Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:12][C@@H:13]1[CH2:15][O:14]1>>[CH2:1]([N:8]([CH2:9][CH2:10][OH:11])[CH2:15][C@H:13]([OH:14])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCNCc1ccccc1
Reactant: C[C@@H]1CO1
Product: C[C@@H](O)CN(CCO)Cc1ccccc1
Temperature: 150 °C
Yield: 98.5 %

Procedure:
2-(benzylamino)ethanol (207 ml, 1454.97 mmol) and (R)-2-methyloxirane (153 ml, 2182.46 mmol) were mixed together and pumped at a flow rate of 1 mL/min through a 10 mL loop heated at 150° C. in a flow chemistry system. The back pressure regulator was adjusted in order to achieve a pressure inside the loop of 250 psi. Excess of propylene oxide was removed under vacuum to afford (R)-1-(benzyl(2-hydroxyethyl)amino)propan-2-ol (300 g, 99%) as a colourless liquid. Mass Spectrum: m/z [M+H]+=210.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][SH:21])[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[Br:30][C:31]1[CH:32]=[C:33]([N+]([O-])=O)[CH:34]=[C:35]([Br:37])[CH:36]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][S:21][C:33]2[CH:32]=[C:31]([Br:30])[CH:36]=[C:35]([Br:37])[CH:34]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCS)c1CCC(=O)OCC
Reactant: O=[N+]([O-])c1cc(Br)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCSc2cc(Br)cc(Br)c2)c1CCC(=O)OCC
Temperature: 90 °C
Reaction time: 3 h
Yield: 70.5 %

Procedure:
To a solution of 4-[2-(2-ethoxycarbonyl-ethyl)-3-(6-mercapto-hexyl)-phenoxy]-butyric acid ethyl ester (162 mg, 0.388 mmol) in DMSO (5 mL), 3,5-dibromonitrobenzene (129 mg, 0.46 mmol) and Cs2CO3 (150 mg, 0.46 mmol) were added and stirred at 90° C. for 3 hrs. At this time, the reaction mixture was diluted with EtOAc (200 mL) and washed with water (100 mL). The EtOAc layer was washed), brine and then dried over Na2SO4. This mixture was filtered and the filtrate was concentrated. The solvent was removed in vacuo to afford an oil. This oil was purified using FCC (15% EtOAc/Hex) to provide a colorless oil (180 mg, yield 72%). 1H NMR (CDCl3): □ 7.42 (s, 1H), 7.32 (s, 2H), 7.09 (dd, 1H), 6.75 (d, 1H), 6.69 (d, 1H), 4.14 (m, 4H), 3.99 (t, 2H), 2.98-2.89 (m, 4H), 2.64-2.46 (m, 6H), 2.13 (m, 2H), 1.67-1.39 (m, 8H), 1.27 (m, 6H).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[O:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:25]1[O:30][CH2:31][CH2:32][N:33]1[CH:37]=[C:36](B2OC(C)(C)C(C)(C)O2)[CH:35]=[N:34]1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:36]5[CH:35]=[N:34][N:33]([CH2:32][CH2:31][O:30][CH:25]6[CH2:26][CH2:27][CH2:28][CH2:29][O:24]6)[CH:37]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Reactant: CC1(C)OB(c2cnn(CCOC3CCCCO3)c2)OC1(C)C
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cnn(CCOC5CCCCO5)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A, 80 mg, 0.215 mmol) and 1-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (Stage 106.1.2, 91 mg, 0.279 mmol) to give the title compound as red sticky oil. Used for next step without further purification. (HPLC: tR 2.66 min (Method A); M+H=488 MS-ES)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[NH:35]1[CH2:40][CH2:39][CH:38]([CH2:41][OH:42])[CH2:37][CH2:36]1>COCCO>[Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33][N:35]3[CH2:40][CH2:39][CH:38]([CH2:41][OH:42])[CH2:37][CH2:36]3)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1
Reactant: OCC1CCNCC1
Reactant: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Solvent: COCCO
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN4CCC(CO)CC4)c(OC)cc23)c2c1OCO2
Yield: 79.9 %

