Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[F:42].CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[F:42])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Fc1ccccc1CBr
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2ccccc2F)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.23 g), potassium carbonate (0.96 g), 1-(bromomethyl)-2-fluorobenzene (0.66 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (0.93 g, 59%).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[C:6]2[C:11](=[O:12])[N:10]3[CH2:13][CH2:14][N:15]([C:16]([C:18]4[C:19]([CH3:23])=[N:20][O:21][CH:22]=4)=[O:17])[C:9]3([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=3)[CH2:8][N:7]2[CH:32]=1)=[N+:2]=[N-:3].[C:33]([Si:35]([CH3:38])([CH3:37])[CH3:36])#[CH:34].C(N(C(C)C)C(C)C)C.[NH4+].[Cl-].N>CN(C=O)C.[Cu](I)I>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([C:9]23[N:15]([C:16]([C:18]4[C:19]([CH3:23])=[N:20][O:21][CH:22]=4)=[O:17])[CH2:14][CH2:13][N:10]2[C:11](=[O:12])[C:6]2[N:7]([CH:32]=[C:4]([N:1]4[CH:34]=[C:33]([Si:35]([CH3:38])([CH3:37])[CH3:36])[N:3]=[N:2]4)[CH:5]=2)[CH2:8]3)=[CH:25][CH:26]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(C23Cn4cc(N=[N+]=[N-])cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Agent: I[Cu]I
Agent: N
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C23Cn4cc(-n5cc([Si](C)(C)C)nn5)cc4C(=O)N2CCN3C(=O)c2conc2C)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 22.7 %

Procedure:
To a solution of 7-azido-10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (50 mg, 0.116 mmol) in DMF (2.5 mL) at 0° C. was added ethynyl-trimethyl-silane (33 μL, 0.23 mmol) followed by ethyl-diisopropyl-amine (24 μL, 0.14 mmol) and copper iodide (11 mg) and the mixture was stirred at 0° C. After one hour the reaction was complete (monitored by LCMS). A saturated aqueous solution of NH4Cl containing a drop of ammonia was added and the mixture extracted with EtOAc (3 times). The organics were washed with brine, dried (Na2SO4), filtrated and concentrated in vacuo. The resulting material was purified by flash chromatography (Biotage SP4, gradient 50-100% EtOAc in hexanes 10 CV; hold 100% EtOAc 7CV) to give 10a-(4-methoxyphenyl)-1-[(3-methyl-1,2-oxazol-4-yl)carbonyl]-7-[4-(trimethylsilyl)-1H-1,2,3-triazol-1-yl]-2,3,10,10a-tetrahydro-1H,5H-imidazo[1,2-a]pyrrolo[1,2-d]pyrazin-5-one (14 mg, yield: 23%). ESI-MI m/z [M+H]+ 532.2.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=4)=[CH:21][CH:20]=3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH:33]1C=CC2N(O)N=NC=2C=1.CO[C@@H](C)C(O)=O.C(N(C(C)C)CC)(C)C.C(Cl)CCl>C(Cl)Cl>[CH3:1][O:2][C@@H:3]([CH3:33])[C:4]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][N:27]=4)=[CH:21][CH:20]=3)=[N:16][CH:15]=[CH:14][N:13]=2)[CH2:10][CH2:11]1)=[O:5]
Reactant: COCC(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(C)cn3)cc2)CC1
Reactant: On1nnc2ccccc21
Agent: CO[C@@H](C)C(=O)O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CO[C@@H](C)C(=O)N1CCC(c2nccnc2Oc2ccc(Nc3ccc(C)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 5-methyl-N-(4-(3-(piperidin-4-yl)pyrazin-2-yloxy)phenyl)pyridin-2-amine (3.58 mL, 0.394 mmol) (See step 3, Example 282), HOBT (0.015 g, 0.099 mmol), (S)-2-methoxypropanoic acid (0.049 g, 0.473 mmol), diisopropylethylamine (0.364 mL, 2.090 mmol), and EDC (0.091 g, 0.473 mmol) in DCM (5 mL) was stirred at RT overnight. The reaction mixture was concentrated, then taken up in H2O. The solid was collected by filtration, air-dried and purified by ISCO column (75% EtOAc/Hexanes) to give the title compound. MS (ESI, pos. ion) m/z: 448.2 (M+1). IC50 (uM) 0.000335.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]([OH:14])=[O:13].N1C2C(=CC=CC=2)C(C(O[CH2:27][C:28]23[CH2:35][CH2:34][N:31]([CH2:32][CH2:33]2)[CH2:30][CH2:29]3)=O)=C1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[C:12]([O:14][CH2:27][C:28]12[CH2:35][CH2:34][N:31]([CH2:32][CH2:33]1)[CH2:30][CH2:29]2)=[O:13]
Reactant: O=C(OCC12CCN(CC1)CC2)c1c[nH]c2ccccc12
Reactant: COc1ccc2[nH]cc(C(=O)O)c2c1
Product: COc1ccc2[nH]cc(C(=O)OCC34CCN(CC3)CC4)c2c1

