Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:36])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:28])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:8][CH:9]=2)[N:4]([CH2:29][CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:3]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:41](C)=O.[Na+]>ClCCCl>[CH3:1][C:2]1([CH3:36])[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12](=[O:28])[C:13]3[CH:18]=[CH:17][CH:16]=[N:15][C:14]=3[NH:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[CH:8][CH:9]=2)[N:4]([CH2:29][CH:30]2[CH2:31][CH2:32][N:33]([CH3:41])[CH2:34][CH2:35]2)[CH2:3]1
Reactant: CC1(C)CN(CC2CCNCC2)c2cc(NC(=O)c3cccnc3NCc3ccc(F)cc3)ccc21
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Product: CN1CCC(CN2CC(C)(C)c3ccc(NC(=O)c4cccnc4NCc4ccc(F)cc4)cc32)CC1
Reaction time: 4 h

Procedure:
To N-(3,3-dimethyl-1-piperidin-4-ylmethyl-2,3-dihydro-1H-indol-6-yl)-2-(4-fluoro-benzylamino)-nicotinamide (0.92 g) dissolved in DCE (20 mL) at RT was added formaldehyde (37% aqueous, 0.42 mL) followed by NaBH(OAc)3 (1.59 g). After 4 h, the mixture was quenched with 1 N HCl (20 mL) and H2O (20 mL). It was basified with sat NaHCO3, extracted with CH2Cl2 (3×50 mL) and the combined extracts were washed with brine, dried (K2CO3) and concentrated onto SiO2 (previously treated with 10% MeOH (2 M NH3 in MeOH/CH2Cl2 and then concentrated in vacuo). The residue was purified by flash chromatography (Isco, 35 g column, 1-7% MeOH (2M NH3 in MeOH/CH2Cl2). The bulk of the crude yellow material was further purified by reverse phase Prep HPLC. The isolated fractions were partially concentrated and basified with 1 N NaOH and dried under vacuum to afford a slightly yellow powder. M+H=502.3. Calc'd for C30H36FN5O: 501.29.
Reaction SMILES: B(Br)(Br)Br.[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([O:31]CC2C=CC=CC=2)=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)(=[O:20])=[O:19])=[C:14]([C:27]([F:30])([F:29])[F:28])[CH:13]=2)[CH:11]=1>C(Cl)Cl>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([OH:31])=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)(=[O:20])=[O:19])=[C:14]([C:27]([F:28])([F:29])[F:30])[CH:13]=2)[CH:11]=1
Reactant: O=S(=O)(c1ccc(-c2cc(Cl)ccc2OCc2ccccc2)cc1C(F)(F)F)N1CCOCC1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=S(=O)(c1ccc(-c2cc(Cl)ccc2O)cc1C(F)(F)F)N1CCOCC1
Reaction time: 0.25 h

Procedure:
Boron tribromide (2.5 ml, 1.0 M in DCM) was added to a solution of the product from step b) (1.16 g) in DCM (15 ml) at 0° C. The solution was stirred for 15 min then quenched with water. The mixture was extracted with DCM (three times), the organic extracts were dried (MgSO4), evaporated and purified by chromatography (silica, petrol-ether as eluent) to give the sub-title compound (851 mg).
Reaction SMILES: CS(O[CH2:6][CH2:7][S:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]2[C:21]([Cl:22])=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=2)[CH:10]=1)(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH2:30][C:31]1[CH:32]=[C:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH:34]=[CH:35][CH:36]=1>CN(C)C=O>[Cl:23][C:18]1[N:17]=[C:16]([NH:15][C:11]2[CH:10]=[C:9]([S:8][CH2:7][CH2:6][NH:30][C:31]3[CH:32]=[C:33]([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])[CH:34]=[CH:35][CH:36]=3)[CH:14]=[CH:13][CH:12]=2)[C:21]([Cl:22])=[CH:20][N:19]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Reactant: CS(=O)(=O)OCCSc1cccc(Nc2nc(Cl)ncc2Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(NCCSc2cccc(Nc3nc(Cl)ncc3Cl)c2)c1
Temperature: 20 °C
Reaction time: 16 h
Yield: 10.6 %