Procedure:
This was prepared using the method described in example 13 using N-[5-chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (192 mg, 0.38 mmol) and 4-piperidinemethanol (220 mg, 1.9 mmol) in 2-methoxyethanol (4 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanolic ammonia in dichloromethane as eluent. There was thus obtained the title compound (177 mg, 80%) as a pale yellow solid; NMR Spectrum:(DMSOd6) 1.10-1.20 (m, 2H), 1.35 (m, 1H), 1.64 (d, 2H), 1.88 (t, 2H), 1.95 (quintet, 2H), 2.45 (t, 2H), 2.72 (t, 2H), 2.89 (d, 2H), 3.26 (t, 2H), 3.32 (s, 3H), 3.53 (t, 2H), 3.94 (s, 3H), 4.18 (t, 2H), 4.37 (t, 1H), 6.14 (s, 2H), 7.07 (s, 1H), 7.17 (s, 1H), 7.82 (s, 1H), 8.32 (s, 1H), 9.48 (s, 1H); Mass Spectrum: M+H+ 583/585.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:29][O:30][C:31]([C@H:33]1[CH2:37][C:36](=[O:38])[N:35]([C:39]2[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=2)[CH2:34]1)=[O:32].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:29][O:30][C:31]([C@H:33]1[CH2:37][C:36](=[O:38])[N:35]([C:39]2[CH:44]=[CH:43][C:42]([O:6][CH2:5][C:4]3[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=3)=[CH:41][CH:40]=2)[CH2:34]1)=[O:32]
Reactant: OCc1cccc(F)c1
Reactant: COC(=O)[C@H]1CC(=O)N(c2ccc(O)cc2)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H]1CC(=O)N(c2ccc(OCc3cccc(F)c3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.1 %

Procedure:
A solution 14.23 g (110.6 mmol) of 3-fluoro-benzylalcohol and 27.19 g (108.8 mmol) of triphenylphosphine in 150 ml of tetrahydrofurane is added dropwise within 50 min under a nitrogen atmosphere at 0° C. to a solution of 23.65 g (100.5 mmol) of (S)-1-(4-hydroxy-phenyl)-5-oxo-pyrrolidine-3-carboxylic acid methyl ester and 21.62 g (100.5 mmol) of diisopropyl azodicarboxylate in 200 ml of tetrahydrofurane. The mixture is left to warm to RT and stirring is continued for 18 hours. For the working-up, the mixture is evaporated under reduced pressure. The solid residue is triturated in 400 ml of ether to leave a white solid mainly consisting of the product and triphenylphosphinoxide. After filtration, the solid material is triturated in 100 ml of cold methanol to yield 23.5 g (68% of theory) of (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylic acid methyl ester as a white solid [MS: m/e=344 (M+H)+] together with traces of triphenylphosphine and diisopropyl hydrazodicarboxylate.
Reaction SMILES: C[Si](C)(C)[N:3]1[CH2:7][CH2:6][NH:5][C:4]1=[S:8].[C:11](Cl)([Cl:13])=[O:12]>C(Cl)Cl>[Cl:13][C:11]([N:3]1[CH2:7][CH2:6][NH:5][C:4]1=[S:8])=[O:12]
Reactant: C[Si](C)(C)N1CCNC1=S
Reactant: O=C(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)N1CCNC1=S
Temperature: 0 °C
Reaction time: 24 h

Procedure:
50 parts by weight of 1-trimethylsilyl-imidazolidine-2-thione in 150 parts by volume of methylene chloride were treated with 35 parts by weight of phosgene in 50 parts by volume of methylene chloride over the course of 2 hours at 0°C. The mixture was stirred for 24 hours at 0°C, the methylene chloride was subsequently stripped off, and the residue was dried in a high vacuum. Semi-solid mass, incompletely soluble in acetone. Crude yield: 97% IR bands at 1830, 1590 and 1240 cm-1.
Reaction SMILES: [CH:1]([CH:13]1[CH2:18][C:17](=[O:19])[O:16][C:14]1=[O:15])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].C([OH:23])C=C>>[CH2:1]([CH:13]([CH2:18][C:17]([OH:16])=[O:19])[C:14]([OH:23])=[O:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCC=CC1CC(=O)OC1=O
Reactant: C=CCO
Product: CCCCCCCCCCCCC(CC(=O)O)C(=O)O

