Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:20][C@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]1[OH:27])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40](O)=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1>>[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:27][C@@H:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C@H:21]2[NH:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@H]1CCCC[C@@H]1O
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@@H]1CCCC[C@H]1OC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 56.8 %

Procedure:
(1S,2S)-2-(N-Oleoylamino)cyclohexanol (3.79 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain 3.52 g of the title compound (yield: 57%)
Reaction SMILES: [C@H:1]12[NH:8][C@H:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH:2]2[C:9]([O:11][CH3:12])=[O:10].[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16]Br.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[F:13][C:14]1[CH:21]=[CH:20][CH:19]=[CH:18][C:15]=1[CH2:16][N:8]1[C@@H:5]2[CH2:6][CH2:7][C@H:1]1[CH:2]([C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:4]2
Reactant: COC(=O)C1CC[C@H]2CC[C@@H]1N2
Reactant: Fc1ccccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1CC[C@H]2CC[C@@H]1N2Cc1ccccc1F
Reaction time: 1 h
Yield: 61 %

Procedure:
To (1S,5S)-methyl 8-azabicyclo[3.2.1]octane-2-carboxylate (185 mg, 1.1 mmol) dissolved in DCM (11 mL) was added 2-fluorobenzylbromide (206 mg, 1.1 mmol), followed by N,N-diisopropylethylamine (424 mg, 3.3 mmol). After stirring for 1 hour, the reaction mixture was quenched with water, and extracted with DCM. Dried and concentrated to give 186 mg of crude product. The crude was carried over the next step without further purification.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]2[C:13]3[C:18]([O:19][CH2:20][C:3]=12)=[CH:17][C:16]([OH:21])=[CH:15][CH:14]=3.[C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)#[N:23]>>[C:22]([C:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=[C:4]3[C:13]4[C:18]([O:19][CH2:20][C:3]=23)=[CH:17][C:16]([OH:21])=[CH:15][CH:14]=4)=[CH:26][CH:25]=1)#[N:23]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: Oc1ccc2c(c1)OCc1c-2nc2ccc(O)cc2c1Br
Product: N#Cc1ccc(-c2c3c(nc4ccc(O)cc24)-c2ccc(O)cc2OC3)cc1
Yield: 96 %

Procedure:
This compound was prepared from 7-bromo-3,9-dihydroxy-6H-chromeno[4,3-b]quinoline (7) using 4-cyanophenylboronic acid according to method M. Ivory powder; Yield: 96%; mp 295° C. (dec.); 1H-NMR (400 MHz, DMSOd-6) δ 4.99 (s, 2H), 6.36 (d, J=2.3 Hz, 1H), 6.53 (d, J=2.7 Hz, 1H), 6.61 (dd, J=8.7, 2.3 Hz, 1H), 7.27 (dd, J=9.1, 2.6 Hz, 1H), 7.62 (d, J=8.5 Hz, 2H), 7.91 (d, J=9.0 Hz, 2H), 8.09 (d, J=8.3 Hz, 1H), 8.16 (d, J=8.6 Hz, 1H), 9.86 (s, 1H), 9.99 (s, 1H); MS (ESI) m/z 365 ([M−H]−), 367 ([M+H]+); HRMS (ESI+) calcd for C23H14N2O3 367.1077 ([M+H]30 ). Found: 367.1074.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:26]=[CH:25][CH:24]=[CH:23][C:10]=2[CH2:11][C:12]2[NH:13][C:14](=[O:22])[C:15]([C:20]#[N:21])=[C:16](SC)[N:17]=2)=[CH:5][CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH:30]([CH2:33][CH2:34][OH:35])[CH2:29][CH2:28]1>>[OH:35][CH2:34][CH2:33][CH:30]1[CH2:31][CH2:32][N:27]([C:16]2[N:17]=[C:12]([CH2:11][C:10]3[CH:23]=[CH:24][CH:25]=[CH:26][C:9]=3[C:6]3[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[NH:13][C:14](=[O:22])[C:15]=2[C:20]#[N:21])[CH2:28][CH2:29]1
Reactant: OCCC1CCNCC1
Reactant: COc1ccc(-c2ccccc2Cc2nc(SC)c(C#N)c(=O)[nH]2)cn1
Product: COc1ccc(-c2ccccc2Cc2nc(N3CCC(CCO)CC3)c(C#N)c(=O)[nH]2)cn1

