Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([C:18]2[N:22]3[N:23]=[C:24](Cl)[CH:25]=[C:26]([NH:27][CH:28]4[CH2:30][CH2:29]4)[C:21]3=[N:20][CH:19]=2)=[O:17])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]1>CO>[NH2:32][C@H:33]1[CH2:38][CH2:37][C@H:36]([NH:39][C:24]2[CH:25]=[C:26]([NH:27][CH:28]3[CH2:30][CH2:29]3)[C:21]3[N:22]([C:18]([C:16]([NH:15][C:11]4[CH:10]=[C:9]([O:8][CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[N:14]=[CH:13][N:12]=4)=[O:17])=[CH:19][N:20]=3)[N:23]=2)[CH2:35][CH2:34]1
Reactant: O=C(Nc1cc(OCc2ccccc2)ncn1)c1cnc2c(NC3CC3)cc(Cl)nn12
Reactant: N[C@H]1CC[C@H](N)CC1
Solvent: CO
Product: N[C@H]1CC[C@H](Nc2cc(NC3CC3)c3ncc(C(=O)Nc4cc(OCc5ccccc5)ncn4)n3n2)CC1

Procedure:
N-(6-(benzyloxy)pyrimidin-4-yl)-6-chloro-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (70 mg, 0.161 mmol) and trans-1,4-diaminocyclohexane (367 mg, 3.21 mmol) were heated at 160° C. for 2 hrs. The reaction mixture was diluted with methanol and purified by preparative HPLC (Phenomenex Axia Luna 5 micron 30×100 mm) 10% B (Solvent B=90% MeOH-10% H2O-0.1% TFA) to 100% B in A (Solvent A=10% MeOH-90% H2O-0.1% TFA)) to isolate 6-((trans)-4-aminocyclohexylamino)-N-(6-(benzyloxy)pyrimidin-4-yl)-8-(cyclopropylamino)imidazo[1,2-b]pyridazine-3-carboxamide (37 mg, 0.072 mmol, 44.9% yield) as light yellow solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA) Rt=1.818 (M+H=514.25).
Reaction SMILES: Br[CH2:2][C:3](OCC)=[O:4].[CH3:8][O:9][C:10]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=[S:13].[OH-].[Na+]>>[CH3:8][O:9][C:10]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[CH:16][C:11]=1[C:12]1[S:13][CH2:2][C:3](=[O:4])[NH:15][N:14]=1
Reactant: COc1ccc(C(=S)NN)c(OC)c1
Reactant: CCOC(=O)CBr
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(C2=NNC(=O)CS2)c(OC)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Ethyl bromoacetate (5.0 g.) was added to a stirred suspension of 2,4-dimethoxythiobenzohydrazide (6.5 g.) in aqueous 3N-sodium hydroxide solution (25 ml.) and the mixture was stirred at 25° C. for 18 hours and then filtered. The solid product was purified by flash chromatography on a silica gel column (Merck 9385) using a 30:1 v/v mixture of chloroform and methanol as eluant. The aqueous filtrate was acidified with aqueous 2N hydrochloric acid and the mixture was filtered. The solid products, both from the chromatographic purification and from the acidification, were combined and crystallised from aqueous methanol. There was thus obtained (2-(2,4-dimethoxyphenyl)-4H,6H-1,3,4-thiadiazin-5-one, m.p. 162°-164° C.
Reaction SMILES: O1CCCC1.[F:6][C:7]1[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:8]=1[O:9][C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([N:19]2[CH2:24][CH2:23][CH:22]([CH2:25][N:26]([CH3:28])[CH3:27])[CH2:21][CH2:20]2)=[O:18])[CH:11]=1.[H][H]>[C].[Pd].CO>[NH2:33][C:31]1[CH:30]=[CH:29][C:8]([O:9][C:10]2[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]([N:19]3[CH2:20][CH2:21][CH:22]([CH2:25][N:26]([CH3:28])[CH3:27])[CH2:23][CH2:24]3)=[O:18])[CH:11]=2)=[C:7]([F:6])[CH:32]=1
Reactant: [H][H]
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc([N+](=O)[O-])cc3F)ncn2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ncn2)CC1
Reaction time: 9 h
Yield: 110.2 %

