Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([O:13]CC2C=CC=CC=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:21]([OH:23])=[O:22])=[N:7]2.Cl>>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[C:9]([OH:13])=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:21]([OH:23])=[O:22])=[N:7]2
Reactant: O=C(O)c1ccc2c(Cl)cc(Cl)c(OCc3ccccc3)c2n1
Agent: Cl
Product: O=C(O)c1ccc2c(Cl)cc(Cl)c(O)c2n1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5,7-dichloro-8-benzyloxy-quinoline-2-carboxylic acid 18 (2.56 g, 7.35 mmol) and concentrated hydrochloric acid (25 mL) was stirred at RT for 48 h, and then concentrated to dryness. The resulting residue was washed with diethyl ether (20 mL×2). This provided 5,7-dichloro-8-hydroxyquinoline-2-carboxylic acid 19 as a yellow solid (1.78 g, 94%). 1H NMR (CDCl3/DMSO-d6 (19:1), 400 MHz): δ 10.60 (br, 1 H), 8.53 (d, J=8.8, 1 H), 8.22 (d, J=8.8, 1 H), 7.60 (s, 1 H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[C:5]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:4]([CH2:20][N:21]([CH3:23])[CH3:22])[N:3]=1.[CH3:24][S:25]([O:27][Na])=[O:26]>CN(C=O)C>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([S:25]([CH3:24])(=[O:27])=[O:26])=[N:3][C:4]([CH2:20][N:21]([CH3:23])[CH3:22])=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc2c(Cl)nc(CN(C)C)c(-c3ccccc3)c2c1
Reactant: CS(=O)O[Na]
Solvent: CN(C)C=O
Product: COc1ccc2c(S(C)(=O)=O)nc(CN(C)C)c(-c3ccccc3)c2c1
Reaction time: 48 h

Procedure:
A mixture of 1-(1-chloro-6-methoxy-4-phenylisoquinolin-3-yl)-N,N-dimethylmethanamine (75 mg), 1 mL DMF, and MeSO2Na (41 mg) was stirred at 80 C for 48 h, then at 100 C for 96 h. The solution was cooled and purified directly by reverse-phase HPLC to give the titled compound.
Reaction SMILES: [C:1]([C:5]1[N:6]([CH2:31][CH:32]([OH:36])[CH2:33][C:34]#[N:35])[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:19][CH2:18]1)=[O:16])=[CH:9][CH:8]=2)([CH3:4])([CH3:3])[CH3:2].[NH4+].[Cl-].[N-:39]=[N+:40]=[N-:41].[Na+]>CN(C=O)C>[C:1]([C:5]1[N:6]([CH2:31][CH:32]([OH:36])[CH2:33][C:34]2[N:39]=[N:40][NH:41][N:35]=2)[C:7]2[C:12]([CH:13]=1)=[CH:11][C:10]([NH:14][C:15]([C:17]1([C:20]3[CH:30]=[CH:29][C:23]4[O:24][C:25]([F:28])([F:27])[O:26][C:22]=4[CH:21]=3)[CH2:18][CH2:19]1)=[O:16])=[CH:9][CH:8]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1CC(O)CC#N
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2n1CC(O)Cc1nn[nH]n1

Procedure:
To a solution of N-(2-tert-butyl-1-(3-cyano-2-hydroxypropyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (27 mg, 0.054 mmol) in anhydrous DMF (1.2 mL) were successively added NH4Cl (35 mg, 0.65 mmol) and NaN3 (43 mg, 0.65 mmol) at room temperature. The reaction mixture was stirred for 4 h at 110° C. in the microwave, at which stage 50% of the starting material was converted to the desired product. The reaction mixture was purified by preparative HPLC to provide N-(2-tert-butyl-1-(2-hydroxy-3-(2H-tetrazol-5-yl)propyl)-1H-indol-5-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide. MS (ESI) m/e (M+H+) 539.0.
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:29]=[CH:28][C:14]2[O:15][CH2:16][CH:17]([C:19]([CH3:27])([CH3:26])[O:20][SiH2:21][C:22]([CH3:25])([CH3:24])[CH3:23])[O:18][C:13]=2[C:12]=1[CH3:30])=[O:10])C1C=CC=CC=1.[H][H].C(Cl)(Cl)Cl>C(Cl)Cl.[Pd]>[C:22]([SiH2:21][O:20][C:19]([CH3:27])([CH3:26])[CH:17]1[CH2:16][O:15][C:14]2[CH:28]=[CH:29][C:11]([C:9]([OH:10])=[O:8])=[C:12]([CH3:30])[C:13]=2[O:18]1)([CH3:25])([CH3:23])[CH3:24]
Reactant: Cc1c(C(=O)OCc2ccccc2)ccc2c1OC(C(C)(C)O[SiH2]C(C)(C)C)CO2
Reactant: [H][H]
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: Cc1c(C(=O)O)ccc2c1OC(C(C)(C)O[SiH2]C(C)(C)C)CO2
Reaction time: 3 h
Yield: 85.1 %