Procedure:
A solution of 2-({3-[(2,5-dichloropyrimidin-4-yl)amino]phenyl}thio)ethyl methanesulfonate (0.17 g, 0.43 mmol) in N,N-dimethylformamide (2 mL) was treated with potassium carbonate (0.15 g, 1.1 mmol) followed by tert-butyl (3-aminophenyl)carbamate (0.17 g, 0.81 mmol) and stirred at 20° C. for 16 h. The reaction mixture was purified by preparative LCMS to give the desired product (23 mg, 10% for 2 steps). LCMS for C23H26Cl2N5O2S (M+H)+: m/z=505.9, 508.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]3[C:14]([CH2:17]Cl)=[N:15][N:16]=[C:7]3[C:6]=2[CH:19]=1.[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.[OH-].[Na+]>COCCOC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]3[C:14]([CH2:17][N:24]4[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]4)=[N:15][N:16]=[C:7]3[C:6]=2[CH:19]=1
Reactant: CN1CCNCC1
Reactant: CN1C(=O)Cn2c(CCl)nnc2-c2cc(Cl)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: COCCOC
Product: CN1CCN(Cc2nnc3n2CC(=O)N(C)c2ccc(Cl)cc2-3)CC1

Procedure:
5 g. of 10-chloro-3-(chloromethyl)-7-methyl-5H-s-triazolo[4,3-d] [1,4]benzodiazepin-6(7H)-one from part (a) is suspended in 50 ml. of 1,2-dimethoxyethane. N-methylpiperazine (5.4 g.) is added to the suspension and the mixture is heated under reflux for 5 hours. The solvent is stripped off, 3N aqueous sodium hydroxide is added to the residue and the mixture is extracted with several portions of chloroform. The combined chloroform extracts are dried over sodium sulfate and the solvent is removed under vacuum to leave a residue which is recrystallized from absolute ethanol to yield 4 g. of the title compound, melting point 228.5°-230.5°.
Reaction SMILES: [CH:1]([OH:3])=[O:2].C(OC(=O)C)(=O)C.[CH:11]([NH:13][C:14]([CH3:19])([CH3:18])[CH2:15][CH2:16]O)=[O:12]>>[CH:1]([O:3][CH2:16][CH2:15][C:14]([NH:13][CH:11]=[O:12])([CH3:19])[CH3:18])=[O:2]
Reactant: CC(C)(CCO)NC=O
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Product: CC(C)(CCOC=O)NC=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Formic acid (6.90 g, 0.15 mol) was added to acetic anhydride (15.30 g, 0.15 mol) and warmed to 45°-50° C. for one hour on a water bath. The resulting solution was cooled to below 0° C. in an ice/acetone bath. 3-Formamido-3-methyl-1-butanol (13.10 g, 0.10 mol) was added and the solution allowed to slowly warm to room temperature with stirring (16 hours). The solution was distilled under vacuum (1 Torr, 105°-110° C.) to yield 12.43 g (78%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][C:6]=2[CH:7]=1.[CH3:18][O:19][C:20](=[O:32])[C@H:21]([N:29]=[C:30]=[O:31])[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N(CC)CC)C>C1COCC1>[CH3:18][O:19][C:20](=[O:32])[C@H:21]([NH:29][C:30]([O:1][CH2:2][C:3]1[O:4][C:5]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[CH:8][C:6]=2[CH:7]=1)=[O:31])[CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: COC(=O)[C@@H](Cc1ccccc1)N=C=O
Reactant: OCc1cc2cc(-c3ccccc3)ccc2o1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H](Cc1ccccc1)NC(=O)OCc1cc2cc(-c3ccccc3)ccc2o1
Temperature: 50 °C
Yield: 63.7 %

