Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C@H:4]([CH3:19])[CH2:5][N:6]1[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:19][C@H:4]([CH2:5][N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[C:3]([O:2][CH3:1])=[O:20]
Reactant: COC(=O)[C@H](C)CN1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)[C@H](C)CN1CCNCC1
Reaction time: 0.17 h
Yield: 91.8 %

Procedure:
A solution of 565 (523 mg, 1.83 mmol) and TFA (5 ml) in DCM (15 ml) was stirred at rt for 3.5 h. The reaction mixture was concentrated (azeotropes with DCM), diluted with water, stirred for 10 min, and the pH was adjusted to around 9 with a saturated aqueous solution of sodium bicarbonate and 1N NaOH. The alkaline solution was extracted with DCM; the extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under high vacuum to afford the desired product 566 (314 mg, 1.68 mmol, 92% yield) as a yellow oil that was used crude in the next step without any further purification. MS (m/z): 187.2 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[S:24][CH:25]=[N:26][N:27]=4)(=[O:21])=[O:20])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.[N:30]1[CH:35]=[CH:34][CH:33]=[C:32](B(O)O)[CH:31]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>[F:8][C:7]1[C:2]([C:32]2[CH:31]=[N:30][CH:35]=[CH:34][CH:33]=2)=[CH:3][C:4]([O:28][CH3:29])=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][C:15]([S:19]([NH:22][C:23]4[S:24][CH:25]=[N:26][N:27]=4)(=[O:20])=[O:21])=[CH:16][CH:17]=3)[CH:12]=[CH:11][N:10]=2)[CH:6]=1
Reactant: COc1cc(Cl)c(F)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Reactant: OB(O)c1cccnc1
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: COc1cc(-c2cccnc2)c(F)cc1-c1nccc2cc(S(=O)(=O)Nc3nncs3)ccc12
Temperature: 120 °C
Yield: 60.6 %

Procedure:
A vial was charged with 1-(4-chloro-5-fluoro-2-methoxyphenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (INTERMEDIATE HHHHH; 74.29 mg, 0.165 mmol) pyridin-3-ylboronic acid (24.30 mg, 0.198 mmol), dicyclohexyl(2′,6′-dimethoxy-[1,1′-biphenyl]-2-yl)phosphine (1.691 mg, 4.12 μmol), chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2-aminoethylphenyl)]palladium(ii) dichloromethane (6.24 mg, 8.24 μmol) and potassium phosphate (105 mg, 0.494 mmol). The vial was flushed with Ar (g), then 1,4-dioxane (749 μl) and water (74.9 μl) were added. The vial was sealed and heated in a Biotage Initiator microwave reactor for 1 h at 120° C. The mixture was extracted with EtOAc (4×). The combined organic extracts were concentrated. The residue was purified by chromatography on silica gel (12-g Redi-Sep Gold column, 0-10% MeOH/DCM) to give 1-(5-fluoro-2-methoxy-4-(pyridin-3-yl)phenyl)-N-(1,3,4-thiadiazol-2-yl)isoquinoline-6-sulfonamide (49.13 mg, 0.100 mmol, 60.4% yield) as a light-yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=14.53 (br. s., 1H), 8.93 (s, 1H), 8.78 (s, 1H), 8.71 (d, J=5.7 Hz, 1H), 8.67 (dd, J=1.3, 4.7 Hz, 1H), 8.57 (d, J=1.7 Hz, 1H), 8.14 (d, J=5.8 Hz, 2H), 7.96-7.87 (m, 1H), 7.86-7.78 (m, 1H), 7.63-7.54 (m, 1H), 7.45-7.36 (m, 2H), 3.73 (s, 3H). m/z (ESI) 494.1 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH:6]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][C:8]2=[O:15].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35]>C1COCC1>[C:34]([CH2:33][CH:7]1[CH:6]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[C:3]=2[O:2][CH3:1])[C:8]1=[O:15])([O:36][CH2:37][CH3:38])=[O:35]
Reactant: COc1ccc2c(c1OC)CC(c1ccccc1)CC2=O
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1C(=O)c2ccc(OC)c(OC)c2CC1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 82.8 %

