Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH:15]1[CH2:20][CH2:19][CH:18]([NH:21]C(=O)OC(C)(C)C)[CH2:17][CH2:16]1)=[N:11][C:10]([C:29]1[CH:34]=[C:33]([F:35])[C:32]([OH:36])=[C:31]([Cl:37])[CH:30]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.C1(N)C(F)=C(F)C(F)=C(N)C=1F.[ClH:57].Cl>>[ClH:37].[ClH:57].[NH2:21][C@H:18]1[CH2:19][CH2:20][C@H:15]([NH:14][C:13]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:29]4[CH:34]=[C:33]([F:35])[C:32]([OH:36])=[C:31]([Cl:37])[CH:30]=4)[N:11]=3)[N:6]=[CH:5][C:4]=2[C:1](=[O:3])[CH3:2])[CH2:16][CH2:17]1
Reactant: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1NC1CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1N[C@H]1CC[C@H](N)CC1

Procedure:
Following general procedure IV-2, tert-butyl (4-{[3-acetyl-6-(3-chloro-5-fluoro-4-hydroxyphenyl)-1,5-naphthyridin-4-yl]amino}cyclohexyl)carbamate (0.20 mmol) was reacted with TFA (2 mL) followed by formation of the dihydrochloride salt to afford the desired product (45 mg, 45% over two steps) as a white solid: 1H NMR (500 MHz, D2O) δ 8.99 (s, 1H), 8.13 (d, J=9.0 Hz, 1H), 8.03 (d, J=9.0 Hz, 1H), 7.40-7.34 (m, 2H), 4.91-4.94 (m, 1H), 3.35-3.28 (m, 1H), 2.72 (s, 3H), 2.30-2.22 (m, 2H), 2.21-2.14 (m, 2H), 1.75-1.68 (m, 2H), 1.56-1.48 (m, 2H); ESI MS m/z 429 [M+H]+; HPLC>99% (AUC), tR=9.10 min.
Reaction SMILES: [CH2:1]([C@@H:3]1[CH2:7][C@@H:6]([OH:8])[CH2:5][C@@H:4]1[C:9]([OH:11])=[O:10])[CH3:2].[CH3:12][C:13]([Si:16](Cl)([CH3:18])[CH3:17])([CH3:15])[CH3:14].N1C=CN=C1>CN(C=O)C.[Si](O[C@H]1C[C@H](C(O)=O)[C@H](CC)C1)(C(C)(C)C)(C)C>[Si:16]([O:8][CH:6]1[CH2:5][CH:4]([C:9]([OH:11])=[O:10])[CH:3]([CH2:1][CH3:2])[CH2:7]1)([C:13]([CH3:15])([CH3:14])[CH3:12])([CH3:18])[CH3:17]
Reactant: CC[C@@H]1C[C@@H](O)C[C@@H]1C(=O)O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1C(=O)O
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CCC1CC(O[Si](C)(C)C(C)(C)C)CC1C(=O)O
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a scalemic mixture enriched in (1S,2R,4R)-2-ethyl-4-hydroxycyclopentanecarboxylic acid (2.56 g, 16.21 mmol) in DMF (10.81 mL) was added TBDMSCl (2.93 g, 19.45 mmol) and imidazole (2.76 g, 40.5 mmol). The reaction mixture was stirred at ambient temperature for about 2 days then extracted with pentane (3×25 mL). The combined pentane layers were washed with water (25 mL) and brine (25 mL), dried over anhydrous MgSO4, filtered and concd under reduced pressure. The residue was purified using silica gel chromatography eluting with 20-100% EtOAc in heptane give a scalemic mixture enriched in (1S,2R,4R)-4-(tert-butyldimethylsilyloxy)-2-ethylcyclopentanecarboxylic acid (1.13 g, 26%): LC/MS (Table 1, Method b) Rt=3.03 min; MS m/z: 273 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:4]=[C:5]([NH2:13])[C:6]2[CH:7]=[CH:8][N:9]=[CH:10][C:11]=2[CH:12]=1.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:27]=[CH:26][C:21]([CH2:22][N:23]=[C:24]=[O:25])=[CH:20][CH:19]=1>>[F:15][C:2]([F:1])([F:14])[C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][N:9]=[CH:10]2)=[C:5]([NH:13][C:24]([NH:23][CH2:22][C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:29])[F:28])=[CH:27][CH:26]=2)=[O:25])[CH:4]=1
Reactant: Nc1cc(C(F)(F)F)cc2cnccc12
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cc(C(F)(F)F)cc2cnccc12

