Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][S:10]([C:13]1[N:23]=[C:16]2[N:17]=[C:18]([CH3:22])[CH:19]=[C:20](O)[N:15]2[N:14]=1)(=[O:12])=[O:11].P(Cl)(Cl)([Cl:26])=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][S:10]([C:13]1[N:23]=[C:16]2[N:17]=[C:18]([CH3:22])[CH:19]=[C:20]([Cl:26])[N:15]2[N:14]=1)(=[O:12])=[O:11]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(O)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Solvent: CC#N
Product: Cc1cc(Cl)n2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1

Procedure:
A suspension of 10.0 g (27.0 mmol) of N-(2,6-dichlorophenyl)-7-hydroxy-5-methyl-1,2,4-triazolo-[1,5-a]-pyrimidine-2-sulfonamide and 100 ml (1.1 mol) of phosphorous oxychloride in 700 ml of acetonitrile (dried over 4A Molecular Sieves) was heated at reflux for 24 hr. As the reaction progressed the mixture became homogeneous. After cooling the solution was concentrated by rotary evaporation in vacuo and the resulting residue was diluted with 300 ml of methylene chloride and 10 ml of water. The methylene chloride solution was decanted off and the solid that had formed was triturated with 100 ml of hexane and 5 ml of water. The resulting yellow solid was collected. Recovered 9.0 g (85 percent) of the desired product; mp 217°-220° C. An analytical sample could be prepared by recrystallization from methanol (mp 218°-221° C.).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:11])[NH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].[Cl:20][C:21]1[C:22]([F:44])=[C:23]([CH:33]2[CH2:36][N:35]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:34]2)[C:24]([O:30][CH2:31][CH3:32])=[C:25]([CH:27](Cl)[CH3:28])[CH:26]=1>CN(C=O)C>[NH2:11][C:9]1[N:8]=[CH:7][N:6]=[C:5]2[N:4]([CH:27]([C:25]3[C:24]([O:30][CH2:31][CH3:32])=[C:23]([CH:33]4[CH2:34][N:35]([C:37]([O:39][C:40]([CH3:42])([CH3:41])[CH3:43])=[O:38])[CH2:36]4)[C:22]([F:44])=[C:21]([Cl:20])[CH:26]=3)[CH3:28])[N:3]=[C:2]([CH3:1])[C:10]=12
Reactant: Cc1n[nH]c2ncnc(N)c12
Reactant: CCOc1c(C(C)Cl)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: CCOc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(F)c1C1CN(C(=O)OC(C)(C)C)C1
Temperature: 90 °C
Reaction time: 3 h
Yield: 63.5 %

Procedure:
To a mixture of 3-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-amine (1.10 g, 7.37 mmol), cesium carbonate (3.2 g, 10 mmol) and potassium iodide (111 mg, 0.670 mmol) in DMF (20 mL) was added tert-butyl 3-[3-chloro-5-(1-chloroethyl)-6-ethoxy-2-fluorophenyl]azetidine-1-carboxylate (2.63 g, 6.70 mmol) and the mixture was stirred at 90° C. for 3 h. The solvent was removed in vacuo. The residue was diluted with ethyl acetate and water. Aqueous layer was extracted with ethyl acetate twice. The combined organic layers were washed with water, brine, dried over Na2SO4, filtered and concentrated. The residue was purified on silica gel column (eluting with 100% ethyl acetate) to give the desired product as a foam (2.15 g, 63%). LCMS calculated for C24H31ClFN6O3 (M+H)+: m/z=505.2; Found: 505.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:19][CH:18]2[CH2:20][CH:10]([CH2:11][C:12]3[CH:13]=[C:14]([O:21][CH3:22])[CH:15]=[CH:16][C:17]=32)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:23]Br>C(Cl)Cl.CC(O)=O>[CH2:1]([N:8]1[CH2:19][CH:18]2[CH2:20][CH:10]([CH2:11][C:12]3[C:13]([Br:23])=[C:14]([O:21][CH3:22])[CH:15]=[CH:16][C:17]=32)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: COc1ccc2c(c1)CC1CC2CN(Cc2ccccc2)C1
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1ccc2c(c1Br)CC1CC2CN(Cc2ccccc2)C1
Yield: 27.7 %

