Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.[F-].[K+].[CH2:29]([N:32]=[C:33]=[O:34])[CH:30]=[CH2:31].O>C1C=CC=CC=1>[CH2:29]([NH:32][C:33]([N:12]1[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=3[C:5]=2[N:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([C:22]#[N:23])([CH3:24])[CH3:25])=[CH:17][CH:16]=2)[C:13]1=[O:26])=[O:34])[CH:30]=[CH2:31]
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Reactant: C=CCN=C=O
Agent: [F-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: C=CCNC(=O)n1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(Br)ccc3ncc21

Procedure:
To a suspension of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 0.040 g, 0.10 mmol) and potassium fluoride (0.009 g, 0.147 mmol) in dry benzene (6 ml) was added allylisocyanate (0.010 g, 0.10 mmol) at RT. The reaction was stirred at reflux temperature for 6 hours. The reaction mixture was cooled and poured into cold water, extracted with ethyl acetate (2×20 ml). Organic layer was washed with water dried over sodium sulfate and concentrated. The crude product was triturated with ethyl acetate, filtered and filtrate was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 0.020 g (41%); 1H NMR (DMSO-d6, 300 MHz): δ 9.653 (s, 1H), 8.723-8.761 (t, 1H), 7.971-8.001 (d, 1H, J=9 Hz), 7.874-7.903 (d, 2H, J=8.7 Hz), 7.769-7.798 (d, 2H, J=8.7 Hz), 7.723-7.761 (dd, 1H, J=9, 2.1 Hz), 6.808-6.814 (d, 1H, J=1.8 Hz), 5.904-5.996 (m, 1H), 5.234-5.296 (dd, 1H, J=17.1, 1.2 Hz), 5.134-5.173 (dd, 1H, J=10.5, 1.2 Hz), 4.010-4.045 (t, 2H), 1.806 (s, 6H); MS: m/z 492 (M+).
Reaction SMILES: C([N:3]([CH:7]([CH3:9])C)[CH:4]([CH3:6])C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][C:20]2([CH2:27][CH2:26][CH:25]([C:28]([OH:30])=O)[CH2:24][CH2:23]2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].O.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[N:3]1([C:28]([CH:25]2[CH2:26][CH2:27][C:20]3([CH2:19][CH2:18][N:17]([C:15]([O:14][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:16])[CH2:22][CH2:21]3)[CH2:23][CH2:24]2)=[O:30])[CH2:4][CH2:6][CH2:9][CH2:7]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(C(=O)O)CC2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CCC(C(=O)N3CCCC3)CC2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-Ethyl-diisopropylamine (4 eq.) was added to a solution of 3-(tert-butoxycarbonyl)-3-azaspiro[5.5]undecane-9-carboxylic acid (commercially obtainable from Anthem, Order No. A1106) (0.35 g, 1.18 mmol, 1 eq.) in methylene chloride. The reaction mixture was cooled to 0° C. and N-ethyl-N′-3-(dimethylamino)-propyl-carbodiimide hydrochloride (1.2 eq.) and 1-hydroxybenzotriazole hydrate (0.2 eq.) were then added. The mixture was stirred at this temperature for 15 min, before the amine (1.1 eq.) was finally added. The reaction mixture was then stirred at room temperature overnight. For working up, the reaction mixture was washed in each case 1× with 10% strength NH4Cl solution, sat. NaHCO3 solution and sat. NaCl solution. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (silica; ethyl acetate/ethanol) in order to obtain the desired product. Yield: 0.23 g (56%)
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6](Cl)=[O:7])#[N:2].O[NH:17][C:18]([C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[CH:23]2)=[NH:19].C(N(CC)CC)C>C(#N)C>[NH:25]1[C:26]2[C:22](=[CH:21][C:20]([C:18]3[N:17]=[C:6]([C:5]4[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:7][N:19]=3)=[CH:28][CH:27]=2)[CH:23]=[N:24]1
Reactant: CC(C)Oc1ccc(C(=O)Cl)cc1C#N
Reactant: N=C(NO)c1ccc2[nH]ncc2c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4[nH]ncc4c3)no2)cc1C#N
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.2 %