Procedure:
A mixture of 2-hydroxmethyl-5-phenyl-benzofuran 17 (1.20 g, 5.85 mmole), (R)-2-isocyanato-3-phenyl-propionic acid methyl ester 5 (1.2 g, 5.9 mmole), triethylamine (1.7 ml), and THF (30 ml) was heated to 50° C. under a nitrogen atmosphere for 6 hrs. The solvent was removed under reduced pressure and the residue was purified by chromatography giving about 1.6 g of (R)-2-(phenyl-benzofuran-2-ylmethoxycarbonylamino)-3-phenyl-propionic acid methyl ester 18, mp. 85-86° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]=[C:3]([CH:7]=O)[CH2:2]1.[C:9]([CH:14]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:11][CH2:12][CH3:13])=[O:10]>ClCCl>[O:1]1[CH2:6][CH2:5][CH:4]=[C:3](/[CH:7]=[CH:14]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2]1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1=CCCOC1
Solvent: ClCCl
Product: CCOC(=O)/C=C/C1=CCCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To 5,6-dihydro-2H-pyran-3-carbaldehyde (5.0 g) in dry dichloromethane (150 ml) at 0° C., was added carbethoxymethylene-triphenylphosphorane (15.53 g). The reaction was allowed to warm to room temperature and stirred overnight. The reaction was diluted with dichloromethane (150 ml) and washed with water (150 ml) and a saturated aqueous solution of brine (150 ml). The organic layer was dried by passing through a hydrophobic frit and concentrated in vacuo. to afford a yellow oil. The product was purified by silica chromatography (120 g) (ISCO) using a gradient elution of 0-10% cyclohexane:ethyl acetate to afford the title compound as a clear oil (5.59 g).
Reaction SMILES: [C:1]1([CH2:11][NH2:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:31]=[CH:30][C:29]([CH2:32][N:33]2[C:41]3[C:36](=[CH:37][C:38]([C:42](O)=[O:43])=[CH:39][CH:40]=3)[C:35]([CH3:45])=[C:34]2[CH3:46])=[CH:28][CH:27]=1)=[O:19])(C)(C)C>>[CH3:46][C:34]1[N:33]([CH2:32][C:29]2[CH:30]=[CH:31][C:26]([C:21]3[C:20]([C:18]([OH:19])=[O:17])=[CH:25][CH:24]=[CH:23][CH:22]=3)=[CH:27][CH:28]=2)[C:41]2[C:36]([C:35]=1[CH3:45])=[CH:37][C:38]([C:42](=[O:43])[NH:12][CH2:11][C:1]1[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=1)=[CH:39][CH:40]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: NCc1cccc2ccccc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)NCc3cccc4ccccc34)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Steps 8-9, Example 1, using 1-naphthylmethylamine and 1-((2′-(tert-butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: [P:1]([O-:53])([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][N+:49]([CH3:52])([CH3:51])[CH3:50])([O:3][CH2:4][CH:5]([O:26]CC1C=CC=CC=1)[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2].[H][H]>C(O)(=O)C.[Pd]>[P:1]([O-:53])([O:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][N+:49]([CH3:52])([CH3:51])[CH3:50])([O:3][CH2:4][CH:5]([OH:26])[CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[O:2]
Reactant: CCCCCCCCCCCCCCCCCCOCC(COP(=O)([O-])OCCCCCCCCCCCCCC[N+](C)(C)C)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CCCCCCCCCCCCCCCCCCOCC(O)COP(=O)([O-])OCCCCCCCCCCCCCC[N+](C)(C)C
Yield: 97.8 %