Procedure:
To a solution of 5,6-dimethoxy-3-phenyl-1,2,3,4-tetrahydronaphthalen-1-one (5 g, 17.7 mmol, 1.0 equivalents), the product of Example 1, in 150 mL of dry THF cooled to -78° C., was added 19.5 mL of lithium bis(trimethylsilyl)amide (1M solution in THF, 19.5 mmol, 1.1 equivalent). The resultant solution was stirred at -78° C. for 1 h and then ethyl bromoacetate (2.2 mL, 19.5 mmol, 1.1 equivalent) was added in one portion. The reaction solution was then allowed to warm to ambient temperature and was stirred for 3 h. The reaction was quenched by the addition of 50 mL of saturated ammonium chloride solution. The resultant light yellow colored THF layer was separated and evaporated to an oil. The oil was taken up into 200 mL of methylene chloride and the methylene chloride solution was washed with 2×50 mL of water and 50 mL of brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluted with ethyl acetate/hexane (1:6) to give 5.4 g (83% yield) of the title compound as a white solid; 1H NMR (CDCl3) δ: 1.2 (t, 3H, J=7.5 Hz), 2.45 (m, 2H), 3.03 (m, 1H), 3.30 (m, 2H), 3.43 (m, 1H), 3.78 (s, 3H), 3.93 (s, 3H), 4.07 (m, 2H), 6.92 (d, 1H, J=9.0 Hz), 7.32 (m, 5H), 7.89 (d, 1H, J=9.0 Hz).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>CN(C=O)C.O>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:23](=[O:25])[C:22]2[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:21]=2[Cl:20])[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
HOBt (213 mg, 1.5 mmol) and DIEA (508 mg, 3.9 mmol) were added to a stirred solution of 2,5-dichlorobenzoicacid (250 mg, 1.3 mmol) in DMF (2.5 mL). The reaction mixture was then cooled to 10° C. and EDCI.HCl (302 mg, 1.5 mmol) followed by piperazine-1-carboxylic acid tert-butyl ester (260 mg, 1.3 mmol) were added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with water and the product extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure to afford the crude residue which was purified by column chromatography using silica gel 60-120 mesh (30% ethyl acetate in hexane) to afford 396 mg (84%) of 4-(2,5-dichloro-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester, LCMS: 360.08 (M+1)+, 98.2%.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([NH2:16])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:17]([C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:34])[CH2:27][CH:28]([CH3:33])[CH2:29][C:30](O)=[O:31])[CH:22]=[CH:23][CH:24]=1)#[N:18].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.C(=O)([O-])O.[Na+]>CN(C=O)C.C(OCC)(=O)C>[C:17]([C:19]1[CH:20]=[C:21]([NH:25][C:26](=[O:34])[CH2:27][CH:28]([CH3:33])[CH2:29][C:30]([NH:16][C:12]2[CH:13]=[CH:14][C:15]3[N:3]([CH2:1][CH3:2])[C:4]4[C:9]([C:10]=3[CH:11]=2)=[CH:8][CH:7]=[CH:6][CH:5]=4)=[O:31])[CH:22]=[CH:23][CH:24]=1)#[N:18]
Reactant: CC(CC(=O)O)CC(=O)Nc1cccc(C#N)c1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c2ccccc2c2cc(NC(=O)CC(C)CC(=O)Nc3cccc(C#N)c3)ccc21
Yield: 64.5 %

Procedure:
A solution of 9-ethyl-9H-carbazol-3-amine (210 mg, 1.00 mmol), the compound obtained in Step 1 (246 mg, 1 mmol), HOBt (306 mg, 2.00 mmol) and WSC (383 mg, 2.00 mmol) in DMF (5 mL) was stirred at room temperature for 14 hr. The reaction mixture was poured into a mixed solution of aqueous sodium hydrogen carbonate solution and ethyl acetate, and the organic layer was separated. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 66 to 80% ethyl acetate/hexane) to give the title compound (283 mg, 0.645 mmol, 64.5%) as a white powder.
Reaction SMILES: C([Sn](Cl)(Cl)CCCC)CCC.[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2[C:21]3[N:22]([N:29]=[C:30]([NH2:32])[N:31]=3)[CH:23]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[CH:25]=2)[CH:16]=[CH:17][C:18]=1[F:19].[CH3:33][C:34]1[N:39]=[CH:38][N:37]=[C:36]([N:40]2[CH2:45][CH2:44][C:43](=O)[CH2:42][CH2:41]2)[CH:35]=1.C1([SiH3])C=CC=CC=1>C1COCC1>[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2[C:21]3[N:22]([N:29]=[C:30]([NH:32][CH:43]4[CH2:44][CH2:45][N:40]([C:36]5[CH:35]=[C:34]([CH3:33])[N:39]=[CH:38][N:37]=5)[CH2:41][CH2:42]4)[N:31]=3)[CH:23]=[C:24]([CH:26]3[CH2:28][CH2:27]3)[CH:25]=2)[CH:16]=[CH:17][C:18]=1[F:19]
Reactant: Nc1nc2c(-c3ccc(F)c(Cl)c3)cc(C3CC3)cn2n1
Reactant: Cc1cc(N2CCC(=O)CC2)ncn1
Agent: CCCC[Sn](Cl)(Cl)CCCC
Agent: [SiH3]c1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(N2CCC(Nc3nc4c(-c5ccc(F)c(Cl)c5)cc(C5CC5)cn4n3)CC2)ncn1
Temperature: 100 °C

