Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([O:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])=[N:4][N:5]([C:14]2[CH:19]=[C:18]([S:20][CH2:21][C:22]([F:25])([F:24])[F:23])[C:17]([CH3:26])=[CH:16][C:15]=2[F:27])[C:6]=1[NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10].[H][H]>C(O)C.[C].[Pd]>[F:27][C:15]1[CH:16]=[C:17]([CH3:26])[C:18]([S:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:19][C:14]=1[N:5]1[C:6]([NH:7][C:8](=[O:13])[C:9]([F:12])([F:10])[F:11])=[CH:2][C:3]([O:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:32])([F:33])[F:34])=[N:4]1
Reactant: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)c(Br)c2NC(=O)C(F)(F)F)cc1SCC(F)(F)F
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(F)c(-n2nc(OCC(F)(F)C(F)(F)F)cc2NC(=O)C(F)(F)F)cc1SCC(F)(F)F
Yield: 95.3 %

Procedure:
1.2 g of 4-bromo-1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)-5-trifluoroacetylaminopyrazole was dissolved in 200 mL of ethanol, and 1.2 g of 10% palladium carbon was added. 430 mL of hydrogen was blown over a period of 10 days at room temperature under reduced pressure, the solvent was distilled off under reduced pressure, and the obtained residue was purified by column chromatography (developing solvent ethyl acetate:hexane:acetic acid=10:40:1) to obtain 1.0 g of 1-{2-fluoro-4-methyl-5-(2,2,2-trifluoroethylthio)phenyl}-3-(2,2,3,3,3-pentafluoropropoxy)-5-trifluoroacetylaminopyrazole.
Reaction SMILES: [C@H:1]1([O:12][CH2:13][C@H:14]2[O:20][C@H:18]([OH:19])[C@H:17]([OH:21])[C@@H:16]([OH:22])[C@@H:15]2[OH:23])[O:9][C@H:8]([CH2:10][OH:11])[C@H:6]([OH:7])[C@H:4]([OH:5])[C@H:2]1[OH:3].S([O-])([O-])(=O)=O.[Ca+2].[C:30](Cl)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OC(=O)C)(=O)C>N1C=CC=CC=1>[C:30]([O:11][CH2:10][C@H:8]1[O:9][C@H:1]([O:12][CH2:13][C@H:14]2[O:20][C@H:18]([OH:19])[C@H:17]([OH:21])[C@@H:16]([OH:22])[C@@H:15]2[OH:23])[C@H:2]([OH:3])[C@@H:4]([OH:5])[C@H:6]1[OH:7])([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: OC[C@H]1O[C@H](OC[C@H]2O[C@H](O)[C@H](O)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@H]1O
Agent: O=S(=O)([O-])[O-]
Agent: [Ca+2]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: O[C@@H]1[C@@H](O)[C@@H](O)O[C@H](CO[C@H]2O[C@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)[C@H](O)[C@H](O)[C@H]2O)[C@H]1O
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A 5.13 g portion of anhydrous 6-O-α-D-galactopyranosyl-α-D-glucopyranose is suspended in 50 ml of pyridine and 5.0 g of anhydrous calcium sulfate is added. This mixture is heated at 90° C. for 30 minutes, then 4.6 g of trityl chloride is added and heating and stirring are continued for 2 hours. The solution is cooled to room temperature, 10 ml of acetic anhydride is added and the mixture is allowed to stand overnight. The mixture is poured into crushed ice and the solid is filtered, washed with water and dried, giving 10 g of 6-O-(6-O-trityl-α-D-galactopyranosyl)-α-D-glucopyranose, heptaacetate as a colorless granular solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9]([O:14][CH3:15])=[C:8]([CH3:16])[C:4]=1[C:5]([OH:7])=O.[NH2:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[CH:21]=[CH:22][C:23]=1[OH:24]>>[OH:24][C:23]1[CH:22]=[CH:21][C:20]([CH2:25][C:26]([O:28][CH3:29])=[O:27])=[CH:19][C:18]=1[NH:17][C:5](=[O:7])[C:4]1[C:8]([CH3:16])=[C:9]([O:14][CH3:15])[C:10]([CH3:13])=[C:11]([CH3:12])[C:3]=1[O:2][CH3:1]
Reactant: COc1c(C)c(C)c(OC)c(C(=O)O)c1C
Reactant: COC(=O)Cc1ccc(O)c(N)c1
Product: COC(=O)Cc1ccc(O)c(NC(=O)c2c(C)c(OC)c(C)c(C)c2OC)c1