Procedure:
In analogy to the preparation of Example 1, 80 mg (0.22 mmol) of 2-[2-(6-methoxypyridin-3-yl)-benzyl]-4-(methylsulphanyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile are reacted with 85 mg (0.65 mmol) of 2-(4-piperidinyl)ethan-1-ol to give 62 mg (63% of theory) of the title compound.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2[CH:33]=[CH:32][C:14]([O:15][C:16]3[CH:25]=[C:24]4[C:19]([CH:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:22][O:23]4)=[CH:18][C:17]=3[Cl:31])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][CH:3]=1.[Cl:34][C:35]1[CH:36]=[C:37](B(O)O)[CH:38]=[CH:39][C:40]=1[Cl:41].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.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:31][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][C:16]=1[O:15][C:14]1[CH:32]=[CH:33][C:11]([C:9](=[O:10])[NH:8][C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([C:38]4[CH:37]=[CH:36][C:35]([Cl:34])=[C:40]([Cl:41])[CH:39]=4)[N:7]=3)=[CH:12][CH:13]=1)[O:23][CH2:22][CH2:21][CH:20]2[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: OB(O)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(Br)n4)cc3)c(Cl)cc21
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: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4cccc(-c5ccc(Cl)c(Cl)c5)n4)cc3)c(Cl)cc21
Temperature: 100 °C
Yield: 90.4 %

Procedure:
To a solution of ethyl 7-(4-(6-bromopyridin-2-ylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (0.050 g, 0.094 mmol), 3,4-dichlorophenylboronic acid (0.023 g, 0.12 mmol), and sodium carbonate (0.030 g, 0.28 mmol) in toluene (1 ml) and water (0.1 ml) degassed with argon was added tetrakis(triphenylphosphine)palladium (0.0054 g, 0.0047 mmol), and the reaction was heated to 100° C. for 16 hours. The reaction was loaded directly onto silica gel and eluted with a linear gradient of 5-70% EtOAc/hexanes to yield the desired compound (0.051 g, 0.085 mmol, 91% yield).
Reaction SMILES: [C:1]1(/[C:7](/[C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=2)=[C:8](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)\[C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Cl[CH2:29][CH2:30][N:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1>C1(C)C(C)=CC=CC=1>[C:1]1(/[C:7](/[C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:29][CH2:30][N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[CH:21][CH:20]=2)=[C:8](/[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)\[C:9]([F:12])([F:11])[F:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCN1CCCC1
Reactant: Oc1ccc(/C(=C(\c2ccccc2)C(F)(F)F)c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: FC(F)(F)/C(=C(\c1ccccc1)c1ccc(OCCN2CCCC2)cc1)c1ccccc1
Yield: 61.4 %

Procedure:
2.72 g (8 mmoles) of (E)-1,2-diphenyl-3,3,3-trifluoro-1-(4-hydroxyphenyl)-propene, prepared as described in Example 26, are reacted in xylene with sodium hydride and then with 2-chloroethyl-pyrrolidine as described in Example 26. The product is crystallized from hexane. 2.15 g (61.4%) of the desired compound are obtained; m.p.: 84.5°-86° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O.[CH2:15]([N:19](CCCC)CCCC)[CH2:16][CH2:17][CH3:18].C(N)CCC>C(Cl)Cl>[CH2:15]([NH:19][C:12](=[O:14])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[CH2:16][CH2:17][CH3:18]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: CCCCN(CCCC)CCCC
Solvent: ClCCl
Solvent: CCCCN
Product: CCCCNC(=O)CCCCCCCCCCBr
Temperature: -10 °C
Reaction time: 3 h

