Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11].C(N(CC)CC)C.[F:38][C:39]1[CH:47]=[CH:46][C:42]([C:43](Cl)=[O:44])=[CH:41][CH:40]=1>CN(C)C=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([C:43](=[O:44])[C:42]4[CH:46]=[CH:47][C:39]([F:38])=[CH:40][CH:41]=4)[CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11]
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: CC(Oc1cc(-c2cn(C3CCNCC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(Oc1cc(-c2cn(C3CCN(C(=O)c4ccc(F)cc4)CC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h

Procedure:
The product of the above mentioned Example 2 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-2-aminopyridine (451 mg, 1 mmol) was added to N,N-dimethyl formamide (10 mL), triethylamine (404 mg, 4 mmol) and p-fluorobenzoyl chloride (475.5 mg, 3 mmol) were added, and the reaction was performed overnight at room temperature. The resultant mixture was washed with water for several times, dried over anhydrous sodium sulfate, filtered, the filtrate was rotatedly concentrated to dryness to yield a solid, which was purified via silica gel column chromatography (dichloromethane/methanol=15:1) to yield the target product as white solid powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[CH3:10])[NH2:6].[CH:11](=O)/[CH:12]=[CH:13]/[CH3:14].[NH4+].[OH-]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:7]([CH:11]=[CH:12][C:13]([CH3:14])=[N:6]2)=[CH:8][C:9]=1[CH3:10]
Reactant: C/C=C/C=O
Reactant: COc1cc(N)ccc1C
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc2nc(C)ccc2cc1C
Yield: 42.5 %

Procedure:
To 3-methoxy-4-methylaniline (1.0 g, 7.29 mmol) in refluxing in 6N HCl (50 mL) was added dropwise (E)-but-2-enal (1.02 g, 14.6 mmol). The reaction was heated to reflux for 2 hours then cooled down and neutralized with NH4OH. The organic phase was extracted with DCM and the combined organic phases dried over MgSO4, filtered and concentrated under reduced pressure to leave a dark residue. The residue was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 7-methoxy-2,6-dimethylquinoline (580 mg, 29.7% yield) as a beige solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C1(C(O)=O)(C(O)=O)CC1.FC1C=CC([NH2:31])=CC=1.[CH3:34][O:35][C:36]1[CH:62]=[CH:61][C:39]([CH2:40][N:41]2[C:45]3=[N:46][CH:47]=[CH:48][C:49]([O:50][C:51]4[C:56]([CH3:57])=[CH:55][C:54](N)=[C:53]([Cl:59])[CH:52]=4)=[C:44]3[C:43]([CH3:60])=[N:42]2)=[CH:38][CH:37]=1>>[Cl:59][C:53]1[CH:52]=[C:51]([O:50][C:49]2[CH:48]=[CH:47][N:46]=[C:45]3[N:41]([CH2:40][C:39]4[CH:61]=[CH:62][C:36]([O:35][CH3:34])=[CH:37][CH:38]=4)[N:42]=[C:43]([CH3:60])[C:44]=23)[C:56]([CH3:57])=[CH:55][C:54]=1[N:8]([C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[C:9]([C:11]1([C:14]([NH2:31])=[O:16])[CH2:12][CH2:13]1)=[O:10]
Reactant: Nc1ccc(F)cc1
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4cc(Cl)c(N)cc4C)ccnc32)cc1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: O=C(O)C1(C(=O)O)CC1
Product: COc1ccc(Cn2nc(C)c3c(Oc4cc(Cl)c(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4C)ccnc32)cc1
Yield: 17 %