Procedure:
2,5-Dimethoxy-3,4,6-trimethylbenzoic acid (m.p. 98°-100° C. was reacted with methyl 3-amino-4-hydroxyphenylacetate to give methyl 4-hydroxy-3-(2,5-dimethoxy-3,4,6-trimethylbenzoylamino)phenylacetate [m.p. 159°-160° C., δ 2.14 (3H), 2.20 (3H), 2.32 (3H), 3.48 (2H), 3.65 (6H), 3.70 (3H), 7.02 (3H), 8.30 (1H), 8.87 (1H)] (11.0 g, 28.4 mmol), which was dehydrated with phosphorus oxychloride (13.1 g) to give methyl 2-[6-(2,5-dimethoxy-3,4,6-trimethylphenyl)benzoxazol-6-yl]acetate m.p. 68°-69° C., δ 2.22 (3H), 2.27 (3H), 3.58 (3H), 3.70(3H), 3.72 (3H), 3.76 (2H), 7.32 (1H), 7.55 (1H), 7.76 (1H)] .
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]([F:18])([F:17])[F:16])(=O)=O)=CC=1.[C:20]([O-])(=[S:22])[CH3:21].[K+].O>CC(C)=O>[C:20]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]([F:16])([F:17])[F:18])(=[S:22])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(F)(F)F)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(=S)OCCOCC(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.3 %

Procedure:
2-(2,2,2-trifluoroethoxy)ethyl p-toluenesulfonate (14.0 g, 47 mmol) and potassium thioacetate (10.0 g, 88 mmol) were dissolved in acetone (100 ml) and the mixture was stirred at room temperature for 2 days. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After concentration, silica gel column chromatography (n-hexane/ethyl acetate=10/1) gave 2-(2,2,2-Trifluoroethoxy)ethyl thioacetate (8.3 g, 87%)
Reaction SMILES: Cl.NC1C=C(OC2C=CC(NC3N=CC=CC=3[C:19]([NH:21]C3C=CC(F)=CC=3F)=[O:20])=CC=2F)C=CN=1.Cl.N1[C:40]2=[N:41][CH:42]=[CH:43][C:44]([O:45][C:46]3[CH:51]=[CH:50][C:49]([NH:52][C:53]4[C:58]([C:59]([NH:61][C:62]5[CH:67]=[CH:66][C:65]([F:68])=[CH:64][C:63]=5[F:69])=[O:60])=[CH:57][N:56]=[CH:55][CH:54]=4)=[CH:48][C:47]=3[F:70])=[C:39]2C=C1>>[F:69][C:63]1[CH:64]=[C:65]([F:68])[CH:66]=[CH:67][C:62]=1[NH:61][C:59]([C:58]1[CH:57]=[N:56][CH:55]=[CH:54][C:53]=1[NH:52][C:49]1[CH:50]=[CH:51][C:46]([O:45][C:44]2[CH:43]=[CH:42][N:41]=[C:40]([C:19]([NH2:21])=[O:20])[CH:39]=2)=[C:47]([F:70])[CH:48]=1)=[O:60]
Reactant: O=C(Nc1ccc(F)cc1F)c1cnccc1Nc1ccc(Oc2ccnc3[nH]ccc23)c(F)c1
Reactant: Nc1cc(Oc2ccc(Nc3ncccc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Agent: Cl
Product: NC(=O)c1cc(Oc2ccc(Nc3ccncc3C(=O)Nc3ccc(F)cc3F)cc2F)ccn1
Yield: 12 %

