Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]3[C:15]([N:32]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])C(=O)OC(C)(C)C)=[N:16][CH:17]=[C:18]([C:20]4[CH:25]=[CH:24][C:23]([S:26]([CH:29]([CH3:31])[CH3:30])(=[O:28])=[O:27])=[CH:22][N:21]=4)[CH:19]=3)[O:11][N:10]=2)=[CH:5][CH:4]=1.C(O)C.[CH3:50][NH2:51]>C(Cl)Cl>[CH:29]([S:26]([C:23]1[CH:24]=[CH:25][C:20]([C:18]2[CH:19]=[C:14]([C:12]3[O:11][N:10]=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][NH:51][CH3:50])=[CH:4][CH:5]=4)[CH:13]=3)[C:15]([NH:32][C:40](=[O:41])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[N:16][CH:17]=2)=[N:21][CH:22]=1)(=[O:27])=[O:28])([CH3:31])[CH3:30]
Reactant: CC(C)S(=O)(=O)c1ccc(-c2cnc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(-c3cc(-c4ccc(CBr)cc4)no3)c2)nc1
Reactant: CN
Solvent: ClCCl
Solvent: CCO
Product: CNCc1ccc(-c2cc(-c3cc(-c4ccc(S(=O)(=O)C(C)C)cn4)cnc3NC(=O)OC(C)(C)C)on2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 48.4 %

Procedure:
tert-Butyl N-[3-[3-[4-(bromomethyl)phenyl]isoxazol-5-yl]-5-(5-isopropylsulfonyl-2-pyridyl)-2-pyridyl]-N-tert-butoxycarbonyl-carbamate (275.5 mg, 0.3861 mmol) was taken into ethanol (1 mL)/DCM (1 mL) and this solution added to stirred methylamine (3.634 g, 38.61 mmol) in an sealed tube. The reaction was stirred at ambient temperature for 2 hours. The reaction mixture was diluted with DCM and washed with saturated aqueous NaHCO3/brine (1:1, ×2), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (ISCO Companion™, 24 g column, eluting with 0 to 10% MeOH/DCM, loaded in DCM) to give the sub-title product as a beige solid (105.4 mg, 48% Yield). 1H NMR (400.0 MHz, DMSO) δ 1.23 (d, 6H), 1.32 (s, 9H), 2.30 (s, 3H), 3.62 (sept, 1H), 3.72 (s, 2H), 7.46 (s, 1H), 7.50 (d, 2H), 7.87 (d, 2H), 8.40 (dd, 1H), 8.49 (d, 1H), 8.91 (d, 1H), 9.11 (d, 1H), 9.28 (d, 1H) and 10.06 (br s, 1H) ppm; MS (ES+) 564.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[C:12]([OH:14])=[O:13].CC1(C)COB([C:22]2[CH:29]=[CH:28][C:27]([C:30]3([OH:34])[CH2:33][CH2:32][CH2:31]3)=[CH:26][C:23]=2[C:24]#[N:25])OC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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:11][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:12]([OH:14])=[O:13])=[CH:6][NH:7]2)=[CH:3][C:2]=1[C:22]1[CH:29]=[CH:28][C:27]([C:30]2([OH:34])[CH2:31][CH2:32][CH2:33]2)=[CH:26][C:23]=1[C:24]#[N:25]
Reactant: O=C(O)c1c[nH]c2cc(Cl)c(Br)cc12
Reactant: CC1(C)COB(c2ccc(C3(O)CCC3)cc2C#N)OC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCO
Product: N#Cc1cc(C2(O)CCC2)ccc1-c1cc2c(C(=O)O)c[nH]c2cc1Cl
Temperature: 85 °C