Procedure:
To a solution of dibutyl tin chloride (10 mg, 0.03 mmol) and 8-(3-chloro-4-fluoro-phenyl)-6-cyclopropyl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (prepared in analogy to example 48a-e, 100 mg, 0.33 mmol) in dry THF (1.5 mL) were added 1-(6-methyl-pyrimidin-4-yl)-piperidin-4-one (example 93b, 63 mg, 0.33 mmol) and phenyl silane (0.016 mL, 0.4 mmol) under an argon atmosphere and heated to 100° C. in the microwave for 40 minutes. The reaction mixture was cooled to room temperature, the solvent was evaporated and the residue was purified by prep-HPLC (acetonitrile/H2O). The title compound was obtained as a white solid (20 mg, 13%). MS ESI (m/z): 477.8 [(M+H)+].
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3](=[O:19])[NH:4][C@H:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([O:8]C(C)(C)C)=[O:7]>C(Cl)Cl>[CH3:1][N:2]([CH3:20])[C:3](=[O:19])[NH:4][C@H:5]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:6]([OH:8])=[O:7]
Reactant: CN(C)C(=O)N[C@@H](C(=O)OC(C)(C)C)c1ccccc1
Solvent: ClCCl
Product: CN(C)C(=O)N[C@@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of ((R)-tert-butyl 2-(3,3-dimethylureido)-2-phenylacetate (0.86 g, 3.10 mmol) in CH2Cl2 (250 mL) was added TPA (15 mL) dropwise and the resulting solution was stirred at rt for 3 hours. The desired compound was then precipitated out of solution with a mixture of EtOAC:Hexanes (5:20), filtered off and dried under reduced pressure. (R)-2-(3,3-dimethylureido)-2-phenylacetic acid was isolated as a white solid (0.59 g, 86%) and used without further purification. 1H NMR (500 MHz, DMSO-d6) δ ppm 2.82 (s, 6H) 5.22 (d, J=7.32 Hz, 1H) 6.58 (d, J=7.32 Hz, 1H) 7.28 (t, J=7.17 Hz, 1H) 7.33 (t, J=7.32 Hz, 2H) 7.38-7.43 (m, 2H) 12.65 (s, 1H). LCMS: Anal. Calcd. for C11H14N2O3: 222.24; found: 223.21 (MSH)+. HPLC XTERRA® C-18 3.0×50 mm, 0 to 100% B over 2 minutes, 1 minute hold time, A=90% water, 10% methanol, 0.2% H3PO4, B=10% water, 90% methanol, 0.2% H3PO4, RT=0.75 min, 93% homogeneity index.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[C:11]1(=[O:16])[CH2:15][CH2:14][CH:13]=[CH:12]1.C(N(CC)CC)C>O1CCOCC1.O.[B-](F)(F)(F)F.C1C2C=CC1C=C2.C1C2C=CC1C=C2.[Rh].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:14][CH2:15][C:11](=[O:16])[CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=C1C=CCC1
Agent: [Rh]
Agent: C1=CC2C=CC1C2
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: O=C1CC[C@H](c2cccc(Cl)c2)C1
Reaction time: 2 h
Yield: 89.2 %