Procedure:
Prepared from 1-((4-fluorophenyl)carbamoyl)cyclopropanecarboxylic acid (0.1796 g, 0.4989 mmol (prepared from cyclopropane-1,1-dicarboxylic acid and 4-fluoroaniline using the methods of WO 2005/030140 and by Shih and Rankin, Synth. Comm. 1996, 26(4), 833-836) and 4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)-2-chloro-5-methylbenzenamine (0.170 g, 0.1996 mmol) according to the procedure of Example 13, Step C. Purified by preparative TLC (0.5 mm) eluting with EtOAc. The product (23 mg, 17%) was obtained as an orange solid. LRMS (esi pos) m/e 614 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[CH2:21]([O:23][C:24](=[O:34])[CH2:25][CH:26]1[CH2:30][CH2:29][C:28](=O)[C:27]1([CH3:33])[CH3:32])[CH3:22].[B][B][B][B][B][B][B][B][B][B]>>[CH2:21]([O:23][C:24](=[O:34])[CH2:25][CH:26]1[CH2:30][CH2:29][CH:28]([NH:19][C:17]2[CH:16]=[CH:15][C:14]([F:20])=[C:13]([C@:4]3([CH3:12])[C:5]([CH3:10])([CH3:11])[C:6](=[O:9])[N:7]([CH3:8])[C:2]([NH2:1])=[N:3]3)[CH:18]=2)[C:27]1([CH3:33])[CH3:32])[CH3:22]
Reactant: CCOC(=O)CC1CCC(=O)C1(C)C
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CCOC(=O)CC1CCC(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)C1(C)C

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and rac-(2,2-dimethyl-3-oxo-cyclopentyl)-acetic acid ethyl ester (prepared according to Bunce, R. A. et al., J. Org. Chem. 1995, 60(9), 2748) using decaborane yielded a mixture of isomers of the title compound as a white foam. MS (ESI): m/z=461.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14]C1C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:14])=[O:5]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1Cl
Solvent: CO
Product: COC(=O)c1cccc([N+](=O)[O-])c1Cl
Yield: 383.4 %

Procedure:
To a suspension of 2-chloro-3-nitrobenzoic acid (100 g, 495 mmol) in MeOH (600 mL) was added TsOH (20 g, 10%). Then the mixture was heated at reflux overnight. The solvent was removed. The residue was diluted with EtOAc (1 L). Then the pH was adjusted to around 9 by progressively adding saturated NaHCO3. The organic layer was separated. The aqueous layer was extracted with EtOAc (1 L×3). The combined organic layers were washed with water and brine successively, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (96 g, 90.6% yield). 1H NMR (400 MHz, CDCl3) δ ppm 7.90 (dd, J=1.8 Hz, 7.9 Hz, 1H), 7.81 (dd, J=1.5 Hz, 7.7 Hz, 1H), 7.45 (dd, J=7.7 Hz, 7.9 Hz, 1H), 3.94 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:3]([C:11]2[CH:16]=[C:15]([OH:17])[C:14]([Cl:18])=[CH:13][C:12]=2[F:19])[N:4]=[C:5]2[C:10]=1[CH2:9][CH2:8][CH2:7][CH2:6]2.C(=O)([O-])[O-].[K+].[K+].[CH2:26](I)[CH3:27].O>CN(C)C=O>[Cl:18][C:14]1[C:15]([O:17][CH2:26][CH3:27])=[CH:16][C:11]([N:3]2[CH:2]=[C:10]3[C:5]([CH2:6][CH2:7][CH2:8][CH2:9]3)=[N:4]2)=[C:12]([F:19])[CH:13]=1
Reactant: Oc1cc(-n2nc3c(c2Cl)CCCC3)c(F)cc1Cl
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(-n2cc3c(n2)CCCC3)c(F)cc1Cl
Temperature: 60 °C
Reaction time: 3 h