Procedure:
3-Cyano-4-[(1-methylethyl)oxy]benzoyl chloride (D106) (545 mg, 2.437 mmol) and N-hydroxy-1H-indazole-5-carboximidamide (D2) (685 mg, 2.437 mmol) were dissolved in acetonitrile (30 ml) before adding triethylamine (0.374 ml, 2.68 mmol). The resulting mixture was stirred at room temperature for 3 h then at 80° C. for 48 h, then cooled at room temperature. The precipitate formed was filtered off and dissolved in EtOAc and washed with water, evaporated and chromatographed [0-15% EtOAc in cyclohexane] to give the title compound (170 mg, 17%) as a pink solid. MS (ES): C19H15N5O2 requires 345; found (MH+) 346
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[N:12]2[N:13]=[C:14]([Cl:17])[CH:15]=[CH:16][C:11]2=[N:10][CH:9]=1)=[O:6].[H-].[Na+]>CN(C=O)C.CCOC(C)=O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]2[N:12]([C:8]([N:7]3[CH2:2][CH2:3][CH2:4][C:5]3=[O:6])=[CH:9][N:10]=2)[N:13]=1
Reactant: O=C(CCCBr)Nc1cnc2ccc(Cl)nn12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C1CCCN1c1cnc2ccc(Cl)nn12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.7 %

Procedure:
To 1.0 g of 4-bromo-N-(6-chloroimidazo[1,2-b]pyridazin-3-yl)butanamide (3.15 mmol) dissolved in 39 mL DMF was added NaH (189 mg, 4.72 mmol), and stirred at rt for 0.5 hr. Dilute with 50 mL EtOAc and separate the organic layer. Wash twice with water, once with brine and dry over MgSO4. Concentrate to obtain the product 0.49 g (66%). No purification was needed.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([N:17]3[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]4[CH2:25][CH2:26][CH2:27][CH:18]34)(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:28]1([N:34]=[C:35]=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN(C=O)C>[C:28]1([NH:34][C:35](=[O:36])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[CH:10][C:11]([S:14]([N:17]4[CH:21]([C:22]([OH:24])=[O:23])[CH2:20][CH:19]5[CH2:25][CH2:26][CH2:27][CH:18]45)(=[O:16])=[O:15])=[CH:12][CH:13]=3)=[CH:4][CH:3]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccccc1)Nc1ccc(-c2ccc(S(=O)(=O)N3C(C(=O)O)CC4CCCC43)cc2)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
500 mg (1.30 mmol) of 1-(4′-aminobiphenyl-4-sulfonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid were dissolved in 3 ml of DMF, after which the solution was cooled down to 0° C. in an ice bath and 1.4 mmol of phenylisocyanate were added. The reaction solution was then stirred at RT for a further 4 h. The crude product was purified using chromatographic methods.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:15])[C@H:4]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[NH2:5].[C:16]1(=[O:23])[O:22][C:20](=[O:21])[CH:19]=[C:17]1[CH3:18]>C(Cl)(Cl)Cl>[C:16]([C:17]([CH3:18])=[CH:19][C:20]([NH:5][C@H:4]([C:3]([NH:2][CH3:1])=[O:15])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=1)=[O:21])([OH:23])=[O:22]
Reactant: CNC(=O)[C@@H](N)Cc1ccc(OC)cc1
Reactant: CC1=CC(=O)OC1=O
Solvent: ClC(Cl)Cl
Product: CNC(=O)[C@H](Cc1ccc(OC)cc1)NC(=O)C=C(C)C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 26 %

