Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].Br[C:16]1[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:16]2[CH:21]=[CH:20][N:19]=[C:18]([CH3:22])[CH:17]=2)=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12]
Reactant: Cc1cc(Br)ccn1
Reactant: OB(O)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1cc(-c2ccc(F)c(C(F)(F)F)c2)ccn1
Temperature: 88 °C
Yield: 99.3 %

Procedure:
To a stirred suspension of 4-fluoro-3-(trifluoromethyl)phenylboronic acid (42.6 g, 205 mmol) in toluene (200 mL) were added 4-bromo-2-methylpyridine (34.4 g, 200 mmol) and 2 M aqueous potassium carbonate (200 mL). After the addition of 1,1′-bis(diphenylphosphino)-ferrocene-palladium(II)dichloride dichloromethane complex (81.7 mg, 0.1 mmol), the two-phase, yellowish reaction mixture was stirred under reflux at 88° C. for 23 h. The resultant brownish reaction mixture was cooled to room temperature and extracted with toluene (200 mL). After washing with 10% brine (200 mL), the toluene layer was dried with Na2SO4 (50 g) and then treated under stirring with charcoal (2 g) for 30 min. Filtration and evaporation (50° C./≧10 mbar) afforded the crude title product (50.7 g, 99.4%) as an off-white, crystalline residue which was used without purification in the next step. 1H NMR (CDCl3, 400 MHz) δ 2.64 (s, 3H), 7.25-7.36 (m, 3H), 7.76-7.82 (m, 1H), 7.84 (dd, J1=6.7 Hz, J2=2.4 Hz, 1H), 8.58 (d, J=5.0 Hz, 1H). ESI-MS (m/z) [M+H]+256.3 (100).
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:28][CH3:29]>>[CH2:20]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[CH2:18][O:19][CH2:28][CH3:29])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CCI
Reactant: O=[N+]([O-])c1cccc(N(Cc2ccccc2)Cc2ccccc2)c1CO
Product: CCOCc1c(N(Cc2ccccc2)Cc2ccccc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 46B and iodoethane were processed as described in Example 46C to provide the title compound.
Reaction SMILES: C[C@@H]1O[C@@H](O[C@H:8]2[C@H:13](O)[C@@H:12](O)[C@H:11](NC(N)=N)[C@@H:10](O)[C@@H:9]2[NH:21][C:22]([NH2:24])=[NH:23])[C@H](O[C@@H]2O[C@@H](CO)[C@H](O)[C@@H](O)[C@@H]2NC)[C@@]1(O)C=O.CC1(C)S[C@@H]2[C@H](N[C:51]([CH2:53][C:54]3C=C[CH:57]=[CH:58][CH:59]=3)=O)C(=O)N2[C@H]1C([O-])=O.[K+]>>[CH3:51][CH2:53][CH2:54][CH2:59][CH2:58][CH2:57][CH2:8][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:21][C:22]([NH2:24])=[NH:23]
Reactant: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)[O-]
Reactant: CN[C@@H]1[C@H](O[C@H]2[C@H](O[C@H]3[C@H](O)[C@@H](O)[C@H](NC(=N)N)[C@@H](O)[C@@H]3NC(=N)N)O[C@@H](C)[C@]2(O)C=O)O[C@@H](CO)[C@H](O)[C@H]1O
Agent: [K+]
Product: CCCCCCCCCCCCNC(=N)N