Procedure:
Into a solution of 3-chloro-2-(4-chloro-2-fluoro-5-hydroxyphenyl)-4,5,6,7-tetrahydro-2H-indazole (0.9 g) in dimethylformamide (10 ml), there were added potassium carbonate (0.25 g) and ethyl iodide (1 g), and the mixture was stirred at 60° C. for 3 hours. After cooling, water was added to the reaction mixture, followed by extraction with ether. The ether layer was washed with water twice, dried and concentrated. The residue was crystallized from hexane to give 0.2 g of 3-chloro-2-(4-chloro-2-fluoro-5-ethoxyphenyl-4,5,6,7-tetrahydro-2H-indazole (Compound No. 1). m.p., 85.1° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:17]([NH:19][NH2:20])=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)=[CH:4][N:3]=1.[Si:21]([O:28][CH2:29][C@:30]1([CH3:39])[S:36][CH2:35][CH2:34][N:33]=[C:32](SC)[CH2:31]1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]>C(O)(C)(C)C>[Si:21]([O:28][CH2:29][C@:30]1([CH3:39])[S:36][CH2:35][CH2:34][N:33]2[C:17]([C:14]3([C:11]4[CH:12]=[CH:13][C:8]([C:5]5[CH:6]=[N:7][C:2]([CH3:1])=[N:3][CH:4]=5)=[CH:9][CH:10]=4)[CH2:15][CH2:16]3)=[N:19][N:20]=[C:32]2[CH2:31]1)([C:24]([CH3:27])([CH3:25])[CH3:26])([CH3:22])[CH3:23]
Reactant: Cc1ncc(-c2ccc(C3(C(=O)NN)CC3)cc2)cn1
Reactant: CSC1=NCCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C1
Solvent: CC(C)(C)O
Product: Cc1ncc(-c2ccc(C3(c4nnc5n4CCS[C@@](C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)cn1
Temperature: 25 °C
Yield: 74 %

Procedure:
A solution of the compound (591 mg, 2.23 mmol) obtained in Example 88-1) and the compound (750 mg, 2.35 mmol) obtained in Example 4-1) in t-butanol (10 mL) was stirred for 7 h under reflux conditions. The obtained reaction mixture was cooled to room temperature and concentrated under reduced pressure, and then the residue was purified by silica gel column chromatography (methanol:ethyl acetate=10:90 to 100:0) to obtain the title compound (861 mg, 70%) as a light yellow solid.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=1.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([F:38])=[C:19]([C@@:21]23[O:29][CH2:28][CH2:27][C@@H:26]2[CH2:25][S:24][C:23]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[N:22]3)[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:13][CH:2]([F:1])[O:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]([NH:14][C:15]2[CH:16]=[CH:17][C:18]([F:38])=[C:19]([C@@:21]34[O:29][CH2:28][CH2:27][C@@H:26]3[CH2:25][S:24][C:23]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])=[N:22]4)[CH:20]=2)=[O:12])=[N:8][CH:9]=1
Reactant: O=C(O)c1ccc(OC(F)F)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc(N)ccc3F)OCC[C@@H]2CS1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1=N[C@]2(c3cc(NC(=O)c4ccc(OC(F)F)cn4)ccc3F)OCC[C@@H]2CS1
Yield: 36.7 %