Procedure:
Prepared from 7-(trifluoromethyl)isoquinolin-5-amine (Description 99) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 414 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:11]=2)[C:5]([C:20]#[N:21])=[C:4]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:28]#[N:29].Cl.[NH:31]1[CH2:34][CH:33]([OH:35])[CH2:32]1.C(N(CC)CC)C.O>O1CCCC1>[C:20]([C:5]1[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:16]([NH:18][CH3:19])=[O:17])[CH:11]=2)=[N:7][C:2]([N:31]2[CH2:34][CH:33]([OH:35])[CH2:32]2)=[C:3]([C:28]#[N:29])[C:4]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)#[N:21]
Reactant: OC1CNC1
Reactant: CNC(=O)c1cc(CSc2nc(Cl)c(C#N)c(-c3ccccc3)c2C#N)ccn1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: CNC(=O)c1cc(CSc2nc(N3CC(O)C3)c(C#N)c(-c3ccccc3)c2C#N)ccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 mg (0.12 mmol) of 4-{[(6-chloro-3,5-dicyano-4-phenylpyridin-2-yl)sulfanyl]methyl}-N-methylpyridine-2-carboxamide Example 75A, 19.6 mg (0.18 mmol) of azetidin-3-ol hydrochloride and 36.2 mg (0.36 mmol) of triethylamine were dissolved in 1 ml of tetrahydrofuran, and the mixture was stirred at RT for 1 h. Water and tetrahydrofuran were added to the reaction mixture until a solution had formed. The solution was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% trifluoroacetic acid).
Reaction SMILES: C[O:2][C:3](=[O:43])[CH2:4][C:5]1[CH:6]=[C:7]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][C:20]=2[CH2:29][N:30]2[C@@H:34]([CH3:35])[C@@H:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[O:32][C:31]2=[O:42])[C:8](OS(C(F)(F)F)(=O)=O)=[CH:9][CH:10]=1.[N:44]1[CH:49]=[CH:48][CH:47]=[C:46](B(O)O)[CH:45]=1>>[CH3:35][C@H:34]1[C@@H:33]([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[O:32][C:31](=[O:42])[N:30]1[CH2:29][C:20]1[CH:21]=[C:22]([C:25]([F:27])([F:26])[F:28])[CH:23]=[CH:24][C:19]=1[C:7]1[C:8]([C:46]2[CH:45]=[N:44][CH:49]=[CH:48][CH:47]=2)=[CH:9][CH:10]=[C:5]([CH2:4][C:3]([OH:2])=[O:43])[CH:6]=1
Reactant: COC(=O)Cc1ccc(OS(=O)(=O)C(F)(F)F)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3ccccc3)[C@@H]2C)c1
Reactant: OB(O)c1cccnc1
Product: C[C@H]1[C@@H](c2ccccc2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)O)ccc1-c1cccnc1