Procedure:
Quinuclidin-4-ylmethyl 5-methoxy-1H-indole-3-carboxylate was prepared starting from 5-methoxyindole-3-carboxylic acid (synthesized as described in J. Med. Chem. 49, 1125 (2006)) following the procedure of (Quinuclidin-4-yl)methyl 1H-indole-3-carboxylate. MS (m/e): 314.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([O:19]C)[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30]C)[CH:25]=1)=[O:22].B(Br)(Br)Br>>[OH:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([OH:19])[CH:14]=3)[CH:9]=2)[C:4]=1[C:21]([NH:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=1)=[O:22]
Reactant: COc1cccc(NC(=O)c2c(OC)ccc3cc(-c4cccc(OC)c4)ccc23)c1
Agent: BrB(Br)Br
Product: O=C(Nc1cccc(O)c1)c1c(O)ccc2cc(-c3cccc(O)c3)ccc12
Yield: 75 %

Procedure:
The compound is prepared by reaction of 2-methoxy-N,6-bis(3-methoxyphenyl)-1-naphthamide (150 mg, 0.36 mmol, 1 eq) with boron tribromide solution (2.9 ml, 2.9 mmol, 8 eq) according to method G. Purification by column chromatography with dichloromethane/methanol 93/7 as the eluent yielded the desired product in a yield of 75%, 100 mg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])[OH:9])=[C:4]([F:23])[CH:3]=1.C(=O)(O)[O-].[Na+].BrN1C(C)(C)C(=O)N(Br)C1=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(C)(C)C.CC1(C)N([O])C(C)(C)CCC1.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([O:17][CH2:18][CH3:19])[O:20][CH2:21][CH3:22])=[O:9])=[C:4]([F:23])[CH:3]=1
Reactant: CCOC(OCC)c1ccccc1C(O)c1ccc(Br)cc1F
Agent: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: CC1(C)CCCC(C)(C)N1[O]
Agent: O=C([O-])O
Solvent: CC(C)(C)O
Solvent: O
Product: CCOC(OCC)c1ccccc1C(=O)c1ccc(Br)cc1F
Yield: 102.3 %