Procedure:
A solution of 5-(difluoromethoxy)picolinic acid (8.49 mg, 0.045 mmol), tert-butyl ((4aS,7aS)-7a-(5-amino-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (11 mg, 0.030 mmol), HATU (17.07 mg, 0.045 mmol) and Hunig's Base (10.46 μL, 0.060 mmol) in DMF (299 μL) was stirred at rt for 10 h. The crude product was purified by reverse phase preparative HPLC on a Luna C18 column (10 μM, 30×100 mm) eluting with 0-100% B (A: 95% eater/5% MeCN/10 nM NH4OAc, B: 5% water/95% MeCN/10 mM NH4OAc) over 12 min to give tert-butyl ((4aS,7aS)-7a-(5-(5-(difluoromethoxy)picolinamido)-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-yl)carbamate (6 mg, 0.011 mmol, 37.2% yield) as a white solid. 1H NMR (500 MHz, CHLOROFORM-d) δ 9.88 (br. s., 1H), 8.50 (br. s., 1H), 8.34 (d, J=8.7 Hz, 1H), 8.01 (dd, J=9.1, 3.4 Hz, 1H), 7.70 (dd, J=8.6, 2.4 Hz, 2H), 7.19-7.07 (m, 1H), 6.89-6.47 (m, 1H), 4.25-4.07 (m, 2H), 3.33 (d, J=12.7 Hz, 1H), 3.07-2.82 (m, 2H), 2.41 (dd, J=12.8, 7.2 Hz, 1H), 2.29-2.14 (m, 1H), 1.51 (br. s., 9H). MS (M+H)+: 539.22.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][CH2:12][C:13]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:26])[C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1)=[O:14].[CH2:27](N(CC)CC)C.ClC(OC)=O>ClCCl.O>[CH3:27][O:24][C:23](=[O:25])[C:22](=[O:26])[C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[CH2:12][O:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)=[CH:17][CH:18]=1
Reactant: O=C(COc1ccc2ccccc2c1)Nc1ccc(C(=O)C(=O)O)cc1
Reactant: CCN(CC)CC
Agent: COC(=O)Cl
Solvent: O
Solvent: ClCCl
Product: COC(=O)C(=O)c1ccc(NC(=O)COc2ccc3ccccc3c2)cc1
Temperature: 0 °C
Yield: 70.5 %

Procedure:
A mixture of 4-[[2-(2-naphthalenyloxy)acetyl]amino]-alpha-oxobenzeneacetic acid (3.0 g) in dichloromethane (50 mL) and triethylamine (2.1 g ) was stirred at 0° C. and treated with methyl chloroformate (1.16 mL). The mixture was stirred for one hour and diluted with water, extracted with dichloromethane, dried (Na2SO4), filtered and evaporated. The residue was crystallized from dichloromethane-hexane to give 2.2 g of 4-[[2-(2-naphthalenyloxy) acetyl]amino]-alpha-oxobenzeneacetic acid methyl ester, mp 175°-176° C.
Reaction SMILES: CO[CH:3](OC)[C:4]1[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=[CH:8][C:7]([O:16][CH3:17])=[C:6]([O:18][CH3:19])[C:5]=1CO.[C:24]([O:32][CH3:33])(=[O:31])/[CH:25]=[CH:26]\[C:27]([O:29][CH3:30])=[O:28].[CH3:34]S(O)(=O)=O>C(O)(=O)C.C1(C)C=CC=CC=1>[N:13]1[CH:12]=[CH:11][C:10]([C:9]2[C:4]3[C:3](=[CH:8][C:7]([O:16][CH3:17])=[C:6]([O:18][CH3:19])[CH:5]=3)[CH:34]=[C:26]([C:27]([O:29][CH3:30])=[O:28])[C:25]=2[C:24]([O:32][CH3:33])=[O:31])=[CH:15][CH:14]=1
Reactant: COc1cc(-c2ccncc2)c(C(OC)OC)c(CO)c1OC
Reactant: COC(=O)/C=C\C(=O)OC
Reactant: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccncc2)c1C(=O)OC
Temperature: 25 °C
Yield: 62.2 %

Procedure:
To a solution of 3,4-dimethoxy-6-(4-pyridyl) hydroxymethylbenzaldehyde dimethylacetal (18.4 g) in a mixture of acetic acid (50 ml) and toluene (50 ml) is added dimethyl maleate (8.64 ml), and the mixture is refluxed for one hour. To the mixture is added methanesulfonic acid (9.33 ml), and the mixture is refluxed for 8 hours while removing the resulting water with a Dean-Stalk apparatus. The mixture is cooled to room temperature, and concentrated. The residue is dissolved in chloroform, and the pH value thereof is adjusted with aqueous potassium carbonate solution to pH 8. The mixture is extracted twice with each 100 ml of chloroform, and the extracts are washed with a saturated sodium chloride solution, dried over magnesium sulfate, and concentrated. The resulting residue is crystallized from diethyl ether to give a diester compound, 1-(4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene (13.5 g).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=[S:5])[NH2:4].Br[CH2:8][C:9](=O)[C:10]([O:12][CH2:13][CH3:14])=[O:11].[O-]S([O-])(=O)=O.[Mg+2]>CC(C)=O>[CH:2]([C:3]1[S:5][CH:8]=[C:9]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1)([CH3:6])[CH3:1]
Reactant: CC(C)C(N)=S
Reactant: CCOC(=O)C(=O)CBr
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(C)=O
Product: CCOC(=O)c1csc(C(C)C)n1
Yield: 86.4 %