Procedure:
1.44 g (1.87 mmole) of 2-(benzyloxy)-3-(octadecyloxy)propyl 14-trimethylammoniotetradecyl phosphate was dissolved in 50 ml of 70% acetic acid and 0.5 g of 10% Pd-C was added as a catalyst. The mixture was stirred at room temperature for 4 hours in a hydrogen atmosphere. The reaction mixture was filtered and concentrated to dryness under reduced pressure. Acetone was added to the residue and the solidified substance was collected by filtration, washed with acetone and dried to give 1.24 g (yield: 97.6%) of the above-mentioned compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]=[CH:17][N:18]3[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:25]N1C(=O)CCC1=O.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:22]=[C:21]([Cl:23])[N:20]=[C:19]3[C:15]=2[N:16]=[C:17]([Cl:25])[N:18]3[CH3:24])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cn1cnc2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(Cl)nc21
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(Cl)nc2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 107.3 %

Procedure:
4-(2-Chloro-9-methyl-9H-purin-6-yl)piperazine-1-carboxylic acid t-butyl ester (7.3 g) was dissolved in N,N-dimethylformamide (70 mL), and then N-chlorosuccinimide (2.9 g) was added to this solution. The reaction solution was stirred at room temperature for 23 hours. Water (260 mL) was added to the reaction solution, and this was stirred at room temperature for one hour. A white precipitate was then collected by filtration. The white solid obtained was washed with water and hexane to give the title compound (8.6 g).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:7][OH:8].CC(C)([O-])C.[Na+].[C:15]([C:19]1[O:23]/[C:22](=[N:24]\[C:25](=[O:37])[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=2F)/[N:21]([CH2:38][C@H:39]2[CH2:43][CH2:42][CH2:41][O:40]2)[CH:20]=1)([CH3:18])([CH3:17])[CH3:16]>C1COCC1>[C:15]([C:19]1[O:23]/[C:22](=[N:24]\[C:25](=[O:37])[C:26]2[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[CH:28][C:27]=2[O:8][CH2:7][C@@H:3]2[CH2:4][CH2:5][CH2:6][N:2]2[CH3:1])/[N:21]([CH2:38][C@H:39]2[CH2:43][CH2:42][CH2:41][O:40]2)[CH:20]=1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)o1
Reactant: CN1CCC[C@H]1CO
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCC[C@H]1COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\oc(C(C)(C)C)cn1C[C@H]1CCCO1
Temperature: 22 °C
Reaction time: 0.33 h

Procedure:
To a solution of (S)-(1-methylpyrrolidin-2-yl)methanol (Aldrich) (0.860 mL, 7.24 mmol) in 15 mL of THF was added sodium tert-butoxide (0.696 g, 7.24 mmol). The reaction was stirred at 22° C. for 20 min. The reaction was cooled to 5° C. and a solution of Example 32C (1.5 g, 3.62 mmol) in 5 mL of THF was added. The reaction was stirred at 5° C. for 2 h, then at 22° C. for 1 h. The solvent was evaporated under reduced pressure. The residue was dissolved with methylene chloride, washed with NaHCO3, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on SiO2 using an Analogix® Intelliflash280™ (solvent A=CH2Cl2; solvent B=3 N NH3/MeOH:CH2Cl2 (1:9); eluting with A:B (100:0) changing to A:B (0:100) over the run time of approximately 30 minutes) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 1.17 (s, 9H), 1.53-1.98 (m, 8H), 1.97-2.15 (m, 2H), 2.19-2.35 (m, 1H), 2.46 (s, 3H), 2.62-2.81 (m, 1H), 3.07 (t, J=8.1 Hz, 1H), 3.62 (dd, J=14.1, 7.6 Hz, 1H), 3.72-3.94 (m, 2H), 4.01-4.21 (m, 2H), 6.53 (s, 1H), 6.96 (d, J=8.8 Hz, 1H), 7.55 (dd, J=9.0, 2.9 Hz, 1H), 7.93 (d, J=2.0 Hz, 1H); MS (ESI) m/z 511 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]([NH:10][CH3:11])=[N:6][C:7]=1[O:8][CH3:9].C(O[CH:15]=[C:16]([C:22]([O:24]CC)=O)[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[I:1][C:2]1[CH:3]=[C:4]2[C:5](=[N:6][C:7]=1[O:8][CH3:9])[N:10]([CH3:11])[CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]2=[O:24]
Reactant: CNc1ccc(I)c(OC)n1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Product: CCOC(=O)c1cn(C)c2nc(OC)c(I)cc2c1=O
Temperature: 140 °C
Yield: 16 %

