Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:14](=[N:15]O)[CH2:13][CH2:12][N:11]([CH3:17])[CH2:10]2)=[CH:5][CH:4]=1>[Ni]>[NH2:15][CH:14]1[CH2:13][CH2:12][N:11]([CH3:17])[CH2:10][CH:9]1[C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(C2CN(C)CCC2=NO)cc1
Agent: [Ni]
Product: COc1ccc(C2CN(C)CCC2N)cc1

Procedure:
Cis-8-methoxy-2-methyl-6-phenyl-1,2,3,4,4a,10b-hexahydrobenzo[c][1,6]naphthyridine is obtained by addition of 3-amino-2-p-methoxyphenylpropionic acid ethyl ester to acrylic acid ethyl ester, reductive methylation of 2-p-methoxyphenyl-3,3'-iminodipropionic acid diethyl ester (M.P. of the hydrogen oxalate 152°) with formaldehyde to obtain 2-p-methoxymethyl-N-methyl-3,3'-iminodipropionic acid diethyl ester, reaction of the latter compound to obtain 3-carbethoxy-5-(p-methoxyphenyl)-1-methyl-4-piperidone (M.P. of the hydrochloride 180°-182°), which is converted by hydrolysis and subsequent decarboxylation into 3-p-methoxyphenyl-1-methyl-4-piperidone (M.P. of the hydrogen oxalate 137°-138°). The resulting piperidone is reacted with hydroxylamine to obtain 3-p-methoxyphenyl-1-methyl-4-piperidone oxime (M.P. 121°-122°), the oxime is hydrogenated with Raney nickel to obtain 4-amino-3-p-methoxyphenyl-1-methyl-piperidine (mixture of the two diastereoisomers), the amino compound is treated with benzoyl chloride, cis-4-benzoylamino-3-p-methoxyphenyl-1-methylpiperidine (M.P. 164°-165°) is isolated from the reaction mixture, and the latter amide is cyclized with phosphorus oxychloride to obtain the desired benzonaphthyridine.
Reaction SMILES: [H-].COCCO[Al+]OCCOC.[Na+].[H-].N1CCOCC1.[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25]([NH:31][C:32]([NH:34][S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44](OC)=[O:45])(=[O:37])=[O:36])=[O:33])[N:24]=1.Cl>O1CCCC1>[CH3:21][O:22][C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[C:25]([NH:31][C:32]([NH:34][S:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[CH:44]=[O:45])(=[O:37])=[O:36])=[O:33])[N:24]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(OC)cc(OC)n1
Agent: COCCO[Al+]OCCOC
Agent: Cl
Agent: [H-]
Solvent: C1COCCN1
Solvent: C1CCOC1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)c2ccccc2C=O)n1
Temperature: -40 °C

Procedure:
A mixture of 3.0 g of sodium bis(2-methoxyethoxy)aluminum hydride and 0.9 g of morpholine in 25 ml of dry tetrahydrofuran was cooled to -40° C. and 1.0 g of N-[(4,6-dimethoxypyrimidin-2-yl)aminocarbonyl]-2-methoxycarbonylbenzenesulfonamide was added. The resulting clear homogeneous solution was allowed to warm to room temperature over a period of 2 hours. Dilute hydrochloric acid was added and the mixture was extracted with methylene chloride. The organic extracts were washed, dried and evaporated. The crude product, which contained the desired aldehyde, the unreacted ester and the over-reduced alcohol, was purified by means of dry column chromatography. The purified product had a m.p. of 180° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([C:14](=O)[CH2:15][Br:16])=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].O>C([SiH](CC)CC)C.FC(F)(F)C(O)=O>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][Br:16])=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCc2c(sc(C)c2C(=O)CBr)C1
Agent: CC[SiH](CC)CC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N1CCc2c(sc(C)c2CCBr)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.3 %