Procedure:
A suspension of 5-bromo-6-chloro-1H-indole-3-carboxylic acid (100 mg, 0.54 mmol), 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-(1-hydroxycyclobutyl)benzonitrile (124 mg, 0.435 mmol), 0.5M aqueous potassium phosphate (1.74 mL, 0.87 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (11 mg, 0.014 mmol) in ethanol (4 mL) was sealed in a microwave tube and heated to 85° C. for 45 minutes. The reaction was diluted with water and extracted with ethyl acetate (2×10 mL). The reaction mixture was filtered through celite and the phases were separated. The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo and the residue was purified by reverse phase chromatography to give the title compound. MS (ES−) 365.1 (M−H)−. Retention time: 1.60 min. Column: Waters Atlantis dC18 4.6×50 mm, 5 μm. Modifier: TFA 0.05%. Gradient: 95% H2O/5% MeCN linear to 5% H2O/95% MeCN over 4.0 min, HOLD at 5% H2O/95% MeCN to 5.0 min. Flow: 2.0 mL/min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)=[CH:19][C:18]=1[CH3:32]>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=3)=[CH:19][C:18]=2[CH3:32])=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1coc(-c2ccc(N)c(C)c2)n1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)co3)cc2C)nc1Cl
Yield: 50.3 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.12 g, 0.69 mmol), thionyl chloride (4 mL), methyl 4-amino-3-methylphenyl)-1,3-oxazole-4-carboxylate obtained in Example (109e) (0.23 g, 0.95 mmol) and pyridine (5 mL), to obtain 135 mg of the title compound as a light brown solid (50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:11]3[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:25][C:26]1[CH:27]=[C:28]([S:32]([NH:35][C:36]([CH3:40])([CH3:39])[CH2:37][OH:38])(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[OH:38][CH2:37][C:36]([NH:35][S:32]([C:28]1[CH:27]=[C:26]([NH:25][C:22]([C:21]2[CH:20]=[N:19][N:12]3[C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)=[N:10][C:11]=23)=[O:24])[CH:31]=[CH:30][CH:29]=1)(=[O:34])=[O:33])([CH3:40])[CH3:39]
Reactant: CC(C)(CO)NS(=O)(=O)c1cccc(N)c1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(Cl)c3)nc12
Product: CC(C)(CO)NS(=O)(=O)c1cccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)c(Cl)c4)nc23)c1

Procedure:
The title compound was prepared from 5-(3,4-dichloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.9) and 3-amino-N-(2-hydroxy-1,1-dimethyl-ethyl)-benzenesulfonamide (example B.8) according to general procedure II. Light yellow solid. MS (ISP) 599.8 [(M−H−]; mp 269° C.
Reaction SMILES: [N+](C1C=CC=CC=1O[C:11](=[O:35])[C@@H:12]([CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26])[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])([O-])=O.[C:36]([NH2:45])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([CH3:38])[CH3:37]>C(Cl)Cl>[C:14]([NH:13][C@@H:12]([C:11]([NH:45][C:36]([CH3:38])([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:37])=[O:35])[CH2:21][CH2:22][CH2:23][NH:24][C:25]([O:27][CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:26])([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15]
Reactant: CC(C)(N)c1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)Oc1ccccc1[N+](=O)[O-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)NC(C)(C)c1ccccc1
Yield: 109.7 %

Procedure:
Prepared according to the method described in Example 4(b) above from Nα -Boc-Nδ -Cbz-(R)-ornithine o-nitrophenyl ester (5.0 g; 11.5 mmol; see Example 4(a) above) and cumylamine (1.55 g; 11.5 mmol) and 160 mL of CH2Cl2. The reaction mixture was heated to reflux for 2 hours. The mixture was concentrated to dryness and dissolved in EtOAc and washed with saturated aqueous KHSO4 and brine, dried with Na2SO4, filtered and concentrated to give 6.1 g of the sub-title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH:9]2[CH2:11][CH2:10]2)[C:4](=[O:12])[CH:3]=1.[N:13]([O-])=[O:14].[Na+]>CC(O)=O>[NH2:1][C:2]1[NH:7][C:6](=[O:8])[N:5]([CH:9]2[CH2:10][CH2:11]2)[C:4](=[O:12])[C:3]=1[N:13]=[O:14]
Reactant: O=N[O-]
Reactant: Nc1cc(=O)n(C2CC2)c(=O)[nH]1
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1[nH]c(=O)n(C2CC2)c(=O)c1N=O
Reaction time: 1 h

