Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH3:6].C([Li])CCC.[S:22](Cl)([Cl:25])(=[O:24])=[O:23]>C1COCC1>[C:10]([O:9][C:7]([N:5]([CH3:6])[C:4]1[CH:14]=[CH:15][CH:16]=[C:2]([S:22]([Cl:25])(=[O:24])=[O:23])[CH:3]=1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=S(=O)(Cl)Cl
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(Br)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cccc(S(=O)(=O)Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
3-Bromo-N-tert-butoxycarbonyl-N-methylaniline (0.358g, 1.2 mmol) was dissolved in freshly distilled THF (5 ml) under a N2 atmosphere. The solution was chilled to −78° C. and n-butyl lithium (0.750 ml, 2.0 M solution in cyclohexane, 1.5 mmol) was added. After 15 minutes, sulfuryl chloride (0.121 ml, 1.5 mmol) was added and the reaction was allowed to warm to room temperature and stirring was continued overnight. THF was removed by evaporation and the resulting residue was diluted in EtOAc. Organic phase was washed with H20 and brine before being dried with MgSO4. The solvent was removed in vacuo. Purification by flash chromatography (1:19/EtOAc/Hex gradient to 1:9 and then to 1:4). Recovered 0.089 g (23%) of the product as a colorless oil. Rf=0.14 (1:9 EtOAc/Hex). 1H NMR (CDCl3) 7.96 (1H,s), 7.80 (1H,d), 7.68 (1H,d), 7.57 (1H,t), 3.33 (3H,s), 1.50 (9H,s).
Reaction SMILES: [SH:1][C:2]1[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[NH:13][S:14]([CH3:17])(=[O:16])=[O:15].[N:18]1([CH2:24][CH2:25][Cl:26])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)C>[ClH:26].[N:18]1([CH2:24][CH2:25][S:1][C:2]2[CH:7]=[C:6]([NH:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:5]=[CH:4][C:3]=2[NH:13][S:14]([CH3:17])(=[O:16])=[O:15])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CS(=O)(=O)Nc1ccc(NS(C)(=O)=O)c(S)c1
Reactant: ClCCN1CCCCC1
Solvent: CCO
Product: CS(=O)(=O)Nc1ccc(NS(C)(=O)=O)c(SCCN2CCCCC2)c1
Product: Cl
Temperature: 25 °C

Procedure:
To a solution containing 8.9 g (0.030 mole) of 2-mercapto-N,N'-p-phenylenebismethanesulfonamide dissolved in 500 ml of ethanol at 60° C. was added 4.7 g (0.032 mole) of 2-(1-piperidinyl)ethyl chloride with stirring. The reaction flask was then removed from the heat, and the mixture was allowed to cool to room temperature. At the end of a period of 15 hours the precipitated white solid product (8.9 g) was collected on a filter and dried. Recrystallization from a mixture of nitromethane and dimethylformamide gave the title compound as white crystals, m.p. 218°-218.5° C. dec.