Procedure:
Prepared according to the procedure described in Example 19, Step 3, using the following starting materials: [2′-((4S,5R)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-ylmethyl)-6-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl]-acetic acid methyl ester and 3-pyridineboronic acid. M+H is 547.
Reaction SMILES: [CH:1]12[NH:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][CH:3]([O:9][CH2:10][C:11]1[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][C:26]([F:29])([F:28])[F:27])=[N:13][O:14][C:15]=1[CH:16]1[CH2:18][CH2:17]1)[CH2:2]2.CN(C)C(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:43]1[S:44][C:45]2[CH:51]=[C:50]([C:52]([O:54][CH3:55])=[O:53])[CH:49]=[C:48]([F:56])[C:46]=2[N:47]=1>C(OCC)(=O)C>[CH:16]1([C:15]2[O:14][N:13]=[C:12]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][C:26]([F:28])([F:27])[F:29])[C:11]=2[CH2:10][O:9][CH:3]2[CH2:2][CH:1]3[N:8]([C:43]4[S:44][C:45]5[CH:51]=[C:50]([C:52]([O:54][CH3:55])=[O:53])[CH:49]=[C:48]([F:56])[C:46]=5[N:47]=4)[CH:5]([CH2:6][CH2:7]3)[CH2:4]2)[CH2:17][CH2:18]1
Reactant: COC(=O)c1cc(F)c2nc(Br)sc2c1
Reactant: FC(F)(F)Oc1ccccc1-c1noc(C2CC2)c1COC1CC2CCC(C1)N2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(F)c2nc(N3C4CCC3CC(OCc3c(-c5ccccc5OC(F)(F)F)noc3C3CC3)C4)sc2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Into a 25-mL round-bottom flask equipped with a stir bar was added sequentially 4-((8-azabicyclo[3.2.1]octan-3-yloxy)methyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)phenyl)isoxazole (I-1H) (0.525 g, 1.29 mmol), 3.6 mL of N,N-dimethylacetamide, cesium carbonate (1.08 g, 3.31 mmol), and methyl 2-bromo-4-fluorobenzo[d]thiazole-6-carboxylate (1.12 g, 3.87 mmoles). After stirring the resulting slurry at room temperature for 10 minutes, the mixture was then warmed to 60° C. and stirred for 1 h. The reaction slurry was allowed to cool to RT, and was diluted with 200 mL of ethyl acetate and washed with water (3×30 mL). The organic extracts were concentrated under vacuum and directly purified using normal phase silica gel chromatography (40 g silica column) with a 15 min gradient of 10% to 60% ethyl acetate/hexanes. Desired fractions were concentrated in vacuo, and the resulting residue crystallized upon standing to give the desired product as a white crystalline solid.
Reaction SMILES: C1(C)C=CC=CC=1.[I:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1.C(N(CC)CC)C.[C:23]([O:26][C@@H:27]1[C@@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:31]([O:37][C:38](=[O:40])[CH3:39])[CH2:30][S:29][C@@H:28]1Br)(=[O:25])[CH3:24]>[Cl-].[Zn+2].[Cl-].C(OCC)(=O)C.O.C(#N)C>[C:23]([O:26][C@@H:27]1[C@@H:32]([O:33][C:34](=[O:36])[CH3:35])[C@H:31]([O:37][C:38](=[O:40])[CH3:39])[CH2:30][S:29][C@H:28]1[O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([I:8])[CH:10]=1)(=[O:25])[CH3:24]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: Oc1cccc(I)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc(I)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37 %

Procedure:
38.63 g (0.28 mol) of zinc chloride are heated until molten under an argon atmosphere in a reactor. After cooling the reaction mass, 800 ml of toluene, 800 ml of acetonitrile and 44 g of 4 Å molecular sieve are added. The reaction mixture is stirred at ambient temperature for 90 minutes and 25 g (0.113 mol) of 3-iodophenol are added. The reaction mixture is brought to 90° C. and, after 2 minutes, 39 ml (0.28 mol) of triethylamine and 44.39 g (0.12 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide are added. The reaction mixture is kept stirred at 80° C. for 30 minutes. After cooling, water and ethyl acetate are added and the insoluble compounds are removed by filtration. The organic phase is washed successively with water, a 1N sodium hydroxide solution and a saturated sodium chloride solution. The organic phase is dried over magnesium sulfate, decolored using active charcoal, filtered and evaporated under reduced pressure. The residue is purified by chromatography on a silica column, elution being carried out using a cyclohexane/ethyl acetate mixture (70/30; v/v), and recrystallized from isopropanol. The expected product is obtained in the form of a white powder with a yield of 37%.
Reaction SMILES: [F:1][CH:2]([F:34])[C:3]1[N:17](COCC[Si](C)(C)C)[C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]=2[C:4]=1[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30]>FC(F)(F)C(O)=O>[F:34][CH:2]([F:1])[C:3]1[NH:17][C:6]2[N:7]=[CH:8][N:9]=[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[C:5]=2[C:4]=1[C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[C:29]#[N:30]
Reactant: C[Si](C)(C)CCOCn1c(C(F)F)c(-c2cccc(C#N)c2)c2c(N3CCOCC3)ncnc21
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cccc(-c2c(C(F)F)[nH]c3ncnc(N4CCOCC4)c23)c1