Procedure:
(4-bromo-2-fluorophenyl)(2-(diethoxymethyl)phenyl)methanol (Compound 1a) (116 g) was dissolved in t-butanol (680 mL) with stirring and to the resulting solution was added water (1.4 ) followed by sodium bicarbonate (54.2 g). Using a water bath used to keep temperature around 20° C., 1,3-dibromo-5,5-dimethylhydantoin (48.3 g) and then TEMPO (0.51 g) was added and the cloudy yellow coloured suspension stirred at room temperature overnight. Saturated sodium bicarbonate (360 mL) and sodium thiosulfate (48 g in water) was added. The resulting mixture was stirred for 10 min then extracted with ethyl acetate, the extracts were washed with brine, dried over anhydrous sodium sulfate and evaporated to give the title product (118 g) as a dark yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[S:10])=[CH:4][CH:3]=1.CC(O)=O.Br.CS(C)=O>CCOC(C)=O>[NH2:11][C:9]1[S:10][C:6]2[CH:7]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N:8]=1
Reactant: Cc1ccc(NC(N)=S)cc1
Agent: Br
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc2nc(N)sc2c1
Temperature: 80 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
(4-Methylphenyl)thiourea (2 mmol) was added to AcOH (4 ml), and the suspension was heated to 80° C. To the solution formed was added 33% HBr in AcOH (4 mmol) followed by DMSO (2.1 mmol). After stirring at 80° C. for 1 h, the reaction mixture was cooled to 50° C., diluted with EtOAc (10 ml) and filtered. The product (as HBr-salt) was taken up in H2O (5 ml) and treated with 1M aq. NaHCO3 (2 ml). Stirring was continued for 0.2 h. The precipitated aminobenzothiazole was then filtered, washed with H2O (10 ml) and dried (16 h at 45° C./20 mb); yield 67%.
Reaction SMILES: FC1(F)CC1C[N:6]1CCN(C2SC(C(O)=O)=C(C)N=2)C1=O.[F:22][C:23]1([F:42])[CH2:25][CH:24]1[CH2:26][N:27]1[C:31](=[O:32])[N:30]([C:33]2[S:34][C:35]([C:39](O)=[O:40])=[C:36]([CH3:38])[N:37]=2)[CH:29]=[N:28]1.[Cl-].[NH4+]>>[F:22][C:23]1([F:42])[CH2:25][CH:24]1[CH2:26][N:27]1[C:31](=[O:32])[N:30]([C:33]2[S:34][C:35]([C:39]([NH2:6])=[O:40])=[C:36]([CH3:38])[N:37]=2)[CH:29]=[N:28]1
Reactant: Cc1nc(-n2cnn(CC3CC3(F)F)c2=O)sc1C(=O)O
Reactant: Cc1nc(N2CCN(CC3CC3(F)F)C2=O)sc1C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1nc(-n2cnn(CC3CC3(F)F)c2=O)sc1C(N)=O
Yield: 62 %

Procedure:
Following the procedure as describe in Example 16, making variations as required to replace 2-(3-((2,2-difluorocyclopropyl)methyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 2-(1-((2,2-difluorocyclopropyl)methyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid to react with ammonium chloride, the title compound was obtained as a colourless solid in 62% yield: mp 273-275° C.; 1H NMR (300 MHz, DMSO-d6) δ 8.74 (s, 1H), 7.60 (br, 2H), 4.02-3.79 (m, 2H), 2.52 (s, 3H), 2.20-2.05 (m, 1H), 1.72-1.60 (m, 1H), 1.48-1.37 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 163.1, 151.7, 151.4, 150.0, 132.4, 123.5, 114.4 (t), 42.7 (d), 20.8, 17.3, 14.9; MS (ES+) m/z 316.0 (M+1).
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.COC1C=CC(C(C2C=CC=CC=2)(C2C=CC=CC=2)[O:20][CH2:21][CH:22]([OH:41])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])=CC=1.O>CN(C)C=O>[C:4]1([CH2:3][O:41][CH:22]([CH2:21][OH:20])[CH2:23][O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH3:40])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COCCOCCOCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOCCOCCCCCCCCOCC(CO)OCc1ccccc1
Reaction time: 8 h

Procedure:
To a stirred suspension of 3.26 g of unwashed 50% sodium hydride and 10.9 g of benzyl bromide in 40 ml of dimethylformamide, under argon, was added a solution of 27.14 g of 20-[(4-methoxyphenyl)diphenylmethoxy]-2,5,8,17-tetraoxaeicosan-19-ol in 50 ml of dimethylformamide over 1/2 hour. This mixture was stirred overnight, water was then added and the mixture extracted with ether. The ether extract was washed with water, dried and the solvent removed. The residue was dissolved in hot methanol and stirred with 10 g of a strongly acidic ion exchange resin. This mixture was filtered and the solvent removed. The residue was purified by HPLC, eluting with hexane:ethyl acetate (65:35) giving the desired compound as 12.9 g of a light yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([O:8][CH3:9])[CH:7]=1.[C:13]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)(=[O:15])[CH3:14].C(=O)([O-])[O-].[Cs+].[Cs+].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>O1CCOCC1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[CH3:9][O:8][C:6]1[CH:7]=[CH:2][C:3]([N:19]2[CH2:20][CH2:21][N:16]([C:13](=[O:15])[CH3:14])[CH2:17][CH2:18]2)=[CH:4][C:5]=1[N+:10]([O-:12])=[O:11]
Reactant: CC(=O)N1CCNCC1
Reactant: COc1cc(Br)ccc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Solvent: C1COCCO1
Product: COc1ccc(N2CCN(C(C)=O)CC2)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 8 h
Yield: 88.5 %