Procedure:
After adding tetrahydrofuran (2 ml) and methanol (2 ml) to 4-(dimethylaminomethyl)piperidine-1-carboxylic acid [6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]amide (88 mg) under a nitrogen atmosphere, 10% palladium-carbon (45 mg) was added, the atmosphere in the reaction vessel was replaced with hydrogen, and the mixture was stirred for 9 hours. The atmosphere in the reaction vessel was then replaced with nitrogen and the catalyst was filtered and washed with methanol. The filtrate was concentrated under reduced pressure to provide a crude product of 4-(dimethylaminomethyl)piperidine-1-carboxylic acid [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]amide (90 mg) as a pale yellow amorphous substance.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH:5]([O:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:4]([CH3:17])[CH2:3]1.[OH-].[K+].[CH2:20](O)C>>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][CH:5]([O:9][C:10]2[CH:11]=[CH:12][C:13]([O:16][CH3:20])=[CH:14][CH:15]=2)[CH:4]([CH3:17])[CH2:3]1
Reactant: CCO
Reactant: CC1CN(C)CCCC1Oc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Product: COc1ccc(OC2CCCN(C)CC2C)cc1
Reaction time: 1 h

Procedure:
23.5 g of 1,3-dimethyl-4-p-hydroxyphenoxy-hexahydroazepine are dissolved in 100 ml of absolute ethanol, 200 ml of 0.5 N ethanolic KOH are added, the reaction mixture is stirred for one hour at 20° and evaporated and the residue is taken up in 250 ml of absolute DMF. 12.6 g of dimethyl sulfate are added in portions, while stirring. The mixture is boiled for 2 hours and evaporated and the residue is worked up in the customary manner, giving 1,3-dimethyl-4-p-methoxyphenoxy-hexahydroazepine, 2 oily isomers, Rf 0.36 and 0.55.
Reaction SMILES: [F:1][C:2]1[CH:14]=[C:12]2[C:13]3[N:8]([CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11]2=[O:15])[CH:7]([CH3:19])[CH2:6][CH2:5][C:4]=3[C:3]=1Cl.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.CN(C)P(=O)(N(C)C)N(C)C.O>C(O)(=O)C>[CH3:21][N:22]1[CH2:27][CH2:26][N:25]([C:3]2[C:4]3=[C:13]4[N:8]([CH:7]([CH3:19])[CH2:6][CH2:5]3)[CH:9]=[C:10]([C:16]([OH:18])=[O:17])[C:11](=[O:15])[C:12]4=[CH:14][C:2]=2[F:1])[CH2:24][CH2:23]1
Reactant: CN1CCNCC1
Reactant: CC1CCc2c(Cl)c(F)cc3c(=O)c(C(=O)O)cn1c23
Solvent: CC(=O)O
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CC1CCc2c(N3CCN(C)CC3)c(F)cc3c(=O)c(C(=O)O)cn1c23

Procedure:
A mixture of 1.8 g of 9-fluoro-8-chloro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid, 36 ml of N-methylpiperazine and 15 ml of hexamethylphosphoric triamide was heated at 150° to 160° C. for 4 hours. After completion of the reaction the solvent was removed by distillation under reduced pressure and the residue was washed with 10 ml of ethyl acetate. The crude crystals thus-obtained were mixed with 100 ml of water and adjusted to a pH of 4 with acetic acid. Insoluble materials were removed by filtration and the filtrate was treated with activated carbon followed by concentration under reduced pressure. The residue was mixed with 20 ml of water and the solution was adjusted to a pH of 9 with a 10% aqueous sodium hydroxide solution and extracted with 80 ml chloroform. After the extract was dried over anhydrous sodium sulfate and concentrated it was purified through a silica gel column chromatography (silica gel: Wako C-200, a trade name for a product of Wako Junyaku Co., Ltd.; eluent: chloroform-methanol (9:1 by volume)) to obtain 0.8 g of 8-(4-methyl-1-piperazinyl)-9-fluoro-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white rhombic crystals having a melting point of 262° to 263° C.
Reaction SMILES: Br[C:2]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=2[CH3:19])=[C:8]([Cl:20])[CH:7]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[CH:39][C:40]([C:43]([NH:45][CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[O:44])=[N:41][CH:42]=2)O1.C([O-])([O-])=O.[K+].[K+].O>O1CCOCC1.CCOC(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:8]1[CH:7]=[C:6]([NH:5][CH2:4][C:3]2[CH:21]=[CH:22][C:23]([C:25]([F:28])([F:27])[F:26])=[CH:24][C:2]=2[C:37]2[CH:38]=[CH:39][C:40]([C:43]([NH:45][CH2:46][CH2:47][C:48]([O:50][CH2:51][CH3:52])=[O:49])=[O:44])=[N:41][CH:42]=2)[CH:11]=[CH:10][C:9]=1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[CH3:19]
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(Cl)ccc1-c1ccc(NCc2ccc(C(F)(F)F)cc2Br)cc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C(F)(F)F)ccc2CNc2ccc(-c3ccc(Cl)cc3C)c(Cl)c2)cn1
Temperature: 25 °C