Procedure:
1.0 ml/l COMBIOTIC® (tradename for a streptomycin-pennicillin mixture) (Streptomycin, Penicillin Mixture, Pfizer Corp.)
Reaction SMILES: [Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]([OH:28])=O)=[N:24][CH:25]=1.[Br:29][C:30]1[CH:31]=[C:32]2[C@:43]3([CH2:48][CH2:47][O:46][C:45]([NH2:49])=[N:44]3)[C:42]3[C:37](=[CH:38][CH:39]=[C:40]([NH2:50])[CH:41]=3)[O:36][C:33]2=[N:34][CH:35]=1.C(=O)(O)[O-]>CO.C1COCC1.CCOC(C)=O.O>[NH2:49][C:45]1[O:46][CH2:47][CH2:48][C@:43]2([C:32]3[C:33](=[N:34][CH:35]=[C:30]([Br:29])[CH:31]=3)[O:36][C:37]3[C:42]2=[CH:41][C:40]([NH:50][C:26](=[O:28])[C:23]2[CH:22]=[CH:21][C:20]([Cl:19])=[CH:25][N:24]=2)=[CH:39][CH:38]=3)[N:44]=1
Reactant: O=C(O)c1ccc(Cl)cn1
Reactant: NC1=N[C@@]2(CCO1)c1cc(N)ccc1Oc1ncc(Br)cc12
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: NC1=N[C@@]2(CCO1)c1cc(NC(=O)c3ccc(Cl)cn3)ccc1Oc1ncc(Br)cc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 20.6 %

Procedure:
4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (228 mg, 0.775 mmol) was added to a solution of 5-chloro-2-pyridinecarboxylic acid (122 mg, 0.775 mmol) in MeOH (0.6 mL), followed by a solution of (S)-3-bromo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazine]-2′,7-diamine (140 mg, 0.388 mmol) in THF (1.6 mL) MeOH (0.5 mL). The reaction mixture was allowed to stir for 20 min at rt. Diluted, aqueous bicarbonate solution was added, followed by additional water and EtOAc. The organic phase was separated and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica gel, 20-100% EtOAc/hexanes). 40 mg of (S)—N-(2′-amino-3-bromo-5′,6′-dihydrospiro[chromeno[2,3-b]pyridine-5,4′-[1,3]oxazin]-7-yl)-5-chloropicolinamide were obtained as an off-white solid. MS m/z=501.7 [M+H]11. Calculated for C21H15BrClN5O3: 500.73. 1H NMR (300 MHz, CHLOROFORM-d) ppm 1.82-1.93 (m, 1H) 1.93-2.02 (m, 1H) 4.07-4.19 (m, 1H) 4.19-4.32 (m, 1H) 7.31 (d, J=8.62 Hz, 1H) 7.71 (d, J=2.48 Hz, 1H) 7.73-7.79 (m, 1H) 7.89 (dd, J=8.33, 2.34 Hz, 1H) 7.93 (d, J=2.48 Hz, 1H) 8.26 (d, J=8.33 Hz, 1H) 8.31 (d, J=2.48 Hz, 1H) 8.58 (d, J=1.90 Hz, 1H) 9.86 (s, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]([O:11][C:12]1[NH:13][C:14]([NH2:23])=[C:15]2[C:19]([N:20]=1)=[N:18][C:17]([O:21][CH3:22])=[N:16]2)[CH3:10].Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][Cl:30]>>[Cl:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][N:18]1[C:17]([O:21][CH3:22])=[N:16][C:15]2[C:19]1=[N:20][C:12]([O:11][CH:9]([CH3:8])[CH3:10])=[N:13][C:14]=2[NH2:23]
Reactant: ClCCCCCBr
Reactant: COc1nc2nc(OC(C)C)[nH]c(N)c-2n1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc2c(N)nc(OC(C)C)nc2n1CCCCCCl

Procedure:
Prepared similarly to Intermediate 44 from 2-[(1-methylethyl)oxy]-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 1-bromo-5-chloropentane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH:27]([NH:30]C(=O)OC(C)(C)C)[CH2:26][CH2:25]2)[CH:21]=[N:20][CH:19]=1.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]2)[CH:21]=[N:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5Cl)cc34)n2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC1CCN(c2cncc(-c3c[nH]c4ccc(-c5c(F)cccc5Cl)cc34)n2)CC1
Reaction time: 1 h