Procedure:
A solution of 3-[6-(difluoromethyl)-4-(morpholin-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-5-yl]benzonitrile (C31) (10 mg, 21 μmol) in trifluoroacetic acid (2 mL) was stirred at room temperature for 24 hours. The reaction mixture was concentrated and purified by preparative reversed phase high-performance liquid chromatography (Column: DIKMA Diamonsil(2) C18, 5 μm; Eluent: 22% acetonitrile in water containing 0.225% formic acid) to provide the product as a white solid. Yield: 2.0 mg, 5.6 μmol, 27%. LCMS m/z 355.9 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 13.06 (brs, 1H), 8.47 (s, 1H), 7.92 (ddd, J=6.7, 2.1, 1.7 Hz, 1H), 7.83-7.85 (m, 1H), 7.69-7.76 (m, 2H), 7.02 (t, JHF=52.5 Hz, 1H), 3.22-3.30 (m, 4H), 3.03-3.10 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:7]2[C:12](=[O:13])[NH:11][C:10]([C:14]([OH:16])=O)=[CH:9][CH:8]=2)=[CH:5][N:6]=1.[F:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][CH:24]=[C:25]2[O:28][CH2:29][CH2:30][NH:31][CH2:32][CH2:33]O)=[CH:20][CH:19]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>ClCCl>[F:17][C:18]1[CH:27]=[C:26]2[C:21]([CH:22]=[CH:23][CH:24]=[C:25]2[O:28][CH2:29][CH2:30][N:31]2[CH2:32][CH2:33][N:11]3[C:12](=[O:13])[C:7]([C:4]4[O:3][C:2]([CH3:1])=[N:6][CH:5]=4)=[CH:8][CH:9]=[C:10]3[C:14]2=[O:16])=[CH:20][CH:19]=1
Reactant: OCCNCCOc1cccc2ccc(F)cc12
Reactant: Cc1ncc(-c2ccc(C(=O)O)[nH]c2=O)o1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ncc(-c2ccc3n(c2=O)CCN(CCOc2cccc4ccc(F)cc24)C3=O)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
5-(2-Methyl-1,3-oxazol-5-yl)-6-oxo-1,6-dihydropyridine-2-carboxylic acid (C39) (45 mg, 0.20 mmol) and 2-({2-[(7-fluoronaphthalen-1-yl)oxy]ethyl}amino)ethanol (C41) (55.8 mg, 1.1 mmol) were combined with dichloromethane (4 mL) and N,N-diisopropylethylamine (178 μL, 1.02 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 97%, 171 mg, 0.45 mmol) was added, and the reaction was stirred at room temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was added and the mixture was extracted three times with ethyl acetate. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. Purification via silica gel chromatography (Gradient: 50% to 100% ethyl acetate in heptane, followed by elution with 20% methanol in ethyl acetate) was followed by high-pressure liquid chromatographic purification (Silica column, 5 μm; Gradient: 5% to 100% ethanol in heptane), to afford the title compound as a solid. Yield: 10 mg, 0.022 mmol, 11%. LCMS m/z 434.5 (M+1). 1H NMR (400 MHz, CDCl3) δ 2.64 (s, 3H), 3.97-4.02 (m, 2H), 4.12-4.16 (m, 2H), 4.39-4.47 (m, 4H), 6.85 (d, J=7.6 Hz, 1H), 7.26-7.31 (m, 1H, assumed; partially obscured by solvent peak), 7.31-7.36 (m, 2H), 7.46 (d, J=8.2 Hz, 1H), 7.71 (dd, J=10.3, 2.5 Hz, 1H), 7.81 (dd, J=9.0, 5.5 Hz, 1H), 7.89 (d, J=7.6 Hz, 1H), 8.00 (s, 1H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].Cl.C([O-])(O)=O.[Na+].[NH:19]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:20]([C:31]([O:33]N1C(=O)CCC1=O)=[O:32])[CH2:21][C:22](=[O:30])[O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>O.C1COCC1>[NH:19]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:20]([C:31]([OH:33])=[O:32])[CH2:21][C:22](=[O:30])[O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OC1CCCCC1)C(=O)ON1C(=O)CCC1=O
Agent: Cl
Agent: NCc1ccccc1CC(=O)O
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)OC1CCCCC1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83 %

