Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(N1CCC2(O[CH2:15][CH2:14][N:13]([CH2:17][C:18]3[S:26][C:25]4[C:24]([N:27]5[CH2:32][CH2:31][O:30][CH2:29][CH2:28]5)=[N:23][C:22]([Cl:33])=[N:21][C:20]=4[CH:19]=3)[CH2:12]2)CC1)=O)(C)(C)C.[C:36]([O:40][C:41]([N:43]1C2[CH2:49][CH2:50][CH:44]1CNC2)=[O:42])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([O:40][C:41]([N:43]1[CH:44]2[CH2:50][CH2:49][CH:15]1[CH2:14][N:13]([CH2:17][C:18]1[S:26][C:25]3[C:24]([N:27]4[CH2:28][CH2:29][O:30][CH2:31][CH2:32]4)=[N:23][C:22]([Cl:33])=[N:21][C:20]=3[CH:19]=1)[CH2:12]2)=[O:42])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)OC(=O)N1C2CCC1CNC2
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)CCO2
Product: CC(C)(C)OC(=O)N1C2CCC1CN(Cc1cc3nc(Cl)nc(N4CCOCC4)c3s1)C2

Procedure:
Prepared according to the method used in the preparation of 4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-1-oxa-4,9-diaza-spiro[5.5]undecane-9-carboxylic acid tert-butyl ester using 3,8-diaza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester in place of 4-ethoxy-4-methylaminomethyl-piperidine-1-carboxylic acid tert-butyl ester. The title compound was obtained as a cream solid (245 mg, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][NH:11][C:12]=2[CH3:13])=[C:4]([C:16](=O)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])[CH:3]=1>[Ni].C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9](=[CH:10][NH:11][C:12]=3[CH3:13])[CH2:14][N:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:4]=2[CH:3]=1
Reactant: Cc1[nH]cc(C#N)c1-c1ccc(Cl)cc1C(=O)c1ccccc1Cl
Agent: [Ni]
Solvent: CC(=O)O
Product: Cc1[nH]cc2c1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2

Procedure:
A mixture of 8.5 g (24 mmol) of 4-[4-chloro-2-(2-chlorobenzoyl)phenyl]-5-methyl-1H-pyrrole-3-carbonitrile, 1 spoonful of Raney nickel and 250 ml of glacial acetic acid was hydrogenated on a Parr apparatus at 55 psi overnight. The catalyst was removed by filtration and the acetic acid was removed at reduced pressure. The residue was diluted with water, basifified with concentrated ammonium hydroxide and the resulting precipitate was collected by filtration. The precipitate was dissolved in tetrahydrofuran, dried over anhydrous sodium sulfate and concentrated at reduced pressure. The residue was crystallized from a mixture of ether and petroleum ether to give off-white crystals (mp 219°-222°). Recrystallization from a mixture of ether and methylene chloride gave colorless crystals, mp 221°-225°.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[CH2:9][O:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17]>[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[C:1]([CH2:5][C:6]1[CH:7]=[C:8]([CH:21]=[CH:22][CH:23]=1)[CH2:9][O:10][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])#[N:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)NCCOCc1cccc(CBr)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Br-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCOCc1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 96 h
Yield: 97.5 %

Procedure:
Sodium cyanide (284 mg, 5.78 mmol) and benzyl triethylammonium bromide (63 mg, 0.23 mmol) were added to a solution of tert-butyl 2-{[3-(bromomethyl)benzyl]oxy}ethylcarbamate (preparation 103) (798 mg, 2.31 mmol) in acetonitrile (5 ml), and the reaction stirred at room temperature for 4 days. The mixture was partitioned between water and ethyl acetate and the layers separated. The organic phase was dried over MgSO4 and evaporated under reduced pressure, to afford the desired product as an oil, (654 mg, 97%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH:19][C:20]2[N:25]=[C:24]([C:26](N)=[O:27])[CH:23]=[CH:22][N:21]=2)[CH2:13][CH2:12]1.[CH3:29][OH:30].Cl>C1CCCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[N:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH2:18][NH:19][C:20]2[N:25]=[C:24]([C:26]([O:30][CH3:29])=[O:27])[CH:23]=[CH:22][N:21]=2)[CH2:15][CH2:16]1
Reactant: CO
Reactant: COc1ccc(OC)c(N2CCN(CCNc3nccc(C(N)=O)n3)CC2)c1
Agent: Cl
Solvent: C1CCCCC1
Product: COC(=O)c1ccnc(NCCN2CCN(c3cc(OC)ccc3OC)CC2)n1