Reaction SMILES: [SH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[C:13]([O-])([O-])=O.[K+].[K+].IC.CN([CH:24]=[O:25])C>>[CH3:13][S:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:25][CH3:24])=[O:12])=[CH:4][CH:3]=1
Reactant: CN(C)C=O
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CCc1ccc(S)cc1
Agent: [K+]
Solvent: CI
Product: COC(=O)CCc1ccc(SC)cc1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
3-(4-Mercaptophenyl)propanoic acid (5 g), K2CO3 (11.4 g) and DMF (30 ml) were combined, and iodomethane (5.12 ml) was added dropwise to the mixture at 0° C. under N2 atmosphere. The reaction mixture was stirred at r.t. for 13 hours, and poured into ice-water. The mixture was extracted with AcOEt. The organic layer was washed with water (twice) and brine, dried over anhydrous MgSO4, and concentrated in vacuo to give methyl 3-[4-(methylthio)phenyl]propanoate (4.19 g) as pale yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]([C:6](/[N:8]=[C:9]2\[NH:10][C:11]3[CH:29]=[CH:28][C:27]([CH2:30]O)=[CH:26][C:12]=3[N:13]\2[C@H:14]2[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]2)=[O:7])=[CH:4][CH:3]=1.S(Cl)(Cl)=O.Cl.[F:39][C:40]1([F:46])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(Cl)Cl>[F:39][C:40]1([F:46])[CH2:45][CH2:44][N:43]([CH2:30][C:27]2[CH:28]=[CH:29][C:11]3[NH:10]/[C:9](=[N:8]\[C:6](=[O:7])[C:5]4[CH:32]=[CH:33][C:2]([F:1])=[CH:3][CH:4]=4)/[N:13]([C@H:14]4[CH2:19][CH2:18][C@@H:17]([C:20](=[O:25])[NH:21][CH:22]([CH3:24])[CH3:23])[CH2:16][CH2:15]4)[C:12]=3[CH:26]=2)[CH2:42][CH2:41]1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CO)cc32)CC1
Reactant: FC1(F)CCNCC1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(C)NC(=O)[C@H]1CC[C@@H](n2/c(=N/C(=O)c3ccc(F)cc3)[nH]c3ccc(CN4CCC(F)(F)CC4)cc32)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
To a 0° C. cooled solution of (E)-4-fluoro-N-(6-(hydroxymethyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)benzamide (100 mg, 0.221 mmol) in DCM (2.5 mL) was added thionyl chloride (0.081 mL, 1.105 mmol) dropwise, and the reaction was stirred at 0° C. for 30 minutes. The solvent was removed, and the residue was resuspended in 2 mL DMSO, cooled to 0° C., and 4,4-difluoropiperidine hydrochloride (348 mg, 2.210 mmol) and TEA (0.308 mL, 2.210 mmol) were added. The reaction was stirred for 30 minutes at 0° C. and then at RT for 16 hours. The reaction was concentrated, and the residue was purified by reverse-phase preparative HPLC, using 0.1% TFA in AC/water (gradient 15% to 90%). The product fractions were combined, neutralized with saturated aqueous NaHCO3, and extracted with EtOAc (×2). The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated to provide (E)-N-(6-((4,4-difluoropiperidin-1-yl)methyl)-1-(cis-4-(isopropylcarbamoyl)cyclohexyl)-1H-benzo[d]imidazol-2(3H)-ylidene)-4-fluorobenzamide as a white powder (71 mg, 57.8% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.11 (s, 6H), 1.54-1.83 (m, 5H), 1.94-2.18 (m, 7H), 2.53 (br. s., 3H), 2.67-2.86 (m, 2H), 3.64 (s, 2H), 3.94-4.09 (m, 1H), 4.91 (br. s., 1H), 7.13 (d, J=8.0 Hz, 1H), 7.25 (dd, J=8.8 Hz, 8.8 Hz, 2H), 7.49 (d, J=8.1 Hz, 1H), 7.60-7.82 (m, 2H), 8.20-8.43 (m, 2H), 12.75 (br. s., 1H). MS, m/z (C30H36F3N5O2): calcd, 555.3. found, 555.9 [M+H].
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13](=O)/[CH:14]=[C:15](\[O-])/[C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].Cl.Cl.[NH2:26][NH2:27]>C(O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]2[CH:14]=[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:27][N:26]=2)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C([O-])=C/C(=O)c1cn(Cc2ccccc2)cn1
Reactant: NN
Agent: Cl
Agent: [Li+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cn(Cc3ccccc3)cn2)n[nH]1
Temperature: 25 °C

Procedure:
Into a suspension containing lithium (Z)-4-(1-benzyl-1H-imidazol-4-yl)-1-ethoxy-1,4-dioxobut-2-en-2-olate (3.0 g, 9.80 mmol) and ethanol (20 ml), hydrazine dihydrochloride (1.337 g, 12.74 mmol) was added and the resulting mixture was refluxed for 3 h with stirring. The mixture was allowed to cool to RT and the mixture was evaporated. The residue was suspended in ethanol, stirred and filtered. The precipitate was washed with cold ethanol and dried with vacuum at 40° C. 1H-NMR (400 MHz; d6-DMSO): 6, 1.31 (t, 3H), 4.33 (q, 2H), 5.82 (s, 2H), 7.18-7.37 (m, 6H), 8.19 (s, 1H), 9.42 (s, 1H), 14.53 (bs, 1H).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH:6]=[N:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[Cl:19].[BH4-].[Na+]>C(O)C>[Cl:19][C:10]1[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]=1[CH2:8][NH:7][CH2:6][C:5]1[CH:20]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:22]=[C:3]([C:2]([F:1])([F:27])[F:28])[CH:4]=1
Reactant: FC(F)(F)c1cc(C=NCc2cc(C(F)(F)F)ccc2Cl)cc(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: FC(F)(F)c1cc(CNCc2cc(C(F)(F)F)ccc2Cl)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the compound from step A in ethanol was added 4 gm of sodium borohydride and the reaction was allowed to stir overnight at ambient temperature. The reaction was quenched with 50 mL of methanol diluted with 100 mL of water and 100 mL of methyl tert-butyl ether. The layers were separated and the organic layer dried over magnesium sulfate, filtered and concentrated to an oil. 10 gm of desired amine was collected which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) 7.84 (s, 2H), 7.77 (s, 1H), 7.66 (s, 1H), 7.48 (s, 2H), 7.47 (s, 4H) 13C NMR (400 MHz, CDCl3) 142.6, 1833, 130.4, 128.4, 127.1, 127.0, 125.6, 121.4, 52.4.