Procedure:
11-Bromoundecanoic acid (45 mmol) was dissolved in dry CH2Cl2 (200 ml) and tributylamine (54 mmol). After the mixture had cooled at −10° C., isobutylchlorofomate (60 mmol) was added and allowed to react for 2 hrs. At this moment, excess N-butylamine (225 mmol) was added and later the cooling bath was removed. After 3 hrs, CH2Cl2 was added and the organic phase was washed with 1 N HCl, saturated NaHCO3, and water. After drying by MgSO4, the solvent was removed and the crude product was purified by column chromatography. The pure amide product was eluted with solvent, hexane (80)—EtOAc (20).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH:15]=[CH2:16].[Cl-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:13]([C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:3][CH2:2][CH:1]=[CH2:6])[C:8]#[N:9])[CH2:14][CH2:15][CH3:16]
Reactant: C=CCCBr
Reactant: N#CCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCCC(C#N)(CCCC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-phenylacetonitrile (1 mL) in DMF (1.0 mL) at 0° C. was added sodium hydride (95% oil dispersion, 547 mg) and the resulting suspension was stirred at 0° C. for 10 min. 4-Bromobut-1-ene (2.2 mL) was added, and the reaction mixture was stirred at room temperature for 2 h. Saturated sodium chloride was added followed by ethyl acetate, the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated in vacuo. The residue was purified by silica gel flash chromatography eluting with 10% ethyl acetate/90% hexanes to give the title compound as an oil (773 mg). 1H NMR (400 MHz, CDCl3) δ 1.8-2.3 (8H, m), 4.95 (4H, m), 5.73 (2H, m), and 7.31 (5H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=1)C=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25](O)(=O)[CH2:26][C:27]([OH:29])=[O:28].N1CCCCC1.Cl>N1C=CC=CC=1>[CH2:18]([O:17][C:15]1[CH:14]=[C:11]([CH:25]=[CH:26][C:27]([OH:29])=[O:28])[CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:16]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1

Procedure:
3.18 g. of 3,5-dibenzyloxy-benzaldehyde [L.A. Svensson, Kem. Tidskr., 87, 289 (1975)] and 1.6 g. of malonic acid are stirred in a mixture of 8 ml. of pyridine and 0.1 ml. of piperidine for 3 hours at 100° C. 25 ml. of 15% hydrochloric acid are then added, whereafter the product is filtered by suction, washed with water and dried. The crude product is crystallized from 150 ml. of methanol and 3 g. of 3-(3,5-dibenzyloxy-phenyl)-propenoic acid melting at 154°-156° C. are obtained. The product is suspended in 250 ml. of abs. ether, 0.90 g. of lithium aluminum hydride is added and the mixture is heated under stirring for 5 hours. After cooling the excess hydride is decomposed by acetone and acidified with 100 ml. of 10% hydrochloric acid. The two layers are separated and the aqueous layer is shaken out with ether again, the combined organic layer is washed with water, dried on magnesium sulphate and evaporated. 2.88 g. of 3-(3,5-dibenzyloxy-phenyl)-1propanol are obtained, m.p.: after recrystallization from n-hexane: 48°-50° C. 5.47 g. of the above alcohol are dissolved in 30 ml. of abs. pyridine and 2.26 g. (1.5 ml., 0.020 mole) of methane sulfonic acid chloride are added and the mixture is poured after 30 minutes to a mixture of 300 g of ice and 75 ml. of cc. HCl. The product is extracted with 125 ml. of dichloromethane and the organic layer is washed with 2×20 ml. of saturated hydrochloric acid solution, dried above magnesium sulphate and evaporated. 6.2 g. of 3-(3,5-dibenzyloxy-phenyl)-1-methanesulfonyloxy-propane are obtained, from which 2.60 g. are heated for 15 minutes with 20 ml. of 1 N sodium methylate and the solution is poured to 220 ml. of 1% hydrochloric acid solution. The product is extracted with dichloromethane, the extract is dried and evaporated. The residue (1.9 g.) is subjected to column chromatography and as eluants benzene and methyl ethyl ketone solvents are used. 1.30 g. of 1-(3,5-dibenzyloxy-phenyl)-3-methoxy-propane are obtaned as colorless oil,
Reaction SMILES: [ClH:1].FC(F)(F)O[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][NH2:12].[F:15][C:16]([F:26])([F:25])[O:17]C1C=CC=CC=1N>>[ClH:1].[F:15][C:16]([F:26])([F:25])[O:17][N:11]([C:6]1[CH:5]=[CH:10][CH:9]=[CH:8][CH:7]=1)[NH2:12]
Reactant: NNc1ccccc1OC(F)(F)F
Reactant: Nc1ccccc1OC(F)(F)F
Agent: Cl
Product: NN(OC(F)(F)F)c1ccccc1
Yield: 54 %