Procedure:
6-Methoxy-N-methyl-2-pyridinamine (17.24 g, 124 mmol) is dissolved in DMF (160 mL) and cooled to 0° C. followed by the addition of NIS (28 g, 124 mmol, 1 equiv), at a rate which keeps the reaction temperature below 10° C. The reaction is then allowed to warm to room temperature and stirred for 1 h. The reaction is distilled to dryness in vacuo and the residue is dissolved in CH2Cl2 and passed through a silica plug eluting with heptane/EtOAc (9/1) affording 32 g of crude 5-iodo-6-methoxy-N-methyl-2-pyridinamine. The crude 5-iodo-6-methoxy-N-methyl-2-pyridinamine is dissolved in diethyl ethoxymethylenemalonate (32 mL) and the mixture is heated at 140° C. for 2 h, then cooled to room temperature and passed through a silica plug eluting with heptane/EtOAc (19/1, 0/1). The product is then dissolved in Eaton's reagent (132 mL) and heated at 100° C. for 40 min, cooled to rt and poured into Na2CO3. The basic aqueous layer is then extracted with CH2Cl2 (3×), washed with water, and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography (heptane/EtOAc, 4/1, 1/1, CH2Cl2/MeOH 19/1) the desired product is then triturated with MeOH to afford 7.9 g (16%) of ethyl 6-iodo-7-methoxy-1-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylate. Physical characteristics are as follows: 1H NMR (CDCl) δ9.04, 8.52, 4.41, 4.13, 3.91, 1.43; IR (diffuse reflectance) 2491, 2427, 2350, 2282, 2242, 1678, 1632, 1613, 1579, 1384, 1309, 1275, 1227, 1106, 804, cm−1; MS (EI) m/z 388, 344, 343, 317, 316, 185, 159, 86, 84, 51; Anal calcd for C13H13IN2O4: C, 40.23; H, 3.38; N, 7.22. Found: C, 40.20; H, 3.40; N, 7.16
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([S:9][CH3:10])[N:3]=1.[IH:11]>CCOC(C)=O>[Cl:8][C:7]1[C:2]([I:11])=[N:3][C:4]([S:9][CH3:10])=[N:5][CH:6]=1
Reactant: I
Reactant: CSc1ncc(Cl)c(Cl)n1
Solvent: CCOC(C)=O
Product: CSc1ncc(Cl)c(I)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
4,5-dichloro-2-(methylthio)pyrimidine (23 g, 0.118 mol) was added to aq. HI (250 mL). The resulting mixture was stirred at room temperature for 24 h. TLC (Petroleum ether:EtOAc=4:1) indicated that the reaction was complete. The solid formed was collected and was treated with H2O (250 mL). The mixture was then adjusted to pH=7˜8 with solid K2CO3 and was extracted with CH2Cl2 (100 mL×4). The combined organic layers were washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated and dried on vacuum to give title compound (29 g, 86%) as a light yellow solid.
Reaction SMILES: [O:1]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1[CH:13]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([S:23]([CH2:26][C:27]#[N:28])(=[O:25])=[O:24])[CH:20]=[CH:21][CH:22]=1>>[O:1]([C:8]1[CH:12]=[CH:11][S:10][C:9]=1/[CH:13]=[C:26](/[S:23]([C:19]1[CH:20]=[CH:21][CH:22]=[C:17]([C:16]([F:30])([F:15])[F:29])[CH:18]=1)(=[O:25])=[O:24])\[C:27]#[N:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1sccc1Oc1ccccc1
Reactant: N#CCS(=O)(=O)c1cccc(C(F)(F)F)c1
Product: N#C/C(=C\c1sccc1Oc1ccccc1)S(=O)(=O)c1cccc(C(F)(F)F)c1