Procedure:
A solution of tert-butyl 1-(6-(5-(2-chloro-6-fluorophenyl)-1H-indol-3-yl)pyrazin-2-yl)piperidin-4-ylcarbamate (0.104 g, 0.199 mmol) in 2 mL DCM and TFA (0.153 mL, 1.992 mmol) was stirred for 1 h. Additional TFA (0.153 mL, 1.992 mmol) was added. After 1 h additional, the reaction was concentrated, and the material suspended in Et2O to give a solid. The solid was collected by filtration, and was dried in vacuo overnight, to give 1-(6-(5-(2-chloro-6-fluorophenyl)-1H-indol-3-yl)pyrazin-2-yl)piperidin-4-amine bis(2,2,2-trifluoroacetate) as a yellow solid. MS (ESI, pos. ion) m/z: 422 (M+1).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]2[O:15][CH:16]1[CH2:21][CH2:20]O[CH2:18][CH2:17]1)=O.[CH:22]1([NH:25][C:26]2[S:27][CH2:28][C:29](=[O:31])[N:30]=2)[CH2:24][CH2:23]1.C([O-])(=O)C.[Na+]>C(O)(=O)C>[CH:22]1([NH:25][C:26]2[S:27]/[C:28](=[CH:1]\[C:3]3[CH:4]=[C:5]4[C:10](=[CH:11][CH:12]=3)[N:9]=[CH:8][C:7]([C:13]#[N:14])=[C:6]4[O:15][CH:16]([CH2:17][CH3:18])[CH2:21][CH3:20])/[C:29](=[O:31])[N:30]=2)[CH2:24][CH2:23]1
Reactant: N#Cc1cnc2ccc(C=O)cc2c1OC1CCOCC1
Reactant: O=C1CSC(NC2CC2)=N1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCC(CC)Oc1c(C#N)cnc2ccc(/C=C3\SC(NC4CC4)=NC3=O)cc12

Procedure:
Similar procedure as described in example 28c was used, starting from 6-formyl-4-(tetrahydro-pyran-4-yloxy)-quinoline-3-carbonitrile (example 64b), 2-cyclopropylamino-thiazol-4-one (example 37c), sodium acetate and acetic acid to give 6-[2-cyclopropylamino-4-oxo-4H-thiazol-(5Z)-ylidenemethyl]-4-(1-ethyl-propoxy)-quinoline-3-carbonitrile. LC-MS m/e 407 (MH+).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(O[BH-](O[C:24](=O)[CH3:25])OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH3:1][N:8]1[CH:9]=[CH:10][N:11]=[C:24]1[CH2:25][N:11]1[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Na+]
Solvent: ClCCCl
Product: Cn1ccnc1CN1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.2 %