Reaction SMILES: [C:1]1([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH:54]=[CH:53][C:48]([C:49]([O:51]C)=[O:50])=[CH:47][CH:46]=3)=[CH:41][CH:40]=2)[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=3)=[CH:9][CH:8]=2)[CH:4]=[C:3]([C:23]2[CH:28]=[CH:27][C:26]([C:29]3[CH:38]=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][CH:30]=3)=[CH:25][CH:24]=2)[CH:2]=1.[OH-].[Na+].C1COCC1.O>CO>[C:1]1([C:39]2[CH:44]=[CH:43][C:42]([C:45]3[CH:46]=[CH:47][C:48]([C:49]([OH:51])=[O:50])=[CH:53][CH:54]=3)=[CH:41][CH:40]=2)[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:13]3[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:21][CH:22]=3)=[CH:11][CH:12]=2)[CH:4]=[C:3]([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:38]=[CH:37][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=3)=[CH:27][CH:28]=2)[CH:2]=1
Reactant: COC(=O)c1ccc(-c2ccc(-c3cc(-c4ccc(-c5ccc(C(=O)OC)cc5)cc4)cc(-c4ccc(-c5ccc(C(=O)OC)cc5)cc4)c3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ccc(-c3cc(-c4ccc(-c5ccc(C(=O)O)cc5)cc4)cc(-c4ccc(-c5ccc(C(=O)O)cc5)cc4)c3)cc2)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Trimethyl 4,4′,4″-(benzene-1,3,5-triyl-tris(benzene-4,1-diyl))tribenzoate (2.00 g, 2.82 mmol), 2.2 g of NaOH, THF, water, and methanol (200, 80, and 50 mL, respectively) were mixed in a 1 L round bottom flask equipped with a magnetic stirring bar, and the mixture was stirred for 2 days at room temperature. The solution was evaporated under vacuum. The residue was acidified with 3 M HCl. The white solid was collected by filtration, washed with methylene chloride and methanol and dried in vacuum overnight (1.80 g, 96%): mp 326° C.; 1H-NMR (DMSO-d6, 400 MHz) δ 13.07 (br, 3H) 8.07 (d, 6H, J=8.0 Hz), 8.06 (s, 3H), 8.05 (d, 6H, J=8.0 Hz), 7.91 (d, 6H, J=7.6 Hz), 7.89 (d, 6H, J=7.2 Hz); 13C-NMR (DMSO-d6, 100 MHz) δ 168.0, 144.6, 141.9, 140.7, 139.2, 130.9, 130.6, 128.8, 128.4, 127.6, 125.3; FT-IR (KBr, 4000-400 cm−1) 3448 (br), 3029 (br), 2661 (w), 2536 (w), 1925 (w), 1686 (s), 1606 (s), 1419 (m), 1276 (m), 1177 (m), 1118 (m), 1003 (m), 824 (s), 773 (s); MALDI-TOF MS (m/z) [M]+ 666.2976 (found), 666.2042 (calcd. for C45H30O6).
