2)c2c(c1)-c1ccccc1C2=O
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
1-(2-Tetrahydropyranyl)oxymethyl-3-(2-pyridyl)thiocarbonyl-9-fluorenone (470 mg) was dissolved in THF (10 ml) and cooled to -15° under N2. A solution of MeMgBr in THF (1.2 eq) was added dropwise over 5 min and the reaction allowed to stir at -10° C. for 0.5 hr. The reaction was quenched with saturated ammonium chloride solution, diluted with EtOAc, and washed with water, sat'd NaCl sol'n then dried and evaporated which gave a residue which was chromatographed on silica gel to give the product (233 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][C@@H:7]2[CH2:12][C@@H:11]([NH2:13])[CH2:10][CH2:9][N:8]2[C:14](=[O:23])[C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=2)=[CH:4][CH:3]=1.[N:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[CH:28][CH:27]=1.B([O-])=O.[Na+].Cl.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C@@H:7]2[CH2:12][C@@H:11]([NH:13][CH2:36][C:29]3[C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:26]=[CH:27][CH:28]=3)[CH2:10][CH2:9][N:8]2[C:14](=[O:23])[C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=2)=[CH:24][CH:25]=1
Reactant: Cc1cc(C)cc(C(=O)N2CC[C@H](N)C[C@H]2Cc2ccc(Cl)cc2)c1
Reactant: O=Cc1ccnc2ccccc12
Agent: Cl
Agent: O=B[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(C(=O)N2CC[C@H](NCc3ccnc4ccccc34)C[C@H]2Cc2ccc(Cl)cc2)c1
Reaction time: 3 h
Yield: 41.7 %

Procedure:
A mixture of 550 mg (1.54 mmol) of (2R*,4S*)-2-(4-chlorobenzyl)-1-(3,5-dimethyl-benzoyl)-4-piperidinamine and 242 mg(1.54 mmol) of 4-quinolinecarboxaldehyde are dissolved in 30 ml of toluene and evaporated to dryness under reduced pressure. This is repeated twice more. The residue is taken up in 10 ml of ethanol, 70 mg (1.85 mmol) of sodium boranate are added and the mixture is stirred at 25° for 3 hours. It is acidified with 1N hydrochloric acid and left to stir for 1 hour. The reaction mixture is poured into saturated aqueous sodium carbonate solution and extracted with ethyl acetate. The organic phase is washed with saturated sodium chloride solution, dried over sodium sulfate and evaporated to dryness under reduced pressure. The crude product is recrystallised twice from ethyl acetate and yields 320 mg of the title compound of the formula ##STR110## in the form of white crystals; melting point 148°-9°; MS:M+497.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12](=[O:13])[C:11]([CH3:15])([CH3:14])[NH:10][C:9]2=[O:16])=[CH:4][C:3]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1.[Br:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[CH2:30]Br>>[Br:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[CH:25][C:24]=1[CH2:30][N:10]1[C:11]([CH3:15])([CH3:14])[C:12](=[O:13])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:17]3[S:18][CH:19]=[CH:20][CH:21]=3)[CH:4]=2)[C:9]1=[O:16]
Reactant: Fc1ccc(CBr)c(Br)c1
Reactant: CC1(C)NC(=O)N(c2ccc(F)c(-c3cccs3)c2)C1=O
Product: CC1(C)C(=O)N(c2ccc(F)c(-c3cccs3)c2)C(=O)N1Cc1ccc(F)cc1Br

Procedure:
Under conditions as described for the preparation of 1.2, compound 267.2 was reacted with 2-bromo-1-bromomethyl-4-fluorobenzene and afforded 267.1. Molecular weight 490.01 (C22H17BrF2N2O2S); retention time Rt=3.05 min. [E]; MS (ESI): 493.08 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:12]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=4)[NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:4][CH:3]=1>[Ni]>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:11]2[C:12]3[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][CH:21]=4)[NH:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(N4CCc5ccc(Cl)cc54)ncnc3[nH]2)cc1
Agent: [Ni]
Product: Nc1ccc(-c2cc3c(N4CCc5ccc(Cl)cc54)ncnc3[nH]2)cc1