Procedure:
9.63 g of 3-(tert-Butyl-dimethyl-silanyloxymethyl)-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid benzyl ester was dissolved in ca. 125 mL of dry CH2Cl2. The solution was transferred to a Parr hydrogenation bottle, and 5 g of 5% Pd on carbon were added. The bottle was charged with hydrogen and shaken on a Parr hydrogenation apparatus for 3 hours; hydrogen uptake ceased after 2 hours, as indicated by pressure monitoring. 100 mL CHCl3 were added, and the Pd/C was filtered off after adding MgSO4 as an aid to increase particle size. The CH2Cl2—CHCl3 phase was washed with 200 mL of 0.1N HCl to remove the by-product benzyl alcohol. The organic layer was dried and evaporated to give 6.47 g 3-(tert-butyl-dimethyl-silanyloxymethyl)-5-methyl-2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid, after trace solvent removal in a vacuum oven. TLC Rf=0.55 (1:1 ethyl acetate:hexane). Note: (a) Pd catalyzed hydrogenation is a far superior method to triethylsilane/palladium diacetate for this benzyl ester cleavage, (b) washing product with weak aqueous acid is a good way to remove benzyl alcohol. 1H NMR (300 MHz, CDCl3) δ (ppm): 7.55 (d, 1H), 6.7 (d, 1H), 4.3 (d, 1H), 4.17 (m, 1H), 4.02 (dd, 1H), 3.82 (dd, 1H), 3.75 (dd, 1H), (2.45 (s, 3H), 0.8 (s, 9H), 0.01 (s, 3H).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:28][CH:27]=3)[CH2:30][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(-c2cc(CCC=O)nn2C(C)(C)C)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(N2CCN(CCCc3cc(-c4ccc(C)cc4)n(C(C)(C)C)n3)CC2)cc1

Procedure:
77 mg (72%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-p-tolyl-1H-pyrazol-3-yl)propanal (60 mg, 0.222 mmol), 1-(4-methoxyphenyl)piperazine (43 mg, 0.222 mmol), DIPEA (0.06 mL, 0.333 mmol) and NaBH(OAc)3 (141 mg, 0.666 mmol).
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][O:4][CH2:5]2.[CH2:7]([OH:10])[CH:8]=[CH2:9].B(F)(F)F>ClCCl>[CH2:7]([O:10][C@H:6]1[C@H:2]([OH:1])[CH2:3][O:4][CH2:5]1)[CH:8]=[CH2:9]
Reactant: C=CCO
Reactant: C1OCC2OC12
Agent: FB(F)F
Solvent: ClCCl
Product: C=CCO[C@@H]1COC[C@H]1O
Temperature: 25 °C

Procedure:
To a 10-L flask fitted with a double surface condenser, overhead stirrer and nitrogen inlet was added 3,4-epoxytetrahydrofuran (750 g, 8.71 mol), dichloromethane (3750 ml, 5 vol) and allyl alcohol (2530 g, 43.56 mol, 5 eq.). The solution was cooled to between 0° and 5° C. and boron trifluoride diethyletherate (61.8 g, 0.436 mol, 0.05 eq.) was added dropwise whilst maintaining the temperature below 10° C. After addition was complete the solution was allowed to warm to room temperature at which point the reaction slowly exothermed to reflux. After 3 hours 1H NMR analysis showed that no epoxide remained and the reaction was quenched with saturated aqueous sodium hydrogen carbonate solution (1500 mL, 2 vol). The phases were separated and the organic phase was washed with a further portion of saturated aqueous sodium hydrogen carbonate solution (1500 mL, 2 vol). The combined aqueous washes were extracted with CH2Cl2 (5×750 ml, 1 vol). After drying the organic phases over MgSO4, filtering and concentrating in vacuo, the trans-3-allyloxy-4-hydroxytetrahydrofuran (I) was isolated by reduced pressure distillation (bp 94° C. @ 3 mbar) to give 1004.0 g (79.9% yield) of a clear colorless liquid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][S:15][S:16][CH3:17])[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:19][C:20]#[N:21].C(NC(C)C)(C)C>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][CH2:14][S:15][S:16][CH3:17])[C:10]([O:12][CH2:19][C:20]#[N:21])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#CCCl
Reactant: CSSCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CSSCC[C@H](NC(=O)OC(C)(C)C)C(=O)OCC#N
Reaction time: 8 h
Yield: 63 %