Procedure:
N-Boc-piperazine (0.930 g, 5.0 mmol, 1.1 eq) was dissolved in 1,2-DCE (14 mL). To this solution, 1-methyl-2-imidazolecarboxy aldehyde (0.50 g, 4.54 mmol, 1 eq) was added followed by the portionwise addition of sodium triacetoxyborohydride (1.350 g, 6.36 mmol, 1.4 eq). The mixture was stirred at room temperature for 4 h and was then washed with a saturated aqueous solution of NaHCO3. The organic layer was dried (MgSO4), and the solvent removed in vacuo. The crude mixture was redissolved in 18 mL of DCM and gently stirred overnight in the presence of PS-isocyanate (2 g, loading: 1.58 mmol/g). The mixture was filtered off, and the resin washed with DCM (2×10 mL). The solvent was removed in vacuo and the resulting mixture was purified by column chromatography on a Biotage SP1 system eluting with methanol (1-8%) in dichloromethane to give the title compound as a off-white solid (0.450 g, 32%); 1H-NMR (500 MHz, CDCl3): δ 1.40 (s, 9H, C(CH3)3), 2.30-2.40 (m, 4H, piperazine N(CH2)2), 3.30-3.38 (m, 4H, piperazine N(CH2)2), 3.66 (s, 2H, NCH2), 3.67 (s, 3H, imidazole Me), 6.81 (s, 1H, imidazole 4-H), 6.90 (s, 1H, imidazole 5-H); GC-MS (ESI, m/z): Rt=4.62 min, 281.1-[(M+H)+, 100%].
Reaction SMILES: Cl.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]3)=[N:8][O:9][C:5]=2[CH:4]=1.C([O-])([O-])=O.[K+].[K+].BrCC[CH2:27][O:28][C:29]1[CH:30]=[C:31]([NH:37][C:38](=[O:40])[CH3:39])[CH:32]=[CH:33][C:34]=1OC.[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45]>CN(C)C=O.C(#N)C.C(O)C>[C:41]([OH:48])(=[O:47])/[CH:42]=[CH:43]/[C:44]([OH:46])=[O:45].[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:42][CH2:43][CH2:44][O:45][CH2:27][O:28][C:29]4[CH:30]=[C:31]([NH:37][C:38](=[O:40])[CH3:39])[CH:32]=[CH:33][CH:34]=4)[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1.[F:2][C:3]1[CH:17]=[CH:16][C:6]2[C:7]([CH:10]3[CH2:11][CH2:12][N:13]([CH2:42][CH2:43][CH2:44][O:45][CH2:27][O:28][C:29]4[CH:30]=[C:31]([NH:37][C:38](=[O:40])[CH3:39])[CH:32]=[CH:33][CH:34]=4)[CH2:14][CH2:15]3)=[N:8][O:9][C:5]=2[CH:4]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: COc1ccc(NC(C)=O)cc1OCCCBr
Agent: Cl
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CC#N
Product: CC(=O)Nc1cccc(OCOCCCN2CCC(c3noc4cc(F)ccc34)CC2)c1
Temperature: 100 °C

Procedure:
A mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole hydrochloride (3.94 g, 15.4 mmol), K2CO3 (3.67 g, 26.6 mmole), N-[3-(3-bromopropoxy)4 -methoxyphenyl]acetamide (5.56 g, 18.6 mmol) in dimethylformamide (75 ml) and acetonitrile (100 ml) was heated at 100° C. for 3 hours. At the end of the reaction, the solvent was concentrated and the mixture was extracted into dichloromethane (500 ml). The organic solution was washed with water (500 ml) and brine (400 ml), dried, then concentrated to a crude oil. The purification was effected by flash chromatography over a silca gel column (SiO2, 65 g, eluted with 1% CH3OH:dichloromethane, 1.2 l; and 3%CH3OH:dichloromethane, 500 ml). The material thus obtained weighed 2.33 g (34.3%) as an oil. This material was dissolved in ethanol and treated with a solution of fumaric acid (661 mg) in ethanol. The N-[3-[3-[4-(6-fluoro-1,2 benzisoxazol-3-yl)-1-piperidinyl]propoxy]methoxy-phenyl]acetamide hemifumarate was obtained as off-white crystals weighing 2.17 g, m.p.=205°-206° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:29])([CH3:28])[C@@H:11]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]([O:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])(=[O:7])=[O:6].[N-:30]=[N+:31]=[N-:32].[Na+]>CS(C)=O>[N:30]([CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:29])([CH3:28])[C@@H:11]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:12]([O:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[O:13])(=[O:7])=[O:6])=[N+:31]=[N-:32]
Reactant: CC(C)CCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)CCOC(=O)[C@H](OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCN=[N+]=[N-]