Procedure:
A solution of 2.35 g (23 mmol) of 2-methylpropane-thioamide and 2.89 ml (23 mmol) of ethyl bromopyruvate in 75 ml of acetone was treated with excess MgSO4 and heated at reflux for 2.5 h. The resulting mixture was allowed to cool, filtered, and concentrated in vacuo to an oil, which was taken up in chloroform, washed sequentially with aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated. The residue was purified by chromatography on silica gel using chloroform as an eluent to provide 3.96 g (86%) of the desired compound, Rf 0.21 (chloroform) as an oil. 1H NMR (CDCl3) δ 1.41 (t, J=8 Hz, 3 H), 1.42 (d, J=7 Hz, 6 H), 3.43 (heptet, J=7 Hz, 1 H), 4.41 (q, J=8 Hz, 2 H), 8.05 (s, 1 H). Mass spectrum: (M+H)+ =200.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[F:21])=[C:9]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:8]=1)(=O)=O.[CH3:29][O:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][SH:38])=[CH:33][CH:32]=1.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.C(N(C(C)C)C(C)C)C>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:21][C:14]1[CH:15]=[CH:16][C:17]([O:19][CH3:20])=[CH:18][C:13]=1[C:10]1[CH:11]=[CH:12][C:7]([S:38][CH2:37][C:34]2[CH:35]=[CH:36][C:31]([O:30][CH3:29])=[CH:32][CH:33]=2)=[CH:8][C:9]=1[CH2:22][C:23]([CH3:25])([CH3:26])[CH3:24]
Reactant: COc1ccc(CS)cc1
Reactant: COc1ccc(F)c(-c2ccc(OS(=O)(=O)C(F)(F)F)cc2CC(C)(C)C)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CSc2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)c2)cc1
Temperature: 120 °C
Reaction time: 20 h

Procedure:
To a solution of 2′-fluoro-5′-methoxy-2-neopentyl-[1,1′-biphenyl]-4-yl trifluoromethanesulfonate (1.88 g) in toluene (22 mL) were added 4-methoxy-α-toluenethiol (748 μL), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (78 mg), N-ethyldiisopropylamine (1.56 mL) and tris(dibenzylideneacetone)dipalladium(0) (123 mg) at room temperature, and the mixture was stirred at 120° C. for 20 hr. The mixture was poured into ice water at room temperature, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (1.68 g) as a colorless oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15]Cl)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2].[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[C:19]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:18]1.C([O-])(=O)C([O-])=O>>[C:1]([N:4]1[CH2:9][CH2:8][C:7]2[C:10]([CH2:14][CH2:15][N:29]3[CH2:30][CH2:31][N:26]([C:19]4[C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=5[S:17][N:18]=4)[CH2:27][CH2:28]3)=[C:11]([CH3:13])[S:12][C:6]=2[CH2:5]1)(=[O:3])[CH3:2]
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Reactant: CC(=O)N1CCc2c(sc(C)c2CCCl)C1
Agent: O=C([O-])C(=O)[O-]
Product: CC(=O)N1CCc2c(sc(C)c2CCN2CCN(c3nsc4ccccc34)CC2)C1
Yield: 55.3 %