Procedure:
To a solution of 6-Amino-3-cyclopropyl-1H-pyrimidine-2,4-dione (5.0 g, 29.9 mmol, 1 eq) in 50% aq AcOH (10 ml) was added NaNO2 (4.13 g, 59.8 mmol, 2 eq) in small portions over a period of 10 min. The mixture was stirred for 1 hr. The purple precipitate was collected by filtration and washed with cold water to give 4.75 g, 81%, m/z (ES+) 197.17), which was used in the following step.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH2:8](O)[CH:9]=[CH2:10].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.N1CCCC1C(O)=O>CS(C)=O.[CH2-]C=C.[CH2-]C=C.Cl[Pd+].Cl[Pd+]>[CH2:10]([CH:3]1[C:4](=[O:7])[CH2:5][CH2:6][O:1][CH2:2]1)[CH:9]=[CH2:8]
Reactant: O=C1CCOCC1
Reactant: C=CCO
Agent: Cl[Pd+]
Agent: C=C[CH2-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: CS(C)=O
Product: C=CCC1COCCC1=O
Temperature: 70 °C

Procedure:
A mixture of tetrahydro-4H-pyran-4-one (6-1) (5.17 g, 51.7 mmol), prop-2-en-1-ol (1.00 g, 17.2 mmol), allylPalladium Chloride dimer (0.157 g, 0.430 mmol), Xantphos (0.498 g, 0.861 mmol), and DL-proline (0.595 g, 5.17 mmol) in DMSO (35 mL) was degassed (2×pump/N2) and heated to 70° C. overnight. The mixture was cooled to rt and partitioned between water and Et2O. Extracted with Et2O. The combined organics were washed with 1:1 brine:water, dried (anhd. Na2SO4), filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (500 MHz, CDCl3) δ 5.70-5.80 (m, 1H), 5.01-5.09 (m, 2H), 4.13-4.22 (m, 2H), 3.72-3.79 (m, 1H), 3.43 (t, 1H, J=11.2 Hz), 2.52-2.66 (m, 3H), 2.39-2.47 (m, 1H), 1.99-2.07 (m, 1H).
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[OH:22])[CH3:2].[H-].[Na+].[CH2:25](Br)[CH:26]=[CH2:27].Cl>C1(C)C(C)=CC=CC=1>[C:26]([O:22][CH:4]1[C@:3]2([CH2:1][CH3:2])[C@H:7]([C@@H:8]3[CH2:19][CH2:18][C:17]4[CH:16]=[C:15]([O:20][CH3:21])[CH:14]=[CH:13][C:12]=4[C@H:9]3[CH2:10][CH2:11]2)[CH2:6][CH2:5]1)(=[CH2:25])[CH3:27]
Reactant: C=CCBr
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: C=C(C)OC1CC[C@H]2[C@@H]3CCc4cc(OC)ccc4[C@H]3CC[C@]12CC

Procedure:
Reflux a suspension of 5.0 g. of dl-13-ethyl-3-methoxygona-1,3,5(10)-triene-17β-ol, 100 mg. of xylene, and 3.9 g. of sodium hydride (50% in mineral oil) for 1.5 hours. Add 14.5 ml. of allyl bromide and reflux for 22 hours. Make the reaction mixture acidic with dilute hydrochloric acid and extract the organic layer with sodium bicarbonate solution. Chromatograph the residue on alumina (Grade I neutral) in hexane and eluate the product with ether to obtain dl-17β-allyloxy-13-ethyl-3-methoxygona-1,3,5(10)-triene.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:16][N:15]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.O.NN>CO.[Fe](Cl)(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([C:11]2[CH2:16][N:15]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:13][CH:12]=2)[CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: CCCN1CCC=C(c2ccc([N+](=O)[O-])c(C)c2)C1
Agent: Cl[Fe](Cl)Cl
Agent: NN
Solvent: O
Solvent: CO
Product: CCCN1CCC=C(c2ccc(N)c(C)c2)C1
Temperature: 64 °C
Reaction time: 5 h
Yield: 81.4 %