Procedure:
Reaction of 3-phenoxythiophen-2-carboxaldehyde and 3-trifluoromethylphenylsulfonylacetonitrile as in Example 1 gave (E)-3-(3-phenoxythien-2-yl)-2-[3-(trifluoromethyl)phenylsulfonyl]acrylonitrile
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([CH3:12])[C:3]=1[C@@H:13]([OH:16])[CH2:14][OH:15].C([Sn](=O)CCCC)CCC.[C:27]1([CH3:37])[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1.CCN(CC)CC>C(Cl)Cl>[CH3:37][C:27]1[CH:32]=[CH:31][C:30]([S:33]([O:15][CH2:14][C@@H:13]([C:3]2[C:4]([CH3:12])=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]=2[Cl:1])[OH:16])(=[O:35])=[O:34])=[CH:29][CH:28]=1
Reactant: Cc1cc2ccccc2c(Cl)c1[C@@H](O)CO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[Sn](=O)CCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@H](O)c2c(C)cc3ccccc3c2Cl)cc1
Reaction time: 15 h

Procedure:
To a stirred solution of (R)-1-(1-chloro-3-methylnaphthalen-2-yl)ethane-1,2-diol (2.30 g, 9.74 mmol) in CH2Cl2 (97 mL), dibutyltinoxide (48.5 mg, 0.19 mmol), p-toluenesulfonyl chloride (2.08 g, 10.90 mmol), and Et3N (1.60 mL, 11.58 mmol) were added at room temperature). After stirring for 15 h, the reaction mixture was quenched with saturated aqueous NH4Cl, and then diluted with CH2Cl2. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 100% ethyl acetate/hexanes) to give (R)-2-(1-chloro-3-methylnaphthalen-2-yl)-2-hydroxyethyl 4-methylbenzenesulfonate. 1H-NMR: 400 MHz, (CDCl3) δ 8.18 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.57-7.54 (m, 5H), 5.82 (t, J=5.6 Hz, 1H), 4.44 (dd, J=10.0, 6.8 Hz, 1H), 4.35 (dd, J=10.4, 5.6 Hz, 1H), 2.59 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]2[CH:10]=[C:11]([N:26](CC3C=CC(OC)=CC=3)[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:12]3[N:13]([C:15]([CH:18]=[CH:19][C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[CH:16][N:17]=3)[N:14]=2)[CH2:4][CH2:3]1.C(O)(C(F)(F)F)=O>ClCCl>[NH2:1][CH:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]2[CH:10]=[C:11]([NH:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:12]3[N:13]([C:15](/[CH:18]=[CH:19]/[C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)=[CH:16][N:17]=3)[N:14]=2)[CH2:6][CH2:7]1
Reactant: COc1ccc(CN(c2ccccc2)c2cc(N[C@H]3CC[C@H](N)CC3)nn3c(C=Cc4ccncc4)cnc23)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCC(Nc2cc(Nc3ccccc3)c3ncc(/C=C/c4ccncc4)n3n2)CC1
Reaction time: 0.5 h
Yield: 89.8 %