Procedure:
The reaction and procedure were conducted in a similar manner as in Example 24 using 1.4 g of 6-acetyl-3-(2-chloroethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine and 0.9 g of 4-(1,2-benzisothiazol-3-yl)piperazine to give 1.0 g of 6-acetyl-3-(2-(4-(1,2-benzisothiazol-3-yl)piperazin-1-yl)ethyl)-4,5,6,7-tetrahydro-2-methylthieno[2,3-c]pyridine as an oil, m.p. 190°-192° C. (decomposition) as oxalate thereof.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:20](=[CH:21][CH:22]=1)[O:19][C:7]1[C:8]([F:18])=[N:9][C:10]([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:11][C:6]=1[C:5]2=[CH2:23].O.II.C([O-])([O-])=[O:28].[K+].[K+]>C1COCC1.[Ag]=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]3([CH2:23][O:28]3)[C:6]3[CH:11]=[C:10]([O:12][CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[N:9]=[C:8]([F:18])[C:7]=3[O:19][C:20]2=[CH:21][CH:22]=1
Reactant: C=C1c2cc(Br)ccc2Oc2c1cc(OCC(C)(C)C)nc2F
Reactant: O=C([O-])[O-]
Agent: O=[Ag]
Agent: II
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)COc1cc2c(c(F)n1)Oc1ccc(Br)cc1C21CO1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
To a solution of 7-bromo-1-fluoro-5-methylene-3-(neopentyloxy)-5H-chromeno[2,3-c]pyridine (995 mg, 2.63 mmol) in THF (60 mL)/Water (10 mL) was added iodine (1335 mg, 5.26 mmol) and silver oxide (1219 mg, 5.26 mmol). The reaction mixture was allowed to stir at rt for 20 min. K2CO3 (545 mg, 3.95 mmol) was added in one portion and the reaction mixture was allowed to stir for 30 min. The reaction mixture was filtered through a pad of celite. The reaction mixture was partitioned between water and EtOAc. The organic phase was separated, dried over Na2SO4. The solvent was removed under reduced pressure to afford 7-bromo-1-fluoro-3-(neopentyloxy)spiro[chromeno[2,3-c]pyridine-5,2′-oxirane] as a yellow solid (1000 mg) which was taken onto the next step without further purification.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:9]=[C:8]2[C:4]=1[NH:5][C:6](=[O:26])[N:7]2[CH2:17][CH2:18][CH2:19][NH:20][CH2:21][CH2:22][N:23]([CH3:25])[CH3:24].[CH:27](=O)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.CO>[NH2:2][C:3]1[N:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:9]=[C:8]2[C:4]=1[NH:5][C:6](=[O:26])[N:7]2[CH2:17][CH2:18][CH2:19][N:20]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:21][CH2:22][N:23]([CH3:25])[CH3:24]
Reactant: O=Cc1ccccc1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCCN(C)C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: CN1CCCC1=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCN(C)C)Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.7 %