Procedure:
8.76 g (22.66 mmol) of 2-[[2-[4-(2,5-dimethoxyphenyl) piperazin-1-yl]ethyl]amino]pyrimidine-4-carboxamide are introduced into 650 ml of methanol in a 1 l round-bottomed flask, a stream of gaseous hydrochloric acid is passed through for a few minutes and the mixture is then heated at the reflux temperature of the methanol for 5 h. The solventis evaporated under reduced pressure, 300 ml of dichloromethane are added to the residue and the mixture is then basified with a saturated aqueous sodium hydrogencarbonate solution. The organic phase is dried over sodium sulphate, filtered and the solvent is then evaporated under reduced pressure. After purification by chromatography on a silica gel column (eluent: 100/0 to 90/10 dichloromethane/methanol mixture) and then by recrystallisation from cyclohexane, 6.93 g (17.26 mmol) of ester are isolated.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].[C:19]1([NH2:29])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>CCCCCC.C(OCC)(=O)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][NH:29][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1)[CH3:18]
Reactant: CCOC(=O)CBr
Reactant: Nc1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 74.8 %

Procedure:
19.3 g(139 mmol) of potassium carbonate was added to 200 ml of dimethylformamide, and then the solution was heated to dissolve potassium carbonate. After cooling to room temperature, 8 ml(70 mmol) of ethyl bromoacetate and 10 g(70 mmol) of 1-naphthylamine were added to the solution, which was then stirred for 48 hours. DMF was removed under reduced pressure and ethyl acetate was added to the residue. The ethyl acetate layer was washed with water 4 times and saturated sodium chloride solution. Ethyl acetate was removed under reduced pressure, and then column chromatography was performed using a mixed solution(9:1) of hexane and ethyl acetate as an eluent to obtain 12 g of the title compound(Yield 75%, MW 229).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:13][N:14]([C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1)[C:15]([C@@H:17]1[CH2:19][C@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1)=[O:16])[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2].[CH:35]#[C:36][CH2:37][CH2:38][CH3:39].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:34])[NH:7][C@H:8]([CH2:13][N:14]([C:15]([C@H:17]1[CH2:19][C@@H:18]1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[N:21]=1)=[O:16])[C:27]1[CH:32]=[CH:31][C:30]([C:35]#[C:36][CH2:37][CH2:38][CH3:39])=[CH:29][CH:28]=1)[C@@H:9]([CH3:12])[CH2:10][CH3:11])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#CCCC
Reactant: CC[C@H](C)[C@@H](CN(C(=O)[C@@H]1C[C@H]1c1cccc(F)n1)c1ccc(Br)cc1)NC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCC#Cc1ccc(N(C[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)CC)C(=O)[C@H]2C[C@@H]2c2cccc(F)n2)cc1
Temperature: 90 °C
Yield: 99.6 %

