Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][NH:12][C:11](=[O:14])[C:10]3[S:15][C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:17][C:9]2=3)=[CH:4][CH:3]=1.CN(C=O)C.[Br:29]N1C(=O)CCC1=O>>[Br:29][C:17]1[C:9]2[CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=3)[CH2:13][NH:12][C:11](=[O:14])[C:10]=2[S:15][C:16]=1[N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1
Reactant: O=C1NCC(c2ccc(Cl)cc2)c2cc(N3CCOCC3)sc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: O=C1NCC(c2ccc(Cl)cc2)c2c1sc(N1CCOCC1)c2Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(4-chlorophenyl)-2-(morpholin-4-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (0.478 g, 1.37 mmol, single enantiomer of unknown absolute configuration) in DMF (8.9 mL, 110 mmol) was added N-bromosuccinimide (0.2561 g, 1.439 mmol), and the mixture was stirred at room temperature for 2 hours. Reaction was quenched via addition of 10% aqueous sodium thiosulfate solution (30 mL), and then diluted with EtOAc (100 mL) and water (10 mL) with sonication to encourage complete dissolution of solids. The layers were separated, and aqueous layer was extracted 1×EtOAc (50 mL). The combined organic layers were washed 1× brine (10 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was adsorbed to Celite (15 mL) and dryloaded onto a silica gel column. Column chromatography (eluent: 0-100% EtOAc:hexanes) then afforded 3-bromo-4-(4-chlorophenyl)-2-(morpholin-4-yl)-5,6-dihydrothieno[2,3-c]pyridin-7(4H)-one (526 mg, 90%). LCMS: (FA) ES+ 427, 429, 431. 1H NMR (400 MHz, CDCl3) δ: 7.26 (d, J=8.3 Hz, 2H), 7.07 (d, J=8.3 Hz, 2H), 5.41 (d, J=4.1 Hz, 1H), 4.20-4.06 (m, 2H), 3.87 (dd, J=4.6, 4.6 Hz, 4H), 3.52 (dt, J=14.4, 3.9 Hz, 1H), 3.35-3.24 (m, 2H), 3.24-3.10 (m, 2H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([O:7][CH:8]([CH3:10])C)=[N:4][CH:3]=1.[C:11]1([CH3:29])[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[C:18]2[N:19]([CH:26]=[CH:27][N:28]=2)[CH:20]=[C:21](B(O)O)[CH:22]=1>>[CH2:8]([O:7][C:5]1[S:6][C:2]([C:21]2[CH:22]=[C:17]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH3:29])[C:18]3[N:19]([CH:26]=[CH:27][N:28]=3)[CH:20]=2)=[CH:3][N:4]=1)[CH3:10]
Reactant: Cc1ccccc1-c1cc(B(O)O)cn2ccnc12
Reactant: CC(C)Oc1ncc(Br)s1
Product: CCOc1ncc(-c2cc(-c3ccccc3C)c3nccn3c2)s1