Procedure:
To 5-(3-methyl-4-nitrophenyl)-1-propyl-1,2,3,6-tetrahydropyridine (5.0 g, 19.2 mmol) in MeOH (100 mL) was added iron (III) chloride (0.93 g, 5.8 mmol, Aldrich) and activated carbon (1.0 g, Aldrich). The reaction mixture was stirred at 64° C. for 20 min before the dropwise addition of hydrazine hydrate (11.5 mL, 230.8 mmol, Aldrich) over 5 min. The reaction was kept stirring at 64° C. for additional 5 h. Filtration removed the solids and the filtrate was concentrated and purified via chromatography on SiO2 (0-10% 2 M NH3 in MeOH/DCM) to afford 2-methyl-4-(1-propyl-1,2,5,6-tetrahydro-3-pyridinyl)aniline (3.6 g, 82% yield.) 1H NMR (400 MHz, CDCl3) δ ppm 0.94 (t, J=7.4 Hz, 3 H), 1.57-1.67 (m, 2 H), 2.16 (s, 3 H), 2.33 (tt, J=5.9, 2.9 Hz, 2 H), 2.44-2.50 (m, 2 H), 2.59 (t, J=5.8 Hz, 2 H), 3.29 (q, J=2.0 Hz, 2 H), 3.58 (s, 2 H), 5.96 (dq, J=3.9, 2.0 Hz, 1 H), 6.61 (d, J=7.9 Hz, 1 H), 7.02-7.06 (m, 2 H).
Reaction SMILES: [Si:1]([C:8]#[CH:9])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].FC(F)(F)S(O[C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][C:17]=1[Cl:28])(=O)=O.C(N(CC)CC)C>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[C:4]([Si:1]([C:8]#[C:9][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][C:17]=1[Cl:28])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: O=S(=O)(Oc1ccc(-c2ccccc2)cc1Cl)C(F)(F)F
Reactant: C#C[Si](C)(C)C(C)(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)C#Cc1ccc(-c2ccccc2)cc1Cl

Procedure:
0.84 g (1.2 mmol) of bis-(triphenylphosphine)palladium (II) chloride, 0.23 g (1.2 mmol) of copper (I) iodide, and 6.28 mL (33.6 mmol) of (tert-butyldimethylsilyl)acetylene is added under an argon atmosphere to a solution of 8.1 g (24 mmol) of 3-chlorobiphenyl-4-yl trifluoromethanesulfonate in 50 mL of absolute DMF and 13.31 mL (96 mmol) of triethylamine.
Reaction SMILES: CS(O[C@@H:6]1[CH2:11][CH2:10][O:9][CH2:8][C@H:7]1[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=O)=O.[N-:20]=[N+:21]=[N-:22].[Na+].C([O-])(=O)C.[Na+]>CN(C=O)C>[N:20]([C@H:6]1[CH2:11][CH2:10][O:9][CH2:8][C@H:7]1[NH:12][C:13](=[O:14])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[N+:21]=[N-:22]
Reactant: CC(C)(C)OC(=O)N[C@@H]1COCC[C@H]1OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1COCC[C@@H]1N=[N+]=[N-]
Temperature: 95 °C
Yield: 99.7 %

