Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[C:12]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:13][S:14][N:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[N:29]([C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=1)=[C:30]=[O:31]>ClCCl.CCOC(C)=O>[F:39][C:38]([F:40])([F:41])[C:36]1[CH:37]=[C:32]([NH:29][C:30]([N:19]2[CH2:20][CH2:21][N:16]([C:12]3[C:11]([O:10][CH2:9][C:6]4[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=4)=[N:15][S:14][N:13]=3)[CH2:17][CH2:18]2)=[O:31])[CH:33]=[C:34]([C:42]([F:45])([F:43])[F:44])[CH:35]=1
Reactant: c1cc(COc2nsnc2N2CCNCC2)ccn1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2OCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
1-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine, dihydrochloride salt (2.13 g, 6.1 mmol), dichloromethane (40 mL), and triethylamine (2.5 mL, 17.9 mmol) were combined and cooled in an icebath. 1-Isocyanato-3,5-bis-trifluoromethyl-benzene (1.89 g, 7.4 mmol) in dichloromethane (10 mL) was added dropwise and the resulting mixture stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and washed with sat'd NaHCO3 (3×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by column chromatography (1:1 hexanes:EtOAc, followed by 1:3 hexanes:EtOAc) to give 2.6 g (80%) of 4-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide as a white solid after lyophilization from: H2O—AcCN. 1H NMR (CDCl3) 8.62 (d, 2H), 7.84 (s, 2H), 7.50 (s, 1H), 7.31 (d, 2H), 7.06 (s, 1H), 5.49 (s, 2H), 3.68-3.60 (m, 8H) ppm. LC-MS (MH+)=533.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][O:19][CH2:20][C:21]3[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=3)[CH2:11][CH2:10]2)=[N:7][CH:8]=1)[CH3:2].C(N)(=[O:31])C>C1COCC1.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:1]([C:3]1[CH:4]=[N:5][C:6]([N:9]2[CH2:10][CH2:11][CH:12]([C@H:15]3[CH2:17][C@H:16]3[CH2:18][O:19][CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([NH2:26])=[O:31])=[CH:27][CH:28]=3)[CH2:13][CH2:14]2)=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(C#N)cc3)CC2)nc1
Reactant: CC(N)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: CCc1cnc(N2CCC([C@H]3C[C@H]3COCc3ccc(C(N)=O)cc3)CC2)nc1
Temperature: 25 °C

Procedure:
The product of step A (150 mg, 0.398 mmol), acetamide (101 mg, 1.71 mmol) and Pd(OAc)2 (13.4 mg, 0.02 mmol) in THF (4.5 mL) and H2O (1.5 mL) was heated at 65° C. for 24 h. The mixture was cooled to RT and diluted with H2O. The solution was extracted with EtOAc (×3). The combined organic layers were washed with brine (1×), dried over anhydrous MgSO4, filtered, and concentrated under vacuum to leave a residue which was purified by silica gel column chromatography (elution with 20:1 DCM:MeOH) to yield the desired compound. MS (ESI) m/z 395 [M+H]+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:11]=[C:12]([C:16]4[O:17][CH2:18]C(C)(C)N=4)[CH:13]=[CH:14][CH:15]=3)[C:4]=2[CH:3]=[CH:2]1.S(=O)(=O)(O)[OH:24].O>CO>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=3)[C:16]([O:17][CH3:18])=[O:24])[C:4]=2[CH:3]=[CH:2]1
Reactant: O=S(=O)(O)O
Reactant: CC1(C)COC(c2cccc(-c3cccc4occc34)c2)=N1
Solvent: CO
Solvent: O
Product: COC(=O)c1cccc(-c2cccc3occc23)c1