Procedure:
[(1S,2S)-1-({(4-Bromo-phenyl)-[trans-2-(6-fluoro-pyridin-2-yl)-cyclopropanecarbonyl]-amino}-methyl)-2-methyl-butyl]-carbamic acid t-butyl ester (0.068 g, 0.127 mmol), 1-pentyne (0.05 mL, 0.509 mmol), PdCl2(PPh3)2 (0.017 g, 0.025 mmol) and 1N TBAF in THF (0.76 mL, 0.762 mmol) were mixed in THF (1 mL) in sealed microwave flask. The reaction mixture was heated at 90° C. at normal setting for 30 minutes. The reaction mixture was quenched with brine. The aqueous phase was extracted by ethyl acetate (3×7 mL). The combined organic layers were washed brine and dried over MgSO4, filtered and concentrated to give yellow oil. The crude product was purified via column chromatography on silica gel with a gradient of 0%-50% of ethyl acetate in hexanes to afford the title product as yellow oil (0.066 g, 99% yield): 1H NMR (400 MHz, CDCl3) δ ppm 7.32 (m, 4H), 6.86 (m, 3H), 6.42 (m, 1H), 4.76 (d, J=9.1 Hz, 1H), 4.11 (m, 1H), 3.48 (m, 1H), 2.95 (td, J=13.1, 3.8 Hz, 1H), 2.42 (m, 1H), 2.16 (td, J=7.0, 3.4 Hz, 2H), 1.67 (m, 1H), 1.40 (m, 4H), 1.22 (m, 11H), 0.84 (m, 3H), 0.63 (m, 6H); LCMS (ESI) m/e 522.4 [(M+H), calcd for C31H41FN3O3 522.7].
Reaction SMILES: OC1C=CC([CH:8]2[CH:13]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH2:26][CH2:27][CH2:28][O:29][CH3:30])[C:20]=4[CH:31]=3)[CH2:12][CH2:11][CH2:10][N:9]2[C:32]([O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])=CC=1.C1(C)C=CC(S([O:51][CH2:52][CH2:53][O:54][S:55]([C:58]2[CH:63]=[CH:62][C:61]([CH3:64])=[CH:60][CH:59]=2)(=[O:57])=[O:56])(=O)=O)=CC=1>>[CH3:30][O:29][CH2:28][CH2:27][CH2:26][N:21]1[C:20]2[CH:31]=[C:16]([CH2:15][O:14][CH:13]3[CH:12]([C:16]4[CH:17]=[CH:18][C:19]([O:51][CH2:52][CH2:53][O:54][S:55]([C:58]5[CH:59]=[CH:60][C:61]([CH3:64])=[CH:62][CH:63]=5)(=[O:56])=[O:57])=[CH:20][CH:31]=4)[CH2:11][CH2:10][N:9]([C:32]([O:34][CH2:35][C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:33])[CH2:8]3)[CH:17]=[CH:18][C:19]=2[O:24][CH2:23][C:22]1=[O:25]
Reactant: Cc1ccc(S(=O)(=O)OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: COCCCN1C(=O)COc2ccc(COC3CCCN(C(=O)OCc4ccccc4)C3c3ccc(O)cc3)cc21
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCOS(=O)(=O)c4ccc(C)cc4)cc3)cc21

Procedure:
Analogously to Method I, 0.417 g of benzyl 4-hydroxyphenyl-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benz[1,4]oxazin-6-ylmethoxy]piperidinecarboxylate and 0.984 g of ethylene di(p-toluenesulphonate) are reacted. The title compound is obtained as a colourless oil. Rf=0.31 (2:1 EtOAc-heptane); Rt=5.35.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19]CC1C=CC=CC=1)[N:15]=[CH:14][N:13]=[C:12]2[N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[C:42](=[O:43])[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:44])[CH:40]=3)[N:35]([CH3:45])[C:34]2=[O:46])[CH2:29][CH2:28]1)C1C=CC=CC=1.CN(C=O)C>C(O)C>[OH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[OH:19])[N:15]=[CH:14][N:13]=[C:12]2[N:27]1[CH2:32][CH2:31][CH:30]([N:33]2[C:42](=[O:43])[C:41]3[C:36](=[CH:37][CH:38]=[C:39]([CH3:44])[CH:40]=3)[N:35]([CH3:45])[C:34]2=[O:46])[CH2:29][CH2:28]1
Reactant: Cc1ccc2c(c1)c(=O)n(C1CCN(c3ncnc4cc(OCc5ccccc5)c(OCc5ccccc5)cc34)CC1)c(=O)n2C
Solvent: CCO
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)c(=O)n(C1CCN(c3ncnc4cc(O)c(O)cc34)CC1)c(=O)n2C
Yield: 68.9 %