Procedure:
In a 4-necked flask 1 mole of dodecenylsuccinic anhydride and 1 mole of allylalcohol were reacted together at 110°±5 ° C. for 2 hours to form a monoallyl ester of dodecylsuccinic acid. The product thus obtained was then converted to its triethanolamine salt whihc is a viscous yellowish brown liquid having a good self-emulsifiability in water.
Reaction SMILES: C([Li])CCC.[CH2:6]([CH:10]([CH2:14]C)[C:11]([OH:13])=[O:12])C(C)C.[CH:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1)([CH3:18])[CH3:17].Cl>O1CCCC1.C(NC(C)C)(C)C>[CH:16]([C:19]1[CH:26]=[CH:25][C:22]([CH2:23][C:10]([CH3:14])([CH3:6])[C:11]([OH:13])=[O:12])=[CH:21][CH:20]=1)([CH3:18])[CH3:17]
Reactant: CCC(CC(C)C)C(=O)O
Reactant: CC(C)c1ccc(CCl)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)c1ccc(CC(C)(C)C(=O)O)cc1
Temperature: 30 °C
Reaction time: 1 h

Procedure:
in tetrahydrofuran (40 ml) was dissolved in diisopropylamine (3.08 ml) and to the mixture was added n-butyl lithium (13.8 ml; 1.6 M hexane solution) at −78° C. and thereto was added isobutylbutyric acid (0.93 ml) dropwise and the mixture was stirred for 1 hour at 30° C. To the reaction mixture was added a solution of 4-isopropylbenzyl chloride (2.19 g) in tetrahydrofuran (10 ml) at −78° C. and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured to cool hydrochloric acid and was extracted with ethyl acetate. The extract was concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to give the title compound (1.73 g) having the following physical data.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N+:2]=1[O-].P([C:20]#[N:21])(=O)(OCC)OCC>C(#N)C>[C:1]1([C:20]#[N:21])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1
Reactant: [O-][n+]1ccc2ccccc2c1
Reactant: CCOP(=O)(C#N)OCC
Solvent: CC#N
Product: N#Cc1nccc2ccccc12

Procedure:
To a stirred solution of isoquinoline 2-oxide (2-Im-9, 5.8 g) in 140 mL of acetonitrile, diethyl phosphoro-cyanidate (1.5 eq) was added under argon followed by slow addition of TEA (3.0 eq). The mixture was refluxed for 18 h and then extracted with DCM. The organic layer was concentrated and purified by silica column chromatography to give isoquinoline-1-carbonitrile (3-Im-9).
Reaction SMILES: Br[C:2]1[C:6]([CH3:8])([CH3:7])[O:5]/[C:4](=[C:9]2/[C:10](=[O:22])[NH:11][C:12]3[C:17]/2=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=3)/[CH:3]=1.Cl.CC1(C)C(C)(C)OB([C:32]2[CH:44]=[CH:43][C:35]([CH2:36][N:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[CH:34][CH:33]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C=O)C.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]>[CH3:7][C:6]1([CH3:8])[O:5]/[C:4](=[C:9]2/[C:10](=[O:22])[NH:11][C:12]3[C:17]/2=[CH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14][CH:13]=3)/[CH:3]=[C:2]1[C:32]1[CH:33]=[CH:34][C:35]([CH2:36][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[CH:43][CH:44]=1
Reactant: COC(=O)c1ccc2c(c1)/C(=C1/C=C(Br)C(C)(C)O1)C(=O)N2
Reactant: CC1(C)OB(c2ccc(CN3CCOCC3)cc2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)/C(=C1/C=C(c3ccc(CN4CCOCC4)cc3)C(C)(C)O1)C(=O)N2
Temperature: 85 °C