Procedure:
A mixture of 2-[3-(benzofuran-4-yl)phenyl]-4,4-dimethyl-4,5-dihydrooxazole (1.4 g), concentrated sulfuric acid (0.8 ml) and water (1 ml) in methanol (20 ml) was refluxed for 48 hours. After evaporating the solvent, the residue was dissolved in a mixture of ethyl acetate (50 ml) and water (50 ml). The organic layer was successively washed with 10% sodium carbonate aqueous solution, brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was purified by column chromatography on silica gel eluting with toluene. The fractions containing the desired products were collected and evaporated in vacuo to afford methyl 3-(benzofuran-4-yl)benzoate (0.77 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.N(CC)(CCC)CCC.[C:19]([O:23][C:24]([NH:26][CH:27]1[CH2:31][CH2:30][NH:29][CH2:28]1)=[O:25])([CH3:22])([CH3:21])[CH3:20]>CN(C=O)C>[C:19]([O:23][C:24]([NH:26][CH:27]1[CH2:31][CH2:30][N:29]([CH2:6][C:5]2[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:28]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: ClCc1ccc(Cl)cc1
Agent: CCCN(CC)CCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(Cc2ccc(Cl)cc2)C1
Temperature: 70 °C
Reaction time: 15 h
Yield: 80.2 %

Procedure:
4-Chlorobenzyl chloride (4.15g, 25.8 mmol) and Pr2NEt (6.67 g, 51.6 mmol) were added to a solution of 3-{(tert-butoxycarbonyl)amino)pyrrolidine (4.81 g, 25.8 mmol) in DMF (50 mL}. The reaction mixture was stirred at 70° C. for 15 h and the solvent was removed under reduced pressure. Recrystallization (CH3CN, 50 mL) provided the desired material, 3-(tert-butoxycarbonyl)amino-1-(4-chlorobenzyl)pyrrolidine as a pale yellow solid (6.43 g, 80.2%): 1H NMR (CDCl3, 300 MHz) δ1.37 (s, 9H), 1.5-1.7 (br, 1H), 2.1-2.4 (m, 2H), 2.5-2.7 (m, 2H), 2.83 (br, 1H), 3.57 (s, 2H), 4.1-4.3 (br, 1H), 4.9-5.1 (br, 1H), 7.15-7.35 (br, 4H); The purity was determined by RPLC/MS (98%); ESI/MS m/e 311.0 (M++H, C16H24ClN2O2).
Reaction SMILES: FC(F)(F)S(O[CH:7]([CH2:11][NH:12][C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])[CH:8]([F:10])[F:9])(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C.O>[N:25]([CH:7]([CH:8]([F:10])[F:9])[CH2:11][NH:12][C:13](=[O:14])[O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N+:26]=[N-:27]
Reactant: O=C(NCC(OS(=O)(=O)C(F)(F)F)C(F)F)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC(CNC(=O)OCc1ccccc1)C(F)F
Reaction time: 3 h

Procedure:
To a solution of 3-{[(benzyloxy)carbonyl]amino}-1,1-difluoropropan-2-yl trifluoromethanesulfonate (580 g, 1.54 mol) in DMF (3000 mL) was added sodium azide (240 g, 3.69 mol). After 3 hours, the reaction mixture was diluted with water (3000 mL) and extracted with diethyl ether (3×1500 mL). The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford benzyl (2-azido-3,3-difluoropropyl)carbamate. The material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1.[NH:12]1[CH2:20][CH2:19][CH:15]([C:16]([NH2:18])=[O:17])[CH2:14][CH2:13]1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:20][CH2:19][CH:15]([C:16]([NH2:18])=[O:17])[CH2:14][CH2:13]2)[C:5]2[CH:10]=[CH:9][NH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: NC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: NC(=O)C1CCN(c2nc(Cl)nc3[nH]ccc23)CC1
Temperature: 70 °C
Reaction time: 20 h
Yield: 98.8 %