Procedure:
Example 190 was prepared using the procedure describe for Example 34, step 4 from 5-bromo-2-(isopropyloxy)thiazole and 8-o-tolylimidazo[1,2-a]pyridin-6-ylboronic acid. LCMS (Conditions C): Tr 2.63 min.; (M+H)': 336.31.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:18]=[C:17]3[C:12]([CH2:13][CH2:14][CH2:15][C:16]3=O)=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1C=CC=CC=1>[CH2:20]([NH:27][CH:16]1[C:17]2[C:12](=[CH:11][CH:10]=[C:9]([O:8][CH2:7][C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH:18]=2)[CH2:13][CH2:14][CH2:15]1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C1CCCc2ccc(OCc3ccncc3)cc21
Reactant: NCc1ccccc1
Solvent: c1ccccc1
Product: c1ccc(CNC2CCCc3ccc(OCc4ccncc4)cc32)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
A solution of Compound 1 (820 mg, 3.24 mmol) and benzyl amine (354 μL, 3.24 mmol) in benzene (10 mL) was heated to reflux under azeotropic conditions. After the calculated amount of water was collected, the reaction was cooled and concentrated in vacuo. The residue was taken-up into ethanol (5 mL) and added to a slurry of sodium boroydride (246 mg, 6.48 mmol) in ethanol (15 mL). The reaction was heated to 80° C., stirred for 30 min, cooled and concentrated in vacuo. The residue was diluted with ethyl acetate followed by the slow addition of 1N hydrochloric acid. The layers were separated. The aqueous phase was adjusted to pH 7 with 2N sodium hydroxide and extracted with methylene chloride (2×). The organics were combined, washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. Chromatography on silica gel (elution with 5% methanol:methylene chloride) provided 1.09 g of Compound 12 as an oil.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=C[CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2[F:35])=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C1(CN)CC1>C(O)(=O)C>[CH:2]1([CH2:1][N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[F:35])[C:10]=3[N:9]=[CH:8]2)[CH2:4][CH2:3]1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Agent: NCC1CC1
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Product: O=c1c2scc(-c3ccccc3F)c2ncn1CC1CC1
Yield: 43 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1.0 ml), cyclopropanemethylamine (0.066 ml, 0.76 mmol), and acetic acid (0.1 ml) were used to give 57.1 mg (0.17 mmol, 43% yield) of the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:27][CH:26]=2)/[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[N:14]=[CH:13]3)=[CH:4][CH:3]=1.[N:40]1[CH:45]=[C:44](B(O)O)[CH:43]=[N:42][CH:41]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.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>[N:40]1[CH:45]=[C:44]([C:2]2[CH:7]=[CH:6][C:5](/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]3[CH:26]=[CH:27][C:28](/[CH:31]=[CH:32]/[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:29][CH:30]=3)/[C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[N:15]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:14]=[CH:13]4)=[CH:4][CH:3]=2)[CH:43]=[N:42][CH:41]=1
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(Br)cc2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Reactant: OB(O)c1cncnc1
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: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2ccc(-c3cncnc3)cc2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Temperature: 90 °C
Yield: 47.5 %

Procedure:
A mixture of (E)-ethyl 3-(4-((E)-2-(4-bromophenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (212 mg, 0.36 mmol), pyrimidin-5-ylboronic acid (67 mg, 0.54 mmol) and potassium carbonate (100 mg, 0.72 mmol) in toluene/ethanol (4:1, 5 mL) was degassed with nitrogen. Pd(PPh3)4 (41 mg, 0.036 mmol) was added and the mixture was heated to 90° C. overnight. The reaction was not done so additional pyrimidin-5-ylboronic acid (67 mg, 0.54 mmol), potassium carbonate (100 mg, 0.72 mmol) and Pd(PPh3)4 (41 mg, 0.036 mmol) were added, and the mixture was heated to 90° C. for an additional 4 h. The mixture was cooled to room temperature and poured into ethyl acetate. The organic phase was washed with brine (3×), dried over sodium sulfate, and purified by flash chromatography on silica gel eluting with 0 to 100% ethyl acetate/hexanes to afford 100 mg of the title compound as a yellow foam. 1H NMR (400 MHz, DMSO-d6): δ 9.16 (s, 1H), 9.15 (s, 2H), 8.13 (s, 1H), 7.76-7.67 (m, 4H), 7.48 (d, 1H), 7.42 (d, 2H), 7.35 (d, 2H), 7.26 (dd, 1H), 6.95 (d, 2H), 6.48 (d, 1H), 5.86 (dd, 1H), 4.14 (qt, 2H), 3.90 (m, 1H), 3.75 (m, 1H), 2.49-2.42 (m, 3H), 2.01 (m, 2H), 1.78 (m, 1H), 1.59 (m, 2H), 1.21 (t, 3H), 0.92 (t, 3H).
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5]([O:20][CH3:21])=[CH:4][N:3]=1.[C:22]([C:24]1[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=1)#[CH:23]>CC#N.CCN(CC)CC.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>[CH3:9][O:8][C:7]1[C:2]([C:23]#[C:22][C:24]2[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=2)=[N:3][CH:4]=[C:5]([O:20][CH3:21])[C:6]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1
Reactant: C#Cc1cnn(C)c1
Reactant: COc1ccc(COc2c(OC)cnc(I)c2OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(COc2c(OC)cnc(C#Cc3cnn(C)c3)c2OC)cc1
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
To a stirred solution of 2-iodo-3,5-dimethoxy-4-(4-methoxy-benzyloxy)-pyridine (95 mg, 0.237 mmol) and 4-ethynyl-1-methyl-1H-pyrazole (30 mg, 0.283 mmol) in dry MeCN (1.5 ml) and NEt3 (0.5 ml) was added Pd(Ph3P)2Cl2 (12 mg, 7 mol %) and the reaction vessel was evacuated and backfilled with nitrogen three times. Copper (I) iodide (5 mg, 11 mol %) was added and the reaction mixture immediately became dark. Stirring was continued for 0.5 hours then the crude mixture was concentrated directly onto silica-gel under reduced pressure and the solid residue was purified by flash chromatography (silica-gel, eluted sequentially with EtOAc:hexanes, 2:1, 3:1, 1:0) to give the product as a white solid (85 mg, 95%). 1H—NMR (300 MHz, CDCl3) δ 7.98 (s, 1H), 7.66 (s, 1H), 7.57 (s, 1H), 7.34 (d, J=8.6 Hz, 2H), 6.86 (d, J=2H), 5.13 (s, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.89 (s, 3H), 3.78 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[N:6]([CH3:17])[S:7](=[O:16])(=[O:15])[C:8]2[CH:14]=[CH:13][S:12][C:9]=2[C:10]=1[OH:11])([O:3]C)=O.[NH2:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1>C1(C)C(C)=CC=CC=1>[OH:11][C:10]1[C:9]2[S:12][CH:13]=[CH:14][C:8]=2[S:7](=[O:16])(=[O:15])[N:6]([CH3:17])[C:5]=1[C:1]([NH:18][C:19]1[S:20][CH:21]=[CH:22][N:23]=1)=[O:3]
Reactant: COC(=O)C1=C(O)c2sccc2S(=O)(=O)N1C
Reactant: Nc1nccs1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2sccc2S1(=O)=O