Procedure:
To a suspension of 2-aminomethylphenylacetic acid.HCl (4.0 g, 20 mmol) in H2O (20 ml) was added NaHCO3 (5.0 g, 60 mmol), followed by a solution of Boc-Asp(OcHex)-OSu (7.5 g, 18 mmol) in THF (20 ml). The reaction mixture was stirred at room temperature for 3 hours, filtered, diluted with H2O, acidified with 1N HCl, and extracted with ethyl acetate. The extracts were washed with H2O, brine, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. This material was triturated with ether to provide the title compound (7.0 g, 83%) as a white powder. 1H NMR (D6 -DMSO) 12.40 (br s, 1H), 8.30 (br t, 1H), 7.20 (m, 5H), 4.65 (m, 1H), 4.35 (q, 1H), 4.25 (m, 2H), 3.65 (s, 2H), 2.70 (dd, 1H), 2.55 (dd, 1H), 1.70 (m, 4H), 1.40 (s, 9H), 1.35 (m, 6H).
Reaction SMILES: S([N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][C:23]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:22]2=[O:32])=[CH:12]1)(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][C:23]3([CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:22]2=[O:32])=[CH:12]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(CN3CCCC4(CCNCC4)C3=O)c3ccccc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C1N(Cc2c[nH]c3ccccc23)CCCC12CCNCC2
Yield: 97.8 %

Procedure:
The mixture of 2-((1-tosyl-1H-indol-3-yl)methyl)-2,9-diazaspiro[5.5]undecan-1-one (15 g, 23 mmol) and Cs2CO3 (45 g, 139 mmol) in methanol (170 ml) was heated under reflux for 2.5 h. The solution was diluted with water, the pH adjusted to 7 with a saturated aqueous potassium carbonate solution and the aqueous phase extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to afford 6.69 g (99%) of the title compound as a beige foam which was not further purified. [1H NMR (400 MHz, DMSO-d6) ♀ ppm 10.91 (br. s., 1H), 7.48-7.55 (m, 1H), 7.32 (d, J=8.2 Hz, 1H), 7.24 (d, J=2.0 Hz, 1H), 7.04 (t, J=7.6 Hz, 1H), 6.88-6.96 (m, 1H), 4.60 (s, 2H), 3.10 (t, J=6.1 Hz, 2H), 2.71-2.89 (m, 2H), 2.51-2.69 (m, 2H), 2.01 (s, 3H), 1.54-1.73 (m, 4H), 1.25-1.38 (m, 2H); LCMS RtC=2.44 min, [M+H]+=298.2].
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[N:15]=[C:14]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=2)=[CH:8][CH:7]=1.[CH:35]([C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1)([CH2:37][CH3:38])[CH3:36]>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]2[CH:17]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=3[Cl:25])[N:15]=[C:14]2[CH2:26][C:27]2[CH:32]=[CH:31][C:30]([C:42]3[CH:43]=[CH:44][C:39]([CH:35]([CH2:37][CH3:38])[CH3:36])=[CH:40][CH:41]=3)=[CH:29][CH:28]=2)=[CH:8][CH:7]=1
Reactant: COC(=O)CNc1ccc(Cn2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Reactant: CCC(C)c1ccc(B(O)O)cc1
Product: CCC(C)c1ccc(-c2ccc(Cc3nc(-c4ccc(Cl)cc4Cl)cn3Cc3ccc(NCC(=O)OC)cc3)cc2)cc1

Procedure:
{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-phenylamino}-acetic acid methyl ester (1.4 g, 2.5 mmol) was coupled with 4-sec-butyl phenyl-boronic acid (600 mg, 3.3 mmol) following general procedure G to give {4-[2-(4′-sec-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-ylmethyl]-phenylamino}-acetic acid methyl ester.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C@@H:11]([CH2:22][CH2:23][O:24][CH3:25])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=1)=[O:13])(=O)C.OS([O-])(=O)=O.[K+]>CO>[OH:10][C@@H:11]([CH2:22][CH2:23][O:24][CH3:25])[C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][N:16]=1)=[O:13]
Reactant: COCC[C@H](OC(C)=O)C(=O)Nc1ccc(C)cn1
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: CO
Product: COCC[C@H](O)C(=O)Nc1ccc(C)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.9 %