Procedure:
To a solution of 5-bromo-1-methoxy-2-nitrobenzene (300 mg, 1.29 mmol) in dioxane, 1-acetyl piperazine (400 mg, 3.12 mmol), cesium carbonate (1.0 g, 3.07 mmol), palladium diacetate (29.0 mg, 0.129 mmol) and 2-(di-t-butylphosphino)biphenyl (77 mg, 0.258 mmol) are added and stirred at 100° C. for 8 hours. After cooling, the mixture is filtered to remove insoluble material. The filtrate is poured into water and extracted with ethyl acetate twice. The organic layer is washed with water and then brine, dried over magnesium sulfate, and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:ethyl acetate gradient) to afford 1-[4-(4-Methoxy-3-nitro-phenyl)-piperazin-1-yl]-ethanone (319 mg, 44%) as yellow solids.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:26])[CH2:16][CH:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[N:23][O:24][CH3:25])[C:12](=[O:27])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10].[Cl:28][CH2:29][CH2:30][N:31]=[C:32]=[O:33].C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:28][CH2:29][CH2:30][NH:31][C:32]([O:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:26])[CH2:16][CH:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[N:23][O:24][CH3:25])[C:12](=[O:27])[N:7]2[C:8]=1[C:9]([OH:11])=[O:10])=[O:33]
Reactant: CON=C1C=CC=CC1CC(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(CO)CS[C@H]12
Reactant: O=C=NCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CON=C1C=CC=CC1CC(=O)N[C@@H]1C(=O)N2C(C(=O)O)=C(COC(=O)NCCCl)CS[C@H]12
Yield: 35.4 %

Procedure:
A solution of 3-hydroxymethyl-7β-(2-methoxyiminophenylacetamido)ceph-3-em-4-carboxylic acid (synisomer) (0.35 g.), 2-chloroethylisocyanate (0.097 g.) and triethylamine (1.79 g.) in dimethylformamide (10 ml.) was stirred at room temperature for 2 hours. The reaction mixture was poured into saturated sodium bicarbonate solution, and the aqueous phase washed with ethyl acetate, acidified and extracted with ethyl acetate. The combined extracts were dried, concentrated to ca. 5 ml. and dropped dropwise with stirring to petroleum spirit (250 ml.). The resulting solid was filtered and dried to give the title acid (0.157 g., 35%) λmax (pH 6 buffer) 258 nm (ε 6,800), λmax (Nujol) 3250 (NH), 2600 and 1715 (CO2H), 1700 and 1530 (NHCO2R), 1660 and 1540 cm.-1 (CONH), τ (DMSO-d6) values include 0.22 (doublet J 9 Hz; 7β-NH), 2.3 to 2.6 (multiplet; aromatic protons), 6.05 (singlet; OCH3), 6.40 (multiplet; C-2 CH2 and --CH2Cl), 6.65 (multiplet; --NHCH2).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[CH:28]1[C:33]([C:34]([OH:36])=[O:35])=[CH:32][C:31]2[C:37]([O:39][C:40](=O)[C:30]=2[CH:29]=1)=[O:38]>>[CH3:9][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:10]2[O:11][C:12]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][C:22]5[O:25][CH2:26][O:27][C:21]=5[CH:20]=4)=[CH:15][C:13]=3[N:14]=2)=[CH:3][C:2]=1[N:1]1[C:37](=[O:38])[C:31]2[C:30](=[CH:29][CH:28]=[C:33]([C:34]([OH:36])=[O:35])[CH:32]=2)[C:40]1=[O:39]
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: COc1ccc(-c2nc3cc(-c4ccc5c(c4)OCO5)ccc3o2)cc1N
Product: COc1ccc(-c2nc3cc(-c4ccc5c(c4)OCO5)ccc3o2)cc1N1C(=O)c2ccc(C(=O)O)cc2C1=O