Procedure:
Bis(norbornadiene)rhodium(I)tetrafluoroborate (0.20 g, 0.53 mmol) and (S)-(−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (0.30 g, 0.48 mmol) are dissolved 1,4-dioxane (18 mL). The solution is degassed with nitrogen for 2 hours. 3-Chlorophenylboronic acid (4.95 g, 31.67 mmol) is dissolved in dioxane (24 mL) and water (6 mL). The mixture is degassed for another 2 hours. The two solutions are combined and stirred for two hours under a nitrogen stream. 2-Cyclopentenone (2.0 g, 24.36 mmol) and triethylamine (2.1 mL, 15.07 mmol) are added to the reaction sequentially, via syringe. This is stirred until completion under a stream of nitrogen. The reaction is filtered through a pad of diatomaceous earth and concentrated in vacuo. The residue is purified via silica gel flash chromatography, eluting with 20% ethyl acetate in hexane to give the title compound (4.23 g, 89.2%) as a clear, yellow oil. 1H NMR (400 MHz, CDCl3) δ 1.9 (1H, M), 2.25 (2H, M), 2.45 (2H, M), 2.65 (1H, M), 3.35 (1H, M), 7.1 (1H, D), 7.25 (3H, M).
Reaction SMILES: COC1C=C(N2CCC(=O)CC2)C=CC=1[N+]([O-])=O.Cl.F[C@H]1CCNC1.[F:26][C:27]1(F)[CH2:32]C[CH2:30][N:29]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[C:41]([O:48][CH3:49])[CH:40]=3)[CH2:35][CH2:34]2)[CH2:28]1>>[F:26][C@H:27]1[CH2:32][CH2:30][N:29]([CH:33]2[CH2:38][CH2:37][N:36]([C:39]3[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[C:41]([O:48][CH3:49])[CH:40]=3)[CH2:35][CH2:34]2)[CH2:28]1
Reactant: COc1cc(N2CCC(N3CCCC(F)(F)C3)CC2)ccc1[N+](=O)[O-]
Agent: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Agent: Cl
Agent: F[C@H]1CCNC1
Product: COc1cc(N2CCC(N3CC[C@H](F)C3)CC2)ccc1[N+](=O)[O-]

Procedure:
1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinone (1.0 g, 4.0 mmol) and (S)-(+)-3-fluoropyrrolidine hydrochloride were subjected to reductive amination analogous to the procedure for 3,3-difluoro-1′-[3-(methyloxy)-4-nitrophenyl]-1,4′-bipiperidine (Intermediate B41) to give 4-[(3S)-3-fluoro-1-pyrrolidinyl]-1-[3-(methyloxy)-4-nitrophenyl]piperidine in quantitative yield. 1H NMR (400 MHz, d6-DMSO) δ 7.84 (d, J=9.6 Hz, 1H), 6.56 (dd, J=9.4 and 2.2 Hz, 1H), 6.47 (d, J=2.0 Hz, 1H), 5.24-5.07 (m, 1H), 3.91-3.87 (m, 5H), 3.05-2.99 (m, 2H), 2.88-2.77 (m, 2H), 2.70-2.58 (m, 1H), 2.38-2.26 (m, 2H), 2.14-1.98 (m,1H), 1.88-1.75 (m, 3H), 1.46-1.36 (m, 2H).
Reaction SMILES: [C:1]1([CH:7]2[CH:12]([C:13]([OH:15])=[O:14])[O:11][C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[CH2:33]([N:35]([CH2:38][CH2:39][O:40][CH:41](O)[CH3:42])[CH2:36][CH3:37])[CH3:34]>C(Cl)(Cl)Cl.O>[C:1]1([CH:7]2[CH:12]([C:13]([O:15][CH2:42][CH2:41][O:40][CH2:39][CH2:38][N:35]([CH2:36][CH3:37])[CH2:33][CH3:34])=[O:14])[O:11][C:10]3[CH:16]=[CH:17][CH:18]=[CH:19][C:9]=3[O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCN(CC)CCOC(C)O
Reactant: O=C(O)C1Oc2ccccc2OC1c1ccccc1
Agent: CCOC(=O)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN(CC)CCOCCOC(=O)C1Oc2ccccc2OC1c1ccccc1
Reaction time: 0.25 h