Procedure:
A mixture of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (140 mg, 0.744 mmol), isonipecotamide (95 mg, 0.742 mmol) and triethylamine (0.300 mL, 2.15 mmol) in dioxane (4 mL) was stirred at 70° C. for 20 h. The precipitates were collected and dried on vacuum to give 1-(2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxamide (205 mg). MS 280.3 and 282.3 (M+H, Cl pattern).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:12]2[C:16]([CH2:17][CH2:18][CH2:19][OH:20])=[N:15][O:14][N:13]=2)=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH3:21][S:22]([O:20][CH2:19][CH2:18][CH2:17][C:16]1[C:12]([C:10]([NH:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=2)=[O:11])=[N:13][O:14][N:15]=1)(=[O:24])=[O:23]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1ccc(F)c(Cl)c1)c1nonc1CCCO
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1nonc1C(=O)Nc1ccc(F)c(Cl)c1
Temperature: 0 °C
Yield: 79.4 %

Procedure:
N-(3-Chloro-4-fluorophenyl)-4-(3-hydroxypropyl)-1,2,5-oxadiazole-3-carboxamide (60 mg, 0.20 mmol) was dissolved in anhydrous DCM (2 mL), followed by addition of TEA (57 μL, 0.41 mmol). The reaction was stirred and cooled to 0° C., and methanesulfonyl chloride (29 μL, 0.37 mmol) was added drop-wise. The reaction was quenched with water and diluted with DCM. The organic layer was separated, dried over Na2SO4, filtered, concentrated and purified by silica gel chromatography (25%-75% EtOAc/hexane) to give the desired product (60 mg, 80%). LCMS for C13H14ClFN3O5S(M+H)+: m/z=378.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([F:10])[CH:3]=1.[H-].[Na+].Br[CH2:14][CH2:15][O:16][CH3:17]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][CH2:14][CH2:15][O:16][CH3:17])=[C:4]([F:10])[CH:3]=1
Reactant: OCc1ccc(Br)cc1F
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOCc1ccc(Br)cc1F
Temperature: 5 °C
Yield: 46.5 %

Procedure:
To a stirred solution of (4-bromo-2-fluorophenyl)methanol (10 g, 49.02 mmol) in THF (250 mL) at 0° C., was added 60% NaH (2.93 g, 73.53 mmol) slowly in portions. After addition, the suspension was heated to 5° C. for 30 min, cooled to RT, then was added 1-bromo-2-methoxy ethane (5 mL, 53.92 mmol) and the mixture was stirred at RT for 20 h until complete consumption of (4-bromo-2-fluorophenyl)methanol, as evidenced by TLC analysis. The reaction mixture was diluted with ice cold water (100 mL) and concentrated under reduced pressure. The obtained aqueous residue was extracted with EtOAc (2×150 mL); the combined EtOAc layers were washed with brine solution (50 mL), dried over anhydrous NaSO4, filtered and concentrated. The obtained crude compound was purified by CC using 5% EtOAc in PE as eluent to afford 4-bromo-2-fluoro-1-((2-methoxyethoxy)methyl)benzene (6 g, 47%) as yellow liquid (TLC solvent system: 30% EtOAc-PE; Rf: 0.4).
Reaction SMILES: OCCCN1C=C(C2C=CC(NC3C(C(F)(F)F)=CN=C(NC4C=CC(CP(=O)(OCC)OCC)=CC=4OC)N=3)=C3C=2CN(C)C3=O)C=N1.Cl[C:51]1[C:56]([C:57]([F:60])([F:59])[F:58])=[CH:55][N:54]=[C:53]([NH:61][C:62]2[CH:74]=[CH:73][C:65]([CH2:66][CH2:67][PH:68](=[O:72])[O:69][CH2:70][CH3:71])=[CH:64][C:63]=2[O:75][CH3:76])[N:52]=1.[NH2:77][C:78]1[C:79]([C:85]([NH:87][CH3:88])=[O:86])=[N:80][C:81]([Br:84])=[CH:82][CH:83]=1>>[Br:84][C:81]1[N:80]=[C:79]([C:85](=[O:86])[NH:87][CH3:88])[C:78]([NH:77][C:51]2[C:56]([C:57]([F:60])([F:59])[F:58])=[CH:55][N:54]=[C:53]([NH:61][C:62]3[CH:74]=[CH:73][C:65]([CH2:66][CH2:67][PH:68](=[O:72])[O:69][CH2:70][CH3:71])=[CH:64][C:63]=3[O:75][CH3:76])[N:52]=2)=[CH:83][CH:82]=1
Reactant: CNC(=O)c1nc(Br)ccc1N
Reactant: CCO[PH](=O)CCc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCO[PH](=O)CCc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1
Yield: 75.4 %