Procedure:
The procedure similar to that described in Example 79 was repeated, except that 200.0 mg (0.33 mmol) of Compound 88 obtained in Example 67 was used in place of Compound 87 and DMF was used as a reaction solvent in place of ethanol. As a result, 98.5 mg (yield: 70%) of Compound 97 was obtained as white crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][O:19]CC3C=CC(OC)=CC=3)=[CH:10][C:9]=2[F:29])=[C:6]([CH:30]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[N:5]2[N:37]=[CH:38][N:39]=[C:4]2[N:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)Cl.O>[Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:15][CH2:16][CH2:17][CH2:18][OH:19])=[CH:10][C:9]=2[F:29])=[C:6]([CH:30]2[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)[N:5]2[N:37]=[CH:38][N:39]=[C:4]2[N:3]=1
Reactant: COc1ccc(COCCCOc2cc(F)c(-c3c(Cl)nc4ncnn4c3C3CCCCCC3)c(F)c2)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: OCCCOc1cc(F)c(-c2c(Cl)nc3ncnn3c2C2CCCCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 77.8 %

Procedure:
To a solution of 5-chloro-7-cycloheptyl-6-(2,6-difluoro-4-{3-[(4-methoxybenzyl)oxy]propoxy}phenyl)[1,2,4]triazolo[1,5-a]pyrimidine (56 mg, 0.1 mmol) in 4 mL of methylene chloride and 0.2 mL of water is added 2,3-dichloro-5,6-dicyano-1,4-bezoquinone (100 mg, 0.44 mmol). The mixture is stirred at room temperature for 20 minutes, then washed with saturated aqueous sodium bicarbonate solution (x2), dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with a gradient of 33% ethyl acetate in hexanes to 66% ethyl acetate in hexanes. Concentration provides 3-[4-(5-chloro-7-cycloheptyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-3,5-difluorophenoxy]propan-1-ol as a light yellow solid (34 mg). MS: m/z 437.2 (M+H).
Reaction SMILES: [ClH:1].[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14](Br)[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]C.C([Li])CCC.FC([I:35])(F)F>>[ClH:1].[CH2:2]([O:9][C:10]1[C:11]([NH:17][C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[N:12][CH:13]=[C:14]([I:35])[CH:15]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1csc(Nc2ncc(Br)cc2OCc2ccccc2)n1
Reactant: FC(F)(F)I
Agent: Cl
Agent: [Li]C
Agent: [Li]CCCC
Product: Cc1csc(Nc2ncc(I)cc2OCc2ccccc2)n1
Yield: 37 %

Procedure:
3-(Benzyloxy)-5-bromo-N-(4-methylthiazol-2-yl)pyridin-2-amine (prepared according to Example 1) (0.250 g, 0.664 mmol), MeLi (0.519 mL, 0.831 mmol), butyllithium (0.332 mL, 0.831 mmol) and trifluoromethyliodide (bubbled in excess) were reacted according to the method of Example 7 to provide 3-(benzyloxy)-5-iodo-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (0.104 g, 37.0% yield). 1H NMR (d6-DMSO) δ 8.14 (d, 1H), 7.82 (m, 1H), 7.58 (m, 2H), 7.40 (m, 3H), 6.79 (s, 1H), 5.31 (s, 2H), 2.28 (s, 3H). Mass spectrum (apci) m/z=424.0 (M+H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][OH:12].[Br:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16](F)[CH:15]=1>>[F:20][C:18]1[CH:17]=[C:16]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH:15]=[C:14]([Br:13])[CH:19]=1
Reactant: OCc1ccc2ccccc2c1
Reactant: Fc1cc(F)cc(Br)c1
Product: Fc1cc(Br)cc(OCc2ccc3ccccc3c2)c1
Yield: 92 %