Procedure:
To N6-(trans-4-aminocyclohexyl)-N8-(4-methoxybenzyl)-N8-phenyl-3-(2-(pyridin-4-yl)vinyl)imidazo[1,2-b]pyridazine-6,8-diamine (30 mg) from step (1c) in dichloromethane at room temperature was added excess TFA. The mixture was stirred for 30 min, concentrated, and the resulting residue was purified by reverse phase preparative HPLC to provide the titled compound as a yellow solid (21 mg). NMR (400 MHz, DMSO-d6) δ ppm 9.05 (1H, s), 8.66 (2H, m), 7.78-7.90 (8H, m), 7.39-7.44 (4H, m), 7.16 (1H, m), 6.68 (1H, m), 6.26 (1H, s), 3.62 (1H, m), 3.08 (1H, m), 2.20 (2H, m), 2.02 (2H, m), 1.51-1.54 (2H, m), 1.25-1.29 (2H, m). LC/MS, m/e 426 (M+1). HPLC Rt, 1.89 min. YMC S5 ODSC18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.2% H3PO4)—Solvent A: (10% MeOH, 90% H2O, 0.2% H3PO4). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [Br:1][C:2]1[C:3]([S:19][CH:20]([CH3:24])[C:21](=[O:23])[CH3:22])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1.[CH3:25][Mg]Br>O1CCCC1>[Br:1][C:2]1[C:3]([S:19][CH:20]([CH3:24])[C:21]([OH:23])([CH3:25])[CH3:22])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([NH2:18])(=[O:17])=[O:16])=[N:13][CH:14]=2)=[N:6][CH:7]=1
Reactant: CC(=O)C(C)Sc1nc(Nc2ccc(S(N)(=O)=O)nc2)ncc1Br
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(Sc1nc(Nc2ccc(S(N)(=O)=O)nc2)ncc1Br)C(C)(C)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
108 mg (0.25 mmol) of 5-[5-bromo-4-(1-methyl-2-oxo-propylsulfanyl)-pyrimidin-2-ylamino]-pyridine-2-sulfonic acid amide is dissolved in tetrahydrofuran p.a. at 4° C. that is mixed in portions with 1 ml (3 mmol) of methylmagnesium bromide (3 M in ether). After 24 hours of stirring at room temperature, it is quenched by adding ammonium chloride solution. After extraction with ethyl acetate, the dried residue is flashed with dichloromethane/methanol.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C:12]([F:22])([F:21])[CH2:13][O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=O)=O)=CC=1.[OH:24][CH:25]1[CH:30]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=2)[CH2:29][CH2:28][N:27]([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:26]1>>[F:21][C:12]([F:22])([CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH:30]2[CH2:29][CH2:28][N:27]([C:38]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:39])[CH2:26][CH:25]2[OH:24])=[CH:36][CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)COc2ccccc2)cc1
Reactant: O=C(OCc1ccccc1)N1CCC(c2ccc(O)cc2)C(O)C1
Product: O=C(OCc1ccccc1)N1CCC(c2ccc(OCC(F)(F)COc3ccccc3)cc2)C(O)C1

Procedure:
Analogously to Method G, 0.350 g of 2,2-difluoro-3-phenoxypropyl toluene-4-sulphonate and 0.452 g of benzyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate are reacted. The title compound is obtained as a yellow oil. Rf=0.25 (1:1 EtOAc-heptane); Rt=5.11.
Reaction SMILES: Cl[C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.O.[CH2:19]([OH:31])[CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][OH:30]>>[OH:30][CH2:29][CH2:28][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][O:21][CH2:20][CH2:19][O:31][C:2]1[C:15]2[C:14](=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:7](=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: OCCOCCOCCOCCO
Reactant: O=C1c2ccccc2C(=O)c2c(Cl)cccc21
Solvent: O
Product: O=C1c2ccccc2C(=O)c2c(OCCOCCOCCOCCO)cccc21
Temperature: 120 °C

Procedure:
A mixture of 1-chloroanthraquinone (4 gm) potassium carbonate, (4 gm) in tetraethyleneglycol (15 ml) was heated for three hours at 120° C., poured into cool water and filtered off. The solid obtained was chromatographed over silica gel and eluted with methylene chloride:methanol (99:1) gave 1-[2-[2-[2-(2-hydroxyethoxy)ethoxy]ethoxy]ethoxy]-9,10-anthraquinone. This compound was crystallized from ether to give a yellow crystalline compound.