Procedure:
Aqueous potassium carbonate 1M (5.257 mL, 5.26 mmol) was added to a solution of (S)-4-methoxy-1-(5-methylpyridin-2-ylamino)-1-oxobutan-2-yl acetate (Intermediate F2) (170 mg, 0.64 mmol) in MeOH (0.3 mL) at 0° C. and the mixture was stirred at room temperature for 2 h. The reaction mixture was neutralized with aqueous KHSO4 (1.0 M, 0.29 mL). The reaction mixture was concentrated and the residue was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in isohexane to afford (S)-2-hydroxy-4-methoxy-N-(5-methylpyridin-2-yl)butanamide (142 mg, 99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([C:16]1[CH:21]=[N:20][CH:19]=[C:18](Cl)[N:17]=1)[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>CCO>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1)[C:16]1[N:17]=[C:18]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=[N:20][CH:21]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(Cc1cccc(F)c1)c1cncc(Cl)n1
Reactant: C1CNCCN1
Solvent: CCO
Product: CC(C)(C)OC(=O)N(Cc1cccc(F)c1)c1cncc(N2CCNCC2)n1

Procedure:
A solution of (6-chloro-pyrazin-2-yl)-(3-fluoro-benzyl)-carbamic acid tert-butyl ester (1.14 g, 3.39 mmol) and piperazine (1.75 g, 20 mmol) in EtOH (34 mL) was stirred at reflux for 19 h. The reaction mixture was cooled and concentrated in vacuo. The residue was dissolved in Ethyl Acetate and washed with H2O (4×50 mL), brine, dried (Na2SO4), and concentrated to dryness. The crude product was chromatographed on Silica Gel (90 g) using 5% MeOH in CH2Cl2 as the eluant to give the title compound I-4c (1.09 g) as a pale yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[CH:3]=1>S1(CCCC1)(=O)=O>[Br:19][C:15]1[CH:16]=[CH:17][C:18]2[C:6](=[O:7])[C:5]3[CH:9]=[CH:10][C:2]([Br:1])=[CH:3][C:4]=3[CH2:11][CH2:12][C:13]=2[CH:14]=1
Reactant: O=C(O)c1ccc(Br)cc1CCc1cccc(Br)c1
Solvent: O=S1(=O)CCCC1
Product: O=C1c2ccc(Br)cc2CCc2cc(Br)ccc21
Temperature: 200 °C

Procedure:
A mixture of the product of step (iv) (6.1 g), polyphosphoric acid (30 ml) and sulpholane (20 ml) was heated at 200° C. for 30 minutes. The cooled mixture was partitioned between ethyl acetate and ice/water. The organic phase was dried (MgSO4) and evaporated under reduced pressure. Purification was by chromatography eluting with 50% toluene in isohexane. Yield 2.71 g.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][CH:12]2[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:24])C>>[C:1]([C:8]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:9]=1[CH2:10][CH2:11][CH:12]2[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: CCOC(=O)C1CCc2c(Cc3ccccc3)cccc21
Product: CCOC(=O)C1CCc2c(C(=O)c3ccccc3)cccc21
Reaction time: 8 h

Procedure:
In 100 ml. of acetic acid is dissolved 7.3 g. of ethyl 4-benzylindan-1-carboxylate and, under cooling with ice, 3.4 g. of chromic anhydride is added. After the mixture is stirred overnight, the reaction mixture is poured over 500 g. of ice and extracted with chloroform. The extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is purified by column chromatography (700 g. silica gel; eluted with a 40:1 mixture of benzene and ethyl acetate). The procedure gives ethyl 4-benzoylindan-1-carboxylate as an oily product.
Reaction SMILES: I.I[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:12]([CH3:24])[CH:11]=2)[C:4]=1[NH2:25].[CH2:26]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])/[CH:27]=[CH:28]/[C:29]#[CH:30]>C(#N)C.C(N(CC)CC)C.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>[NH2:25][C:4]1[C:3]([C:30]#[C:29]/[CH:28]=[CH:27]/[CH2:26][NH:31][C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[N:8][CH:7]=[N:6][C:5]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[C:12]([CH3:24])[CH:11]=1
Reactant: C#C/C=C/CNC(=O)OC(C)(C)C
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(I)c3N)cc2C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(Oc2ccc(Nc3ncnc(C#C/C=C/CNC(=O)OC(C)(C)C)c3N)cc2C)cn1
Yield: 45.9 %

Procedure:
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydriodide (500 mg) was dissolved in a mixed solvent of acetonitrile (14.8 mL)/triethylamine (11.0 mL), and tert-butyl (2E)-2-penten-4-yn-1-ylcarbamate (194 mg), trans-dichlorobis(triphenylphosphine)palladium(II) (31.3 mg) and copper(I) iodide (10.2 mg) were sequentially added. The title compound (199 mg) was obtained as a powder by the reaction in the same manner as in Example 9 (iv).