Procedure:
Boc-L-Hcm-OH (43 mg, 153 μmol) was dissolved in THF (1 mL). To the solution were added chloroacetonitrile (484 μL, 7.65 mmol) and diisopropylamine (53 μL, 306 μmol). The mixture was stirred overnight under N2 atmosphere. After 18 h, additional chloroacetonitrile (484 L, 7.65 mmol) was added. Concentration under reduced pressure followed by flash chromatography over silica gel with AcOEt-Hexane (3:1) gave the titled compound in (31.3 mg, 63% yield): 1H NMR (360 MHz, CDCl3) δ 5.02 (s, 1H), 4.73 (dd, J=31.3 Hz, 2H) 4.49 (s, 1H), 2.77-2.73 (m, 2H), 2.37 (m, 3H), 2.37-2.27 (m, 1H), 2.13-2.02 (m, 1H), 1.46 (s, 9H); LRMS (ESI) m/z calcd for C12H21N2O4S2 (M+H)+ 321.1. found 321.0.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:19][CH2:18][C:11]2([NH:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CI.[C:22](=O)([O-])[O-].[K+].[K+]>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]2([NH:15][C:14](=[O:16])[N:13]([CH3:22])[C:12]2=[O:17])[CH2:18][CH2:19]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)NC(=O)NC2=O
Agent: [K+]
Solvent: CI
Solvent: CS(C)=O
Product: CN1C(=O)NC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Temperature: 25 °C
Reaction time: 18 h
Yield: 103.2 %

Procedure:
To a solution of 2,4-dioxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (3.60 g, 13 mmol) in DMSO (30 ml), MeI (2.27 g, 16 mmol) and potassium carbonate (2.40 g, 17 mmol) are added at ambient temperature. The mixture is stirred for 18 h at ambient temperature. The reaction mixture is quenched with water and extracted with AcOEt. The combined extracts are washed with brine, dried over magnesium sulfate, filtrated and evaporated to afford 3.8 g of the desired product.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].N1C=CC=CC=1.[CH2:12]([C:14]1([CH2:32][CH3:33])[N:19]=[C:18]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[C:17]2[CH:27]=[CH:28][C:29]([NH2:31])=[CH:30][C:16]=2[O:15]1)[CH3:13]>C(Cl)(Cl)Cl>[CH2:32]([C:14]1([CH2:12][CH3:13])[N:19]=[C:18]([C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[C:17]2[CH:27]=[CH:28][C:29]([NH:31][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:30][C:16]=2[O:15]1)[CH3:33]
Reactant: CS(=O)(=O)Cl
Reactant: CCC1(CC)N=C(c2ccc(F)cc2)c2ccc(N)cc2O1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCC1(CC)N=C(c2ccc(F)cc2)c2ccc(NS(C)(=O)=O)cc2O1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (63 μL) and pyridine (131 μL) were added dropwise to a solution of 2,2-diethyl-4-(4-fluorophenyl)-2H-1,3-benzoxazin-7-amine (a compound of Reference Example 4, 81 mg) in chloroform (5 mL), and the mixture was stirred at 40° C. overnight. The reaction mixture was purified by column chromatography on NH-silica gel (Chromatorex NH-silica gel, Solvent: chloroform/methanol=100/0 to 90/10), and the resultant powder was suspended in diisopropyl ether. The resultant precipitates were collected by filtration and washed with hexane-diisopropyl ether to give the titled compound (69 mg) as a colorless powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:35][CH:36]([CH:40]1[CH2:42][CH2:41]1)[CH2:37][CH2:38][OH:39]>>[CH:40]1([CH:36]([NH:35][C:29]([C:14]2[C:15](=[O:28])[N:16]([CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]3=[O:27])[C:17]3[C:12]([C:13]=2[OH:34])=[N:11][CH:10]=[C:9]([CH2:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH:18]=3)=[O:30])[CH2:37][CH2:38][OH:39])[CH2:42][CH2:41]1
Reactant: NC(CCO)C1CC1
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O
Product: O=C(NC(CCO)C1CC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN2CCCCC2=O)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-[2-(2-oxo-1-piperidinyl)ethyl]-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 3-amino-3-cyclopropyl-1-propanol using methods similar to Example 563 to provide an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 0.24-0.34 (m, 2 H), 0.38-0.46 (m, 1 H), 0.52 (t, J=8.74 Hz, 1 H), 1.00-1.11 (m, 1 H), 1.54-1.67 (m, 4 H), 1.75-1.88 (m, 2 H), 2.04 (s, 2 H), 3.28 (t, J=5.69 Hz, 3 H), 3.46-3.60 (m, 5 H), 4.17 (s, 2 H), 4.41 (t, J=6.95 Hz, 2 H), 7.11-7.17 (m, 2 H), 7.38-7.45 (m, 2 H), 8.22 (s, 1 H), 8.56 (d, J=1.47 Hz, 1 H), 10.36 (d, J=8.63 Hz, 1 H), 17.23 (s, 1 H); ES+ MS: 537 (M+H+).
Reaction SMILES: F[C:2]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:3]=1[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1.[C:19]1([OH:25])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC([O-])(C)C.[K+]>C1(C)C=CC=CC=1.O>[N+:16]([C:13]1[CH:14]=[CH:15][C:2]([O:25][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:3]([CH:12]=1)[CH2:4][O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)([O-:18])=[O:17]
Reactant: O=[N+]([O-])c1ccc(F)c(COC2CCCCO2)c1
Reactant: Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2ccccc2)c(COC2CCCCO2)c1
Temperature: 120 °C
Yield: 89.8 %