Procedure:
This product is obtained in a manner analogous to that described in Example 7 by hydrogenation of 4-(6-chloro-2,3-dihydroindol-1-yl)-6-(4-nitro-phenyl)-7H-pyrrolo[2,3-d]-pyrimidine (Example 8) with Raney nickel.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:30]=1.[CH:31]1([C:36](Cl)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1.C(N(CC)CC)C>O1CCCC1>[CH:31]1([C:36]([NH:1][C:2]2[N:3]=[C:4]3[CH:9]=[CH:8][C:7]([O:10][C:11]4[CH:12]=[C:13]([NH:17][C:18](=[O:29])[C:19]5[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=5)[CH:14]=[CH:15][CH:16]=4)=[N:6][N:5]3[CH:30]=2)=[O:37])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: O=C(Cl)C1CCCC1
Reactant: Nc1cn2nc(Oc3cccc(NC(=O)c4cccc(C(F)(F)F)c4)c3)ccc2n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CCCC4)cn3n2)c1)c1cccc(C(F)(F)F)c1
Yield: 56.9 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(trifluoromethyl)benzamide (150 mg, 0.362 mmol), cyclopentanecarbonyl chloride (53 μL, 0.435 mmol), triethylamine (75 μL, 0.544 mmol) and tetrahydrofuran (5 mL) as starting materials and in the same manner as in Example 388, the title compound (105 mg, 57%) was obtained as a white powder.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][N:6]2[C:7](=[O:10])[C:8]=1[I:9].[C:15]([O-:18])(=[O:17])[CH3:16].[K+].O>CN(C=O)C>[C:15]([O:18][CH2:2][C:3]1[N:4]=[C:5]2[CH:14]=[CH:13][CH:12]=[CH:11][N:6]2[C:7](=[O:10])[C:8]=1[I:9])(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: O=c1c(I)c(CCl)nc2ccccn12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1nc2ccccn2c(=O)c1I
Temperature: 40 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
A mixture of 20.0 g (62.4 mmol) of the product from Step 2 (12) and 9.2 g (93.6 mmol) of potassium acetate in 200 mL DMF was stirred at 40° C. under nitrogen for three hours. The reaction mixture was allowed to cool to ambient temperature and the addition of excess water to the reaction solution caused the product to precipitate out of solution. The product was filtered, washed with water (3×), and drying under reduced pressure at 40° C. overnight yielded 19.4 g (56.4 mmol, 90%) of (3-iodo-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)methyl acetate (13) as a white solid.
Reaction SMILES: C(O)C.[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=1.Cl[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17]>C1(C)C=CC=CC=1>[CH3:4][O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]2[O:11][CH:15]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:8][CH:7]=1
Reactant: COc1ccc(C=O)cc1
Reactant: CCOC(=O)CCl
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)C1OC1c1ccc(OC)cc1
Temperature: 24 °C
Reaction time: 16 h