Procedure:
A mixed solution consisting of 50 g of N,O-dimethyltyrosine amide, 400 ml of dry chloroform and 27 g of citraconic anhydride was stirred at room temperature for 6 hours, concentrated under a reduced pressure, subjected to a silica gel column chromatography and eluted with chloroform-methanol-acetic acid to obtain 20 g of Nα -(3-carboxy-2-butenoyl)-N,O-dimethyltyrosine amide.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([C:15]([OH:17])=O)=[C:13]([CH2:18][CH3:19])[N:12]=[C:11]([S:20][CH3:21])[N:10]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:22]1([CH2:28][CH2:29][CH2:30][NH2:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[Cl:8][C:6]1[CH:5]=[C:4]([C:9]2[C:14]([C:15]([NH:31][CH2:30][CH2:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:17])=[C:13]([CH2:18][CH3:19])[N:12]=[C:11]([S:20][CH3:21])[N:10]=2)[CH:3]=[C:2]([Cl:1])[CH:7]=1
Reactant: CCc1nc(SC)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)O
Reactant: NCCCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCc1nc(SC)nc(-c2cc(Cl)cc(Cl)c2)c1C(=O)NCCCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
183 mg (0.533 mmol) of 4-(3,5-dichlorophenyl)-6-ethyl-2-(methylthio)-pyrimidine-5-carboxylic acid and 86.5 mg (0.640 mmol) of phenylpropylamine were dissolved in 10 ml of dichloromethane. 153 mg (0.800 mmol) of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (hereinafter referred to as WSC hydrochloride) was added under cooling with ice and stirred at room temperature overnight. After concentration under reduced pressure, the reaction mixture was diluted with ethyl acetate. The reaction mixture was washed with 1 N hydrochloric acid, saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1 to 1/1) to obtain the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([NH:18][C:17](=[O:19])[C:16]3[CH:20]=[C:21](Br)[CH:22]=[CH:23][C:15]=3[O:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27]>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[CH3:30][O:29][C:25](=[O:28])/[CH:26]=[CH:27]/[C:21]1[CH:22]=[CH:23][C:15]2[O:14][C:11]3([CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]3)[NH:18][C:17](=[O:19])[C:16]=2[CH:20]=1
Reactant: C=CC(=O)OC
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)c1cc(Br)ccc1O2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Product: COC(=O)/C=C/c1ccc2c(c1)C(=O)NC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Yield: 99.6 %

Procedure:
6-Bromo-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-1′-carboxylic acid tert-butyl ester (5.00 g, 12.6 mmol) was dissolved in hot DMF (15 ml) and then TEA (5.26 ml, 37.8 mmol), tris(o-tolyl)phosphine (153 mg, 0.504 mmol), Pd(OAc)2 (56 mg, 0.25 mmol) and methyl acrylate (3.25 g, 37.8 mmol) were added at RT. The mixture was heated at 100° C. for 6 h under N2 with a further addition of tris(o-tolyl)phosphine (153 mg, 0.504 mmol) and Pd(OAc)2 (56 mg, 0.25 mmol) after three hours) and then partitioned between brine and AcOEt. The organic phase was rinsed with water and brine, dried over Na2SO4 and evaporated. The residue was triturated in AcOEt and petroleum ether to give (E)-3-{1′-tert-butoxycarbonyl-3,4-dihydro-4-oxo-spiro[2H-(1,3)-benzoxazine-2,4′-piperidin]-6-yl}-acrylic acid methyl ester (5.05 g)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[C:20](=[O:27])[O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:29][C:30]([N:32]2[CH2:37][CH2:36][O:35][CH2:34][CH2:33]2)=[O:31])=[CH:4][CH:3]=1
Reactant: O=C(CCl)N1CCOCC1
Reactant: O=C1OC2(CCN(C(=O)c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21
Product: O=C1OC2(CCN(C(=O)c3cn(CC(=O)N4CCOCC4)c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
Following the general procedure V as described hereinabove, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidin]-3-one (the preparation of which has been described in example 16) with commercially available 2-chloro-1-morpholin-4-yl-ethanone as electrophile, the title compound was obtained as a white powder.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25](O)=[O:26])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:29]1[CH2:32][CH2:31][CH2:30]1>>[F:1][C:2]1[C:7]([C:8]2[N:28]=[C:11]3[CH:12]=[C:13]([NH:16][C:17]([C:19]4[N:23]([CH3:24])[N:22]=[CH:21][C:20]=4[C:25]([N:29]4[CH2:32][CH2:31][CH2:30]4)=[O:26])=[O:18])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: C1CNC1
Reactant: Cn1ncc(C(=O)O)c1C(=O)Nc1ccn2nc(-c3cccnc3F)nc2c1
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(-c3cccnc3F)nc2c1
Yield: 43.3 %