Procedure:
A mixture of methyl (3E)-3-(4-bromo-5,5-dimethylfuran-2(5H)-ylidene)-2-oxoindoline-5-carboxylate (90 mg, 0.25 mmol), 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)morpholine hydrochloride (92 mg, 0.27 mol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (complex with CH2Cl2, 20 mg, 0.027 mmol) and 2M Na2CO3 (0.5 mL, 1.0 mmol) in 8 mL of DMF was heated in 85° C. bath under nitrogen for 90 minutes. The mixture was cooled to room temperature and poured into 100 mL of water. The precipitates were filtered, washed with water and dried to give the crude product, which was purified through silica gel column with 1-5% MeOH/CHCl3 to give methyl (3E)-3-{5,5-dimethyl-4-[4-(morpholin-4-ylmethyl)phenyl]furan-2(5H)-ylidene}-2-oxoindoline-5-carboxylate as yellow solid. Yield: 20 mg, 18%.
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][CH2:9][C@H:8]2[C:11]3[C@H:20]([CH2:21][CH2:22][C@:6]12[CH3:7])[C:19]1[CH2:18][CH2:17][CH:16]([O:23][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:15][C:14]=1[CH2:13][CH:12]=3)(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO.ClCCl>[Si:24]([O:23][CH:16]1[CH2:17][CH2:18][C:19]2[C@@H:20]3[C:11]([C@H:8]4[C@@:6]([CH2:22][CH2:21]3)([CH3:7])[C@@H:5]([OH:4])[CH2:10][CH2:9]4)=[CH:12][CH2:13][C:14]=2[CH2:15]1)([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(=O)O[C@H]1CC[C@H]2C3=CCC4=C(CCC(O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)C4)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)[Si](OC1CCC2=C(CC=C3[C@@H]2CC[C@]2(C)[C@@H](O)CC[C@@H]32)C1)(c1ccccc1)c1ccccc1
Reaction time: 16 h
Yield: 65.3 %

Procedure:
To the acetates 11 (2.2 g, 4.0 mmol) in a mixture of methanol (60 mL) and dichloromethane (10 mL) was added potassium carbonate (0.1 eq, 55 mg, 0.4 mmol). After stirring for 4 h an additional portion of potassium carbonate (1.0 eq, 0.55 g, 4.0 mmol) was added. The mixture was stirred 16 h and more potassium carbonate (1.0 eq, 0.55 g, 4.0 mmol) was added. After 24 h water (100 mL) was added, the layers were separated and the aqueous layer was extracted with dichloromethane (3×100 mL). The organic layers were combined, washed with saturated aqueous NaCl solution (100 mL), dried over magnesium sulfate and concentrated under reduced pressure to give an oil that was purified by flash column chromatography on silica gel eluting with 20% EtOAc/hexane to give the alcohols 12 (1.34 g), Rf0.5 (30% EtOAc/hexane), as a white foam which was used directly.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[F:31][C:32]([F:36])([F:35])[CH2:33][NH2:34]>C1COCC1>[F:31][C:32]([F:36])([F:35])[CH2:33][NH:34][C:12]1[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[CH3:30])[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:10]=2[N:11]=1
Reactant: NCC(F)(F)F
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Solvent: C1CCOC1
Product: Cc1cc(F)ccc1-c1nc(NCC(F)(F)F)nc2c1ccc(=O)n2-c1ccccc1F

Procedure:
The product of Example 59 (200 mg, 0.47 mmol) and trifluoroethylamine (200 mg, 2 mmol) were dissolved in THF (7 ml) and sealed in a vial under Ar. The mixture was heated in an oil bath to 60° for 4 days. The solvents were removed in vacuo, and the residue was flash chromatographed with 60-90% CH2Cl2/hexane. Recrystallization from CH2Cl2/hexane gave the title compound as a white crystalline solid. mp 187-188°, LC MS m/z=447(MH+) Retention time=2.27 min.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].CO[C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[O:10][CH3:11].C(N(CC)CC)C>CCCCCC>[Cl:1][C:2]1[C:3](=[O:4])[C:9]([O:10][CH3:11])([O:12][CH3:13])[C:8]=1[O:14][CH3:15]
Reactant: O=C(Cl)CCl
Reactant: COC(OC)=C(OC)OC
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: COC1=C(Cl)C(=O)C1(OC)OC
Temperature: 20 °C
Reaction time: 3 h
Yield: 0.5 %