Procedure:
The product from step (iii) (0.1 g) and benzaldehyde (0.0362 g, 0.0347 ml) were combined in NMP (4 mL) and stirred at RT for 15 mins. Sodium triacetoxyborohydride (0.0904 g) was added. The reaction mixture was stirred for 16 h. The reaction mixture was diluted with methanol and purified by RP-prep-HPLC 75:05 NH3:acetonitrile over 15 mins to give title compound (0.068 g)
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:7][CH:6]([O:8][CH:9]([CH:49]2[CH:53]([OH:54])[CH:52]([OH:55])[CH:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]([C:46](O)=[O:47])[NH:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])C(C)C)[NH:18][C:19](=[O:39])[CH:20]([CH:32]2[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]2)[NH:21][C:22](=[O:31])[NH:23][CH:24](C(C)C)[C:25]([OH:27])=[O:26])[CH:5]([O:64][CH3:65])[CH:4]1[OH:66].[CH2:67]([N:73]=[C:74]=[O:75])[CH2:68][CH2:69][CH2:70][CH2:71][CH3:72]>CO.N1C=CC=CC=1.CC(=O)CC(=O)C>[NH2:1][CH2:2][C@H:3]1[O:7][CH:6]([O:8][C@@H:9]([C@@H:49]2[C@@H:53]([OH:54])[C@@H:52]([OH:55])[C@H:51]([N:56]3[CH:61]=[CH:60][C:59](=[O:62])[NH:58][C:57]3=[O:63])[O:50]2)[CH:10]2[N:11]([CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:45])[CH:17]([CH:40]([OH:44])[CH:9]([CH3:49])[CH3:10])[NH:18][C:19](=[O:39])[CH:20]([CH:32]3[CH2:37][CH2:36][NH:35][C:34](=[NH:38])[NH:33]3)[NH:21][C:22](=[O:31])[NH:23][CH:24]([CH:3]([CH3:4])[CH3:2])[C:25]([OH:27])=[O:26])[C:74](=[O:75])[N:73]([CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH3:72])[C:46]2=[O:47])[C@H:5]([O:64][CH3:65])[C@H:4]1[OH:66]
Reactant: CCCCCCN=C=O
Reactant: COC1C(OC(C(NCCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C(=O)O)C2OC(n3ccc(=O)[nH]c3=O)C(O)C2O)OC(CN)C1O
Solvent: CC(=O)CC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: CCCCCCN1C(=O)C([C@@H](OC2O[C@H](CN)[C@H](O)[C@H]2OC)[C@H]2O[C@@H](n3ccc(=O)[nH]c3=O)[C@H](O)[C@@H]2O)N(CCCNC(=O)C(NC(=O)C(NC(=O)NC(C(=O)O)C(C)C)C2CCNC(=N)N2)C(O)C(C)C)C1=O
Yield: 56.9 %

Procedure:
The title compound is prepared by the procedure of Example 1, using 47.3 mg (50 μmol) of 16-({[5-(aminomethyl)-4-hydroxy-3-methoxytetrahydro-2-furanyl]oxy}{5-[2,4-dioxo-3,4-dihydro-1 (2H)-pyrimidinyl]-3,4-dihydroxytetrahydro-2-furanyl}methyl)-9-(1-hydroxy-2-methylpropyl)-6-(2-iminohexahydro-4-pyrimidinyl)-2-isopropyl-4,7,10-trioxo-3,5,8,11,15-pentaazaheptadecane-1,17-dioic acid (λmax nm in water=259) in 3.0 ml of methanol, 200 μl of pyridine, 200 μl of 2,4-pentanedione and 50 μmol of hexylisocyanate to give 15 mg of the desired product.
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:14]=[C:13]([NH:15][CH:16]2[CH2:18][CH2:17]2)[N:12]2[N:19]=[CH:20][C:21]([CH:22]=[C:23]3[NH:27][C:26](=[O:28])[NH:25][C:24]3=[O:29])=[C:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.FC(F)(F)C(O)=O>[CH2:1]([S:8][C:9]1[CH:14]=[C:13]([NH:15][CH:16]2[CH2:18][CH2:17]2)[N:12]2[N:19]=[CH:20][C:21](/[CH:22]=[C:23]3/[C:24](=[O:29])[NH:25][C:26](=[O:28])[NH:27]/3)=[C:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(SCc4ccccc4)nc23)N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1NC(=O)/C(=C/c2cnn3c(NC4CC4)cc(SCc4ccccc4)nc23)N1
Reaction time: 1 h
Yield: 96.8 %

Procedure:
5-((5-(Benzylthio)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (60 mg, 0.15 mmol) was dissolved in dichloromethane (1 mL) and trifluoroacetic acid (1 mL). After 1 h, the solution was concentrated under a stream of air. The residue was triturated with Et2O (3 mL) and the precipitate was collected to provide (Z)-5((5-(benzylthio)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (59 mg, 98%). LCMS (ES): >95% pure, m/z 407 [M+1]+.