Procedure:
N-(2-bromo-4-(trifluoromethyl)benzyl)-2,4′-dichloro-2′-methyl-[1,1′-biphenyl]-4-amine (2.7 g, 5.5 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate, prepared as in Step A above, (2.3 g, 6.6 mmol), Pd(dppf)Cl2 (452 mg, 0.6 mmol), and K2CO3 (1.5 g, 11.0 mmol) were dissolved in 1,4-dioxane (50 mL) and water (13 mL) and the resulting mixture was heated to 80° C. After 16 h the resulting mixture was cooled to room temperature, diluted with EtOAc, washed with water and brine, dried (Na2SO4), and dry packed onto silica gel. Column chromatography yielded the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)[N:13]=[C:12]([O:27][CH3:28])[N:11]=2)=[CH:6][C:3]=1[CH:4]=O.C([O-])(=O)C.[Na+].Cl.[NH2:35][OH:36]>CCO>[F:1][C:2]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:13]=[C:12]([O:27][CH3:28])[N:11]=2)=[CH:6][C:3]=1[CH:4]=[N:35][OH:36]
Reactant: COc1ccc(CCNc2cc(-c3ccc(F)c(C=O)c3)nc(OC)n2)cc1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(CCNc2cc(-c3ccc(F)c(C=NO)c3)nc(OC)n2)cc1
Temperature: 20 °C
Reaction time: 20 h
Yield: 117.9 %

Procedure:
A mixture of 2-fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzaldehyde [700 mg, 1.84 mmol, Example 35(j)], sodium acetate (2.5 g, 18.4 mmol) and hydroxylamine hydrochloride (1.3 g, 18.4 mmol) in EtOH (95%, 20 mL) is stirred for 20 hours at 20° C. The reaction mixture is concentrated, diluted with water, and extracted with ethyl acetate. The extracts are dried over magnesium sulfate, filtered through a plug of silica, and concentrated to afford 2-fluoro-5-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-benzaldehyde oxime [0.86 g, Example 26]. LCMS: RT=2.53 minutes. MS: 397 (M+H). IC50=4.5 nM
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[C:23]3[C:22]([OH:24])=[C:21]([C:25]#[N:26])[C:20](=[O:27])[NH:19][C:18]=3[S:17][CH:16]=2)=[CH:11][CH:10]=1)=[O:2].[BH4-].[Na+]>CO.ClCCl>[OH:24][C:22]1[C:23]2[C:15]([C:12]3[CH:11]=[CH:10][C:9]([C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[CH2:1][OH:2])=[CH:14][CH:13]=3)=[CH:16][S:17][C:18]=2[NH:19][C:20](=[O:27])[C:21]=1[C:25]#[N:26]
Reactant: N#Cc1c(O)c2c(-c3ccc(-c4ccccc4C=O)cc3)csc2[nH]c1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1c(O)c2c(-c3ccc(-c4ccccc4CO)cc3)csc2[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 3-(2′-formyl-1,1′-biphenyl-4-yl)-4-hydroxy-6-oxo-6,7-dihydrothieno[2,3-b]pyridine-5-carbonitrile (0.03 g, 0.08 mmol) in MeOH (2 mL) and dichloromethane (0.5 mL) was added NaBH4 (0.012 g, 0.32 mmol) in a single portion. The reaction was stirred at room temperature for 18 h. It was then cooled to 0° C. in an ice bath, quenched by slow addition of 1N HCl (10 mL) and extracted with dichloromethane (3×10 mL). The organic layers were dried with anhydrous sodium sulfate, concentrated and purified by RP-HPLC to give the title compound as a white solid. MS (ESI) m/e 372.9 (M−H)+; 1H NMR (400 MHz, DMSO-d6): δ ppm 12.42 (br s, 1H), 7.60 (dd, 1H), 7.50 (d, 2H), 7.32–7.42 (m, 4H), 7.26 (dd, 1H), 7.07 (s, 1H), 4.46 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH:19]=O)[CH:6]=1.[NH2:22][CH2:23][C@H:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[OH:25]>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:22][CH2:23][C@@H:24]([OH:25])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Reactant: NC[C@@H](O)c1ccccc1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CNC[C@@H](O)c2ccccc2)c1