Procedure:
To a suspension of 12.8 g of (3-phenyl-1,4-benzodioxan-2-yl)-carboxylic acid in 100 cc of CHCl3, 5.1 g of triethylamine are added. The mixture is chilled and 5.4 g of ethyl chlorocarbonate are added dropwise. After stirring for 15 minutes, 8.8 g of N,N-diethylaminoethoxyethanol are added. After 2 hours the mixture is treated with water, the organic phase is separated and dried over Na2SO4. The solvent is removed under vacuum and the residue is transformed in the corresponding citrate (m.p. 73°-74°, from isopropanol).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[Cl:38])[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)(C)(C)C.Cl>C(O)C>[Cl:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][NH:30][C:26]1[N:25]=[C:24]([C:21]2[N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][CH:11]4[CH2:10][CH2:9][CH:8]([NH2:7])[CH2:13][CH2:12]4)[C:16]3=[N:23][CH:22]=2)[CH:29]=[CH:28][N:27]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4ccnc(NCc5ccccc5Cl)n4)cnc23)CC1
Agent: Cl
Solvent: CCO
Product: NC1CCC(Nc2nccn3c(-c4ccnc(NCc5ccccc5Cl)n4)cnc23)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of crude (4-{3-[2-(2-chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester (60 mg, 0.11 mmol) in ethanol (5 mL) was added concentrated hydrochloric acid (5 mL) slowly. The reaction mixture was stirred at room temperature for 15 hours. The solvent was removed under reduced pressure and then the solid was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford N-{3-[2-(2-chloro-benzylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-yl}-cyclohexane-1,4-diamine; hydrochloride. (Yield 23 mg, 24.2%).
Reaction SMILES: [CH2:1]([N:5]([CH2:16][CH2:17][OH:18])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4].CC(C)=[O:21].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[CH2:1]([N:5]([CH2:16][C:17]([OH:21])=[O:18])[S:6]([C:9]1[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][CH:14]=1)(=[O:8])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)=O
Reactant: CCCCN(CCO)S(=O)(=O)c1ccc(C)cc1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: CCCCN(CC(=O)O)S(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Dissolve N-butyl-N-(2-hydroxy-ethyl)-4-methyl-benzenesulfonamide (10 mmol) in acetone (50 mL) and cool to 0° C. Add a slight excess of Jones reagent dropwise and allow the reaction to stir for 4 hours at 0° C. Add excess isopropanol and filter the reaction through a plug of diatomaceous earth. Rinse the plug with acetone (2×50 mL) and methylene chloride (3×50 mL). Combine the filtrates and concentrate under vacuum. Purify the residue by flash chromatography (silica gel, methanol/methylene chloride) to provide [butyl-(toluene-4-sulfonyl)-amino]-acetic acid.
Reaction SMILES: [C:1]1([C:7]2[N:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:10]3=[C:9]([C:17]([OH:19])=O)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:20][C@@H:21]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:22]([NH:24][CH3:25])=[O:23].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[CH3:27][C:26]([CH3:29])([CH3:28])[C@H:21]([NH:20][C:17]([C:9]1[N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:10]=12)=[O:19])[C:22]([NH:24][CH3:25])=[O:23]
Reactant: CNC(=O)[C@@H](N)C(C)(C)C
Reactant: O=C(O)c1nc(-c2ccccc2)n2c1CCCCC2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](NC(=O)c1nc(-c2ccccc2)n2c1CCCCC2)C(C)(C)C
Reaction time: 3 h
Yield: 89.2 %