Procedure:
1.9 G. of 3-carbomethoxy-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine 1,1-dioxide are suspended together with 0.9 g. of 2-aminothiazole in 250 ml. of absolute xylene and heated to reflux for 7 hours, by which means 150 ml. of xylene are slowly distilled off. The residual xylene is then evaporated in vacuo. The crystalline residue is recrystallized from ethanol. There is obtained 4-hydroxy-2-methyl-N-(2-thiazolyl)-2H-thieno[2,3-e]-1,2-thiazine-3-carboxamide1,1-dioxide of melting point 217° C. (decomposition).
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:5]=1)([O-])=O.[CH2:16]([N:18](CC)[CH2:19][CH3:20])[CH3:17].C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>C(Cl)Cl.CCOCC>[CH2:16]([N:18]([CH2:19][CH3:20])[C:9]1[CH:4]=[CH:5][C:6]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:7][CH:8]=1)[CH3:17]
Reactant: CCN(CC)CC
Reactant: O=[N+]([O-])c1ccnc(N2CCNCC2)c1
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: CCN(CC)c1ccc(N2CCNCC2)nc1
Reaction time: 1 h

Procedure:
The amine (21 g), triethylamine (17.9 g) and methylene chloride (600 ml) are cooled to 0°. Di-t-butyl dicarbonate (25.8 g) in methylene chloride (200 ml) is added over 30 min at 0°. The reaction mixture is stirred at 0° for 1 hr and allowed to warm to 20-25°. The reaction mixture is washed with saturated sodium bicarbonate (3×200 ml), dried over potassium carbonate and the solvent removed under reduced pressure to give a solid. The solid is dissolved in ether, petroleum ether is added until the mixture is cloudy, the mixture is filtered thru celite and the filtrate is concentrated to give the protected piperazine compound.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:20]=1[CH2:21]Br>>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Reactant: Clc1cccc(Cl)c1CBr
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1c(Cl)cccc1Cl

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,6-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([C:5]([OH:7])=[O:6])[NH2:4].[CH2:8]([O:15][C:16](Cl)=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+]>>[CH2:8]([O:15][C:16]([NH:4][C@H:3]([C:5]([OH:7])=[O:6])[CH2:2][Cl:1])=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@@H](CCl)C(=O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C(N[C@@H](CCl)C(=O)O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 3 h
Yield: 99.6 %