Procedure:
A mixture of 28 g of 6-acetyl-3-bromoacetyl-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine in 42 ml of triethylsilane and 140 ml of trifluoroacetic acid was stirred at room temperature for 5 hours. The mixture was poured into water, made alkaline and extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated. To the residue was added isopropyl ether and the precipitated crystals were collected by filtration to give 14 g of 6-acetyl-3-(2-bromoethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as white crystals, m.p. 93°-95° C.
Reaction SMILES: [C:1]([C:5]1([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]3([CH:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)[O:23][C:22](=[O:24])[CH2:21][C:20](=[O:25])[CH2:19]3)=[CH:12][CH:11]=2)OCC[O:6]1)([CH3:4])([CH3:3])[CH3:2]>CC(C)=O>[CH:26]1([C:18]2([CH2:17][CH2:16][C:13]3[CH:14]=[CH:15][C:10]([C:5](=[O:6])[C:1]([CH3:3])([CH3:2])[CH3:4])=[CH:11][CH:12]=3)[O:23][C:22](=[O:24])[CH2:21][C:20](=[O:25])[CH2:19]2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)C1(c2ccc(CCC3(C4CCCC4)CC(=O)CC(=O)O3)cc2)OCCO1
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 6-{2-[4-(2-tert-Butyl-[1,3]dioxolan-2-yl)-phenyl]-ethyl}-6-cyclopentyl-dihydro-pyran-2,4-dione from Example A(34), (0.173 g) in acetone (1 mL) was added Amberlyst 15 (0.05 g). The reaction mixture was stirred at room temperature overnight, and then filtrated. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (40% EtOAc in Hexanes) to yield the product as a white foam (0.04 g, 95%). 1H NMR (CDCl3): δ 1.35 (s, 9H), 1.47-1.84 (m, 8H), 1.91-2.03 (m, 2H), 2.25-2.34 (m, 1H), 2.72 (t, J=8.0 Hz, 2H), 2.78 (s, 2H), 3.44 (s, 2H), 7.18 (d, J=8.2 Hz, 2H), 7.67 (d, J=8.2 Hz, 2H). Anal. Calcd. For C23H30O4: C, 74.56; H, 8.16. Found: C, 74.86; H, 8.43. ESIMS (MH+): 371
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[BH4-].[Na+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=S(O)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 4-fluorobenzenesulfonyl chloride (2 g, 10.28 mmol) in 50 mL of THF (distilled from Na-benzophenone) is cooled to 0° C. and sodium borohydride (1.9 g, 51.4 mmol) is added portionwise. The reaction is stirred at 0° C. for 2 h, then warmed to RT, and after 2 h, quenched with water (5 mL). The solvent is evaporated and the aqueous residue is acidified by addition of aqueous 6N HCl. The product is taken up in EtOAc, washed with brine, dried over anhydrous Na2SO4 and concentrated to give 4-fluorobenzenesulfinic acid: NMR (DMSO-d6) 7.12 (app t, 2H, J=8.3), 7.5 (dd, 2H, J=8.3, 6); ESI-MS 159 [M-1]−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:12][O:13][Si](C(C)C)(C(C)C)C(C)C)[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[CH2:24]([O:31][C@@H:32]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:47][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[O:35][CH:33]1O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([O:31][C@@H:32]1[C@@H:38]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C@H:37]([O:47][CH2:48][C:49]2[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=2)[C@@H:36]([CH2:55][O:56][CH2:57][C:58]2[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=2)[O:35][CH:33]1[C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: CC(C)[Si](OCc1cc(Br)cc2ccccc12)(C(C)C)C(C)C
Product: OCc1cc(C2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)cc2ccccc12