Procedure:
Prepared analogously to Compound 1B using ethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)methylphosphinate (Compound 61 D, 270 mg, 0.64 mmol) and 3-amino-6-bromo-N-methylpyridine-2-carboxamide (Compound 6D, 154 mg, 0.669 mmol) to afford 298 mg of the title compound (76%). 1H NMR (400 MHz, CD-3OD) δ 9.00 (br. s., 1H), 8.36 (s, 1H), 7.63-7.73 (m, 1H), 7.51-7.61 (m, 1H), 7.07 (t, J=1.9 Hz, 1H), 6.93 (td, J=2.2, 8.1 Hz, 1H), 4.04-4.16 (m, 2H), 3.89 (s, 3H), 3.33 (s, 1H), 3.29 (s, 1H), 2.93 (s, 3H), 1.51 (s, 3H), 1.33 (t, J=7.1 Hz, 3H). MS (ESI): m/z=617.06/619.06 [M+H]+. HPLC: tR=1.01 min (UPLC-TOF: polar—3 min).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].C(N(CC)CC)C.O1CCCC1.[I:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>O>[I:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: Nc1ccccc1O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccccc1O)c1ccc(I)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 96.2 %

Procedure:
In a 300 mL three-neck flask were put 10 g (92 mmol) of 2-aminophenol, 7.0 mL of triethylamine, and 100 mL of tetrahydrofuran (THF). This solution was stirred at 0° C. for 20 minutes. Then, a mixed solution of 4-iodobenzoic acid chloride (0.10 mol) and 100 mL of tetrahydrofuran (abbreviation: THF) was dripped to the solution. This solution was stirred under a nitrogen stream at 0° C. for 5 hours. After that, about 300 mL of water was added to this solution, followed by extraction with ethyl acetate. Then, the organic layer and the extract were combined and washed with 1M hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine in that order. After that, magnesium sulfate was added to the organic layer to dry it. Next, this mixture was suction filtered through Celite (produced by Wako Pure Chemical Industries, Ltd., Catalog No. 531-16855). The resulting filtrate was concentrated to give a solid. This solid was recrystallized with a mixed solvent of ethyl acetate and hexane to give 30 g of a white powdered solid in a yield of 97% through the two steps, Synthesis Schemes (D-1) and (D-2).
Reaction SMILES: C(N(CC)CC)C.[NH2:8][C:9]1[C:21]([C:22]([OH:24])=[O:23])=[C:12]2[N:13]=[C:14]([C:17]([F:20])([F:19])[F:18])[CH:15]=[CH:16][N:11]2[N:10]=1.CN(C(O[N:33]1[N:41]=[N:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)(Cl)Cl>[NH2:8][C:9]1[C:21]([C:22]([O:24][N:40]2[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[N:41]2)=[O:23])=[C:12]2[N:13]=[C:14]([C:17]([F:20])([F:18])[F:19])[CH:15]=[CH:16][N:11]2[N:10]=1
Reactant: Nc1nn2ccc(C(F)(F)F)nc2c1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Nc1nn2ccc(C(F)(F)F)nc2c1C(=O)On1nnc2ccccc21
Temperature: 50 °C