Procedure:
Ethanol free sodium ethoxide was mixed with 200 ml. of toluene and cooled to 0°C. A solution of p-methoxybenzaldehyde, 56.0 g. (0.412 mole), and ethyl chloroacetate, 50.5 g. (0.412 mole), in 200 ml. of toluene was added at such a rate that the temperature remained below 10°C. After stirring at 24°C. for 16 hours, the mixture was washed twice with 400 ml. portions of water and dried over anhydrous sodium sulfate. The solvent was evaporated to give a yellow liquid of about 80% purity (81.2 g.). The liquid solidified on standing at 5°C. and was further purified by washing with a small volume of cold ethanol to give pale yellow crystals of ethyl 3-(4-methoxyphenyl)-2,3-epoxypropionate having a melting point of between 40° and 43°C.
Reaction SMILES: [CH2:1]([C:9]1([O:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH2:13][C:12](=[O:14])[CH:11]=[CH:10]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(N(C(C)C)CC)(C)C.O1C=CC=C1C([O-])=O.O1C=CC=C1C([O-])=O.O1C=CC=C1C([O-])=O.C([B+3]CCCC)CCC.[C:62]([O:65][C@H:66]([C@H:71]([O:77][C:78]([O:81][CH3:82])([CH3:80])[CH3:79])[CH2:72][O:73][C:74](=[O:76])[CH3:75])[CH:67]=[CH:68][CH:69]=[O:70])(=[O:64])[CH3:63].[Cl-].[NH4+]>CCOCC.CCCCCC>[C:62]([O:65][C@H:66]([C@H:71]([O:77][C:78]([O:81][CH3:82])([CH3:80])[CH3:79])[CH2:72][O:73][C:74](=[O:76])[CH3:75])[CH:67]=[CH:68][CH:69]([CH:13]1[C:12](=[O:14])[CH:11]=[CH:10][C:9]1([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[O:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[OH:70])(=[O:64])[CH3:63]
Reactant: CCCCCCCCC1(O[Si](C)(C)C)C=CC(=O)C1
Reactant: COC(C)(C)O[C@H](COC(C)=O)[C@H](C=CC=O)OC(C)=O
Agent: O=C([O-])c1ccco1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCCCCCCCC1(O[Si](C)(C)C)C=CC(=O)C1C(O)C=C[C@H](OC(C)=O)[C@@H](COC(C)=O)OC(C)(C)OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
A solution composed of 1 g (3.55 mmoles) of 4-octyl-4-trimethylsilyloxy-2-cyclopentenone, 5 ml of dry hexane and 5 ml of dry ether was cooled to -78° C. under a nitrogen stream, and 870 microliters (5 mmoles) of diisopropylethylamine and then 4.6 ml (4.6 mmoles) of dibutylboron trifurate (lM CH2Cl2 solution) were added. The mixture was stirred at -78° C. for 1 hour. An ether solution (3 ml) of 1070 mg (3.55 mmoles) of (4S,5R)-4,6-diacetoxy-5-(1-methoxy-1-methylethyloxy)-2-hexenal was added, and the mixture was stirred for 2 hours. After the reaction, an aqueous solution of ammonium chloride was added to terminate the reaction, and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous potassium hydrogen sulfate solution, an aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution in this sequence, and dried over anhydrous magnesium sulfate solution. The solvent was evaporated under reduced pressure, and the resulting oily product was subjected to Florisil column chromatography (hexane:ethyl acetate: 5:1→3:1) to give 1.24 g (59%) of an aldol product.
Reaction SMILES: [CH3:1][N:2]1[C:9](=[O:10])[CH2:8][C:6](=[O:7])[N:5]([CH3:11])[C:3]1=[O:4].[C:12]12([C:22](O)=[O:23])[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:12]12([C:22]([CH:8]3[C:9](=[O:10])[N:2]([CH3:1])[C:3](=[O:4])[N:5]([CH3:11])[C:6]3=[O:7])=[O:23])[CH2:19][CH:18]3[CH2:17][CH:16]([CH2:15][CH:14]([CH2:20]3)[CH2:13]1)[CH2:21]2
Reactant: O=C(O)C12CC3CC(CC(C3)C1)C2
Reactant: CN1C(=O)CC(=O)N(C)C1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CN1C(=O)C(C(=O)C23CC4CC(CC(C4)C2)C3)C(=O)N(C)C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 69.6 %

Procedure:
A mixture of 1,3-dimethylbarbituric acid (5.00 g, 32.05 mmol), 1-adamantanecarboxylic acid (8.65 g, 48.03 mmol), 4-dimethylaminopyridine (1.95 g, 16.01 mmol) in dry CH2Cl2 (30 ml) was cooled to 0° C. and 1,3-dicyclohexylcarbodiimide (7.26 g, 35.22 mmol) added. The reaction mixture was stirred at room temperature overnight and filtered. The solid was washed with CH2Cl2 (150 ml) and the combined solution was washed with 2 N HCl solution (40 ml). The organic phase was dried over MgSO4 and evaporated. The residue was crystallized from MeOH giving 5-(1-adamantanecarbonyl)-1,3-dimethyl-2,4,6(1H,3H,5H)-pyrimidinetrione 12 (7.10 g, 69%).