Procedure:
Prepared according to the procedure described in Example 45, Step 3, using the following starting materials: [3-(4-bromo-2-formyl-phenoxy)-phenyl]-acetic acid methyl ester and (S)-(+)-2-amino-1-phenylethanol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[C:18]([CH2:20]O)[S:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Br)(Br)[Br:23].O>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:19]=[C:18]([CH2:20][Br:23])[S:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrP(Br)Br
Reactant: OCc1nc(-c2ccc(OCc3ccccc3)cc2)ns1
Solvent: Cc1ccccc1
Solvent: O
Product: BrCc1nc(-c2ccc(OCc3ccccc3)cc2)ns1
Temperature: 120 °C
Yield: 70 %

Procedure:
To a solution of [3-(4-benzyloxyphenyl)-[1,2,4]thiadiazol-5-yl]-methanol (0.052 g, 0.17 mmol) in toluene (5 ml) was added PBr3 (0.027 ml, 0.26 mmol) and the resulting reaction mixture was refluxed at 120° C. for 15 min. After the completion of the reaction (TLC monitoring), the reaction mixture was cooled to 0° C., added water (50 ml) and extracted with ethyl acetate (3×50 ml). The combined organics was washed with saturated NaHCO3 solution, dried over Na2SO4, filtered and concentrated under vacuum to get the desired product (0.043 g, 68%).
Reaction SMILES: C1([O:7][C:8](=S)[NH:9][C:10]2[C:11]([O:18][CH3:19])=[N:12][C:13]([CH3:17])=[C:14]([CH3:16])[CH:15]=2)C=CC=CC=1.[Cl:21][C:22]1[CH:23]=[C:24]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[CH:25]=[C:26]([Cl:28])[CH:27]=1>>[CH3:16][C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:32]2[CH2:31][CH2:30][N:29]([C:24]3[CH:23]=[C:22]([Cl:21])[CH:27]=[C:26]([Cl:28])[CH:25]=3)[CH2:34][CH2:33]2)=[O:7])[C:11]([O:18][CH3:19])=[N:12][C:13]=1[CH3:17]
Reactant: COc1nc(C)c(C)cc1NC(=S)Oc1ccccc1
Reactant: Clc1cc(Cl)cc(N2CCNCC2)c1
Product: COc1nc(C)c(C)cc1NC(=O)N1CCN(c2cc(Cl)cc(Cl)c2)CC1
Yield: 82 %

Procedure:
Phenyl-N-(5,6-dimethyl-2-methoxypyridin-3-yl)thiocarbamate and 1-(3,5-dichlorophenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22]O)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].P(Br)(Br)Br.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>ClCCl.C(O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][C:9]2[NH:10][C:11]3[C:16]([C:17]=2[C:18]=1[CH2:19][O:20][CH3:21])=[C:15]([CH2:22][N:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2[nH]c3cccc(CO)c3c2c1COC
Reactant: C1COCCN1
Agent: BrP(Br)Br
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)c1ncc2[nH]c3cccc(CN4CCOCC4)c3c2c1COC
Reaction time: 8 h

Procedure:
5-Hydroxymethyl-4-methoxymethyl-beta-carboline-3-carboxylic acid ethyl ester (0.20 g) is dissolved in dichloromethane (5 ml). A solution of phosphorous tribromide (0.17 g) in dichloromethane (3 ml) is added drop by drop with stirring. After three hours of stirring, the mixture is cooled to +10° C. and mixed with a solution of morpholine (1.0 ml) in ethanol (5 ml) drop by drop. After standing overnight the solvent is evaporated, the residue is chromatographed on silica gel with a mixture of dichloromethane (19 parts) and ethanol (1 part) and the title compound (0.16 g) with a melting point of 195°-196° C. is obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([C:17]([OH:20])([CH3:19])[CH3:18])=[CH:13][C:10]=3[C:11](=[O:12])[C:5]2=[CH:4][C:3]=1[C:21]([O:23]CC)=[O:22].[OH-].[Na+]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]2[O:8][C:9]3[CH:16]=[CH:15][C:14]([C:17]([OH:20])([CH3:18])[CH3:19])=[CH:13][C:10]=3[C:11](=[O:12])[C:5]2=[CH:4][C:3]=1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1cc2c(=O)c3cc(C(C)(C)O)ccc3oc2nc1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(O)c1ccc2oc3nc(N)c(C(=O)O)cc3c(=O)c2c1
Temperature: 50 °C
Reaction time: 2 h
Yield: 94.9 %