Procedure:
The product was prepared in the same manner as described in example 3 using 5-(2-(2-fluoropyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (80 mg, 210 μmol) and azetidine (42.8 μl, 629 μmol) as starting materials. The reaction affords 4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carboxylic acid [2-(2-fluoro-pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (38.2 mg, 43.3%) as white solid. MS: m/z=421.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.FC(F)(F)C1C=C([C:19]23[CH2:28][CH:23]([O:24][C:25]2([CH3:27])[CH3:26])[N:22]([CH3:29])[CH2:21][CH2:20]3)C=CC=1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[C:19]1([C:25]([CH3:27])([CH3:26])[OH:24])[CH2:28][CH2:23][N:22]([CH3:29])[CH2:21][CH2:20]1
Reactant: CN1CCC2(c3cccc(C(F)(F)F)c3)CC1OC2(C)C
Reactant: COc1ccc(OC)cc1
Solvent: CC(C)=O
Product: COc1ccc(OC)c(C2(C(C)(C)O)CCN(C)CC2)c1

Procedure:
4-(2',5'-Dimethoxyphenyl)-α,α,1-trimethyl-4-piperidinemethanol was prepared from 1,4-dimethoxybenzene by the procedure described in Example 3 except that acetone was used in place of cyclopentanone in the synthesis of III; m.p. 139°-140°; NMR (in CDCl3): τ 3.0-3.3 (m, 3H); 6.2 (2s, 6H); 6.6-8.5 (m+s, 12H) and 8.9 (broad, 6H). Anal. Calcd. for C17H27NO3 : C, 69.59; H, 9.29; N, 4.77. Found: C, 69.66; H, 9.09; N, 4.66.
Reaction SMILES: C([O:8][C:9]1[C:14]2[NH:15][C:16](=[O:19])[CH2:17][O:18][C:13]=2[C:12]([C:20](=[O:24])[CH:21](O)O)=[CH:11][CH:10]=1)C1C=CC=CC=1.[F:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:27]=1[CH2:28][C:29]1([NH2:32])[CH2:31][CH2:30]1.FC(F)(F)C([O-])=O>>[F:25][C:26]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:27]=1[CH2:28][C:29]1([NH:32][CH2:21][CH:20]([C:12]2[C:13]3[O:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[C:9]([OH:8])=[CH:10][CH:11]=2)[OH:24])[CH2:30][CH2:31]1
Reactant: NC1(Cc2c(F)cccc2F)CC1
Reactant: O=C1COc2c(C(=O)C(O)O)ccc(OCc3ccccc3)c2N1
Agent: O=C([O-])C(F)(F)F
Product: O=C1COc2c(C(O)CNC3(Cc4c(F)cccc4F)CC3)ccc(O)c2N1

Procedure:
Prepared according to general method 3 from 329 mg (1 mmol) 5-benzyloxy-8-(2,2-dihydroxy-acetyl)-4H-benzo[1,4]oxazin-3-one and 183 mg (1 mmol) 1-(2,6-difluoro-benzyl)-cyclopropylamine. Yield: 108 mg (21%, trifluoroacetate); mass spectroscopy: [M+H]+=391.
Reaction SMILES: [CH3:1][N:2]1[C:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]3[O:22][CH2:21]3)=[CH:14][CH:13]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:23].[C:24]([NH2:28])([CH3:27])([CH3:26])[CH3:25]>>[CH3:1][N:2]1[C:11]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH:20]([OH:22])[CH2:21][NH:28][C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:16][CH:17]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:23]
Reactant: CC(C)(C)N
Reactant: Cn1c(-c2ccc(OCC3CO3)cc2)cc2ccccc2c1=O
Product: Cn1c(-c2ccc(OCC(O)CNC(C)(C)C)cc2)cc2ccccc2c1=O
Yield: 84 %