Procedure:
With similar method described in Step 3 of Example 92, ((3-bromonaphthalen-1-yl)methoxy)triisopropylsilane (compound 76, 18.0 g, 45.6 mmol) and 2,3,4,6-tetra-O-benzyl-D-glucopyranose (2, 20.5 g, 38.0 mmol) were converted to title compound (23.3 g, 90%, ca. 2:1 mixture of anomers (13:0) as a white solid.
Reaction SMILES: BrC1C=CC(S([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/C(O)=O)=C2)(=O)=O)=CC=1.[C:21]([O:25][C:26](=[O:44])/[CH:27]=[CH:28]/[C:29]1[CH:33]=[CH:32][N:31]([S:34]([C:37]2[CH:42]=[CH:41][C:40](Br)=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:30]=1)([CH3:24])([CH3:23])[CH3:22].N1C=CC=C(B(O)O)C=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd](Cl)Cl>[C:21]([O:25][C:26](=[O:44])/[CH:27]=[CH:28]/[C:29]1[CH:33]=[CH:32][N:31]([S:34]([C:37]2[CH:42]=[CH:41][C:40]([C:16]3[CH:17]=[N:11][CH:15]=[CH:14][CH:13]=3)=[CH:39][CH:38]=2)(=[O:36])=[O:35])[CH:30]=1)([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1
Reactant: O=C(O)/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: OB(O)c1cccnc1
Solvent: COCCOC
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(-c3cccnc3)cc2)c1

Procedure:
0.18 g (E)-3-[1-(4-bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-acrylic acid tart-butyl ester (compound D4) and 62 mg 3-pyridylboronic acid are dissolved in 10 ml DME. A catalytic amount of bis-(triphenylphosphin-palladium (II)-chloride and 0.6 ml of an aqueous solution of sodium carbonate are added and the mixture is heated to reflux temperature overnight. The title compound is isolated by means of chromatography.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:16]([O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][CH:24]=1)[CH3:17].C(OCC)(=O)C>C1(C)C=CC=CC=1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:16]([O:18][C:19]1[CH:24]=[C:23]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([F:9])[CH:3]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:17]
Reactant: CCOc1cccc(B(O)O)c1
Reactant: Nc1ccc(Br)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOc1cccc(-c2ccc(N)c(F)c2)c1
Temperature: 80 °C
Yield: 95.9 %