Procedure:
Triethylamine (994.9 mg, 1.370 mL, 9.832 mmol) was added to a suspension of 2-amino-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid 5d (2.2 g, 8.938 mmol) in chloroform (22 mL). TBTU (2.870 g, 8.938 mmol) was added to the solution and the reaction mixture was heated at 50° C. for 20 min, during which time a yellow precipitate formed. The reaction mixture was cooled to ambient temperature. The precipitate was isolated by filtration and washed with chloroform to leave the product (benzotriazol-1-yl 2-amino-5-(trifluoromethyl)pyrazolo[1,5-a]pyrimidine-3-carboxylate) 6d as an off white solid (2.8 g, 86% yield).
Reaction SMILES: [CH2:1]([SH:5])[C:2]([OH:4])=[O:3].[OH-].[Na+].CS(O[CH2:13][CH2:14][C:15]#[CH:16])(=O)=O.O.[CH2:18](O)C>>[CH2:16]([S:5][CH2:1][C:2]([O:4][CH3:18])=[O:3])[CH2:15][C:14]#[CH:13]
Reactant: O=C(O)CS
Reactant: C#CCCOS(C)(=O)=O
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: C#CCCSCC(=O)OC
Reaction time: 24 h

Procedure:
Thioglycollic acid (6.0 g) was added to a stirred solution of sodium hydroxide (8.0 g) in ethanol (50 ml). But-3-ynyl methanesulphonate (7.4 g) was added and the mixture was stirred at 20° for 24 hours. The reaction mixture was poured into water and the aqueous mixture was extracted with diethyl ether. The aqueous alkaline extracts were acidified with hydrochloric acid and the mixture was extracted with diethyl ether. The ethereal extracts were dried over anhydrous magnesium sulphate and evaporated in vacuo. The resulting oil was stirred in dry dimethylformamide (100 ml) and anhydrous sodium carbonate (15 g) was added. Methyl iodide (7.0 ml) was added and the reaction mixture was stirred at 20° for 3 days. Water was added and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with water and dried over anhydrous magnesium sulphate. The solvent was removed in vacuo and the residue was chromatographed on silica, eluting with 1:4 diethylether: hexane. Methyl 2-(but-3-ynylthio)acetate was obtained as a colourless oil (1.2 g) (a small amount of methyl 2-(but-3-yn-1-ylthio)propionate was present). A mixture of methyl 2-(but-3-ynylthio)acetate (0.6 g) and sodium hydroxide solution (20 ml, 2N, 1:1 methanol:water) was stirred for 24 hours at 20°. Water was added and the aqueous mixture was extracted with diethyl ether. The aqueous alkaline extracts were acidified with hydrochloric acid and the mixture was extracted with diethyl ether. The ethereal extracts were dried over anhydrous magnesium sulphate and the solvent was removed in vacuo. 2-(But-3-ynylthio)acetic acid was obtained as a colourless oil (0.5 g). (A small amount of 2-(but-3-ynylthio)propionic acid was present.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:15](Cl)(=[O:19])[C:16]([CH3:18])=[CH2:17]>ClCCl>[C:15]([O:7][CH:4]1[CH2:5][CH2:6][S:1][CH2:2][CH2:3]1)(=[O:19])[C:16]([CH3:18])=[CH2:17]
Reactant: C=C(C)C(=O)Cl
Reactant: OC1CCSCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OC1CCSCC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 64 %