Procedure:
A mixture of 394B (125 mg, 0.49 mmol), phenol (55 mg, 0.59 mmol) and t-BuOK (65 mg, 0.58 mmol) in toluene (1 ml) was heated at 120° C. for 2 h. and then diluted with water, extracted with EtOAc, dried and concentrated to give 394C (145 mg, 90%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:14]3[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[CH:16][CH:15]=3)=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=[CH:4][N:3]=1.[NH:32]([CH2:36]CO)[CH2:33]CO.O>CN(C)C=O>[CH3:33][N:32]([CH3:36])[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([C:14]3[CH:31]=[CH:30][C:17]([O:18][CH2:19][C:20]4[CH:29]=[CH:28][C:27]5[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=5)[N:21]=4)=[CH:16][CH:15]=3)=[N:10][N:11]([CH3:13])[CH:12]=2)[CH:5]=[CH:4][N:3]=1
Reactant: OCCNCCO
Reactant: Cn1cc(-c2ccnc(Cl)c2)c(-c2ccc(OCc3ccc4ccccc4n3)cc2)n1
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1cc(-c2cn(C)nc2-c2ccc(OCc3ccc4ccccc4n3)cc2)ccn1
Temperature: 130 °C

Procedure:
To a solution of 2-{4-[4-(2-Chloro-pyridin-4-yl)-1-methyl-1H-pyrazol-3-yl]-phenoxymethyl}-quinoline (100 mg) in dimethyl formamide (1 ml) was added diethanolamine (0.035 ml) and the reaction mixture heated at 130° C. for 72 h. The reaction mixture was poured into water and extracted with ethyl ether, dried magnesium sulfate, filtered and concentrated. Prep TLC eluting with 60% ethyl acetate/hexane provided the title compound as a Free base. The product was stirred in ethyl acetate and 1 eq. of succinic acid was added. After 18 h, the white precipitate was filtered to provide the succinate salt (24 mg). 1H NMR (400 MHz, DMSO) δ 8.40 (d, J=8.3 Hz, 1 H), 8.03 (s, 1 H), 7.98 (m, 2 H), 7.90 (d, J=5.4 Hz, 1 H), 7.77 (m, 1H), 7.65 (d, J=8.3 Hz, 1 H), 7.59 (m, 1 H), 7.31 (d, J=6.6 Hz, 2H), 7.04 (d, J=9.1 Hz, 2 H), 6.37 (m, 2 H), 5.35 (s, 2H), 3.84 (s, 3H), 2.80 (s, 6H) 2.37 (s, 4H); MS: M+H m/z=436.0).
Reaction SMILES: [CH2:1]([C@H:3]1[CH2:7][NH:6][CH2:5][C@H:4]1[NH:8][C:9]1[C:10]2[N:11]([CH:18]=[C:19]([C:21]3[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=3)[CH:20]=2)[N:12]=[CH:13][C:14]=1[C:15]([NH2:17])=[O:16])[CH3:2].[C:34]([C:36]([CH3:41])([CH3:40])[C:37](O)=[O:38])#[N:35].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:34]([C:36]([CH3:41])([CH3:40])[C:37]([N:6]1[CH2:7][C@H:3]([CH2:1][CH3:2])[C@H:4]([NH:8][C:9]2[C:10]3[N:11]([CH:18]=[C:19]([C:21]4[CH:22]=[N:23][C:24]([CH2:27][NH:28][C:29](=[O:33])[CH2:30][O:31][CH3:32])=[CH:25][CH:26]=4)[CH:20]=3)[N:12]=[CH:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH2:5]1)=[O:38])#[N:35]