Procedure:
Using the procedure described in the first paragraph of the portion of Example 3 which is concerned with the preparation of starting materials, 2-naphthalenemethanol was reacted with 1-bromo-3,5-difluorobenzene to give 5-fluoro-3-(naphth-2-ylmethoxy)bromobenzene (92%), m.p. 65°-67° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6](Cl)[CH:7]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C.[OH-].[NH4+].[Cu]I>[Cl:1][C:2]1[C:3]([C:9]#[N:10])=[N:4][CH:5]=[C:6]([C:12]#[C:11][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH:7]=1
Reactant: C#Cc1ccc(C)cc1
Reactant: N#Cc1ncc(Cl)cc1Cl
Agent: [Cu]I
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C#Cc2cnc(C#N)c(Cl)c2)cc1
Temperature: 25 °C

Procedure:
A solution of 3,5-dichloropicolinonitrile (commercially available) (1.0 eq.), 1-ethynyl-4-methylbenzene (commercially available) (1.0 eq.), trans-dichlororbis(triphenylphosphine)palladium (II) (10 mol %), copper (I) iodide (20 mol %), and triethylamine (5.0 eq.) in DMF (0.3 M) was stirred at 50° C. for 3 hours. After cooling to ambient temperature, the reaction mixture was diluted with ethyl acetate and 10% aqueous ammonium hydroxide. The two phases were separated, and the aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous MgSO4, and concentrated en vaccuo. The crude material was purified by stirring in hot ether/hexane mixtures and filtered to give 3-chloro-5-(p-tolylethynyl)picolinonitrile.
Reaction SMILES: C([N:20]1[C:24]2[N:25]=[CH:26][CH:27]=[C:28]([C:29](=[S:31])[NH2:30])[C:23]=2[CH:22]=[N:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Br[CH:33]1[CH2:38][CH2:37][CH2:36][C:35]([CH3:41])([C:39]#[N:40])[C:34]1=O.C1COCC1>CCO>[CH3:41][C:35]1([C:39]#[N:40])[C:34]2[N:30]=[C:29]([C:28]3[CH:27]=[CH:26][N:25]=[C:24]4[NH:20][N:21]=[CH:22][C:23]=34)[S:31][C:33]=2[CH2:38][CH2:37][CH2:36]1
Reactant: NC(=S)c1ccnc2c1cnn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC1(C#N)CCCC(Br)C1=O
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C#N)CCCc2sc(-c3ccnc4[nH]ncc34)nc21
Yield: 39 %

Procedure:
A solution of 1-tritylpyrazolo[5,4-b]pyridine-4-carbothioamide (220 mg, 0.5232 mmol) and 3-bromo-1-methyl-2-oxo-cyclohexane-1-carbonitrile (125.0 mg, 0.5785 mmol) in EtOH (10 mL)/THF (1.5 mL) was heated at 90° C. overnight under nitrogen. The reaction mixture was concentrated in vacuo and purified by column chromatography (70:9:1 DCM/MeOH/NH4OH) to give a white solid after precipitation (67 mg, 39% Yield). MS (ES+) 296.08
Reaction SMILES: [NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8](SC)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1.[CH3:14][N:15]([CH3:24])[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[CH2:19][NH2:20]>C(O)(C)C>[NH2:1][C:2]1[N:11]=[CH:10][C:9]2[C:8]([NH:20][CH2:19][C:18]3[CH:21]=[CH:22][CH:23]=[C:16]([N:15]([CH3:24])[CH3:14])[CH:17]=3)=[N:7][CH:6]=[N:5][C:4]=2[CH:3]=1
Reactant: CN(C)c1cccc(CN)c1
Reactant: CSc1ncnc2cc(N)ncc12
Solvent: CC(C)O
Product: CN(C)c1cccc(CNc2ncnc3cc(N)ncc23)c1
Yield: 40 %