Procedure:
The title compound (115.8 g, 54%) is prepared essentially according to the preparation of (2-trifluoromethoxy-phenyl)-hydrazine hydrochloride using 2-trifluoromethoxy-phenylamine.
Reaction SMILES: [N:1]1([C:7]2[C:17]3[O:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(OCC)(=O)C.[ClH:31]>C(OCC)(=O)C>[ClH:31].[ClH:31].[N:1]1([C:7]2[C:17]3[O:16][CH2:15][CH2:14][NH:13][CH2:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCOc2c(cccc2N2CCCCC2)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: c1cc2c(c(N3CCCCC3)c1)OCCNC2
Yield: 78.7 %

Procedure:
A solution of tert-butyl 9-(piperidin-1-yl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (130 mg, 0.391 mmol) and 4N hydrogen chloride-ethyl acetate (4 ml) in ethyl acetate (1 ml) was stirred for 1 hr at room temperature, and the solvent was evaporated under reduced pressure. The residue was recrystallized from a mixed solvent of methanol and ether to give the desired product (93.6 mg, 78.7%) as a solid.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH:8]([CH2:10][CH3:11])[O:7][C:5]1=[O:6])(=[O:3])[CH3:2].S(Cl)([Cl:15])(=O)=O.O>C1C=CC=CC=1>[Cl:15][C:4]1([C:1](=[O:3])[CH3:2])[CH2:9][CH:8]([CH2:10][CH3:11])[O:7][C:5]1=[O:6]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCC1CC(C(C)=O)C(=O)O1
Solvent: c1ccccc1
Solvent: O
Product: CCC1CC(Cl)(C(C)=O)C(=O)O1
Temperature: 25 °C

Procedure:
Into a solution of 58.2 g (0.37 moles) of α-acetyl-γ-ethyl-γ-butyrolactone [prepared according to J. Pharm. Sci. 52, 733 (1963)] in 60 cm3 benzene 50 g of (0.37 moles) of sulphuryl chloride are added dropwise under stirring and cooling in 2 hours, keeping the temperature of the reaction mixture between 5 and 10° C. After completing the addition the reaction mixture is let to warm to room temperature and stirred at this temperature until the gas formation ceases. Then it is poured into 400 cm3 of water, the phases are separated and the water is extracted with 200 cm3 of benzene. The benzene containing solution is washed with 100 cm3 of 5% sodium hydrogencarbonate solution. After evaporation the residual oil is distilled in vacuo. The title compound is obtained in the form of a colourless liquid in an amount of 58.9 g (82.5%), its boiling point is 91° C. at a pressure of 80 Pa, nD20 =1,4623.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][C:7]3([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]3)[C:8]2=O)=[CH:4][CH:3]=1.[CH3:19][Si:20]([CH3:28])([CH3:27])[CH2:21][CH2:22][S:23]([NH2:26])(=[O:25])=[O:24].CCN(CC)CC>C(Cl)CCl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[CH2:6][C:7]1([CH2:16][CH2:15][CH:14]([O:17][CH3:18])[CH2:13][CH2:12]1)[C:8]2=[N:26][S:23]([CH2:22][CH2:21][Si:20]([CH3:28])([CH3:27])[CH3:19])(=[O:25])=[O:24]
Reactant: C[Si](C)(C)CCS(N)(=O)=O
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COC1CCC2(CC1)Cc1ccc(Br)cc1C2=NS(=O)(=O)CC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 91 %