Procedure:
(3R,4R)-3-((tert-butoxycarbonyl)amino)tetrahydro-2H-pyran-4-yl methanesulfonate (2.2 g, 7.45 mmol), sodium azide (0.968 g, 14.90 mmol) and sodium acetate (1.222 g, 14.90 mmol) were taken up in DMF (15 ml). The reaction mixture was heated to 95° C. overnight. The reaction mixture was removed from heat and 20 ml of water was added and stirred while cooling. The reaction mixture was extracted with EtOAc. The organic layers were combined and washed with water. The organics were dried and solvent removed to give tert-butyl ((3S,4S)-4-azidotetrahydro-2H-pyran-3-yl)carbamate (1.8 g, 7.43 mmol, 100% yield) as a yellow oil. MS (ES+) C10H18N4O3 requires: 242, found: 265 [M+Na]+.
Reaction SMILES: [NH2:1][C:2](=[O:36])[C@@H:3]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](B2OC(C)(C)C(C)(C)O2)=[CH:7][CH:6]=1.Br[C:38]1[CH:39]=[CH:40][C:41]([C:44]#[N:45])=[N:42][CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[NH2:1][C:2](=[O:36])[C@@H:3]([NH:20][C:21]([C@@H:23]1[CH2:28][CH2:27][CH2:26][CH2:25][N:24]1[C:29]([O:31][C:32]([CH3:33])([CH3:35])[CH3:34])=[O:30])=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:38]2[CH:43]=[N:42][C:41]([C:44]#[N:45])=[CH:40][CH:39]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(N)=O
Reactant: N#Cc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccc(C#N)nc2)cc1)C(N)=O
Reaction time: 0.17 h
Yield: 79.1 %

Procedure:
A solution of (S)-tert-butyl 2-((S)-1-amino-1-oxo-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propan-2-ylcarbamoyl)piperidine-1-carboxylate (0.150 g) in dioxane (1 mL) was added to a stirred solution of 5-bromopicolinonitrile (0.055 g) and bis[bis(1,2-diphenylphosphino)ethane]palladium (0) (0.003 g) in dioxane (1 mL) under nitrogen. The resulting mixture was stirred for 10 min. A solution of potassium carbonate (0.124 g) in water (0.75 mL) was added and the resulting solution was stirred at 75° C. for 16 h. The cooled mixture was evaporated to dryness. The residue was taken up in ethyl acetate and washed with saturated brine, dried over sodium sulfate and adsorbed onto silica. The crude product was purified by flash silica chromatography, eluting with 3:1 ethyl acetate/isohexane). Pure fractions were evaporated to dryness to afford the subtitle compound (0.113 g).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17]C(=O)C)=[CH:13][CH:12]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.[OH-].[NH4+]>B(F)(F)F.CO>[Cl:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(OCc2nc(Cl)ccc2Cl)cc1
Agent: FB(F)F
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(OCc2nc(Cl)ccc2Cl)cc1
Temperature: 0 °C

Procedure:
N-(4-((3,6-Dichloro-2-pyridinyl)methoxy)phenyl)acetamide (30.27 grams; 0.097 mole) was mixed with a 270 ml. solution of boron trifluoride-methanol (1 gram per 10 ml.) and the resulting reaction mixture refluxed for a period of 41/2 hours. The reaction mixture was then diluted and cooled with ice water to a temperature of between about 0° to about 10° C. Concentrated ammonium hydroxide was added until the reaction mixture was basic. The reaction mixture was then extracted with portions of methylene chloride, the extracts combined and the solvent removed by evaporation. The residue thus obtained was extracted with five 500 ml. portions of hexane. The crystalline material which precipitated from the hexane mixture upon cooling was recovered by filtration. As a result of these operations, the desired 4-((3,6-dichloro-2-pyridinyl)methoxy)benzenamine compound was recovered as a light yellow crystalline solid having a melting point of 74° -75° C.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:11]2([CH2:15][CH2:14][NH:13][CH2:12]2)[CH2:10][CH:9]1[NH:16][C:17]([O:19][CH2:20][C:21]1[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=1)=[O:18].F[C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=2)=[CH:34][N:33]=1.C(N(CC)C(C)C)(C)C>>[F:44][C:41]1[CH:40]=[CH:39][C:38]([C:35]2[CH:36]=[CH:37][C:32]([N:13]3[CH2:14][CH2:15][C:11]4([CH2:10][CH:9]([NH:16][C:17]([O:19][CH2:20][C:21]5[O:25][N:24]=[C:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH:22]=5)=[O:18])[CH2:8]4)[CH2:12]3)=[N:33][CH:34]=2)=[CH:43][CH:42]=1
Reactant: Fc1ccc(-c2ccc(F)nc2)cc1
Reactant: CCOC(=O)c1cc(COC(=O)NC2CC3(CCNC3)C2)on1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(COC(=O)NC2CC3(CCN(c4ccc(-c5ccc(F)cc5)cn4)C3)C2)on1
Yield: 19.4 %