Procedure:
A mixture of 7-amino-4-methylthiopyrido[4,3-d]pyrimidine (236 mg, 1.23 mmol) (described in a previous experimental) and 3-dimethylamino-benzylamine (1.36 g, 9.07 mmol) in isopropanol (5 mL) is stirred under N2 at reflux for 1 h, and the resulting product is chromatographed on silica gel (10-15% EtOH/EtOAc), then on alumina (1% EtOH/CHCl3) to give 7-amino-4-(3-dimethylaminobenzylamino)pyrido[4,3-d]pyrimidine (145 mg, 40%) as a white solid. 1H NMR (DMSO) δ 9.11 (1H, s), 8.79 (1H, t, J=5.9 Hz), 8.26 (1H, s), 7.11 (1H, dd, J=8.0, 7.7 Hz), 6.73 (1H, brs), 6.63 (1H, d, J=7.6 Hz), 6.60 (1H, dd, J=8.1, 2.2 Hz), 6.44 (2H, brs), 6.35 (1H, S), 4.67 (2H, d, J=5.8 Hz), 2.86 (6H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:31]=[C:30]([CH3:32])[O:29][N:28]=2)[CH:24]=1)[C:9]([NH:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][CH:13]=1)=[O:10].[OH-].[Na+].Cl>C1COCC1.O>[CH3:1][C:2]1[CH:36]=[CH:35][CH:34]=[CH:33][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:31]=[C:30]([CH3:32])[O:29][N:28]=2)[CH:24]=1)[C:9]([NH:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1)=[O:10]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(OCc3cc(C)on3)cc(OCc3ccccc3C)c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(COc2cc(OCc3ccccc3C)cc(C(=O)Nc3ccc(C(=O)O)cn3)c2)no1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.4 %

Procedure:
Methyl 6-{[3-(2-methylbenzyloxy)-5-(5-methylisoxazol-3-ylmethoxy)benzoyl]amino}-3-pyridinecarboxylate (98 mg, 0.201 mM) was dissolved in THF (4 ml) and a solution of NaOH (24 mg, 0.603 mM) in water (0.24 ml) was added. Water (4 ml) was added to the reaction mixture until it became monophasic. The reaction was stirred for 16 hours at ambient temperature and was then acidified to pH=1 with 1N aqueous HCl. The white solid which precipitated from the mixture was isolated by filtration and was dried ‘in vacuo’ to give the title compound as a white solid (67 mg, 70% yield); H1 NMR δ (d6-DMSO) 2.30 (3H s) 2.39 (3H s) 5.16 (2H s) 5.22 (2H s) 6.33 (1H s) 6.91 (1H s) 7.11–7.42 (6H m) 8.30 (2H s) 8.87 (1H s). MS [MH]+ 474
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1C2C=CC=C(O[P+](N3CCCC3)(N3CCCC3)N3CCCC3)C=2N=N1.[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH:51][C:52](=[O:65])[C:53]1[CH:58]=[CH:57][C:56]([CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)=[CH:55][CH:54]=1>CN(C=O)C>[NH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[NH:51][C:52](=[O:65])[C:53]1[CH:58]=[CH:57][C:56]([CH:59]2[CH2:64][CH2:63][N:62]([C:6](=[O:8])[C:5]3[CH:4]=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=3)[CH2:61][CH2:60]2)=[CH:55][CH:54]=1
Reactant: O=C(O)c1ccc(Br)cc1
Reactant: Nc1ccccc1NC(=O)c1ccc(C2CCNCC2)cc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1cc(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)c2nn[nH]c2c1
Solvent: CN(C)C=O
Product: Nc1ccccc1NC(=O)c1ccc(C2CCN(C(=O)c3ccc(Br)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
To a solution of 4-bromobenzoic acid (1.0 g, 3.3 mmol) in DMF (5 ml) was added benzotriazolyloxytripyrollidinophosphonium hexafluorophosphate (99 mg, 0.19 mmol) and the mixture stirred at ambient temperature for 30 minutes. N-(2-aminophenyl)-4-piperidin-4-ylbenzamide (Example 5, 50 mg, 0.17 mmol) was added and the mixture stirred for a further 24 hours. The resulting solution was absorbed onto an SCX-2 column, washed with methanol (2 column volumes) and eluted with a 2M solution of ammonia in methanol (2 column volumes) to afford the product. This was purified by flash chromatography (eluting with 0-20% methanol/dichloromethane) to afford the title compound as a colourless solid (29 mg, 18%); NMR Spectrum: (DMSO-d6) 1.70 (m, 4H), 2.60 (m, 1H), 2.91 (m, 2H), 3.31 (m, 2H), 4.89 (s, 2H), 6.60 (t, 1H), 6.78 (d, 1H), 6.97 (t, 1H), 7.16 (d, 1H), 7.43 (d, 4H), 7.67 (d, 2H), 7.93 (d, 2H), 9.60 (s, 1H); Mass Spectrum: M+H+ 478.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([N:19]([CH3:28])[C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[CH:9]=[C:10]([NH:11]C(=O)OC(C)(C)C)[C:5]2=[N:4][N:3]=1.Cl>C1COCC1>[CH3:28][N:19]([C@H:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21])[C:8]1[CH:9]=[C:10]([NH2:11])[C:5]2[N:6]([C:2]([CH3:1])=[N:3][N:4]=2)[N:7]=1
Reactant: Cc1nnc2c(NC(=O)OC(C)(C)C)cc(N(C)[C@@H](C)c3ccccc3)nn12
Agent: Cl
Solvent: C1CCOC1
Product: Cc1nnc2c(N)cc(N(C)[C@@H](C)c3ccccc3)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.9 %