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:48]([OH:50])=O)[CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([O:34][CH:35]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[O:33])[C:17](=[O:25])[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[CH:12][CH:11]=1)=[O:6])[CH:2]=[CH2:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH2:83][CH2:84][CH2:85][CH2:86][CH2:87][O:88][C:89]1[CH:98]=[CH:97][CH:96]=[C:95]([OH:99])[C:90]=1[C:91]([O:93][CH3:94])=[O:92].C(N(CC)CC)C>CN(C=O)C.O>[CH2:1]([O:4][C:5]([NH:7][C@H:8]([C:48]([NH:83][CH2:84][CH2:85][CH2:86][CH2:87][O:88][C:89]1[CH:98]=[CH:97][CH:96]=[C:95]([OH:99])[C:90]=1[C:91]([O:93][CH3:94])=[O:92])=[O:50])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]([O:34][CH:35]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)=[O:33])[C:17](=[O:25])[C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])=[CH:14][CH:15]=1)=[O:6])[CH:2]=[CH2:3]
Reactant: COC(=O)c1c(O)cccc1OCCCCN
Reactant: C=CCOC(=O)N[C@@H](Cc1ccc(N(C(=O)C(=O)OC(C)(C)C)c2ccccc2C(=O)OC(c2ccccc2)c2ccccc2)cc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)N[C@@H](Cc1ccc(N(C(=O)C(=O)OC(C)(C)C)c2ccccc2C(=O)OC(c2ccccc2)c2ccccc2)cc1)C(=O)NCCCCOc1cccc(O)c1C(=O)OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
To a stirring mixture of N-[(allyloxy)carbonyl]-4-{{2-[(benzhydryloxy)carbonyl]phenyl}[tert-butoxy(oxo)acetyl]amino}-L-phenylalanine (100 mg, 0.147 mmol), TBTU (67 mg, 0.206 mmol), and HOBT (3 mg, 0.02 mmol) in DMF (2 mL) was added methyl 2-(4-aminobutoxy)-6-hydroxybenzoate, followed by addition of triethylamine (75 μL, 0.53 mmol). The resulting mixture was then stirred at ambient temperature for 2 hours, diluted with the addition of water. The crude product was extracted with ethyl acetate (2×10 mL). The combined organic layer were washed with aqueous NaHCO3 (2×25 mL) and brine (2×25 mL), dried (Na2SO4), filtered and concentrated under reduced pressure. The resulting residue was purified on an AllTech sep-pak to provide the titled compound (89 mg, 68%).
Reaction SMILES: Cl[C:2]1[C:3]([C:25]2[CH:26]=[N:27][N:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=23)=[N:4][C:5]([NH:8][C:9]2[C:14]([O:15][CH3:16])=[CH:13][C:12]([N:17]3[CH2:20][CH:19]([N:21]([CH3:23])[CH3:22])[CH2:18]3)=[C:11]([NH2:24])[CH:10]=2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(CCC)=CC(CCC)=CC=2CCC)CCCCC1.[C:68]([Zn]C#N)#[N:69]>CC(N(C)C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:24][C:11]1[C:12]([N:17]2[CH2:20][CH:19]([N:21]([CH3:22])[CH3:23])[CH2:18]2)=[CH:13][C:14]([O:15][CH3:16])=[C:9]([NH:8][C:5]2[N:4]=[C:3]([C:25]3[CH:26]=[N:27][N:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=34)[C:2]([C:68]#[N:69])=[CH:7][N:6]=2)[CH:10]=1
Reactant: N#C[Zn]C#N
Reactant: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Pd]
Agent: CCCc1cc(CCC)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(CCC)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CC(=O)N(C)C
Product: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1ncc(C#N)c(-c2cnn3ccccc23)n1