Procedure:
To 86.19 g of an aqueous solution containing 7.47 g of β-chloroalanine was added 11.35 g of benzyloxycarbonyl chloride (1.1 moles per mole of β-chloroalanine) dropwise over 1 hour under constant stirring at about 5° C., with the reaction system being maintained at pH 9.7 with a 30% aqueous solution of sodium hydroxide. The reaction was further continued for 3 hours, at the end of which time the reaction mixture was washed with 50 ml of toluene. This washed reaction mixture, 89.53 g, contained 15.52 g (yield 100%) of N-benzyloxycarbonyl-β-chloroalanine.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)O1.[F-].[Cs+].[C:19]([O:22][C@H:23]1[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@:27]2([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([CH2:46]Br)[CH:40]=3)[O:38][C@@:24]1([CH2:48][O:49][C:50](=[O:52])[CH3:51])[CH2:25][O:26]2)(=[O:21])[CH3:20]>O1CCOCC1.C(OC(=O)C)C>[C:19]([O:22][C@H:23]1[C@H:29]([O:30][C:31](=[O:33])[CH3:32])[C@@H:28]([O:34][C:35](=[O:37])[CH3:36])[C@:27]2([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[C:41]([CH2:46][C:9]4[CH:10]=[CH:11][C:12]([OH:15])=[CH:13][CH:14]=4)[CH:40]=3)[O:38][C@@:24]1([CH2:48][O:49][C:50](=[O:52])[CH3:51])[CH2:25][O:26]2)(=[O:21])[CH3:20]
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(CBr)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(O)cc4)c3)(O1)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]2OC(C)=O
Temperature: 110 °C
Yield: 41 %

Procedure:
To a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (500 mg, 2.25 mmol), CsF (865.83 mg, 5.70 mmol) in Dioxane (9.5 mL), (1R,2S,3S,4R,55)-1-(acetoxymethyl)-5-(3-(bromomethyl)-4-chlorophenyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triyl triacetate (1.07 g, 1.90 mmol, Intermediate 2) and Pd(PPh3) (173.3 mg, 0.15 mmol) were added under N2 atmosphere. The reaction mixture was heated to 110° C. for 1 h. After completion of the reaction as confirmed by TLC, the reaction mixture was diluted with ethylacetate (100 mL) and washed with water (20 mL) and brine (20 mL) successively. The organic layer was dried over Na2SO4 and the volatiles were evaporated in vacuo. The residue obtained was purified by column chromatography (silica gel, 2:8 Acetone:hexane) to provide title compound (450 mg, 41.3%) as off-white solid.
Reaction SMILES: [C:1]12([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]45[CH2:28][CH:23]6[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]6)[CH2:20]4)[CH2:26]5)[CH:15]=[C:14](Cl)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[C:1]12([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]45[CH2:28][CH:23]6[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]6)[CH2:20]4)[CH2:26]5)[CH:15]=[C:14]([N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: Clc1cc(NC23CC4CC(CC(C4)C2)C3)nc(NC23CC4CC(CC(C4)C2)C3)n1
Reactant: C1CNCCN1
Product: c1c(NC23CC4CC(CC(C4)C2)C3)nc(NC23CC4CC(CC(C4)C2)C3)nc1N1CCNCC1
Yield: 83.36 %

Procedure:
The reaction of 2,4-bis(1-adamantylamino)-6-chloropyrimidine with piperazine as described in Example 4 gives the title compound in a yield of 83.36%, m.p.: 168°-175° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12](=[O:14])[CH3:13])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.Cl.[Cl:16]([O-])(=O)=O.[Na+].C([O-])([O-])=O.[K+].[K+]>C(O)(=O)C.O>[Cl:16][C:6]1[C:7]([O:9][CH3:10])=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[NH:11][C:12](=[O:14])[CH3:13]
Reactant: [O-][Cl+2]([O-])[O-]
Reactant: COc1cc(NC(C)=O)cc(OC)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(NC(C)=O)c(Cl)c(OC)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 71.3 %

Procedure:
To a stirred solution of N-(3,5-dimethoxy-phenyl)-acetamide (5 g, 25.64 mmol) in acetic acid (17 mL) was added 32% aqueous hydrochloric acid solution (14 mL), followed by a solution of sodium chlorate (1.16 g, 11 mmol) in water (1.5 mL) at 0° C. The resulting reaction mixture was stirred for 30 min. at 0° C. Thereafter reaction mixture was poured into ice water and made it basic with K2CO3 powder. The precipitate was filtered off and washed with water. The residue was purified by silica gel column chromatography (Hexane/EtOAc, 88:12) to afford the title compound (1.8 g, 31% of yield) as a white solid. 1HNMR (DMSO-d6, 300 MHz): δ 9.36 (s, 1H), 7.03 (d, 1H), 6.53 (d, 1H), 3.84 (s, 3H), 3.74 (s, 3H), 2.08 (s, 3H); MS (ESI): 230.2 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:15][CH:16]=2)[NH:11][N:10]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH:33][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Reactant: COc1ccccc1CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccccc1CNC(=O)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 115.2 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), o-methoxybenzylamine (21.8 μL, 0.17 mmol), triethylamine (58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 46 mg (81%) of the title compound as a TFA salt (1.5 H2O, 1.5 TFA, effective MW=673.59). 1H NMR (DMSO-d6): δ 9.83 (1H, s), 9.03 (1H, t, J=3.4), 8.70 (1H, d, J=3.7), 8.08 (4H, m), 7.82 (1H, d, J=7.4), 7.49 (4H, m), 7.21 (3H, m), 6.96 (4H, m), 4.48 (2H, d, J=6.3). ESIMS (M+H+): 476.1.
Reaction SMILES: O[CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1.CCN(CC)CC.CS(Cl)(=O)=O.[N-:24]=[N+:25]=[N-:26].[Na+]>C(Cl)Cl.CCOC(C)=O.O>[N:24]([CH2:2][CH2:3][C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)=[N+:25]=[N-:26]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(CCO)cc1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc(CCN=[N+]=[N-])cc1
Temperature: 0 °C
Reaction time: 3.5 h