Procedure:
The process is performed according to the procedure described in Example 1 (step 1.3.). Starting with 0.45 g (1.04 mmol) of ethyl 5-(6-azaspiro[3.4]oct-2-ylcarbamoyloxymethyl)isoxazole-3-carboxylate trifluoroacetate, described in step 6.6., 0.198 g (1.04 mmol) of 2-fluoro-5-(4-fluorophenyl)pyridine, prepared in step 6.7. and 0.40 g (3.12 mmol) of N,N-diisopropylethylamine, and after purification by chromatography on preparative plates, eluting with a 96/4 mixture of dichloromethane and methanol, 0.10 g of pure product is obtained in the form of a wax, which is used without further purification in the following step.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[S:8][C:9]3([C:15](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]OC3=O>C(O)C.O>[CH3:1][C:2]1[C:7]2[S:8][C:9]3([C:15](=[O:16])[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]3
Reactant: Cc1cccc2c1SC1(CCOC1=O)C2=O
Solvent: CCO
Solvent: O
Product: Cc1cccc2c1SC1(CC1)C2=O

Procedure:
7-Methylspiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one was prepared by a similar procedure to that of Example 8 except for the use of 7-methyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]-3,2'-dione obtained in Reference Example 11. Pale yellow needles [from C2H5OH--H2O (1:1)], mp 74°-75° C. Anal. Calcd. for C11H10OS: C, 69.44; H, 5.30. Found: C, 69.32; H, 5.07.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:15]2[N:14]3[CH:16]=[CH:17][N:18]=[C:13]3[C:12](=[O:19])[NH:11][C:10]=2[C:9]2[CH:8]=[C:7]([Cl:20])[CH:6]=[CH:5][C:4]1=2.C(N(CC)CC)C.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CS(C)=O.CN(C)C=O>[Cl:20][C:7]1[CH:6]=[CH:5][C:4]2[CH:3]([NH:2][C:35]([NH:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[O:36])[C:15]3[N:14]4[CH:16]=[CH:17][N:18]=[C:13]4[C:12](=[O:19])[NH:11][C:10]=3[C:9]=2[CH:8]=1
Reactant: NC1c2ccc(Cl)cc2-c2[nH]c(=O)c3nccn3c21
Reactant: O=C=Nc1ccccc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)NC1c2ccc(Cl)cc2-c2[nH]c(=O)c3nccn3c21
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To 0.5 g of 10-amino-7-chloro-5H,10H-imidazo-[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride suspended in 8 ml of dimethyl sulphoxide is added dropwise 0.45 ml of triethylamine, followed by a solution of 0.9 ml of phenyl isocyanate in 2 ml of dimethylformamide. The reaction medium is stirred for 2 hours at a temperature in the region of 20° C. and the precipitate formed is filtered off, washed with water and dried under reduced pressure (1 mmHg; 0.13 kPa) at 50° C. 0.15 g of 7-chloro-10-(3-phenylureido)-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one is thus obtained, in the form of a white solid the melting point of which is greater than 260° C. (Analysis C20H14ClN5O2 ·0.6 DMF·0.8 H2O % calculated C: 61.31; H: 3.60; Cl: 9.05; N: 17.87; % found C: 61.1; H: 3.5; Cl: 9.4; N: 17.7).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23]CC2C=CC=CC=2)=[CH:12][CH:11]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:32])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:31])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][OH:23])=[CH:14][CH:15]=1
Reactant: COC(=O)CCCCCOc1ccc(NC(=O)CCCCCOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCOc1ccc(NC(=O)CCCCCO)cc1
Reaction time: 20 h
Yield: 62.8 %