Procedure:
To a solution of compound (S)-tert-butyl 3-methyl-6-(methyl(1-phenylethyl)amino)-[1,2,4]triazolo[4,3-b]pyridazin-8-ylcarbamate (55 mg) in THF (10 mL) was added 6 N HCl (2 mL) dropwise under ice bath and then stirred at room temperature for 2 hrs. The mixture was quenched by saturated aqueous sodium bicarbonate solution (30 mL) and extracted with EA (20 mL×3). The combined organic layers were dried over Na2SO4, concentrated in vacuum to give product (S)-N6, 3-dimethyl-N6-(1-phenylethyl)-[1,2,4]triazolo[4,3-b]pyridazine-6,8-diamine (Compound 6) as a yellow solid (30 mg, 73.9%). 1H NMR (300 MHz, CD3OD) δ: 7.22˜7.25 (m, 4H), 7.15˜7.18 (m, 1H), 6.30 (s, 12H), 5.69˜5.72 (q, 1H), 2.79 (s, 3H), 2.68 (s, 3H),1.53 (d, 3H, J=4.8 Hz). LRMS (M+H+) m/z: calcd 283; found 283.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:15][Cl:16])[CH2:13][CH:12]([OH:14])[CH2:11][O:10]1>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:15][Cl:16])[CH2:13][C:12](=[O:14])[CH2:11][O:10]1
Reactant: OC1COC(CCl)(c2ccc(Cl)cc2Cl)C1
Solvent: CC(=O)O
Product: O=C1COC(CCl)(c2ccc(Cl)cc2Cl)C1

Procedure:
The oily residue obtained in stage a) is then heated in toluene (100 cc) and butanol (200 cc) in the presence of paratoluenesulphonic acid (0.5 g), with the separation of the water formed. After evaporating the reaction medium, the residue is chromatographed on a silica column (40:60 ethyl acetate/heptane eluant) to obtain a colourless oil (14.5 g) corresponding to a mixture of alcohol diastereoisomers, namely 2-(2,4-dichlorophenyl)-4-hydroxy-2-chloromethyltetrahydrofuran. This product is directly oxidized with chromic anhydride in acetic acid to obtain, after purification by silica column chromatography, furanone in the form of white crystals, m.p. 99° C.
Reaction SMILES: C(/N=[CH:6]/[C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:14][CH3:15])CCC.S(=O)(=O)(O)[OH:17]>>[CH2:14]([C:8]1[CH:9]=[CH:10][CH:11]=[C:12]([F:13])[C:7]=1[CH:6]=[O:17])[CH3:15]
Reactant: CCCC/N=C/c1c(F)cccc1CC
Reactant: O=S(=O)(O)O
Product: CCc1cccc(F)c1C=O

Procedure:
Prepared in analogy to Example 59(a) from butyl-[1-(2-ethyl-6-fluoro-phenyl)-meth-(E)-ylidene]-amine and aqueous sulphuric acid.