Procedure:
2-Methyl-3-[4-(2-hydroxy-3-tert. butylamino-propoxy)-phenyl]-isoquinolin-1(2H)-one was prepared analogous to Example 1b from 2-methyl-3-[4-(2,3-epoxypropoxy)-phenyl]-isoquinolin-1(2H)-one and tert. butylamine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1.[H-].[Na+].F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[C:16]([CH3:22])[CH:15]=1.Cl>CN(C=O)C.CCOCC>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1)[O:10][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[C:16]([CH3:22])[CH:15]=1
Reactant: Cc1cc(F)ccc1C=O
Reactant: COc1cc(O)cc(F)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COc1cc(F)cc(Oc2ccc(C=O)c(C)c2)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 31.8 %

Procedure:
A 0° C. solution of 3-fluoro-5-methoxy-phenol (2.40 g, 16.9 mmol) in dry DMF (20 mL) is treated with a 60% suspension of NaH (0.74 g, 18.5 mmol) and then stirred for 15 minutes under N2. A solution of 4-fluoro-2-methyl-benzaldehyde (2.33 g, 16.9 mmol) in DMF (10 mL) is added dropwise, and the mixture is warmed to 60° C. for 4 hours. The mixture is cooled and acidified with 1 N HCl. The mixture is then diluted with Et2O and extracted with water. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to afford crude product that is absorbed on silica gel and purified by flash chromatography using 6/1 hexanes/ethyl acetate to afford 1.40 g (32%) of the title compound. Rf=0.41 (2/1 hexanes/EtOAc). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C15H13O3F 260, found 261 (M+1, 100%).
Reaction SMILES: [C:1]([C:7]1[CH:12]=[CH:11][N:10]([C@@H:13]2[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:38])[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:17]([O:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:14]2[O:15][CH3:16])[C:9](=[O:39])[N:8]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH3:6].CC(C)=[O:42]>O.C(O)(=O)C>[OH:42][C:2]([CH2:3][CH2:4][CH2:5][CH3:6])=[CH:1][C:7]1[CH:12]=[CH:11][N:10]([C@@H:13]2[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:38])[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C@@H:17]([O:18][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@H:14]2[O:15][CH3:16])[C:9](=[O:39])[N:8]=1
Reactant: CCCCC#Cc1ccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC)c(=O)n1
Reactant: CC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCCCC(O)=Cc1ccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC)c(=O)n1
Temperature: 25 °C
Reaction time: 5 h
Yield: 19 %

Procedure:
4-(1-Hexyn-1-yl)-1-(2-O-methyl-3,5,-di-O-benzoyl-β-D-ribofuranosyl)pyrimidin-2-one was dissolved in acetone (40 ml) and to this solution was added mercuric sulfate dissolved in H2O (10 ml) and acetic acid (10 ml). This solution was stirred at room temperature for 5 hours. The reaction was purified by silica gel column chromatography. Pooling of appropriate fractions and concentration gave 225 mg (19%) of the title compound.
Reaction SMILES: O=[C:2]1[C:11]2[CH2:12][CH2:13]O[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=2[NH:3]1.[CH3:20][C:21]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:22]=1[NH2:23]>C(O)COCCO.[Cl-].[Na+].O>[CH3:20][C:21]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:22]=1[N:23]1[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:15][C:16]([F:19])([F:18])[F:17])[C:4]=3[N:3]=[C:2]([NH:3][CH2:4][CH2:5][OH:15])[C:11]=2[CH2:12][CH2:13]1
Reactant: O=c1[nH]c2c(OC(F)(F)F)cccc2c2c1CCO2
Reactant: Cc1cccc(N)c1C
Agent: [Cl-]
Agent: [Na+]
Solvent: OCCOCCO
Solvent: O
Product: Cc1cccc(N2CCc3c(NCCO)nc4c(OC(F)(F)F)cccc4c32)c1C
Temperature: 250 °C
Yield: 113.5 %