Procedure:
To a solution of 4-bromo-2-fluoroaniline (3.2 g, 17.05 mmol), 2M K2CO3 (24 ml, 48.00 mmol), Pd(PPh3)4 (1.2 g, 1.02 mmol) in toluene (120 ml) under nitrogen atmosphere was added dropwise a solution of the 3-ethoxyphenylboronic acid (4.25 g, 25.61 mmol) in 31 ml of MeOH. The mixture was heated to 80° C. overnight and then cooled to room temperature. Ethyl acetate was added and washed twice with a K2CO3 aqueous solution. The organic layer was washed with brine, dried over magnesium sulphate, filtered and the solvent evaporated under vacuum. The residue obtained was purified by flash chromatography eluting with Hexane/AcOEt (from 10/1 to 8/1). The solid obtained was recrystallized in hexane to yield 3.78 g of the desired compound as a white solid. Yield=72%
Reaction SMILES: [CH2:1]([C:5]1[CH:21]=[CH:20][C:8]([O:9][CH2:10][C:11]2[O:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[C:2]([CH3:4])=O.[OH:22][CH:23]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=1)[CH2:24][NH2:25].O>C1C=CC=CC=1>[Cl:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH:23]([OH:22])[CH2:24][NH:25][CH:2]([CH3:4])[CH2:1][C:5]1[CH:21]=[CH:20][C:8]([O:9][CH2:10][C:11]2[O:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1
Reactant: COC(=O)c1ccc(COc2ccc(CC(C)=O)cc2)o1
Reactant: NCC(O)c1cccc(Cl)c1
Solvent: c1ccccc1
Solvent: O
Product: COC(=O)c1ccc(COc2ccc(CC(C)NCC(O)c3cccc(Cl)c3)cc2)o1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of methyl 5-[4-acetonylphenoxymethyl]furan-2-carboxylate (1.76 g) and 2-hydroxy-2-(3-chlorophenyl) ethanamine (1.05 g) in dry benzene (100 ml) was heated under reflux with azeotropic removal of water, for 2 hr. The solvent was evaporated and sodium borohydride (2 g) added, in portions, to a stirred solution of the residual oil in methanol (80 ml) with cooling in ice. The mixture was stirred at ambient temperature for 3 hr. the solvent was evaporated and the residue was partitioned between water and dichloromethane. The organic layer was dried (MgSO4) and evaporated to an oil which was purified by column chromatography on silica gel. Elution with methanol:chloroform (4:96) gave an oil which was crystallised from n-hexane to give methyl 5-[4-[2-[(3-chloro-β-hydroxyphenethyl)amino]propyl]phenoxymethyl]furan-2-carboxylate, m.pt 75°-86° C., as a 19:81 mixture of diastereoisomers. The mother liquor was evaporated; crystallisation from Petroleum ether (60:80)--ether gave a second crop, m.pt. 75°-83° C., as a 55:45 mixture of diastereoisomers.
Reaction SMILES: C(=S)(OC1C=CC=CC=1)O[C@@H:3]1[C@@H:7]2[O:8][Si:9]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[O:10][Si:11]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[O:12][CH2:13][C@H:6]2[CH2:5][C@H:4]1[N:26]1[CH:34]=[N:33][C:32]2[C:27]1=[N:28][CH:29]=[N:30][C:31]=2[Cl:35].C([SnH](CCCC)CCCC)CCC.N(C(C)(C)C#N)=NC(C)(C)C#N>C1(C)C=CC=CC=1>[Cl:35][C:31]1[N:30]=[CH:29][N:28]=[C:27]2[C:32]=1[N:33]=[CH:34][N:26]2[C@H:4]1[CH2:3][C@@H:7]2[O:8][Si:9]([CH:20]([CH3:22])[CH3:21])([CH:23]([CH3:25])[CH3:24])[O:10][Si:11]([CH:17]([CH3:18])[CH3:19])([CH:14]([CH3:15])[CH3:16])[O:12][CH2:13][C@H:6]2[CH2:5]1
Reactant: CC(C)[Si]1(C(C)C)OC[C@H]2C[C@@H](n3cnc4c(Cl)ncnc43)[C@H](OC(=S)Oc3ccccc3)[C@@H]2O[Si](C(C)C)(C(C)C)O1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)[Si]1(C(C)C)OC[C@H]2C[C@@H](n3cnc4c(Cl)ncnc43)C[C@@H]2O[Si](C(C)C)(C(C)C)O1
Yield: 0 %

Procedure:
To a solution of O-[(6aR,8R,9S,9aR)-8-(6-chloro-9H-purin-9-yl)-2,2,4,4-tetraisopropylhexahydrocyclopenta[f][1,3,5,2,4]trioxadisilocin-9-yl] O-phenyl thiocarbonate (0.851 g, 1.28 mol) in toluene (20 mL) was added tri-n-butyltin hydride (0.680 mL, 2.53 mmol) and 2,2′-azo-bis-isobutyronitrile (0.075 g, 0.46 mmol). This solution was refluxed for 1 h. The reaction mixture was concentrated and purified by flash chromatography (0 to 50% EtOAc/hexanes) to afford the title compound (0.14 g, 74%).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2([OH:20])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(O)C.C[C:34]([N:36](C)C)=O>ClCCl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:34]([C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2([OH:20])[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1)#[N:36]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccc(Br)cc2)CC1
Reactant: CC(=O)N(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC(C)O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(O)(Cc2ccc(C#N)cc2)CC1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
A mixture of tert-butyl 4-(4-bromobenzyl)-4-hydroxypiperidine-1-carboxylate (35 g), K4Fe(CN)6 (12 g), palladium(II) acetate (1.1 g), sodium carbonate (11 g), 2-propanol (7.5 mL) and DMA (150 mL) was stirred at 120° C. for 12 hr. The reaction mixture was allowed to cool to room temperature, diluted with dichloromethane, and filtered through celite. The filtrate was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (17 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[N:10]([O:11][CH:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[CH:23]1([NH:26][C:27]([C:29]2[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=2)=[O:28])[CH2:25][CH2:24]1>>[CH:23]1([NH:26][C:27](=[O:28])[C:29]2[CH:34]=[CH:33][C:32]([C:2]3[CH:3]=[C:4]4[N:10]([O:11][CH:12]([C:14]5[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=5[Cl:22])[CH3:13])[CH:9]=[CH:8][C:5]4=[N:6][CH:7]=3)=[CH:31][CH:30]=2)[CH2:24][CH2:25]1
Reactant: CC(On1ccc2ncc(Br)cc21)c1c(Cl)ccc(F)c1Cl
Reactant: O=C(NC1CC1)c1ccc(B(O)O)cc1
Product: CC(On1ccc2ncc(-c3ccc(C(=O)NC4CC4)cc3)cc21)c1c(Cl)ccc(F)c1Cl