Procedure:
A suspension consisting of ethyl 2-amino-7-(1-hydroxy-1-methylethyl)-5-oxo-5H-[1]benzopyrano[2,3-b]-pyridine-3-carboxylate (37.3 g), ethanol (2.3 l) and 0.5N sodium hydroxide (620 ml) was stirred at 50° C. for 2 hours, then ethancl was evaporated off. The concentrate was acidified with hydrochloric acid (pH 3-4), then the resulting precipitates were collected by filtration and washed with water, followed by recrystallization from dimethylformamide-water. The crystals were washed with ethanol to give 2-amino-7-(1-hydroxy-1-methylethyl)-5-oxo-5H-[1]benzopyrano[2,3-b]-pyridine-3-carboxylic acid (32.5 g).
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C:4](=[O:13])[N:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[N:6]=1.[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[O:23][CH3:24].N1CCCCC1>C(O)C.O.Cl>[OH:14][C:15]1[CH:22]=[CH:21][C:18](/[CH:19]=[C:3]2/[C:4](=[O:13])[N:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=3)[N:6]=[C:2]/2[CH3:1])=[CH:17][C:16]=1[O:23][CH3:24]
Reactant: CC1=NN(c2ccccn2)C(=O)C1
Reactant: COc1cc(C=O)ccc1O
Agent: Cl
Solvent: O
Solvent: C1CCNCC1
Solvent: CCO
Product: COc1cc(/C=C2/C(=O)N(c3ccccn3)N=C2C)ccc1O
Temperature: 0 °C

Procedure:
1.4 g (7.99 mmol) of 5-methyl-2-(2-pyridinyl)-2,4-dihydro-3H-pyrazol-3-one and 1.84 g (11.98 mmol) of 4-hydroxy-3-methoxybenzaldehyde are stirred under reflux with the addition of 3 ml of piperidine in absolute ethanol for 2 hours. The mixture is then diluted with water and slowly rendered neutral with 2N hydrochloric acid. After cooling in the ice bath, the orange precipitate which settles out is filtered off, washed with water and dried under reduced pressure.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([NH:12][NH:13][S:14]([NH:17][C:18]([N:20]2[CH2:23][C@H:22]([NH:24]C(=O)OCC3C=CC=CC=3)[C:21]2=[O:35])=[O:19])(=[O:16])=[O:15])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].FC(F)(F)C(O)=O.C1(SC)C=CC=CC=1>CCOCC>[NH2:24][C@H:22]1[CH2:23][N:20]([C:18]([NH:17][S:14]([NH:13][NH:12][C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([OH:1])[CH:3]=2)=[O:11])(=[O:16])=[O:15])=[O:19])[C:21]1=[O:35]
Reactant: O=C(NNS(=O)(=O)NC(=O)N1C[C@H](NC(=O)OCc2ccccc2)C1=O)Nc1ccc(O)c(O)c1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: CSc1ccccc1
Product: N[C@H]1CN(C(=O)NS(=O)(=O)NNC(=O)Nc2ccc(O)c(O)c2)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., 1.02 g (2.0 mmol) of (S)-[1-[[[[2-[[(3,4-dihydroxyphenyl)amino]carbonyl]hydrazino]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester was added to a mixture of 3.31 ml of trifluoroacetic acid and 0.78 ml (6.63 mmol) of thioanisole. After stirring overnight at room temperature, the dark brown solution was dropped into 40 ml of dry ether (0° C.) and the precipitated material was collected by suction (1.15 g) and stirred with 10 ml of dry dichloromethane; yield: 0.92 g. This material was used in the next step without further purification.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][C@H:13]([C:19](OC)=[O:20])[CH2:14]2.Cl>O1CCCC1>[CH3:7][O:8][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH2:11][CH2:12][CH:13]([CH2:19][OH:20])[CH2:14]2
Reactant: COC(=O)[C@H]1CCc2c(cccc2OC)C1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cccc2c1CCC(CO)C2
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a mixture of lithium aluminum hydride (0.28 g) in dry tetrahydrofuran (THF) (5 ml) was added dropwise a solution of (S)-methyl [5-methoxy-1,2,3,4-tetrahydro-2-naphthyl]formate (1.65 g) in THF (7 ml) at -60° C. under nitrogen. After 1 hour, a mixture of 1N hydrochloric acid solution (5 ml) and THF (5 ml) was added dropwise to the reaction mixture at -60° C. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated, washed with 1N hydrochloric acid solution, sodium hydrogencarbonate solution and brine, dried over magnesium sulfate, and evaporated En vacuo to give (5-methoxy-1,2,3,4-tetrahydro-2-naphthyl)methanol as a white powder (1.23 g).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]#[C:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:2]=1.[C:13](O)(=[O:15])[CH3:14]>CO.[Pt](=O)=O>[C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH:3]1[CH2:4][CH2:5][CH2:6][NH:1][CH2:2]1)(=[O:15])[CH3:14]
Reactant: CC(=O)O
Reactant: OCCCC#Cc1cccnc1
Agent: O=[Pt]=O
Solvent: CO
Product: CC(=O)OCCCCCC1CCCNC1