Procedure:
4-Oxo-6-trifluoromethoxy-2,3,4,5-tetrahydrofuro[3,2-c]quinoline(5.0 g, 19 mmol) was dissolved in diethylene glycol(30 ml), and 2,3-dimethylaniline(5.6 ml, 46 mmol) was added under nitrogen. The reaction mixture was refluxed at 250° C. for 15 hours. The reaction mixture was diluted in brine(20 ml), and the aqueous layer was extracted with dichloromethane(15 ml) for 3 times. The organic layer was washed with water(15 ml) for 3 times, dried with by anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography with ethyl acetate as eleunt to obtain 4.5 g of desired compound as solid in 65% of yield.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([CH:16]=[C:17]([C:23]([OH:25])=O)[C:18](=[O:22])[O:19]2)=[CH:14][CH:13]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:50]1[C:51]([C:59]2[CH:60]=[C:61]([NH2:65])[CH:62]=[CH:63][CH:64]=2)=[CH:52][N:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=12>CN(C)C=O>[N:50]1[C:51]([C:59]2[CH:60]=[C:61]([NH:65][C:23]([C:17]3[C:18](=[O:22])[O:19][C:20]4[C:15]([CH:16]=3)=[CH:14][CH:13]=[C:12]([O:11][CH3:10])[CH:21]=4)=[O:25])[CH:62]=[CH:63][CH:64]=2)=[CH:52][N:53]2[CH:58]=[CH:57][CH:56]=[CH:55][C:54]=12
Reactant: COc1ccc2cc(C(=O)O)c(=O)oc2c1
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2cc(C(=O)Nc3cccc(-c4cn5ccccc5n4)c3)c(=O)oc2c1
Temperature: 25 °C
Yield: 88.5 %

Procedure:
DIEA (0.027 mL, 0.16 mmol) was added to 7-methoxy-3-carboxy-coumarin (0.031 g, 0.14 mmol) and HATU (0.060 g, 0.16 mmol) in 2 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-Imidazo[1,2-a]pyridin-2-yl-phenylamine (0.030 g, 0.14 mmol) was added and allowed to react for approximately 30 minutes, when a yellow solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 0.051 g of 1541C in an 86% yield: 1H NMR (400 MHz, CD3OD/CDCl3) δ 10.95 (s, 1H), 8.96 (s, 1H), 8.23 (dd, J=1.8, 1.9 Hz, 1H), 8.20 (d, J=7.1 Hz, 1H), 7.99 (s, 1H), 7.79 (d, J=7.7 Hz, 1H), 7.75 (d, J=8.1 Hz, 1H), 7.68 (d, J=8.6 Hz, 1H), 7.63 (d, J=9.1 Hz, 1H), 7.48 (dd, J=7.9, 8.0 Hz, 1H), 7.25 (dd, J=5.5, 6.8 Hz, 1H), 7.01 (dd, J=2.4, 8.8 Hz, 1H), 6.95 (d, J=2.4 Hz, 1H), 6.85 (dd, J=7.0, 7.3 Hz, 1H), 3.96 (s, 3H); LCMS (ESI) m/z 412 (MH+).
Reaction SMILES: C(N(CC)CC)C.Br.[NH2:9][CH:10]1[CH2:15][CH2:14][O:13][C:11]1=[O:12].[O:16]([C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>ClCCl>[O:16]([C:23]1[CH:28]=[CH:27][C:26]([S:29]([NH:9][CH:10]2[CH2:15][CH2:14][O:13][C:11]2=[O:12])(=[O:31])=[O:30])=[CH:25][CH:24]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: NC1CCOC1=O
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1OCCC1NS(=O)(=O)c1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
Triethylamine (20.0 ml, 143.9 mmol) was added to a suspension of α-amino-γ-butyrolactone hydrobromide (7.28 g, 40.0 mmol) in dichloromethane (80 ml), and then 20 minutes were spent in adding dropwise a solution of 4-phenoxybenzenesulfonyl chloride (11.0 g, 40.9 mmol) in dichloromethane (40 ml) to the mixture with ice-cooling. After this mixture was stirred at room temperature for 2 hours, the solvent of the reaction mixture was evaporated under reduced pressure. The residue was acidified with water and hydrochloric acid (1N), and then extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=2/1 as the eluant to give the title compound (8.74 g, yield 73%) as a white powder.