Procedure:
Tetrahydrothiapyran-4-ol (4.81 g, 40.7 mmol) and triethylamine (6.2 mL, 44.5 mmol) were dissolved in anhydrous dichloromethane (60 mL) and cooled to 0° C. Methacryloyl chloride (4.0 mL, 45.0 mmol) then was added slowly, dropwise. The reaction then was warmed slowly to room temperature. After stirring overnight, the reaction was washed with DIW (20 mL), 1 M NaOH (2×20 mL), DIW (20 mL), 1 M HCl (20 mL), DIW (20 mL) and brine (20 mL). The organic layer then was dried over sodium sulfate, filtered, and then concentrated by rotary evaporation and dried in vacuo to afford tetrahydro-2H-thiopyran-4-yl methacrylate as a pale yellow liquid (4.85 g, 61%). 1H NMR (600 MHz, CDCl3, ppm) δ 6.07 (s, 1H), 5.52 (s, 1H), 4.88 (m, 1H), 2.77 (m, 2H), 2.55 (m, 2H), 2.07 (m, 2H), 1.90 (m, 5H). 13C NMR (150 MHz, CDCl3, ppm) δ 166.29, 166.23 (minor), 136.55, 13.70 (minor), 125.40 (multiplet: 126.58, 126.31, 125.72, 125.28, 125.07, 124.65, 124.19), 70.86, 69.86 (minor), 32.33 (multiplet: 32.59, 32.44, 32.21, 32.04), 25.71 (multiplet: 26.66, 26.19, 25.71, 25.44, 24.95), 18.26 (multiplet: 18.43, 18.09).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:21][O:22][CH:23]([C:27]2[C:35]3[C:31](=[CH:32][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:34]=3)[CH:30]=[C:29]([Cl:44])[CH:28]=2)[C:24](O)=[O:25])([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N.C1C[N:49]([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C)C=O>[NH2:49][C:24](=[O:25])[CH:23]([C:27]1[C:35]2[C:31](=[CH:32][N:33]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:34]=2)[CH:30]=[C:29]([Cl:44])[CH:28]=1)[O:22][CH2:21][C:11]1([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:3])([CH3:2])[CH3:4])=[O:7])[CH2:13][CH2:12]1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Reactant: CC(C)(C)OC(=O)N1CCC(COC(C(=O)O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(COC(C(N)=O)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
To a solution of 2-((1-(tert-butoxycarbonyl)-4-(4-fluorophenyl)piperidin-4-yl)methoxy)-2-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)acetic acid (100 mg, 0.154 mmol) and ammonia (7 M in methanol, 0.110 mL, 0.771 mmol) in dimethylformamide (2 mL) at 0° C. was added PyBOP (96 mg, 0.19 mmol). The ice bath was removed and stirring continued for 1 h. The reaction was quenched by addition of water and diluted with diethyl ether. The ethereal was washed with water (2×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (50%→85% ethyl acetate/n-hexane) gave 89 mg (89%) as a foam solid. 1H-NMR (CDCl3, 500 MHz) δ 8.02 (s, 1H), 7.57 (d, J=1.8 Hz, 1H), 7.27 (dd, J=8.9, 5.2 Hz, 2H), 7.00 (dd, J=8.6, 8.5 Hz, 2H), 6.95 (d, J=1.5 Hz, 1H), 6.48 (d, J=2.7 Hz, 1H), 6.05 (d, J=2.4 Hz, 1H), 5.65 (s, 2H), 5.23 (s, 1H), 3.66 (m, 2H), 3.60 (t, J=8.1 Hz, 2H), 3.51 (d, J=8.9 Hz, 1H), 3.41 (d, J=8.9 Hz, 1H), 3.01 (m, 2H), 2.10 (m, 2H), 1.80 (m, 2H), 1.40 (s, 9H), 0.91 (m, 2H), −0.05 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 172.5, 161.5 (d, J=246 Hz), 155.0, 146.1, 138.42, 138.39, 128.7 (d, J=7.7 Hz), 128.5, 127.8, 125.5, 122.9, 122.6, 119.7, 115.4 (d, J=21 Hz), 82.1, 79.5, 78.3, 67.8, 41.2, 40.0 (br), 32.2, 32.1, 28.5, 17.9, −1.3. Mass spec.: 647.35 (MH)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH:11]=[C:10]([C:12]3[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[C:9]([NH2:20])=[N:8][C:6]=2[N:7]=1.S(=O)(=O)(O)[NH2:22].[CH2:26]([N:28]([CH2:31][CH2:32]N)[CH2:29][CH3:30])[CH3:27]>>[Cl:19][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]([Cl:18])[C:12]=1[C:10]1[C:9]([NH2:20])=[N:8][C:6]2[N:7]=[C:2]([NH:1][CH2:27][CH2:26][N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[N:3]=[CH:4][C:5]=2[CH:11]=1.[NH3:22]
Reactant: CCN(CC)CCN
Reactant: Nc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Reactant: NS(=O)(=O)O
Product: CCN(CC)CCNc1ncc2cc(-c3c(Cl)cccc3Cl)c(N)nc2n1
Product: N
Temperature: 150 °C
Yield: 1 %