Procedure:
Following the general procedure for the preparation of azides of Description 16, 3-methylbutyl (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(phenylmethoxy)butanoate (29a) (0.32 g, 0.74 mmol) dissolved in 5 mL of anhydrous dimethyl sulfoxide (DMSO) was reacted with 0.11 g (1.5 mmol) of sodium azide (NaN3). After work-up, the crude material (29b) was used in the next step without further purification. MS (ESI) m/z 478.18 (M+Na)+.
Reaction SMILES: [C:1]([C:3]([C:10]1[CH:11]=[CH:12][C:13]2[O:22][C:17]3=[N:18][CH:19]=[CH:20][CH:21]=[C:16]3[C:15](=[O:23])[C:14]=2[CH:24]=1)(C)[C:4]([O:6]CC)=[O:5])#N.Cl>C(O)(=O)C>[O:23]=[C:15]1[C:16]2[C:17](=[N:18][CH:19]=[CH:20][CH:21]=2)[O:22][C:13]2[CH:12]=[CH:11][C:10]([CH:3]([CH3:1])[C:4]([OH:6])=[O:5])=[CH:24][C:14]1=2
Reactant: CCOC(=O)C(C)(C#N)c1ccc2oc3ncccc3c(=O)c2c1
Agent: Cl
Solvent: CC(=O)O
Product: CC(C(=O)O)c1ccc2oc3ncccc3c(=O)c2c1
Yield: 79.8 %

Procedure:
A mixture of 16.5 g of ethyl 2-cyano-2-(5-oxo-5H-[1]benzopyrano-[2,3-b]pyridin-7-yl)propionate, 80 ml of acetic acid and 35 ml of concentrated hydrochloric acid is heated under reflux for 24 hours. After concentration, water is added to the residue, and further a 10% sodium hydroxide solution is added to dissolve the residue. An insoluble material is removed by extraction with chloroform. The aqueous layer is made acid with acetic acid, and the crystalline precipitate is collected and recrystallized from aqueous dioxane to give 11 g of 2-(5-oxo-5H-[1]benzopyrano[2,3-b]pyridin-7-yl)propionic acid as white needles melting at 194°-195°C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[N:7][N:6]2[CH:9]=[C:10]([C:13]([NH2:15])=O)[C:11]([CH3:12])=[C:5]2[C:4]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:39])=CC=1>C1(C)C=CC=CC=1>[C:1]([C:3]1[CH:8]=[N:7][N:6]2[CH:9]=[C:10]([C:13](=[S:39])[NH2:15])[C:11]([CH3:12])=[C:5]2[C:4]=1[NH:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:19][CH:18]=1)#[N:2]
Reactant: Cc1c(C(N)=O)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: Cc1c(C(N)=S)cn2ncc(C#N)c(Nc3ccc(Oc4ccccc4)cc3)c12
Temperature: 100 °C
Yield: 25 %

Procedure:
A mixture of 3-cyano-5-methyl-4-(4-phenoxy-phenylamino)-pyrrolo[1,2-b]pyridazine-6-carboxylic acid amide (Example 9) (23 mg, 0.06 mmol) and Lawessons Reagent (48.5 mg, 0.12 mmol) in toluene (2 ml) was heated at 100° C. for 5 min. After regular workup, the residue was purified by prep. TLC to give impure 423A (6 mg, 25%) (5% MeOH—CHCl3). It has a retention time of 6.19 min (standard LC1 method, 8 min run). LCMS Found: (M+H)+=400.2
Reaction SMILES: C([O:8][C:9]1[CH:41]=[CH:40][CH:39]=[C:11]2[C:12]([N:14]([CH2:17][P:18]([CH2:21][CH:22]([C:27](=[O:38])[NH:28][C@H:29]([C:34](=[O:37])[NH:35][CH3:36])[CH2:30][CH:31]([CH3:33])[CH3:32])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:20])[OH:19])[C:15](=[O:16])[C:10]=12)=[O:13])C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:41]=[CH:40][CH:39]=[C:11]2[C:12]([N:14]([CH2:17][P:18]([CH2:21][CH:22]([C:27](=[O:38])[NH:28][C@H:29]([C:34](=[O:37])[NH:35][CH3:36])[CH2:30][CH:31]([CH3:32])[CH3:33])[CH2:23][CH:24]([CH3:26])[CH3:25])(=[O:19])[OH:20])[C:15](=[O:16])[C:10]=12)=[O:13]
Reactant: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(O)CN1C(=O)c2cccc(OCc3ccccc3)c2C1=O
Agent: [Pd]
Solvent: CO
Product: CNC(=O)[C@H](CC(C)C)NC(=O)C(CC(C)C)CP(=O)(O)CN1C(=O)c2cccc(O)c2C1=O
Reaction time: 4 h
Yield: 94.6 %