Procedure:
A solution of 5-(3-pyridinyl)-4-pentyn-1-ol (4.99 g, 31.0 mmol) in acetic acid (150 mL) was hydrogenated over platinum (IV) oxide (1.4 g, 6.16 mmol) for 18 hours. The mixture was filtered through a Celite cartridge, washed through with acetic acid and evaporated in vacuo to give a yellow oil. This was loaded in methanol and eluted on an aminopropyl (NH2) cartridge (70 g) with methanol (400 ml). The solvent was evaporated in vacuo to give the title compound as a colourless oil which solidified after being under vacuum for 18 hours (7.4 g).
Reaction SMILES: [C:1](#[N:3])[CH3:2].C(O[C:7]([C:9]1[N:10]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl-].[NH4+]>O.O1CCCC1>[C:21]1([S:18]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:17]=[C:9]2[C:7](=[O:8])[CH2:2][C:1]#[N:3])(=[O:19])=[O:20])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCOC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Reactant: CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#CCC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 144.4 %

Procedure:
Acetonitrile (10.6 g, 0.202 mol) was added to a tetrahydrofuran (THF) solution (135 ml) of 1-benzenesulfonyl-1H-indole-2-carboxylic acid ethyl ester (33.4 g, 0.101 mol), and cooled to −78° C. A tetrahydrofuran (THF) solution of 1 M lithium bis(trimethylsilyl) amide (213 ml, 0.213 mol) was added dropwise thereto, and stirred for 30 minutes. A saturated aqueous solution (83 ml) of ammonium chloride was added to the reaction mixture, and stirred for 10 minutes. Water (50 ml) was added to the mixture and warmed to room temperature. The solvent was distilled off under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The desiccant was removed by filtration. The filtrate was concentrated under reduced pressure. The resulting crude product was washed with ethanol to give 3-(1-benzenesulfonyl-1H-indol-2-yl)-3-oxo-propionitrile (47.3 g, 70%).
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2].[N:18]1([CH2:24][CH2:25][NH2:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>CCO.Cl>[CH2:1]([N:3]([CH2:16][CH3:17])[C:4](=[O:15])[C:5]1[CH:10]=[CH:9][C:8]([NH:26][CH2:25][CH2:24][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[C:7]([N+:12]([O-:14])=[O:13])[CH:6]=1)[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: NCCN1CCCCC1
Agent: Cl
Solvent: CCO
Product: CCN(CC)C(=O)c1ccc(NCCN2CCCCC2)c([N+](=O)[O-])c1
Temperature: 85 °C
Yield: 58 %

Procedure:
Following general procedure 2B: A mixture of N,N-diethyl-4-fluoro-3-nitrobenzamide (1.0 g, 4.2 mmol), 2-(1-piperidinyl)ethanamine (0.564 mL, 3.96 mmol) in 80% aq. EtOH (30 mL) was heated at 85° C. for 10 hours. After the usual work-up, the crude mixture was dissolved in 1 N HCl (40 mL) and washed with CH2Cl2 (2×10 mL). The aqueous layer was basified with 5 N NaOH (10 mL) and extracted with CH2Cl2 (3×10 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo to provide the title compound (0.800 g, 57%) as a bright yellow solid which was used without further purification. 1H-NMR (CDCl3): δ 8.64 (br s, 1H), 8.25 (d, J=2.4 Hz, 1H), 7.53 (d, J=8.8 Hz, 1H), 6.82 (d, J=8.8 Hz, 1H), 3.41 (br s, 4H), 3.35 (br s, 2H), 2.64 (br s, 2H), 2.53 (br s, 4H), 1.61 (br s, 4H), 1.44 (br s, 2H), 1.19 (t, J=7.0 Hz, 6H).