Procedure:
11-Benzyl-5-methoxy-11-aza-tricyclo[7.3.1.02.7]trideca-2(7),3,5-triene (300 g, 10.2 mmol) was stirred at 0° C. in CH2Cl2 (10 mL) and AcOH (5 mL) and treated with bromine (3.21 g, 20 mmol) in CH2Cl2 (10 mL) and AcOH (5 mL). After 18 hours the reaction was quenched with 20% aq. NaHSO3 soin. (100 mL). The produce was extracted with CH2Cl2 (3×40 mL) and washed with sat. aq. NaHCO3 soin. (3×50 mL). The combined organic layer was dried through a cotton plug, concentrated and chromatographed on Silica gel to provide an oil (1.05 g, 28%). (TLC 30%EtOAc/hexanes Rf 0.48). 1H NMR (CDCl3) δ 7.13 (m, 3H), 6.91 (m, 3H), 6.68 (d, J=8.0 Hz, 1H), 3.90 (s, 3H), 3.36 (s, 2H), 2.88-2.79 (4H), 2.67 (br d, J=9.0 Hz, 1H), 2.31 (br s, 1H), 2.28 (br s, 1H), 2.22 (br s, 1H), 1.78 (AB d, J=13.0 Hz, 2H). GCMS m/e 373,371 (M+).
Reaction SMILES: [C-:1]#[N:2].[K+].CS(O[CH2:9][C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH2:15][N:16]([S:20]([C:23]3[C:28]([CH3:29])=[CH:27][C:26]([O:30][CH3:31])=[CH:25][C:24]=3[CH3:32])(=[O:22])=[O:21])[CH2:17]2)=[CH:12][CH:11]=1)(=O)=O>CCO.O.C(OCC)(=O)C>[CH3:31][O:30][C:26]1[CH:25]=[C:24]([CH3:32])[C:23]([S:20]([N:16]2[CH2:15][CH2:14][C:13]3[C:18](=[CH:19][C:10]([CH2:9][C:1]#[N:2])=[CH:11][CH:12]=3)[CH2:17]2)(=[O:22])=[O:21])=[C:28]([CH3:29])[CH:27]=1
Reactant: [C-]#N
Reactant: COc1cc(C)c(S(=O)(=O)N2CCc3ccc(COS(C)(=O)=O)cc3C2)c(C)c1
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(C)c(S(=O)(=O)N2CCc3ccc(CC#N)cc3C2)c(C)c1
Yield: 71 %

Procedure:
KCN (2.73 mmol, 1.2 equiv.) was added to a solution of (2-(4-methoxy-2,6-dimethylphenylsulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)methyl methanesulfonate (2.28 mmol, 1 equiv.) in EtOH/water (10 ml), and the mixture was refluxed for 24 h. The reaction mixture was then cooled and diluted with ethyl acetate. Extraction with sat. FeSO4 solution, water and sat. NaCl solution was carried out, and the organic phase was dried over Na2SO4 and concentrated in vacuo. The resulting crude product was purified by column chromatography (silica gel). Yield: 71%
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:32][CH2:31][C:17]2([C:21](=O)[N:20]([CH3:23])[C:19](=O)[CH:18]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[Na+]>O>[CH2:7]([N:14]1[CH2:32][CH2:31][C:17]2([CH2:21][N:20]([CH3:23])[CH2:19][CH:18]2[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:15]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CN1C(=O)C(c2ccccc2)C2(CCN(Cc3ccccc3)CC2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Product: CN1CC(c2ccccc2)C2(CCN(Cc3ccccc3)CC2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.7 %

Procedure:
Lithium aluminium hydride (1.39 g, 37 mmol) was dissolved in tetarhydrofuran (20 mL) and the intermediate (rac)-8-benzyl-2-methyl-4-phenyl-2,8-diaza-spiro[4.5]decane-1,3-dion (2.55 g, 7.32 mmol, dissolved in 20 mL dry tetrahydrofuran) was added slowly. The reaction mixture was stirred at room temperature for 2 h. Water (1.4 mL), sodium hydroxide (15% in water, 1.5 mL) and water (4.2 mL) were added dropwise. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by flash chromatography (hexane/ethyl acetate/triethyl amine 30:20.1) to yield the intermediate (rac)-8-benzyl-2-methyl-4-phenyl-2,8-diaza-spiro[4.5]decane (1.40 g, 60%).
Reaction SMILES: [S:1]1[C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2.S1C(C(O)=O)=CC2C=CC=CC1=2.C(Cl)(=O)C(Cl)=O.[NH2:31][CH:32]([P:41](=[O:48])([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44])[P:33](=[O:40])([O:37][CH2:38][CH3:39])[O:34][CH2:35][CH3:36].[Cl-]>C(Cl)Cl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C.N1C=CC=CC=1>[S:1]1[C:5]([C:6]([NH:31][CH:32]([P:33](=[O:40])([O:34][CH2:35][CH3:36])[O:37][CH2:38][CH3:39])[P:41](=[O:48])([O:45][CH2:46][CH3:47])[O:42][CH2:43][CH3:44])=[O:7])=[CH:4][C:3]2[CH:9]=[CH:10][CH:11]=[CH:12][C:2]1=2
Reactant: CCOP(=O)(OCC)C(N)P(=O)(OCC)OCC
Reactant: O=C(Cl)c1cc2ccccc2s1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cc2ccccc2s1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCOP(=O)(OCC)C(NC(=O)c1cc2ccccc2s1)P(=O)(OCC)OCC