Procedure:
The entitled compound was prepared from 6-bromo-1-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-1H-pyrrolo[3,2-b]pyridine and [4-(cyclopropylcarbamoyl)phenyl]boronic acid according to the procedure described in example 4.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[CH:15]3[CH:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O.[OH-].[Na+]>N1C=CC=CC=1>[C:27]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[CH:18]=[C:19]([O:24][CH3:25])[C:20]([O:22][CH3:23])=[CH:21][C:16]=3[C@H:15]3[C@H:10]([CH2:11][CH2:12][N:13]([CH3:26])[CH2:14]3)[N:9]=2)=[CH:4][CH:3]=1)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc2c(cc1OC)C1CN(C)CCC1N=C2c1ccc(N)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2c(cc1OC)[C@@H]1CN(C)CC[C@@H]1N=C2c1ccc(NC(=O)c2ccccc2)cc1
Reaction time: 15 h

Procedure:
2 g of 6-(4-aminophenyl)-8,9-dimethoxy-2-methyl-1,2,3,4,4a,10b-hexahydro-benzo[c][1,6]naphthyridine are dissolved in 30 ml of pyridine, 1 g of benzoylchloride is added to the solution and the reaction mixture is allowed to stand at room temperature for 15 hours. The reaction mixture is then treated with 10 ml of water, allowed to stand for 10 minutes and is then reduced in volume under vacuum. The resulting residue is rendered alkaline with dilute sodium hydroxide and is then extracted with methylenechloride. After evapaorating off of the organic phase, the crude product is dissolved in ethanol and rendered acid with an ethanolic hydrochloric acid solution, whereby the dihydrochloride of the title compound crystallizes out in yellowish prisms of M.P. 240°-245°.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([CH:16]=[N:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:12][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2].Cl.C([BH3-])#N.[Na+]>CO.C(OCC)(=O)C>[CH2:1]([O:3][CH:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][NH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:14][CH:15]=1)[C:5]([O:7][CH3:8])=[O:6])[CH3:2]
Reactant: CCCCCCCN=Cc1ccc(CC(OCC)C(=O)OC)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCCCCCNCc1ccc(CC(OCC)C(=O)OC)cc1
Reaction time: 2.5 h
Yield: 60 %

Procedure:
The crude methyl 2-ethoxy-3-[4-(N-heptylimiomethyl)phenyl]propanoate obtained in step (i) above (2.95 g), was dissolved in methanol (40 ml), and treated with conc. HCl (850 μl, 1 eq, 8.51 mmol) and sodium cyanoborohydride (535 mg, 1 eq, 8.51 mmol) at 0° C. The progress of the reaction was monitored by TLC. After 2-3 h, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The residue was chromatographed using methanol and chloroform to afford the title compound (1.71 g, yield 60%) as viscous liquid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([OH:18])=O)[N:13]=2)=[N:6][CH:7]=1.C1C=CC2N(O)N=[N:32][C:30]=2C=1.O.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.CN>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]([O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([NH:32][CH3:30])=[O:18])[N:13]=2)=[N:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Agent: CCN=C=NCCCN(C)C
Agent: CN
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Solvent: O
Product: CNC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 69.8 %