Procedure:
To a mixture of 6′-bromo-4-methoxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (3) (0.9822 g, 3.18 mmol, 1.0 equiv) and 2-(trimethylsilyl)ethanesulfonamide) (SESNH2)(0.6338 g, 3.50 mmol, 1.1 equiv) in C1CH2CH2Cl (10 mL), cooled to 0° C., were successively added Et3N (0.9 mL, 6.46 mmol, 2.0 equiv) and TiCl4 (1.0 M in CH2Cl2, 3.4 mL, 3.4 mmol, 1.1 equiv). After 10 min, the ice bath was removed. The reaction mixture was stirred at room temperature for 3 h and then heated at 110° C. for 42 h. The reaction mixture was cooled to room temperature, quenched with water, and extracted with CH2Cl2. The combined organic phase was dried (Na2SO4) and evaporated. The residue was purified by chromatography on silica gel eluted with hexanes/ethyl acetate to afford 1.3685 g (91%) of N-(5′-bromo-4-methoxyspiro[cyclohexane-1,2′-indene]-3′(1′H)-ylidene)-2-(trimethylsilyl)ethanesulfonamide (8) as a solid. LC-MS tR=2.31 min in 3 min chromatography, m/z 472, 474 (MH+); 1H NMR (400 MHz, CDCl3) δ 8.78 (br s, 1H), 7.67 (dd, J=8.2, 1.8 Hz, 1H), 7.29 (d, J=8.2 Hz, 1H), 3.39 (s, 3H), 3.29-3.21 (m, 3H), 2.98 (s, 2H), 2.16-2.12 (m, 2H), 1.80-1.76 (m, 2H), 1.62-1.57 (m, 2H), 1.42-1.33 (m, 2H), 1.21-1.17 (m, 2H), 0.10 (s, 9H); 13C NMR (100 MHz, CDCl3) δ 189.97, 151.30, 137.91, 133.35, 127.50, 121.43, 78.10, 55.80, 51.79, 51.39, 39.55, 33.97, 28.60, 9.98, −1.93.
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]([CH2:19][OH:20])/[CH:7]=[CH:8]/[P:9](=[O:18])([O:14][CH:15]([CH3:17])[CH3:16])[O:10][CH:11]([CH3:13])[CH3:12])(=[O:3])[CH3:2].N1C=CN=C1.[Si:26](Cl)([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[C:1]([O:4][CH2:5][CH:6]([CH2:19][O:20][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)/[CH:7]=[CH:8]/[P:9](=[O:18])([O:14][CH:15]([CH3:16])[CH3:17])[O:10][CH:11]([CH3:13])[CH3:12])(=[O:3])[CH3:2]
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC(=O)OCC(/C=C/P(=O)(OC(C)C)OC(C)C)CO
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(=O)OCC(/C=C/P(=O)(OC(C)C)OC(C)C)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To a solution of diisopropyl (E)-3-acetoxymethyl-4-hydroxybut-1-enylphosphonate (3 g, 9.7 mmol ) and imidazole (1.7 g, 25 mmol) in anhydrous THF (60 ml) at 0° C. was added t-butyldiphenylsilylchloride (3.2 ml, 12.7 mmol). After stirring at room temperature for 3 h, the solvent was removed and the residue was partitioned between chloroform (100 ml) and brine (30 ml). The organic phase was dried (MgSo4), evaporated in vacuo and chromatographed on silica gel, eluting with chloroform of increasing polarity to chloroform-methanol (100:1) to give diisopropyl (E)-3-acetoxymethyl-4-t-butyldiphenylsilyloxybut-1-enylphosphonate as an oil (5 g, 94%); υmax (film) 3071, 3050, 2977, 2931, 2858, 1743, 1630, 1582, 1472,and 1425 cm-1 ; δH (CDCl3) 1.05 [9H, s, C(CH3)3 ], 1.26 (3H, d, J 6 Hz, CH3CH), 1.27 (3H, d, J 6 Hz, CH3CH), 1.32 [6H, d, J 6.3 Hz, (CH3)2CH], 1.98 (3H, s, CH3CO), 2.74 (1H, m, CH), 3.72 (2H, m, CH2), 4.22 (2H, m, CH2), 4.65 (2H, m, 2×CH(CH3)2 ], 5.76 (1H, ddd, J 1, 17 and 18 Hz, PCH=CH), 6.99 (1H, ddd, J 7, 17 and 22 Hz, PCH=CH), 7.3-7.7 (10H, m, 2×C6H5) (Found: C, 63.42; H, 8.22%. C29H43O6PSi requires C, 63.71; H, 7.93%.).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+].[Br:26][CH2:27][CH2:28][CH2:29]Br>CC(C)=O>[Br:26][CH2:27][CH2:28][CH2:29][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([C:11]1[C:12]2[CH:13]=[CH:14][NH:15][C:16]=2[CH:17]=[CH:18][CH:19]=1)=[O:10]
Reactant: BrCCCBr
Reactant: O=C(Nc1ccccc1O)c1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(Nc1ccccc1OCCCBr)c1cccc2[nH]ccc12