Procedure:
To a solution of 2-benzo[b]thiophenecarbonyl chloride prepared from 2-benzo[b]thiophenecarboxylic acid (356 mg) and oxalyl chloride (0.35 ml) in methylene chloride (2 ml) was added dropwise a mixture of tetraethyl (aminomethylene)bis(phosphonate) (606 mg), pyridine (316 mg) and trace amounts of 4-(dimethylamino)pyridine in methylene at 5° C. The mixture was stirred for 2 chloride (8 ml) hours at ambient temperature followed by the addition of ethyl acetate. The mixture was washed with water, 1N hydrochloric acid, saturated aqueous solution of sodium bicarbonate and brine successively. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was treated with diisopropyl ether to give tetraethyl [(2-benzo[b]thiophenecarboxamido)-methylene]bis(phosphonate) (790 mg) as a white powder which was recrystallized from a mixture of ethyl acetate and n-hexane.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([CH2:48][CH2:49][C:50]([N:52]2[CH2:57][CH2:56][N:55]([CH3:58])[CH2:54][CH2:53]2)=[O:51])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[C:44]([CH2:48][CH2:49][C:50]([N:52]6[CH2:53][CH2:54][N:55]([CH3:58])[CH2:56][CH2:57]6)=[O:51])[CH:45]=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: CN1CCN(C(=O)CCc2cccc(Br)c2)CC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(CCC(=O)N4CCN(C)CC4)c3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (200 mg) and 3-(3-bromo-phenyl)-1-(4-methyl-piperazin-1-yl)-propan-1-one (173 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 3-[3-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-1-(4-methyl-piperazin-1-yl)-propan-1-one was obtained, and further PMB group was removed according to the above Deprotection method 2, to obtain the desired compound (D-190) as a pale brown powder (110 mg, 58%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([S:13][C:14](=O)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].FC1C=[C:26]2[C:31](=[CH:32][C:33]=1[Cl:34])[CH:30]=[N:29][CH:28]=[CH:27]2.C1CCN2C(=NCCC2)CC1>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([S:13][C:14]2[CH:15]=[C:26]3[C:31](=[CH:32][C:33]=2[Cl:34])[CH:30]=[N:29][CH:28]=[CH:27]3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)S[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1cc2ccncc2cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)N1CC[C@H](Sc2cc3ccncc3cc2Cl)C1
Yield: 86.8 %