Temperature: 120 °C
Yield: 80.3 %

Procedure:
N-(5-Chloro-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)-4-(3-dimethylaminoazetidin-1-yl)-6-methoxybenzene-1,3-diamine (Intermediate 24, 297 mg, 0.64 mmol), tris(dibenzylidene-acetone)dipalladium(0) (14.62 mg, 0.02 mmol), 2-(dicyclohexylphosphino)-2′,4′,6′-tri-1-propyl-1,1′-biphenyl (‘XPhos’, 30.5 mg, 0.06 mmol), and dicyanozinc (45.0 mg, 0.38 mmol) were placed in a microwave tube under N2. Poly(methylhydrosiloxane) (12 mg, 0.06 mmol) was then added in degassed DMA (1.92 mL). The resulting mixture was then heated at 120° C. for 2 h in a microwave. The crude mixture was loaded on to a SCX column. The column was flushed with water followed by CH3OH/CH2Cl2. The desired product was eluted from the column using 7M methanolic ammonia in CH2Cl2 and pure fractions were combined and concentrated in vacuo. The residue was dissolved in CH3OH/CH2Cl2 and allowed to pass through a stratospheres SPE cartridge PL-Thiol MP SPE (available from Polymer Laboratories) under gravity. The resulting solution was concentrated in vacuo. Purification by FCC, eluting with 0-5% CH3OH in CH2Cl2 gave the title compound (139 mg, 48%) as a brown solid after trituration with diethyl ether; 1H NMR: (100° C.) 2.18 (6H, s), 3.17 (1H, t), 3.60 (2H, t), 3.69 (3H, s), 3.87 (2H, br s), 4.00 (2H, t), 6.32 (1H, s), 6.86 (1H, s), 7.11 (1H, t), 7.34-7.46 (1H, m), 8.34 (1H, d), 8.61 (1H, s), 8.72 (1H, br s), 8.76 (1H, d), 8.90 (1H, s); m/z: ES+ MH+ 456.23.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]#[C:13][CH2:14]O)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Cl:42])C(=O)C1>C(Cl)Cl>[Cl:42][CH2:14][C:13]#[C:12][C:5]1[CH:6]=[CH:7][C:8]([N+:9]([O-:11])=[O:10])=[C:3]([O:2][CH3:1])[CH:4]=1
Reactant: COc1cc(C#CCO)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc(C#CCCl)ccc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 97.5 %

Procedure:
To 3-[3-(methyloxy)-4-nitrophenyl]-2-propyn-1-ol (1.6 g, 7.72 mmol) in 75 mL of DCM was added, triphenylphosphine (2.7 g, 10.27 mmol), and NCS (1.37 g, 10.27 mmol). The mixture stirred for 1 h. 10 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound of step B (1.7 g, 7.53 mmol, 97%). 1H NMR (400 MHz, CDCl3) δ ppm 7.80 (d, J=8.42 Hz, 1H), 7.13 (d, J=1.47 Hz, 1H), 7.08 (dd, J=8.33, 1.56 Hz, 1H), 4.37 (s, 2 H), 3.95 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Cl>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:23][C:22]2[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=2[Cl:20])[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Reactant: ClCc1ccccc1Cl
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(Cc3ccccc3Cl)n2)ccc1F
Yield: 76.4 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 2-chlorobenzyl chloride were reacted to yield a crude product. Without purification, the crude product was reacted further in accordance with the procedure of Example 1(7) to yield the title compound as pale yellow needles (76.4%).