Procedure:
4-(4-Amino-2-fluorophenoxy)picolinamide (0.12 g, 0.50 mmol, Compound C of Example 3) was converted to the desired compound (0.030 g, 12%) in a manner similar to the preparation of 4-(4-(1H-pyrrolo[2,3-b]pyridin-4-yloxy)-3-fluorophenylamino)-N-(2,4-di-fluorophenyl)nicotinamide (Step D of Example 1).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([OH:12])=[CH:4][CH:3]=1.[H-].[Na+].Br[C:16]1[CH:17]=[N+:18]([O-:25])[CH:19]=[CH:20][C:21]=1[N+:22]([O-:24])=[O:23].O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:12][C:16]2[CH:17]=[N+:18]([O-:25])[CH:19]=[CH:20][C:21]=2[N+:22]([O-:24])=[O:23])=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:11]=1
Reactant: COC(=O)c1cc(Br)ccc1O
Reactant: O=[N+]([O-])c1cc[n+]([O-])cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)ccc1Oc1c[n+]([O-])ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 5-bromosalicylate (5.78 g, 25.00 mmol) in 30 mL of dry THF was added slowly sodium hydride (0.600 g, 25.00 mmol, 60 wt %) and the solution was stirred at rt for 15 minutes. The solvent was evaporated and the residue was dissolved in 10 mL of dry DMF. To this was added 3-bromo-4-nitropyridine 1-oxide (4.38 g, 20.00 mmol) and the reaction mixture was stirred at 50° C. for 4 h and 40° C. overnight. Water was added and the resulting solid was washed with water, filtered and dried under vacuum. Purification of the crude residue by column chromatography (CH2Cl2 to CH2Cl2/EA=10:1 to 5:1 to 3:1 to 1:1 to pure EA) gave 3-(4-bromo-2-(methoxycarbonyl)phenoxy)-4-nitropyridine 1-oxide as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[C:8]3[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:13][C:9]=3[N:10]=[CH:11][N:12]=2)=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>C1(C)C=CC=CC=1.C(#N)C>[CH2:19]([O:18][C:16]([C:14]1[NH:13][C:9]2[N:10]=[CH:11][N:12]=[C:7]([O:6][C:5]3[CH:21]=[CH:22][C:2]([NH:1][C:31]([NH:30][C:27]4[CH:28]=[CH:29][C:24]([F:23])=[CH:25][CH:26]=4)=[O:32])=[CH:3][CH:4]=3)[C:8]=2[CH:15]=1)=[O:17])[CH3:20]
Reactant: CCOC(=O)c1cc2c(Oc3ccc(N)cc3)ncnc2[nH]1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1cc2c(Oc3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ncnc2[nH]1
Reaction time: 1 h

Procedure:
After dissolving 90 mg of ethyl 4-(4-aminophenoxy)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylate in 3 ml of toluene and 1 ml of acetonitrile at 110° C., 16.6 μl of 4-fluorophenyl isocyanate was added and the mixture was stirred for 1 hour under reflux. After standing at room temperature, the precipitated crystals were filtered out and dried to obtain 110 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[F:31][C:32]([F:41])([F:40])[C:33]1[CH:34]=[CH:35][C:36](Br)=[N:37][CH:38]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:17])[F:19])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:36]1[CH:35]=[CH:34][C:33]([C:32]([F:41])([F:40])[F:31])=[CH:38][N:37]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(B2OC(C)(C)C(C)(C)O2)c1
Reactant: FC(F)(F)c1ccc(Br)nc1
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccc(C(F)(F)F)cn2)c1