Procedure:
A mixture of 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoic acid (0.100 g, 0.238 mmol) (Example 315) HOBT-H2O (0.0547 g, 0.357 mmol), DIEA (d 0.742) (0.0870 mL, 0.500 mmol), EDCI (0.0684 g, 0.357 mmol), and methanamine (0.238 mL, 0.476 mmol) in 10 mL acetonitrile was stirred at ambient temperature for 5 hours and then heated at 50° C. overnight. The mixture was concentrated to a residue, dissolved in THF and precipitated with the addition of water. The solids were filtered, washed with water and dried on high vacuum overnight to give the title compound (0.072 g, 69.8% yield) as white solids. 1H NMR (d6 DMSO) δ 2.41 (t, J=7.8 Hz, 2H), 2.56 (d, J=4.7 Hz, 3H), 2.79 (t, J=7.7 Hz, 2H), 6.62 (s, 1H), 7.10 (d, J=8.0 Hz, 2H), 7.21 (t, J=7.3 Hz, 1H), 7.40 (d, J=2.0 Hz, 1H), 7.43 (t, J=7.9 Hz, 2H), 7.77 (d, J=4.3 Hz, 1H), 8.21 (d, J=2.0 Hz, 1H), 10.94 (br s, 1H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]1([CH2:12][CH:13]([C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:14](OC)=[O:15])[CH:11]=[N:10][CH:9]=[N:8]1.CO>C(OCC)C>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([CH:13]([CH2:12][N:7]2[CH:11]=[N:10][CH:9]=[N:8]2)[CH2:14][OH:15])=[CH:19][CH:20]=1
Reactant: COC(=O)C(Cn1cncn1)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: CO
Product: OCC(Cn1cncn1)c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
1.3 g of LiAlH4 is suspended in 170 ml of anhydrous diethyl ether under N2 atmosphere. Within one hour, 8 g of methyl α-(1H-1,2,4-triazol-1-ylmethyl)-4-chlorophenylacetate is introduced. The reaction is exothermic, and proceeds with solvent reflux. At the end of heat evolution, 10 ml of methanol in 50 ml of diethyl ether is added to destroy the excess of hydride.
Reaction SMILES: Cl[CH2:2][CH2:3][C:4](=[O:6])[CH3:5].[S:7]1([C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:12])[NH:10]1)(=[O:9])=[O:8].[Na]>CN(C)C=O>[O:6]=[C:4]([CH2:3][CH2:2][N:10]1[C:11](=[O:12])[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[S:7]1(=[O:9])=[O:8])[CH3:5]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: CC(=O)CCCl
Agent: [Na]
Solvent: CN(C)C=O
Product: CC(=O)CCN1C(=O)c2ccccc2S1(=O)=O
Temperature: 80 °C
Yield: 86.1 %

Procedure:
9.0 g (76 millimoles) of 4-chlorobutan-2-one were slowly added dropwise to 10.0 g (50 millimoles) of sodium saccharin in 100 ml of absolute dimethylformamide, while stirring. The temperature was then gradually increased to 80° C., and the reaction mixture was stirred at this temperature for 5 hours, after which it was cooled. An excess of ice-water was added, and stirring was continued for a further hour. The precipitated solid was filtered off under suction, recrystallized from ethanol and dried in a drying oven under reduced pressure at 50° C. to give 10.9 g (86%) of N-(2-oxobut-4-yl)-saccharin of melting point 118°-119° C.