Procedure:
To a solution of 4-(2-hydroxyethyl)benzonitrile (10.0 g, 67.94 mmol) in CH2Cl2 (175 mL) at 0° C. was added Et3N (11.36 mL, 8.25 mmol) and MsCl (6.31 mL, 81.53 mmol). After stirring at 0° C. for 3.5 hours, the reaction was poured into water (100 ml) and separated. Organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Crude residue was dissolved in DMF (100 mL) and NaN3 (9.15 g, 140.72 mmol) and water (5 mL) were added. The resulting solution was heated to 125° C. After overnight stirring at 125° C., the crude reaction mixture was cooled, diluted with EtOAc (200 mL) and poured into water (150 mL). Organic layer was washed with water (5×150 mL), dried over sodium sulfate, filtered, and concentrated to give 4-(2-azidoethyl)benzonitrile which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][NH:13][C:14]([CH:16]1[CH2:20][CH2:19][O:18][CH2:17]1)=O.O=S(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1>[Br:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:6])[N:13]([CH3:12])[C:14]([CH:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[N:1]2)=[CH:7][CH:8]=1
Reactant: CNC(=O)C1CCOC1
Reactant: Nc1cc(Br)ccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: Cn1c(C2CCOC2)nc2cc(Br)ccc2c1=O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
The mixture of 2-amino-4-bromobenzoic acid (349 mg, 1.62 mmol), N-methyltetrahydrofuran-3-carboxamide (190 mg, 1.47 mmol), SOCl2 (0.13 mL, 1.76 mmol) and toluene (10 mL) was stirred at 80° C. for 5 h, and Na2CO3 aqueous solution was added after the mixture was cooled to room temperature. The water layer was extracted with ethyl acetate (3×10 mL) and the combined organic layers were dried over Na2SO4, filtered, and evaporated to give the desired product, which was directly used for the next step. MS (ESI): 309, 311 (MH+).
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[CH2:7][CH2:6][CH2:5][C@H:4]([CH3:8])[C@@H:3]1[CH2:9][CH2:10][CH:11](O)[CH3:12].[OH2:15]>C1C=CC=CC=1>[C:9]([CH:3]1[CH:4]([CH3:8])[CH2:5][CH2:6][CH2:7][C:2]1([CH3:14])[CH3:1])(=[O:15])/[CH:10]=[CH:11]/[CH3:12]
Reactant: O
Reactant: CC(O)CC[C@H]1[C@@H](C)CCCC1(C)C
Solvent: c1ccccc1
Product: C/C=C/C(=O)C1C(C)CCCC1(C)C

Procedure:
A solution of 320 g (1.5 moles) of the ketol prepared in Example 2 in 1000 ml of benzene containing 2 g p-toluenesulphonic acid is heated in an apparatus for azeotropical water separation (Dean-Stark) till no more water separates. The reaction mixture is washed with a solution of sodium bicarbonate till neutral reaction and dried over anhydrous sodium sulfate. The solvent is removed by distillation at reduced pressure and the residue is distilled through a short Vigreux column. The product, cis, E-1-crotonoyl-2,2,6-trimethyl-cyclohexane (III, contains about 10% of the trans isomer) is collected at 76°C/1 mm; yield 273 g (94%). Recrystallization from pentane gives cis, E-1-crotonoyl-2,2,6-trimethylcyclohexane in high purity (m.p. 27°-28°C).