Procedure:
0.2 g of [[3-(benzyloxy)phthalimido]methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid was dissolved in 50 ml of methanol containing 0.1 g of 10% palladium-on-charcoal. The mixture was hydrogenated for 4 hours and then filtered. The filtrate was evaporated to give 0.16 g of [(3-hydroxyphthalimido)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid in the form of an off-white foam.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[CH:22])=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:24][O:25][C:26](=[O:53])[NH:27][CH:28]([C:32]([N:34]1[CH2:38][CH2:37][CH2:36][CH:35]1[C:39]1[NH:40][C:41]([C:44]#[C:45][C:46]2[CH:51]=[CH:50][C:49](Br)=[CH:48][CH:47]=2)=[CH:42][N:43]=1)=[O:33])[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C>CN(C=O)C.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.[Cu]I>[CH3:1][O:2][C:3](=[O:23])[NH:4][CH:5]([C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[NH:17][C:18]([C:21]#[C:22][C:49]2[CH:50]=[CH:51][C:46]([C:45]#[C:44][C:41]3[NH:40][C:39]([CH:35]4[CH2:36][CH2:37][CH2:38][N:34]4[C:32](=[O:33])[CH:28]([NH:27][C:26]([O:25][CH3:24])=[O:53])[CH:29]([CH3:31])[CH3:30])=[N:43][CH:42]=3)=[CH:47][CH:48]=2)=[CH:19][N:20]=1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: C#Cc1cnc(C2CCCN2C(=O)C(NC(=O)OC)C(C)C)[nH]1
Reactant: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#Cc2ccc(Br)cc2)[nH]1)C(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(C#Cc2ccc(C#Cc3cnc(C4CCCN4C(=O)C(NC(=O)OC)C(C)C)[nH]3)cc2)[nH]1)C(C)C
Temperature: 80 °C
Reaction time: 4 h
Yield: 17 %