Procedure:
3.5 g (14.2 mmol) (S)-3-Acetylsulfanyl-pyrrolidine-1-carboxylic acid tert-butyl ester (266) were dissolved in 95 ml MeOH and treated with 2.34 g (16.9 mmol) potassium carbonate and stirred over night. After evaporation of all volatiles the residue was taken up in 60 ml of degassed DMF, 1.27 g (15 mmol) 6-Fluoro-7-chloroisoquinoline and 2.25 ml (15 mmol) DBU were added. After 3 h at RRT the mixture was concentrated, taken up in ethyl acetate and washed with brine. The organic phases were dried over Sodium sulfate and evaporated. Purification over silica gel (10% to 40% ethyl acetate in heptane) gave 4.5 g of the expected compound.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][NH:10][C:11](=[O:46])[C@H:12]([CH3:45])[CH2:13][C@H:14]([OH:44])[C@@H:15]([NH:36]C(OC(C)(C)C)=O)[CH2:16][C@@H:17]([CH:33]([CH3:35])[CH3:34])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH2:4][CH2:3]1.[ClH:47]>O1CCOCC1>[ClH:47].[ClH:47].[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][NH:10][C:11](=[O:46])[C@H:12]([CH3:45])[CH2:13][C@H:14]([OH:44])[C@@H:15]([NH2:36])[CH2:16][C@@H:17]([CH:33]([CH3:35])[CH3:34])[CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH2:28][CH2:29][CH2:30][O:31][CH3:32])[CH:20]=2)[CH2:6][CH2:7]1
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCN2CCC(O)CC2)C(C)C)ccc1OC
Agent: Cl
Solvent: C1COCCO1
Product: COCCCOc1cc(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C)C(=O)NCCN2CCC(O)CC2)C(C)C)ccc1OC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
100 mg of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acid N-[2-(4-hydroxy-piperidin-1-yl)-ethyl]-amide are dissolved in 3 ml of 4N hydrochloric acid in dioxane at 0° C., and the mixture is stirred for 2 hours at 0° C. The reaction mixture is lyophilised and the title compound is obtained: Rf (dichloromethane/methanol=8:2)=0.08; HPLC Rt =8.85 minutes; FAB-MS (M+H)+ =552.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.C1C(=O)N([Br:19])C(=O)C1>OS(O)(=O)=O>[Br:19][C:3]1[C:2]([F:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2
Reactant: Fc1ccc2cnccc2c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Product: Fc1ccc2cnccc2c1Br

Procedure:
To a stirring mixture of 6-fluoroisoquinoline in H2SO4 (5 mL) at 0° C. was added solid NBS (1.5 EQ) slowly over 5 min. The reaction mixture was reacted at 0° C. for 1 h. To this reaction mixture was added NBS (0.5 EQ). The cold bath was then removed. The reaction mixture was reacted until all the starting material was consumed. To this reaction mixture was neutralized with a cold solution of NaOH (5N) until the pH of this mixture >10. The white solid was filtered off and dissolved in DCM and washed with a solution of NaOH (1N). The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified via a column to give 5-bromo-6-fluoroisoquinoline. Retention time (min)=2.810, method [3], MS (ESI) 226.0 (M+H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[CH2:26]([N:33]1[C:37]([C:38](Cl)=[O:39])=[CH:36][C:35]([C:41]([CH3:44])([CH3:43])[CH3:42])=[N:34]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH2:26]([N:33]1[C:37]([C:38]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH:15]=3)[CH2:10][CH2:9]2)=[O:39])=[CH:36][C:35]([C:41]([CH3:44])([CH3:43])[CH3:42])=[N:34]1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Reactant: CC(C)(C)c1cc(C(=O)Cl)n(Cc2ccccc2)n1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)c3cc(C(C)(C)C)nn3Cc3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 1-benzyl-3-tert-butyl-1H-pyrazole-5-carbonyl chloride: ESMS m/e: 586.3 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([CH3:20])([CH3:19])/[CH:15]=[CH:16]/[C:17]#[N:18])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1>C(COC)OC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([C:14]([CH3:20])([CH3:19])[CH2:15][CH2:16][C:17]#[N:18])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CC(C)(/C=C/C#N)N1CCN(c2ccc(F)cc2)CC1
Solvent: COCCOC
Product: CC(C)(CCC#N)N1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To the stirred solution of (E)-4-(4-(4-fluorophenyl)piperazin-1-yl)-4-methylpent-2-enenitrile (1.5 g), was added sodumborohydride (0.453 mg) in dimethoxyethane (30 ml) and stirred at room temperature for 1 hour before being heated to 75° C. for 2 h. The solution was cooled to room temperature and allowed to stirrer at 25° C. for 24 h then quenched with saturated ammonium chloride (50 mL). The aqueous phase was extracted with dichloromethane (3×50 ml). The organic phase was dried over sodium sulphate and concentrated under vacuum. The residue was purified by flash column chromatography using 20% ethyl acetate in hexane as an eluent to obtain the title compound (1.3 g, 58.6%).
Reaction SMILES: B(Br)(Br)Br.[C:5]([C:7]1[C:12]([F:13])=[CH:11][C:10]([C:14]2[CH:19]=[CH:18][C:17]([O:20]C)=[CH:16][CH:15]=2)=[CH:9][C:8]=1[F:22])#[N:6].O>ClCCl>[C:5]([C:7]1[C:8]([F:22])=[CH:9][C:10]([C:14]2[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=2)=[CH:11][C:12]=1[F:13])#[N:6]
Reactant: COc1ccc(-c2cc(F)c(C#N)c(F)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: N#Cc1c(F)cc(-c2ccc(O)cc2)cc1F
Temperature: 25 °C