Procedure:
N-(4-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (˜0.5 mmol) was used in Procedure A with 5-trifluoromethyl-2-bromopyridine (113 mg, 0.5 mmol). Purified by silica gel chromatography (5-50% ethyl acetate/hexanes) to yield N-(4-chloro-3-(5-(trifluoromethyl)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a white foam: TLC Rf=0.30 (15% ethyl acetate/hexanes); MS (Q1) 460 (M)+.
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[N:14]=[C:13]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:35])[CH2:24][C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)=[O:26])=[CH:18][C:17]=3[F:36])[CH:12]=[CH:11][N:10]=2)=CC=1.C1(OC)C=CC=CC=1>C(O)(C(F)(F)F)=O>[NH2:8][C:9]1[N:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:35])[CH2:24][C:25]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)=[O:26])=[CH:18][C:17]=2[F:36])[CH:12]=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2nccc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: Nc1nccc(Oc2ccc(NC(=O)CC(=O)Nc3ccc(F)cc3)cc2F)n1
Temperature: 85 °C
Yield: 62.6 %

Procedure:
A mixture of N1-(4-(2-(4-methoxybenzylamino)pyrimidin-4-yloxy)-3-fluorophenyl)-N3-(4-fluorophenyl)malonamide (Example 14, 25 mg, 0.048 mmol), anisole (52 mg, 0.48 mmol) in TFA (1 mL) was heated at 85° C. for 6 h. The TFA was removed under vacuum and the residue partitioned between EtOAc and saturated aq. NaHCO3 solution. The EtOAc phase was washed with brine, dried (MgSO4), and concentrated in vacuo. Flash chromatography on SiO2 using EtOAc then 1-2% MeOH in CH2Cl2 as eluents gave the title compound (12 mg, 63%) as an off-white solid. 1H NMR (DMSO-d6) δ 11.00 (s, 1H), 10.51 (s, 1H), 8.02 (s, 1H), 7.66 (dd, 1H, J=12.6, 2.0 Hz), 7.42-7.31 (m, 2H), 7.32-7.27 (m, 1H), 7.23 (t, 2H, J=8.6 Hz), 7.16 (t, 2H, J=9.1 Hz), 6.91 (s, 2H), 3.73 (s, 2H); MS(ESI+) m/z 400.11 (M+H)+.
Reaction SMILES: O=[C:2]([CH:8]1[C:17](=O)[C:13]2[S:14][CH:15]=[CH:16][C:12]=2[CH2:11][CH2:10][CH2:9]1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].Cl.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[NH:28][NH2:29]>C(O)C>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[N:28]1[C:17]2[C:13]3[S:14][CH:15]=[CH:16][C:12]=3[CH2:11][CH2:10][CH2:9][C:8]=2[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])=[N:29]1
Reactant: NNc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)C(=O)C1CCCc2ccsc2C1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1nn(-c2ccc(Cl)cc2Cl)c2c1CCCc1ccsc1-2
Yield: 35 %