Procedure:
Prepared by the method of Example 15f), from 2-(3-amino-4-methoxyphenyl-5-[3,4-(methylenedioxy)phenyl]benzoxazole (120 mg, 0.33 mmol) and 1,2,4-benzenetricarboxylic anhydride (70 mg, 0.36 mmol) the title compound was obtained (82 mg, 46%). 1H NMR (DMSO) δ 8.45(dd, 1H), 8.37–8.32(m, 3H), 8.12(d, 1H), 7.96(d, 1H), 7.79(d, 1H), 7.63(dd, 1H), 7.49(d, 1H), 7.33(d, 1H), 7.20(dd, 1H), 7.02(d, 1H), 6.06(2H, s), 3.88(s, 3H). MS m/z 535.0 (M+H)+.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[CH:13][CH:14]=[C:15]2[CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])=[CH:10][CH:9]=1.[I:24]I.I>O.C(O)(=O)C>[I:24][C:13]1[CH:14]=[C:15]([CH2:18][CH2:19][NH:20][C:21](=[O:23])[CH3:22])[C:16]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([O:7][CH3:6])[CH:17]=2
Reactant: II
Reactant: COc1ccc2cccc(CCNC(C)=O)c2c1
Agent: I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: COc1ccc2cc(I)cc(CCNC(C)=O)c2c1
Temperature: 65 °C
Reaction time: 2 h

Procedure:
A solution is formed by adding 46.25 ml of glacial acetic acid and 1.25 ml of concentrated sulphuric acid to 2.5 ml of water. 2.5 g of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide (10.31 mmol) are dissolved in 30 ml of that solution. 2.09 g of iodine (8.25 mmol) and 0.91 g of HIO3 (5.16 mmol) are then added to the reaction mixture, causing a grey precipitate to appear in a solution that has turned red. The reaction mixture is heated for 15 hours at 65° C., 5.14 ml of concentrated hydriodic acid (13.41 mmol) are added and heating is continued for 2 hours. The suspension is then poured into 200 ml of water and the precipitate that forms is filtered off. The precipitate is dissolved in ethyl acetate and washed with 1M NaHCO3, the organic phase is then concentrated, and purified by chromatography on silica gel, using a dichloromethane/methanol mixture, 99.5/0.5, as eluant, to yield the title product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](Cl)=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1.[CH3:15][CH:16]([NH2:18])[CH3:17]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([NH:18][CH:16]([CH3:17])[CH3:15])=[C:8]([C:11]([NH2:13])=[O:12])[CH:7]=[N:6][N:5]2[CH:14]=1
Reactant: CC(C)N
Reactant: NC(=O)c1cnn2cc(Br)cc2c1Cl
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Yield: 95.4 %

Procedure:
A solution of 6-bromo-4-chloropyrrolo[1,2-b]pyridazine-3-carboxamide (Preparation 5, 865 mg, 3.15 mmol) and propan-2-amine (3.725 g, 63.0 mmol) in DMF (3 mL) was heated at 120° C. for 1 h. The reaction mixture was cooled to room temperature and diluted with water. The precipitated product was filtered, washed with water and dried in vacuo to obtain the title compound as a white solid (893 mg, 95% yield). HPLC (condition B): retention time=3.28 min. LCMS MH+ m/z 297.00. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.22 (1 H, s), 7.86 (1 H, d, J=1.76 Hz), 7.02 (1 H, d, J=1.76 Hz), 4.24-4.53 (1 H, m), 1.29 (6 H, d, J=6.16 Hz).
Reaction SMILES: [N:1]1[CH:2]=[N:3][N:4]2[C:9]=1[C:8]1[C:10]([C:13]#[N:14])=[CH:11][S:12][C:7]=1[N:6]=C2.CNCCN.[NH4+].[Cl-]>CO>[NH2:6][C:7]1[S:12][CH:11]=[C:10]([C:13]#[N:14])[C:8]=1[C:9]1[NH:1][CH:2]=[N:3][N:4]=1
Reactant: N#Cc1csc2ncn3ncnc3c12
Agent: CNCCN
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: N#Cc1csc(N)c1-c1nnc[nH]1
Temperature: 60 °C