Procedure:
A solution of boron tribromide (25.0 ml, 61.5 g, 0.25 mol) in dry dichloromethane (140 ml) was added dropwise to a stirred, cooled (-78° C.) solution of compound 8 (12.22 g, 0.05 mol) in dry dichloromethane (250 ml) under dry nitrogen. The stirred mixture was allowed to warm to room temperature over 9 h (i.e., until glc analysis revealed absence of starting material). The mixture was cooled to -10° C., water was added slowly (exothermic) and cooled to 2° C. The product was filtered off, washed with water and dried (CaCl2) in vacuo to give a pale-yellow powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[CH:4]=1.C([Li])CCC.[CH2:27]1[O:29][CH2:28]1.O>C1COCC1.C(O)(=O)C>[OH:29][CH2:28][CH2:27][C:4]1[C:5]([NH:15][C:16](=[O:21])[C:17]([CH3:18])([CH3:20])[CH3:19])=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(-c2ccccc2)c(NC(=O)C(C)(C)C)c1
Reactant: C1CO1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc(-c2ccccc2)c(NC(=O)C(C)(C)C)c1CCO
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A mechanically stirred solution of N-(4-methoxybiphenyl-2-yl)-2,2-dimethylpropionamide (17.91 g, 63.2 mmol) in anhydrous THF at -68° C. was treated dropwise with butyllithium (2.46 M in hexane, 72.0 mL, 177 mmol), stirred 1 h, allowed to warm to -5° C., stirred 1 h, cooled to -78° C., and treated with ethylene oxide (10.0 mL, 8.82 g, 200 mmol) in one portion. The suspension was allowed to warm to room temperature and stirred for 12 h. The suspension was treated with water (50 mL) and glacial acetic acid (2 mL), stirred 10 min, and concentrated in vacuo. The residue was treated with water (500 mL) and Et2O (300 mL), and the layers were separated. The aqueous layer was further extracted with diethyl ether (2×300 mL), the combined organic extracts were washed with saturated sodium bicarbonate (500 mL), brine (500 mL), dried (K2CO3), filtered, and concentrated in vacuo to give a solid. Recrystallization from Et2O/hexanes gave 10.85 g (52%, 2 crops) of the compound as white crystals: 1H NMR (300 MHz, CDCl3) δ 1.04 (s, 9H), 2.00 (br s, 1H), 2.89 (t, J=6 Hz, 2H), 3.85 (s, 3H), 3.91 (t, J=6 Hz, 2H), 6.88 (d, J=8 Hz, 1H), 7.18 (d, J=8 Hz, 1H), 7.26-7.36 (m, 5H), 7.50 (br s, 1H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([OH:9])=O)[CH:2]=1.CCN=C=NCCCN(C)C.C(N(CC)CC)C.[NH2:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][C:38](=[O:47])[N:39]([CH3:46])[C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[CH:33][CH:32]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:28][CH2:29][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:37][C:38](=[O:47])[N:39]([CH3:46])[C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)=[CH:35][CH:36]=2)=[O:9])[CH:2]=1
Reactant: O=C(O)c1cccnc1
Reactant: CN(C(=O)Oc1ccc(CCN)cc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)Oc1ccc(CCNC(=O)c2cccnc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 15 %

Procedure:
A solution of 3-pyridinecarboxylic acid (0.3 mmol), EDAC (0.36 mmol) and triethylamine (0.36 mmol) in CH2Cl2 (10 mL) was added N-hydroxybenzoetriazole and N-methyl-N-phenyl-carbamic acid 4-(2-amino-ethyl)phenyl ester as its TFA salt (0.3 mmol). The mixture was stir-stirred 16 h at rt and purified by preparative HPLC (Gilson) to give the title compound in 15% yield as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH:5]=1.I[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[Cs+].[Cs+].S([O-])([O-])(=O)=O.[Mg+2].CC(=NO)C(C)=NO>C(#N)C.[Cu-]=O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([O:10][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:7]=[C:6]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][CH:13]=2)[CH:5]=1
Reactant: Ic1ccccc1
Reactant: COC(=O)c1cc(O)cc(Oc2ccc(Br)cc2)c1
Agent: O=[Cu-]
Agent: CC(=NO)C(C)=NO
Agent: O=C([O-])[O-]
Solvent: CC#N
Product: COC(=O)c1cc(Oc2ccccc2)cc(Oc2ccc(Br)cc2)c1
Yield: 23.5 %