Procedure:
560 mg of ethyl 2-oxo-2-(8-oxo-5,6,7,8-tetrahydro-4H-cyclo hepta[b]thiophen-7-yl)acetate prepared in example 9d are solubilized in absolute ethanol (11 mL). 580 mg of 2,4-dichlorophenyl-hydrazine hydrochloride are added. The reaction mixture is heated under reflux conditions for 14 hours. The solvent is removed under vacuum and the obtained residue is purified by chromatography on silica gel by using as eluent a mixture of ligroin/ethyl acetate 9:1 volume/volume. 300 mg of ethyl 1-(2′,4′-dichlorophenyl)-1,4,5,6-tetrahydro-thieno[3′,2′:6,7]-cyclo-hepta[1,2-c]pyrazol-3-carboxylate are obtained (orange solid; yield 35%). Rf=0.20 (ligroin/ethyl acetate 9/1 volume/volume); 1H NMR (CDCl3) δ (ppm): 7.55 (d, 1H, ArH), 7.48 (d, 1H, ArH), 7.42 (dd, 1H, ArH), 7.03 (d, 1H, ArH), 6.79 (d, 1H, ArH), 4.44 (q, 2H, OCH2), 3.29 (m, 2H, CH2), 2.99 (m, 2H, CH2), 2.06 (m, 2H, CH2), 1.42 (t, 3H, CH3); 13C NMR (CDCl3) δ (ppm): 162.8, 143.2, 142.4, 137.2, 136.4, 135.3, 131.9, 130.3, 130.0, 128.1, 124.8, 124.2, 122.4, 61.0, 30.9, 26.1, 24.4, 14.5; FT-IR (film) νmax: 3092.7, 2928.9, 1712.5, 1486.6, 1446.9, 1245.6, 1190.9, 1100.3, 947.0, 713.9, 641.6, 610.6 cm−1.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[NH:29][CH:30]=[CH:31][C:24]=34)[CH:20]=[N:19]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([O:16]C)=[O:15])=[N:12][CH:13]=2)[CH2:5]1)#[N:2].O.[OH-].[Li+]>CO.O>[C:1]([CH2:3][C:4]1([N:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[NH:29][CH:30]=[CH:31][C:24]=34)[CH:20]=[N:19]2)[CH2:5][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([OH:16])=[O:15])=[N:12][CH:13]=2)[CH2:7]1)#[N:2]
Reactant: COC(=O)c1cnc(N2CC(CC#N)(n3cc(-c4ccnc5[nH]ccc45)cn3)C2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: N#CCC1(n2cc(-c3ccnc4[nH]ccc34)cn2)CN(c2cnc(C(=O)O)cn2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of methyl 5-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyrazine-2-carboxylate (0.15 g, 0.36 mmol) and lithium hydroxide monohydrate (46 mg, 1.1 mmol) in methanol (3 mL) and water (1 mL) was stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure to afford the desired product (quantitative) which was directly used in the next step reaction without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][O:4]C1CCCCO1.[ClH:11].[CH:12]1[C:21]2[C:16](=[C:17]([NH:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([NH2:29])[CH2:25][CH2:24]3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1>>[ClH:11].[CH:12]1[C:21]2[C:16](=[C:17]([NH:22][C@H:23]3[CH2:24][CH2:25][C@H:26]([NH:29][CH2:2][CH2:3][OH:4])[CH2:27][CH2:28]3)[CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][N:13]=1
Reactant: BrCCOC1CCCCO1
Reactant: N[C@H]1CC[C@H](Nc2cccc3cnccc23)CC1
Agent: Cl
Product: OCCN[C@H]1CC[C@H](Nc2cccc3cnccc23)CC1

Procedure:
According to the method of Example 144, an alkylation reaction with 2-(2-bromoethoxy)tetrahydro-2H-pyran and a deprotection reaction were performed by using the compound of Example 24 to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19](B5OC(C)(C)C(C)(C)O5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.Br[C:36]1[C:41]([CH3:42])=[CH:40][C:39]([C:43]2[N:44]=[N:45][C:46]([CH3:49])=[CH:47][CH:48]=2)=[CH:38][C:37]=1[CH3:50].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[CH3:1][O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([C:36]5[C:37]([CH3:50])=[CH:38][C:39]([C:43]6[N:44]=[N:45][C:46]([CH3:49])=[CH:47][CH:48]=6)=[CH:40][C:41]=5[CH3:42])[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: Cc1ccc(-c2cc(C)c(Br)c(C)c2)nn1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(-c6ccc(C)nn6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-7-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 3-(4-bromo-3,5-dimethyl-phenyl)-6-methyl-pyridazine following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 26): tR=0.75 min; Mass spectrum (ESI+): m/z=539 [M+H]+.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[NH:8]1[CH:12]=[CH:11][N:10]=[CH:9]1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH:22]2[O:24][CH2:23]2)=[CH:16][CH:15]=1>O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][CH:22]([OH:24])[CH2:23][N:8]2[CH:12]=[CH:11][N:10]=[CH:9]2)=[CH:18][CH:19]=1
Reactant: c1c[nH]cn1
Reactant: Brc1ccc(CCC2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OC(CCc1ccc(Br)cc1)Cn1ccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.1 %