Reactant: CC[C@H]1CNC[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Reactant: CC(C)(C#N)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)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: CC[C@H]1CN(C(=O)C(C)(C)C#N)C[C@H]1Nc1c(C(N)=O)cnn2cc(-c3ccc(CNC(=O)COC)nc3)cc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 26 %

Procedure:
A mixture of 4-(((3S,4S)-4-ethylpyrrolidin-3-yl)amino)-6-(6-((2-methoxyacetamido)methyl)pyridin-3-yl)pyrrolo[1,2-b]pyridazine-3-carboxamide, 2hydroiodide (30 mg, 0.042 mmol), 2-cyano-2-methylpropanoic acid (14.39 mg, 0.127 mmol), BOP (56.3 mg, 0.127 mmol) and Hunig's Base (0.052 mL, 0.297 mmol) in DMF (0.25 mL) was stirred at rt for 2 hr. The reaction mixture was purified via preparative LC/MS with the following conditions: Column: Waters XBridge C18, 19×150 mm, 5-μm particles; Guard Column: Waters XBridge C18, 19×10 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile:water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile:water with 10-mM ammonium acetate; Gradient: 5-100% B over 15 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford the title compound (6 mg, 0.011 mmol, 26% yield). 1H NMR (500 MHz, METHANOL-d4) δ 8.79 (dd, J=9.4, 2.0 Hz, 1H), 8.14 (d, J=5.0 Hz, 1H), 8.06-7.93 (m, 2H), 7.38 (dd, J=8.2, 3.2 Hz, 1H), 7.20-7.10 (m, 1H), 5.07-4.87 (m, 1H), 4.57 (s, 2H), 4.36-4.14 (m, 2H), 3.97 (s, 2H), 3.95-3.68 (m, 2H), 3.46 (s, 3H), 2.68-2.44 (m, 1H), 1.83-1.39 (m, 8H), 1.07-0.95 (m, 3H). MS (ES+) m/z: 547.1 (M+H); LC retention time: 1.19 min (analytical LCMS Method H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6]([OH:9])=[N:7][O:8][C:4]=2[CH:3]=1.[F:12][C:13]([F:24])([F:23])[CH:14]1[CH2:19][CH2:18][N:17]([C:20](Cl)=[O:21])[CH2:16][CH2:15]1>>[F:23][C:13]([F:12])([F:24])[CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:9][C:6]2[C:5]3[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[O:21])[CH2:16][CH2:15]1
Reactant: O=C(Cl)N1CCC(C(F)(F)F)CC1
Reactant: Oc1noc2cc(Cl)ccc12
Product: O=C(Oc1noc2cc(Cl)ccc12)N1CCC(C(F)(F)F)CC1