Procedure:
Thieno[3,2-e][1,2,4]triazolo[1,5-c]pyrimidine-9-carbonitrile (251 mg, 1.25 mmol) was dissolved in MeOH (6.2 mL), and N1-methylethane-1,2-diamine (0.22 mL, 2.5 mmol) was added. This was heated to 60° C. for 20 min, then immediately cooled in an ice bath. Saturated NH4Cl (30 mL) was added, then the aqueous mixture was extracted with 10% iPrOH/CHCl3 (3×). The organic layers were combined, dried (MgSO4), filtered and concentrated under reduced pressure to give the titled compound as a single peak on LC/MS: method [4], retention time=0.658 min; MS (ESI) 192.0 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[CH2:15]3)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[N:22]1([CH2:27][CH2:28][O:29][C:30]2[CH:31]=[C:32]3[C:36](=[CH:37][CH:38]=2)[NH:35][C:34]([CH:39]=O)=[CH:33]3)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][S:9]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][C:16](=[O:21])[C:15]3=[CH:39][C:34]2[NH:35][C:36]3[C:32]([CH:33]=2)=[CH:31][C:30]([O:29][CH2:28][CH2:27][N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:38][CH:37]=3)(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3cccc(Cl)c3)ccc2N1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Product: O=C1Nc2ccc(S(=O)(=O)Nc3cccc(Cl)c3)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid (3-chloro-phenyl)-amide was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.OCC1CCN(CC2C=CC=CC=2)C1.C([O:33][C@H:34]1[CH2:38][N:37]([C:39](=[O:60])[CH2:40][C:41]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@H:36]([C:61]([N:63]2[CH2:67][CH2:66][CH2:65][C@@H:64]2[C:68](O)=[O:69])=[O:62])[CH2:35]1)(C)(C)C>>[OH:33][C@H:34]1[CH2:38][N:37]([C:39](=[O:60])[CH2:40][C:41]([C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C@H:36]([C:61]([N:63]2[CH2:67][CH2:66][CH2:65][C@@H:64]2[C:68]([NH:1][CH2:2][CH:3]2[CH2:7][CH2:6][NH:5][CH2:4]2)=[O:69])=[O:62])[CH2:35]1
Reactant: CC(C)(C)O[C@@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)O)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)C1
Agent: OCC1CCN(Cc2ccccc2)C1
Product: O=C(NCC1CCNC1)[C@H]1CCCN1C(=O)[C@@H]1C[C@@H](O)CN1C(=O)CC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared by successively conducting procedures similar to Step 5 of Example 1 and Example 46, using 3-aminomethyl-1-(t-butoxycarbonyl)pyrrolidine [which was synthesized by a method similar to the one described in Japan Kokai Hei 11(1999)-193232, using 3-hydroxymethyl-1-benzylpyrrolidine [taught in Japan Kokai (laid-open) Hei 4(1992)-112868]] and (2R)-1-{(2S,4R)-4-(tert-butoxy)-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonyl-pyrrolidine-2-carboxylic acid.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=3)[N:15]=[CH:14][C:13]2=[O:23])[CH2:6][CH2:5]1.O=[C:25]1[CH2:30][O:29][C:28]2[CH:31]=[CH:32][C:33]([CH:35]=O)=[N:34][C:27]=2N1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>CO.C(N(CC)CC)C.C(Cl)(Cl)Cl>[ClH:1].[ClH:1].[O:29]1[C:28]2=[CH:27][N:34]=[C:33]([CH2:35][NH:3][CH:4]3[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][N:12]4[C:21]5[C:16](=[CH:17][CH:18]=[C:19]([F:22])[CH:20]=5)[N:15]=[CH:14][C:13]4=[O:23])[CH2:8][CH2:9]3)[CH:32]=[C:31]2[CH2:25][CH2:30]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: NC1CCN(CCn2c(=O)cnc3ccc(F)cc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=c1cnc2ccc(F)cc2n1CCN1CCC(NCc2cc3c(cn2)OCC3)CC1
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 91 %

Procedure:
A solution of 1-[2-(4-amino-1-piperidinyl)ethyl]-7-fluoro-2(1H)-quinoxalinone dihydrochloride (60 mg; 0.166 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carboxaldehyde (for a synthesis see WO2003087098, Example 31(e))(35 mg, 0.20 mmol) in MeOH (3 ml), chloroform (3 ml) and triethylamine (0.06 ml) was heated under reflux with 3A molecular sieves overnight. It was cooled and sodium triacetoxyborohydride (0.11 g; 0.52 mmol) was added, and the mixture was stirred at rt for 7-8 h. Aqueous sodium bicarbonate solution was added to basify and the aqueous phase was extracted several times with 10% MeOH-DCM. The organic fractions were dried and evaporated. Chromatography on silica gel, eluting with 0-20% MeOH-DCM gave the free base of the title compound (68 mg, 91%).