Procedure:
A suspension of 2 g of N-(2-hydroxyphenyl)-1H-indol-4-carboxamide and 2.18 g of potassium carbonate in 20 ml of acetone was admixed with 3.2 ml of 1,3-dibromopropane and the mixture was refluxed for 90 minutes and was filtered. The solvent was evaporated under reduced pressure and the residue was chromatographed over silica (eluant: chloroform/ethyl acetate/triethylamine 6:3:1 to obtain 2.37 g of N-[2-[3-bromopropoxy)phenyl]-1H-indole-4-carboxamide melting at 145° C.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([OH:13])=O)=[CH:5][CH:4]=1.Cl.Cl.[NH:16]1[CH2:19][CH:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:17]1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[O:13]=[C:11]([N:16]1[CH2:19][CH:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:17]1)/[CH:10]=[CH:9]/[C:6]1[CH:5]=[CH:4][C:3]([NH2:2])=[N:8][CH:7]=1
Reactant: c1cc(COC2CNC2)ccn1
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(/C=C/C(=O)N2CC(OCc3ccncc3)C2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
To a solution of (2E)-3-(6-aminopyridin-3-yl)acrylic acid hydrochloride (42 mg, 0.21 mmol; which may be prepared as described in Step 2) in DMF (5 mL) were added 4-[(azetidin-3-yloxy)methyl]pyridine dihydrochloride (50 mg, 0.25 mmol; which may be prepared as described in Step 4), DIPEA (171 μL, 1.04 mmol), DMAP (2.5 mg, 0.02 mmol) and EDAC (48 mg, 0.25 mmol). The reaction mixture was stirred at room temperature overnight and concentrated to dryness. The residue was partitioned between a NaHCO3 5% solution and DCM. The aqueous phase was extracted twice with DCM, dried over sodium sulfate, filtered and concentrated under vacuum to give an orange solid. The crude was purified on preparative TLC (eluent: 90/10 DCM/MeOH+1% NH4OH) to give the title compound (21 mg, 33%) as a pale yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[N:9]=[C:10]([N:15]([CH3:36])[C:16]3[CH:17]=[C:18]([NH:22][C:23](=[O:35])[C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([C:33]#[N:34])([CH3:32])[CH3:31])[CH:25]=4)[CH:19]=[CH:20][CH:21]=3)[N:11]=[CH:12][C:13]=2[N:14]=1)=[O:4].C(N(CC)CC)C.Cl.[F:45][CH:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1.C(=O)([O-])O.[Na+]>O1CCCC1>[C:33]([C:30]([C:26]1[CH:25]=[C:24]([CH:29]=[CH:28][CH:27]=1)[C:23]([NH:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([N:15]([C:10]2[N:11]=[CH:12][C:13]3[N:14]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][N:49]4[CH2:50][CH2:51][CH:46]([F:45])[CH2:47][CH2:48]4)[S:7][C:8]=3[N:9]=2)[CH3:36])[CH:17]=1)=[O:35])([CH3:32])[CH3:31])#[N:34]
Reactant: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CCl)sc2n1
Reactant: FC1CCNCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(c1cccc(NC(=O)c2cccc(C(C)(C)C#N)c2)c1)c1ncc2nc(NC(=O)CN3CCC(F)CC3)sc2n1
Temperature: 60 °C
Reaction time: 20 h
Yield: 50.1 %

Procedure:
To a solution of N-{3-[{2-[(chloroacetyl)amino][1,3]thiazolo[5,4-d]pyrimidin-5-yl}(methyl)amino]phenyl}-3-(1-cyano-1-methylethyl)benzamide (140 mg, 269 μmol) produced in Example D10 in tetrahydrofuran (4 mL) were added triethylamine (112 μL, 807 μmol) and 4-fluoropiperidine hydrochloride (113 mg, 807 μmol), and the mixture was stirred at 60° C. for 20 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (10 mL), and the mixture was extracted with ethyl acetate (15 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=40/60→20/80), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from ethyl acetate and hexane to give the title compound (79 mg, 50%) as colorless crystals.
Reaction SMILES: O[CH2:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[C:5]#[N:6].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Br)(Br)(Br)[Br:33]>C1COCC1>[Br:33][CH2:2][C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: BrC(Br)(Br)Br
Reactant: COc1ccc(CO)c(C#N)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CBr)c(C#N)c1
Reaction time: 21 h

Procedure:
2-Hydroxymethyl-5-methoxy-benzonitrile from step 3 (1.12 g, 7.62 mmol) was dissolved in THF (38 ml) and treated with Ph3P (3 g, 11.4 mmol) followed by CBr4 (3.8 g, 11.4 mmol). The reaction mixture was stirred at room temp. for 21 hours. The solvent was removed in vacuo and the residue purified by flash chromatography (15% EtOAc/Hexane) to yield the desired product.