Procedure:
In analogy to example 1,200 mg (1.18 mmol) of 6-chlorobenzo[d]isoxazol-3-ol were reacted with 305 mg (1.41 mmol) of 4-trifluoromethylpiperidine-1-carbonyl chloride. Yield: 229 mg (56%), M+H+: 349.05.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]Cl)=[C:6]([Cl:10])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH:17][C:18](=[O:31])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[NH:28][CH3:29])=[CH:23][CH:22]=1.[CH3:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[C:36]([OH:43])[CH:37]=[CH:38][CH:39]=2)[N:34]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[C:7]([CH2:8][O:43][C:36]2[CH:37]=[CH:38][CH:39]=[C:40]3[C:35]=2[N:34]=[C:33]([CH3:32])[CH:42]=[CH:41]3)=[C:6]([Cl:10])[CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[CH2:16][NH:17][C:18](=[O:31])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:30])[NH:28][CH3:29])=[CH:23][CH:22]=1
Reactant: CNC(=O)c1ccc(C=CC(=O)NCc2cccn2-c2ccc(Cl)c(CCl)c2Cl)cc1
Reactant: Cc1ccc2cccc(O)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1ccc(C=CC(=O)NCc2cccn2-c2ccc(Cl)c(COc3cccc4ccc(C)nc34)c2Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 1-(2,4-dichloro-3-chloromethylphenyl)-2-[4-(methylcarbamoyl)cinnamoylaminomethyl]pyrrole (50 mg), 2-methyl-8-hydroxyquinoline (17 mg) and potassium carbonate (44 mg) in N,N-dimethylformamide (2 ml) was stirred at ambient temperature for 1 day. The mixture was poured into water and extracted with chloroform. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin-layer chromatography on silica gel to give 1-[2,4-dichloro-3-(2-methylquinolin-8-yloxymethyl)phenyl]-2-[4-(methylcarbamoyl)-cinnamoylaminomethyl]pyrrole (40 ml) as an amorphous powder.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:11].N[C:13]1C(Cl)=NC(C)=NC=1NC>>[Cl:1][C:2]1[N:10]=[C:9]([CH3:13])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH3:11]
Reactant: CNc1nc(C)nc(Cl)c1N
Reactant: Cn1cnc2c(Cl)ncnc21
Product: Cc1nc(Cl)c2ncn(C)c2n1
Reaction time: 6 h
Yield: 97 %

Procedure:
This was prepared in a manner similar to that described in Example 9 for 6-chloro-9-methylpurine, except that 5-amino-4-chloro-2-methyl-6-methylaminopyrimidine was used as the starting material and the reaction was carried out at 60° C. for 6 hrs. The title compound was obtained in 97% yield.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[CH3:26][O:27][CH:28]([CH2:32][CH2:33][CH2:34][CH3:35])[C:29](O)=[O:30].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:1][N:2]([CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[C:29](=[O:30])[CH:28]([O:27][CH3:26])[CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Reactant: CCCCC(OC)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCCC(OC)C(=O)N(C)C1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
A mixture of compound 7B (30 mg, 0.088 mmol), 2-methoxy caproic acid (20 mg, 0.137 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodimide hydrochloride (34 mg, 0.177 mmol), 1-hydroxybenzotriazole (24 mg, 0.177 mmol) and dichloromethane (1 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in minimum amount of dichloromethane and purified on silica gel column, which was eluted with 0.3% ammonium hydroxide and 3% methanol in dichloromethane to give the desired product (38 mg, 92% yield).
Reaction SMILES: Cl[C:2]1[C:3](=[O:21])[N:4]([CH2:19][CH3:20])[S:5](=[O:18])(=[O:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[N:22]1([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>>[CH2:19]([N:4]1[C:3](=[O:21])[C:2]([NH:32][C:31]2[CH:30]=[CH:29][C:28]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:34][CH:33]=2)=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[S:5]1(=[O:18])=[O:17])[CH3:20]
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: CCN1C(=O)C(Cl)=C(c2ccc(C(F)(F)F)cc2)S1(=O)=O
Product: CCN1C(=O)C(Nc2ccc(N3CCOCC3)cc2)=C(c2ccc(C(F)(F)F)cc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-ethyl-5-[4-(trifluoromethyl)phenyl]isothiazol-3(2H)-one 1,1-dioxide and 4-morpholin-4-ylaniline in a similar manner as described for Example 11. 1H NMR (500 MHz, CDCl3): δ 1.51 (t, 3H), 2.98-3.01 (m, 4H), 3.81-3.83 (m, 4H), 3.88 (q, 2H), 6.52 (d, 2H), 6.64 (d, 2H), 7.22 (d, 2H), 7.36 (d, 2H).