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][CH:5]([NH:8][NH2:9])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([NH:24][C:25](=[O:27])[CH3:26])=[C:19]([C:28](=O)/[CH:29]=[CH:30]/N(C)C)[CH:18]=1.O.C(OCC)(=O)C>C(O)C>[Br:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([NH:24][C:25](=[O:27])[CH3:26])=[C:19]([C:28]2[N:8]([CH:5]3[CH2:6][CH2:7][O:2][CH2:3][CH2:4]3)[N:9]=[CH:30][CH:29]=2)[CH:18]=1
Reactant: NNC1CCOCC1
Reactant: CC(=O)Nc1cc(C)c(Br)cc1C(=O)/C=C/N(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1cc(C)c(Br)cc1-c1ccnn1C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To a solution of 3.37 g of tetrahydro-2H-pyran-4-ylhydrazine hydrochloride in 120 mL of ethanol was added 3.82 g of powdery potassium carbonate, followed by stirring at room temperature for 30 minutes. To a mixture was added 6 g of N-{4-bromo-2-[(2E)-3-(dimethylamino)prop-2-enoyl]-5-methylphenyl}acetamide, followed by stirring at 80° C. for 16 hours and cooling to room temperature. The mixture was poured into a mixture of water/ethyl acetate, and the aqueous layer was separated. The organic layer was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain 3.96 g of N-{4-bromo-5-methyl-2-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]phenyl}acetamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11][NH2:12])[N:10]=[C:4]2[CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[CH:8]=[C:9]([CH2:11][NH:12][S:21]([CH3:20])(=[O:23])=[O:22])[N:10]=[C:4]2[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1cn2ccc(Br)cc2n1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCc1cn2ccc(Br)cc2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.2 %

Procedure:
To a stirred solution of C-(7-Bromo-imidazo[1,2-a]pyridin-2-yl)-methylamine (310 mg, 1.371 mmol) in CH2Cl2 (5 mL) is added triethyl amine (0.23 mL), 1.64 mmol) followed by methane sulfonyl chloride (0.112 mL, 1.371 mmol) at 0° C. then stirred at room temperature for 2 hours. The reaction mixture is diluted with water and extracted with CH2Cl2. Organic layer is dried over sodium sulphate, solvent is evaporated in vacuo and purified by column chromatography eluting in 2% methanol:CH2Cl2 to afford the title compound (130 mg). 1H-NMR (400 MHz, DMSO-d6) δ: 2.91 (s, 3H), 4.25 (d, J=6.08 Hz, 2H), 7.04-7.06 (dd, J1=1.88 Hz, J2=7.24 Hz, 1H), 7.58 (t, J=6.12 Hz, 1H), 7.81 (d, J=0.88 Hz, 1H), 7.89 (s, 1H), 8.51 (d, J=7.04 Hz, 1H). LC-MS (m/z): [M+H]=306.0.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([Cl:21])=[CH:4][N:3]=1.CO>CN(C=O)C.CCOC(C)=O.[Pt]=O>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH:16]([CH3:20])[C:17]([NH2:19])=[O:18])[C:5]([Cl:21])=[CH:4][N:3]=1
Reactant: CC(C(N)=O)c1ccccc1C#Cc1nc(Cl)ncc1Cl
Agent: O=[Pt]
Solvent: CN(C)C=O
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C(N)=O)c1ccccc1CCc1nc(Cl)ncc1Cl

Procedure:
A solution of 2-(2-((2,5-dichloropyrimidin-4-yl)ethynyl)phenyl)propanamide A29 (1.0 g, 3.1 mmol) in DMF (55 mL) and MeOH (5 mL) was stirred with platinum(II)oxide (0.21 g, 0.94 mmol) under an atmosphere of hydrogen for 120 hours at ambient temperature. The reaction mixture was diluted with EtOAc and filtered through a plug of Celite. The filter cake was washed with EtOAc and the solvents were removed in vacuo to give a crude residue that was purified by silica gel column chromatography (Combiflash Rf, 0-90% EtOAc in cyclohexane), giving the title compound A30 as an off white solid (0.65 g, 64%). LCMS-C: rt 4.98 min; m/z 324 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:30][CH3:31])[N:6]2[CH2:16][CH:17]1[CH2:22][CH2:21]N(C(OC(C)(C)C)=O)CC1.FC(F)(F)C(O)=O.C(OC1N=C2C(N=C(OC)N2)=C(N)N=1)CCC.BrCCC1C[CH2:63][N:62]([C:65]([O:67][C:68]([CH3:71])([CH3:70])[CH3:69])=[O:66])[CH2:61][CH2:60]1>C(Cl)(Cl)Cl.CO>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([O:30][CH3:31])[N:6]2[CH2:16][CH2:17][CH:22]1[CH2:21][CH2:63][N:62]([C:65]([O:67][C:68]([CH3:69])([CH3:71])[CH3:70])=[O:66])[CH2:61][CH2:60]1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Reactant: CC(C)(C)OC(=O)N1CCC(CCBr)CC1
Agent: CCCCOc1nc(N)c2nc(OC)[nH]c2n1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCN(C(=O)OC(C)(C)C)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 13 from 2-butoxy-8-methoxy-9H-purin-6-amine trifluoroacetate salt and 1,1-dimethylethyl 4-(2-bromoethyl)-1-piperidinecarboxylate. TLC chloroform/methanol 9:1:Rf 0.81