Procedure:
A solution of 23.7 g (0.21 mole) of chloroacetyl chloride is added dropwise, in the course of 40 minutes, to a solution, cooled to 0°-5° C. and vigorously stirred, of 14.8 g (0.1 mole) of 1,1,2,2-tetramethoxyethylene and 23.2 g (0.23 mole) of triethylamine in 100 ml of absolute n-hexane. The greyish-brown suspension formed is stirred for 3 hours at 20° C.; the resulting salt is then filtered off with suction and washed with n-hexane, and the yellow filtrate is concentrated by evaporation. The intensive IR-absorption bands of the residue (30.4 g) confirm the formation of 2-chloro-3,3,4,4-tetramethoxy-1-chloroacetoxycyclobutene (5.71μ) and 2-chloro-3,4,4-trimethoxycyclobutenone (5.58; 6.1μ). According to the NMR spectrum, the reaction mixture contains 80±5% by weight of 2-chloro-3,3,4,4,-tetramethoxy-1-chloroacetoxybutene and 12±3% by weight of 2-chloro-3,4,4-trimethoxycyclobutenone, besides small amounts of unidentifiable by-products. By rapid separation by columnchromatography of 0.5 g of the crude residue, it is possible to obtain 0.1 g of pure 2-chloro-3,4,4-trimethoxycyclobutenone (eluant: hexane/diethyl ether in a volume ratio of 4:1).
Reaction SMILES: [C:1]([C:3]1[C:7]([S:8][C:9]([F:12])([F:11])[F:10])=[C:6]([CH:13]=[O:14])[N:5]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[N:4]=1)#[N:2].[BH4-].[Na+].Cl.O>C(O)C>[C:1]([C:3]1[C:7]([S:8][C:9]([F:10])([F:12])[F:11])=[C:6]([CH2:13][OH:14])[N:5]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:24])([F:25])[F:23])=[CH:17][C:16]=2[Cl:26])[N:4]=1)#[N:2]
Reactant: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(C=O)c1SC(F)(F)F
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: N#Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(CO)c1SC(F)(F)F
Reaction time: 1 h

Procedure:
The product of Example 3 (5.0 g, 0.012 mol) was added to a mixture of sodium borohydride (0.5 g, 0.013 mol) in anhydrous ethanol at 5° C. After 1 hour, 10% aqueous hydrochloric acid solution (35 ml) was added slowly with copious gas evolution. The mixture was poured into water and washed with diethyl ether. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and concentrated under reduced pressure to provide the title compound as a white solid, m.p. 118° C.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:28]=[CH:27][C:15]4[N:16]=[C:17]([NH:19][C@@H:20]5[CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]5[OH:26])[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.[CH3:29][N:30](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:26][C@@H:21]1[CH2:22][CH2:23][CH2:24][CH2:25][C@H:20]1[NH:19][C:17]1[S:18][C:14]2[CH:13]=[C:12]([CH2:11][N:8]3[C:6]4=[N:7][C:2]([C:29]#[N:30])=[CH:3][CH:4]=[C:5]4[N:10]=[CH:9]3)[CH:28]=[CH:27][C:15]=2[N:16]=1
Reactant: CN(C)C=O
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: N#Cc1ccc2ncn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)c2n1
Temperature: 100 °C
Reaction time: 2 h
Yield: 39 %