Procedure:
3-phenyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine-1-carboxylic acid (Intermediate B1) (100 mg, 0.390 mmol) was dissolved in DCM (10 mL) in a 40 mL screw-cap vial. (S)-2-amino-N,3,3-trimethylbutanamide (59.1 mg, 0.410 mmol) and DIEA (204 μl, 1.171 mmol) were added, followed by TBTU (132 mg, 0.410 mmol), and the reaction was stirred for 3 hours. LCMS showed complete consumption of starting material. The solution was extracted with saturated aqueous sodium bicarbonate (10 mL) and the organic layer was removed. The aqueous layer was extracted with DCM (10 ml). The combined organic extracts were dried with anhydrous sodium sulfate, filtered and evaporated under reduced pressure to a brown oil which was purified by flash chromatography (silica gel, 25% Hex/EtOAc to 100% EtOAc). Fractions were combined to yield the desired (S)—N-(3,3-dimethyl-1-(methylamino)-1-oxobutan-2-yl)-3-phenyl-6,7,8,9-tetrahydro-5H-imidazo[1,5-a]azepine-1-carboxamide as a white solid (133 mg, 89%). LCMS (+ESI) m/z 383.2 [MH]+. 1H-NMR (CDCl3) δ 7.90 (d, 1H), 7.45-7.55 (m, 5H), 5.90 (m, 1H), 4.30 (d, 1H), 4.05 (m, 2H), 3.40 (m, 2H), 2.80 (d, 3H), 1.90 (m, 2H), 1.80 (m, 2H), 1.65 (m, 2H), 1.10 (s, 9H).
Reaction SMILES: [C:1]([C:14]1[CH:25]=[CH:24][C:17]([CH:18]=[CH:19][C:20]([O:22]C)=[O:21])=[CH:16][CH:15]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].O.[OH-].[Li+].Cl>O1CCCC1.O>[C:1]([C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[CH:19][C:20]([OH:22])=[O:21])=[CH:24][CH:25]=1)#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC#Cc1ccc(C=CC(=O)OC)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCCCCCCCC#Cc1ccc(C=CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 4-(1-tridecynyl)cinnamate (680 mg, 2 mmole) in tetrahydrofuran (25 ml) was added a solution of lithium hydroxide monohydrate (0.84 g) in water (25 ml) and the mixture was stirred overnight at room temperature. The cloudy mixture was acidified with dilute hydrochloric acid and then extracted with ether. The ethereal extracts were washed with brine, dried (MgSO4) and evaporated to a white crystalline solid. Yield 0.650 g (100%). Recrystallisation from methanol afforded material of mp 156°-157° C., υmax mull, 2650 (broad), 1710, 1685, 1630 cm-1, δ(DMSO), 0.85 (3H, distorted t, terminal CH3), 1.25 (18H, m, alkylene chain), ca 2.43 (2H, m, C≡C--CH2), 6.50 (1H, d, J 15.8 Hz, =CHCO2), 7.51 (4H, ABq, J 8.4 Hz, Δν22.4 Hz, arom), 7.57 (1 H, d, J 15.8 Hz, ArCH=), 12.5 (1H, broad, exchangeable, CO2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C[Si]([C:14]#[CH:15])(C)C.[OH-].[K+]>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.[Cu]I.CN(C=O)C.CCN(CC)CC>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]#[CH:15])=[CH:3][CH:4]=1
Reactant: C#C[Si](C)(C)C
Reactant: COc1ccc(Br)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C#Cc1ccc(OC)cc1

Procedure:
Using Method D above, 4-bromoanisole (Aldrich) was coupled with trimethylsilylacetylene (Aldrich) using (Ph3P)2PdCl2 and CuI as catalyst in DMF and Et3N as solvent and was heated at reflux for 1 day. The resulting trimethylsilyl derivative was hydrolized with aqueous potassium hydroxide to give 4-methoxyphenyl acetylene.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][OH:13].N1C=CN=C1.[CH:19]([Si:22](Cl)([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])([CH3:21])[CH3:20]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:11])[F:9])=[CH:4][C:3]=1[CH2:12][O:13][Si:22]([CH:26]([CH3:28])[CH3:27])([CH:23]([CH3:25])[CH3:24])[CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: OCc1cc(C(F)(F)F)ccc1Br
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)[Si](OCc1cc(C(F)(F)F)ccc1Br)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 102.7 %

Procedure:
To a solution of (2-bromo-5-(trifluoromethyl)phenyl)methanol (10 g; 39 mmol) in N,N-dimethylformamide (100 mL) was added imidazole (6.82 g; 100.1 mmol) and triisopropylsilyl chloride (9.6 mL; 55.2 mmol) under N2. The reaction was stirred at room temperature for 48 hours. The reaction was diluted with ethyl acetate and washed with water (4×) and brine. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by 80 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-10% ethyl acetate in heptane) to yield the title compound (16.47 g, 100%) as a colorless oil. MS (GC) Calc: 410.0, Found: 391 (M−F). 1H NMR (400 MHz, CDCl3) δ ppm 7.94 (s, 1H), 7.62 (d, J=8.30 Hz, 1H), 7.39 (d, J=8.30 Hz, 1H), 4.84 (s, 2H), 1.25 (m, 3H), 1.12(d, 18H).