Procedure:
To a solution of 3-(4-bromophenoxy)-5-hydroxybenzoic acid methyl ester (200 mg, 0.619 mmol) in 10 mL of acetonitrile was added iodobenzene (189 mg, 0.928 mmol), cesium carbonate (403 mg, 1.24 mmol), copper(I)oxide (5 mg, 0.03 mmol), magnesium sulfate (185 mg), and dimethylglyoxime (14 mg, 0.124 mmol). The mixture was stirred at reflux for 16 h. Then the mixture was filtered through a pad of Celite and the filtrate was evaporated. The residue was chromatographied on silica gel using an ethyl acetate-hexane gradient afforded 58 mg (23%) of 3-(4-bromophenoxy)-5-phenoxybenzoic acid methyl ester: 1H NMR (300 MHz, DMSO-d6) δ 3.79 (s, 3H), 7.00-7.02 (m, 1H), 7.08-7.18 (m, 6H), 7.20-7.26 (m, 1H), 7.43-7.46 (m, 2H), 7.61 (d, 2H, J=9 Hz).
Reaction SMILES: [F:1][C:2]1([F:28])[CH2:7][CH2:6][CH:5]([CH2:8][C:9]2[N:13]3[CH:14]=[C:15]([O:22][CH3:23])[C:16]([C:18]([O:20]C)=[O:19])=[CH:17][C:12]3=[N:11][C:10]=2[C:24]([F:27])([F:26])[F:25])[CH2:4][CH2:3]1.C1COCC1.[OH-].[Na+]>O>[F:28][C:2]1([F:1])[CH2:3][CH2:4][CH:5]([CH2:8][C:9]2[N:13]3[CH:14]=[C:15]([O:22][CH3:23])[C:16]([C:18]([OH:20])=[O:19])=[CH:17][C:12]3=[N:11][C:10]=2[C:24]([F:25])([F:26])[F:27])[CH2:6][CH2:7]1
Reactant: COC(=O)c1cc2nc(C(F)(F)F)c(CC3CCC(F)(F)CC3)n2cc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cn2c(CC3CCC(F)(F)CC3)c(C(F)(F)F)nc2cc1C(=O)O
Temperature: 25 °C
Yield: 98.4 %

Procedure:
Methyl 3-(4,4-difluorocyclohexylmethyl)-6-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridine-7-carboxylate (23 mg, 0.057 mmol) obtained in step 4 was suspended in a mixed solvent of THF (1.0 mL) and water (1.0 mL), and the suspension was stirred under heat and reflux for 3 hours after adding sodium hydroxide (11 mg, 0.283 mmol). The reaction mixture was allowed to cool to room temperature, and the solvent was evaporated under reduced pressure. The residue was extracted with water after adding chloroform, then neutralized with 1 mol/L hydrochloric acid, the solvent was evaporated under reduced pressure. After adding a mixed solution of chloroform/methanol=4/1 to the residue, the insoluble matter was removed by filtration. The filtrate solvent was evaporated under reduced pressure to give 3-(4,4-difluorocyclohexylmethyl)-6-methoxy-2-(trifluoromethyl)imidazo[1,2-a]pyridine-7-carboxylic acid (22.0 mg, yield 99%).
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH3:10])=[CH:8][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:6][C:5]=1[CH3:15])([O-])=O.[H][H]>>[CH3:15][C:5]1[CH:6]=[C:7]([C:11]([CH3:13])([CH3:12])[CH3:14])[CH:8]=[C:9]([CH3:10])[C:4]=1[NH2:1]
Reactant: [H][H]
Reactant: Cc1cc(C(C)(C)C)cc(C)c1[N+](=O)[O-]
Product: Cc1cc(C(C)(C)C)cc(C)c1N

Procedure:
contacting the 2-nitro-1,3-dimethyl-5-tertiarybutylbenzene with hydrogen in the presence of a hydrogenation catalyst at a temperature of from about 0° C. to about 200° C. and a pressure of from about 0 psig to about 2000 psig to form 2,6-dimethyl-4-tertiary-butylaniline;