Procedure:
A stirred mixture of (1R,2R)-2-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (100 mg, 0.218 mmol) from Example 78, zinc cyanide (77 mg, 0.654 mmol), and 1,1′-bis(diphenylphosphino)ferrocene (18 mg, 0.0327 mmol) in anhydrous DMF (2 mL) at rt was purged for 15 min with a stream of argon. To the resulting mixture was added tris(dibenzylideneacetone)dipalladium (18 mg, 0.0218 mmol). The reaction vessel was sealed and the mixture was stirred at 100° C. for 2 h. After cooling to rt, the reaction mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford 3-((2-(((1R,2R)-2-hydroxycyclohexyl)amino)benzo[d]thiazol-6-yl)methyl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (34 mg, 39%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.91 (s, 1H), 8.34 (d, J=8.3 Hz, 1H), 8.01 (d, J=7.3 Hz, 1H), 7.92 (d, J=8.1 Hz, 1H), 7.67 (d, J=1.1 Hz, 1H), 7.32 (m, 1H), 7.22 (m, 1H), 5.53 (s, 2H), 4.77 (br s, 1H), 3.51 (m, 1H), 3.30 (m, 1H), 2.03 (m, 1H), 1.85 (m, 1H), 1.65-1.67 (m, 2H), 1.08-1.37 (m, 4H). LCMS (ESI) m/z 405 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:16][N:17]1[CH2:22][CH2:21][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:19][CH2:18]1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2.[CH3:29][C:30](C)=[O:31].C(Cl)(=O)C.N.O>O>[C:30]([O:1][CH:2]([CH2:16][N:17]1[CH2:18][CH2:19][N:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:21][CH2:22]1)[CH2:3][O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:15])[NH:10]2)(=[O:31])[CH3:29]
Reactant: CC(C)=O
Reactant: O=C1CCc2c(cccc2OCC(O)CN2CCN(c3ccccc3)CC2)N1
Agent: N
Solvent: CC(=O)Cl
Solvent: O
Product: CC(=O)OC(COc1cccc2c1CCC(=O)N2)CN1CCN(c2ccccc2)CC1

Procedure:
2 grams of 5-[2-hydroxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril are mixed with 30 ml of acetone and further 12 ml of acetyl chloride are added, followed by heating for 10 hours under refluxing conditions. After cooling the reaction mixture, the product precipitated is collected by filtration and washed with acetone. The crude crystals thus obtained are dissolved in 80 ml of water and made basic with ammonia-water, then extracted with chloroform, dried and chloroform is removed by distillation. The residue is purified by silica gel chromatography to obtain 0.5 g of 5-[2-acetyloxy-3-(4-phenylpiperazinyl)propoxy]-3,4-dihydrocarbostyril in the form of colorless crystals with a melting point of 159°-161° C.
Reaction SMILES: C([O:8][C:9]1[C:14](=[O:15])[N:13]=[C:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2Br)[N:11]2[CH2:24][CH2:25][N:26]([CH:29]([CH3:31])[CH3:30])[C:27](=[O:28])[C:10]=12)C1C=CC=CC=1.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][C:38]=1[Cl:39].C([O-])([O-])=O.[Na+].[Na+].ClCCl>CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:32][C:33]1[CH:34]=[C:35]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[CH2:16][C:12]2[N:11]3[CH2:24][CH2:25][N:26]([CH:29]([CH3:30])[CH3:31])[C:27](=[O:28])[C:10]3=[C:9]([OH:8])[C:14](=[O:15])[N:13]=2)[CH:36]=[CH:37][C:38]=1[Cl:39]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)N1CCn2c(Cc3ccccc3Br)nc(=O)c(OCc3ccccc3)c2C1=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)N1CCn2c(Cc3ccccc3-c3ccc(Cl)c(Cl)c3)nc(=O)c(O)c2C1=O
Reaction time: 8 h
Yield: 15.2 %

Procedure:
9-Benzyloxy-6-(2-bromobenzyl)-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (71) (0.1 g, 207 μmol, Eq: 1.00, ˜40% pure), 3,4-dichlorophenylboronic acid (47.5 mg, 249 μmol, Eq: 1.2), Na2CO3 (65.9 mg, 622 μmol, Eq: 3) and tetrakis(triphenylphosphine)palladium (0) (24.0 mg, 20.7 μmol, Eq: 0.1) were stirred in methanol (0.9 ml)/dichloromethane (300 μl) in the microwave at 115° C. for 30 minutes. The reaction mixture stood at room temperature overnight. The supernatant was pipetted off, concentrated and purified by SiO2 flash chromatography (4 g SiO2, dichloromethane/methanol 0-5% methanol) to afford 6-(3′,4′-dichloro-biphenyl-2-ylmethyl)-9-hydroxy-2-isopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (72) (0.016 g, 31.4 μmol, 15.2% yield, 90% pure) as a light yellow solid.