Procedure:
A mixture of 2,7-diamino-6-(2,6-dichlorophenyl)-pyrido[2,3-d]pyrimidine (4.0 g) from Example 1, sulfamic acid (2.53 g), and diethylaminoethylamine (40 mL) was heated to approximately 150° C. for 20 hours. The excess diethylaminoethylamine was removed in vacuo. The resulting oil was dissolved in diethyl ether, diluted with hexane, and then filtered. The resulting solid was dissolved in dichloromethane which was washed several times with water, dried with magnesium sulfate, and concentrated in vacuo. The residue was crystallized from ethyl acetate to give the title compound 6-(2,6-dichlorophenyl)-N2 -(2-diethylamino-ethyl)-pyrido[2,3-d]pyrimidine-2,7-diamine, CIMS (1% NH3 in CH4): 433=M+ +C2H5, 405=M+ +H, 389=M+ -Et, 360; mp 216°-219.5° C.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([O:32][CH3:33])=[CH:9][C:10]2[C:11]3[C:12]4[C:29](=[O:30])[NH:28][C:27](=[O:31])[C:13]=4[C:14]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[Cl:26])=[CH:15][C:16]=3[NH:17][C:18]=2[CH:19]=1)(=O)=O.C([Sn](CCCC)(CCCC)/[CH:41]=[CH:42]/[CH2:43][CH2:44][OH:45])CCC.[Cl-].[Li+].C(OCC)(=O)C>CN(C=O)C.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>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:14]1[C:13]2[C:27](=[O:31])[NH:28][C:29](=[O:30])[C:12]=2[C:11]2[C:10]3[CH:9]=[C:8]([O:32][CH3:33])[C:7](/[CH:41]=[CH:42]/[CH2:43][CH2:44][OH:45])=[CH:19][C:18]=3[NH:17][C:16]=2[CH:15]=1
Reactant: COc1cc2c(cc1OS(=O)(=O)C(F)(F)F)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Reactant: CCCC[Sn](/C=C/CCO)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cc2c(cc1/C=C/CCO)[nH]c1cc(-c3ccccc3Cl)c3c(c12)C(=O)NC3=O
Yield: 95.9 %

Procedure:
A solution of the triflate (169) (0.20 g, 0.35 mmol) prepared as described in example 308, (3E)-4-(tributylstannyl)-3-buten-1-ol (0.19 g, 0.53 mmol) and lithium chloride (29 mg, 0.70 mmol) in DMF (10 mL) was purged by bubbling nitrogen through the liquid for 10 min. Bis(triphenylphosphine)palladium dichloride (12 mg, 0.017 mmol) was added last and the solution was flushed with nitrogen for 2 min more, then warmed under an atmosphere of nitrogen for 3 h. The mixture was diluted with brine, extracted with ethyl acetate and worked up to give an oil which was chromatographed on silica. Elution with ethyl acetate/petroleum ether (1:5) gave foreruns, while ethyl acetate/petroleum ether (1:1) increasing to pure ethyl acetate gave (170) as a yellow solid (0.15 g, 95%), mp 271–275° C. 1H NMR δ [(CD3)2SO] 11.86 (br s, 1H), 11.07 (br s, 1H), 8.45 (s, 1H), 7.70 (s, 1H), 7.58 (dd, J=8.1, 2.2 Hz, 1H), 7.55 (s, 1H), 7.51–7.41 (m, 3H), 6.87 (d, J=16.0 Hz, 1H), 6.44 (dt, J=16.0, 7.1 Hz, 1H), 4.62 (t, J=5.3 Hz, 1H), 3.94 (s, 3H), 3.58 (m, 2H), 2.42 (m, 2H). Found: C, 67.09; H, 4.36; N, 5.98. C25H19ClN2O4 requires C, 67.19; H, 4.28; N, 6.27.