Procedure:
{1-[2-(5-Ethynyl-1H-imidazol-2-yl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (49 mg, 0.154 mmol), (1-{2-[5-(4-bromo-phenylethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (43 mg, 0.0908 mmol), Pd(PPh3)4 (10 mg, 0.00908 mmol), CuI (2 mg, 0.00908 mmol) and triethylamine (0.127 mL, 0.908 mmol) were suspended in DMF (2 mL) and the mixture was degassed for 10 min with nitrogen. The reaction mixture was stirred at 80° C. for 4 hours then cooled to RT. Formic acid (0.1 mL) and water (1 mL) were added and the mixture was purified by reverse phase preparative HPLC, giving (1-{2-[5-(4-{2-[1-(2-Methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-ylethynyl}-phenylethynyl)-1H-imidazol-2-yl]-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester (11 mg, 17%). 1H NMR (MeOH-d4, 400 MHz) 7.46 (d, J=3.9 Hz, 4H), 7.25 (s, 2H), 6.96 (d, J=8.4 Hz, 2H), 5.10 (m, 2H), 4.20 (m, 2H), 3.97 (m, 2H), 3.83 (m, 2H), 3.64 (s, 6H), 2.32-2.00 (m, 10H), 0.98-0.88 (m, 12H); MS (ESI) m/z 711 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:22][C:23](O)=[O:24])[C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH3:27]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([C:15]2[CH:16]=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[CH2:22][C:23]([N:28]([CH2:26][CH3:27])[CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[O:24])(=[O:13])=[O:12])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCNCc1ccccn1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccc(C)nc1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(6-methyl-pyridin-3-yl)-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
Reaction SMILES: ClC1N=C2C(NC=N2)=C(Cl)N=1.C(N1C=NC2C1=NC=NC=2)=C.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([P:30](=[O:33])([CH3:32])[CH3:31])=[CH:26][CH:25]=1.CCN(C(C)C)C(C)C.[Cl:43][C:44]1[N:52]=[C:51]2[C:47]([N:48]=[CH:49][N:50]2[CH:53]=[CH2:54])=[C:46](Cl)[N:45]=1>CCO>[Cl:43][C:44]1[N:52]=[C:51]2[C:47]([N:48]=[CH:49][N:50]2[CH:53]=[CH2:54])=[C:46]([NH:23][C:24]2[CH:25]=[CH:26][C:27]([P:30]([CH3:31])([CH3:32])=[O:33])=[CH:28][CH:29]=2)[N:45]=1
Reactant: CP(C)(=O)c1ccc(N)cc1
Reactant: C=Cn1cnc2c(Cl)nc(Cl)nc21
Agent: C=Cn1cnc2cncnc21
Agent: Clc1nc(Cl)c2[nH]cnc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: C=Cn1cnc2c(Nc3ccc(P(C)(C)=O)cc3)nc(Cl)nc21

Procedure:
To a sealed tube were added 2,6-dichloropurine-9-vinyl purine (0.43 g, 2 mmol), 4-aminophenyl-dimethylphosphine oxide (0.37 g, 2.2 mmol), and the solids were dissolved in ˜15 mL anhydrous EtOH under Ar. Then DIEA (1.0 mL, 6 mmol) was added. The reaction was heated at 105° C. for 3 overnights until the starting material 2,6-dichloro-9-vinylpurine had disappeared. Volatiles were removed by rotavaporing and the residue was partitioned between EtOAc/water. The organic layer was washed with water once more and dried over Na2SO4. The final product was purified by silica gel column chromatography (4˜8% MeOH/DCM).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([CH3:23])[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:7]1)=[O:5])[CH3:2].[CH2:24](I)C>>[CH2:1]([O:3][C:4]([C:6]1([CH2:23][CH3:24])[CH2:11][CH2:10][CH2:9][N:8]([CH2:12][CH:13]2[O:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[O:15][CH2:14]2)[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCI
Reactant: CCOC(=O)C1(C)CCCN(CC2COc3ccccc3O2)C1
Product: CCOC(=O)C1(CC)CCCN(CC2COc3ccccc3O2)C1

Procedure:
Prepared according to the procedure described above for 1-(2,3-dihydrobenzo[1,4]dioxin-2-ylmethyl)-3-methylpiperidine-3-carboxylic acid ethyl ester except that ethyl iodide was used instead of methyl iodide.
Reaction SMILES: [CH2:1]([CH:5]1C(=O)O[C:8](C)([CH3:12])[O:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].C([OH:17])C>>[O:17]=[C:1]([CH2:2][CH2:3][CH3:4])[CH2:5][C:6]([O:7][CH2:8][CH3:12])=[O:14]
Reactant: CCO
Reactant: CCCCC1C(=O)OC(C)(C)OC1=O
Product: CCCC(=O)CC(=O)OCC
Yield: 72 %

Procedure:
The 5-butyl-2,2-dimethyl-1,3-dioxane-4,6-dione thus obtained was allowed to reflux in ethanol for 2 hours, and then concentrated under reduced pressure. The resulting residue was purified using silica gel chromatography (developing solvent: n-hexane/ethyl acetate=8/2) to obtain the ethyl 3-oxohexanoate shown by the formula below.