Procedure:
6-[4-(6-Benzyloxyhexanoylamino)-phenoxy]-hexanoic acid methyl ester 61 (10 g, 22.67 mmol) was dissolved in methanol (100 ml) in a pressure vessel. Palladium on carbon (5%, 6 grm) was added and the mixture stirred under a hydrogen atmosphere (4 kg) for 20 hrs. The catalyst was removed by filtration, and methanol distilled off. Crude 62 was purified by column chromatography on silica gel using chloroform as eluant to give pure 62 (5 g, 62.8%) as a white powder with a m.p. between 73-75.5° C.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7](Cl)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21]([CH3:43])[C:22]2[O:28][C:27]3[C:29]([Cl:39])=[CH:30][C:31]([N:33]4[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]4)=[CH:32][C:26]=3[CH2:25][S:24](=[O:41])(=[O:40])[C:23]=2[CH:42]=1)=[O:18]>CN(C=O)C>[CH3:15][O:16][C:17]([C:19]1[CH:20]=[C:21]([CH3:43])[C:22]2[O:28][C:27]3[C:29]([Cl:39])=[CH:30][C:31]([N:33]4[CH2:34][CH2:35][N:36]([CH2:7][C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[CH2:37][CH2:38]4)=[CH:32][C:26]=3[CH2:25][S:24](=[O:40])(=[O:41])[C:23]=2[CH:42]=1)=[O:18]
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCNCC3)cc(Cl)c1O2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(N3CCN(Cc4ccccc4)CC3)cc(Cl)c1O2
Temperature: 80 °C

Procedure:
A mixture of cesium carbonate (0.33 g, 0.82 mmol) and benzyl chloride (0.1 mL, 0.82 mmol) was added to a solution of 4-chloro-6-methyl-10,10-dioxo-2-piperazin-1-yl-10,11-dihydro-5-oxa-10lambda*6*-thia-dibenzo[a,d]cyclo heptene-8-carboxylic acid methyl ester (free base of example 16, 0.3 g, 0.68 mmol) in DMF (10 mL) and heated at 80° C. for 5 h. Reaction mixture was concentrated, water (10 mL) was added and the solid filtered. The crude obtained was purified by column chromatography (silica gel, 1% to 3% methanol in chloroform) to obtain the title compound. Yield: 0.11 g, (30.4%); 1H NMR (DMSO-d6, 300 MHz): δ 2.62 (s, 3H, CH3), 3.18 (s, 4H, 2CH2), 3.31 (s, 4H, 2CH2), 3.50 (s, 2H, CH2), 3.85 (s, 3H, OCH3), 5.14 (s, 2H, CH2), 7.04 (s, 1H, Ar), 7.11 (s, 1H, Ar), 7.3-7.32 (m, 5H, Ar), 8.08 (s, 1H, Ar), 8.14 (s, 1H, Ar); MS: m/e (ES+) 528 (M+1); analysis: C27H27ClN2O5S requires C, 61.53; H, 5.16; N, 5.32; Cl, 6.73; S, 6.08. found: C, 61.22; H, 4.99; N, 4.82; Cl, 6.91; S, 6.15%.