Procedure:
To a sample of pure sodium hydride (1.60 g, 66.58 mmol, 1.4 equiv) under a N2 atmosphere was added DMF (40 mL). The mixture was cooled to 0° C. and imidazole (4.86 g, 71.34 mmol, 1.5 equiv) was added in many small portions over 1 h. Stirring was continued for an additional 0.5 h at 0° C. To the mixture was added dropwise the neat epoxide 12a (10.80 g, 47.56 mmol, 1 equiv); the epoxide container was rinsed with DMF (10 mL) and the rinse solution was added to the reaction mixture. The mixture was stirred at 0° C. for 0.5 h and then at rt for 24 h. Monitoring by TLC (silica gel, EtOAc) confirmed the completion of the reaction. Water (20 mL) was added, the mixture cooled to 0° C., and more water (200 mL) was added without stirring. After 1 h at 0° C. an additional 100 mL of water were added. The white solid was removed by filtration and washed with water (3×250 mL), and then with hexanes (200 mL). High-vacuum drying gave the imidazole-alcohol 13a (11.80 g, 39.98 mmol, 84%) as a white solid: mp 121-122° C., Rf=0.08 (ethyl acetate); 1H NMR (400 MHz, CDCl3): δ 1.68-1.82 (m, 2H), 2.68-2.76 (m, 1H), 2.82-2.89 (m, 1H), 3.75-3.94 (m, 3H), 6.80 (s, 1H), 6.84 (s, 1H), 7.08 (d, J=8.4 Hz, 2H), 7.31 (s, 1H), 7.40 (d, J=8.4 Hz, 2H); 13C NMR (100 Adz, CDCl3): δ 31.3, 36.0, 54.1, 69.5, 119.9, 128.5, 130.4, 131.6, 140.6; HAS (EI) Calcd. for C13H15BrN2O: 294.0368 (M+). Found: 294.0375.
Reaction SMILES: C([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][C:12]=2F)[CH2:6][CH2:5]1)(=O)C.O.[NH2:21][NH2:22]>>[Br:17][C:14]1[CH:13]=[C:12]2[C:11]([C:10]([CH:7]3[CH2:8][CH2:9][NH:4][CH2:5][CH2:6]3)=[N:21][NH:22]2)=[CH:16][CH:15]=1
Reactant: CC(=O)N1CCC(C(=O)c2ccc(Br)cc2F)CC1
Reactant: NN
Solvent: O
Product: Brc1ccc2c(C3CCNCC3)n[nH]c2c1
Reaction time: 20 h
Yield: 32 %

Procedure:
A mixture of 9.6 g of 1-acetyl-4-(4-bromo-2-fluorobenzoyl)piperidine and 50 ml of hydrazine hydrate was stirred in an autoclave at 135°-140° C. for 20 hr. The reaction mixture was quenched with water and the solid was collected. The solid was recrystallized from acetonitrile (charcoal) to yield 2.6 g (32%) of product, mp 163°-165° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([CH3:8])[CH:7]=1.C([Li])(C)(C)C.[CH2:15]([C@@H:17]1[O:19][CH2:18]1)[Cl:16]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:16][CH2:15][C@H:17]([OH:19])[CH2:18][C:2]1[CH:3]=[CH:4][C:5]([Cl:9])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)ccc1Cl
Reactant: ClC[C@H]1CO1
Agent: [Li]C(C)(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1cc(C[C@@H](O)CCl)ccc1Cl
Reaction time: 0.5 h
Yield: 44.8 %

Procedure:
The solution of 1.0 g (4.9 mmol) 5-bromo-2-chlorotoluene in 10 mL toluene was cooled down to −70° C. and treated dropwise with 3.6 mL (5.4 mmol; 1.5M solution in toluene) tert-butyllithium. After 30 min. 0.42 mL (5.3 mmol) (R)-(−)-epichlorohydrin was added and the temperature was allowed to rise to 0° C. After 1 h the reaction mixture was diluted with ethyl acetate and extracted with 10% aqueous sodium bicarbonate solution followed by brine. The organic layer was dried over magnesium sulfate, filtered and evaporated and the residue was purified by column chromatography on silica gel with n-hexane:ethyl acetate (1:1) as eluant to give the title compound as a colorless oil (44.8%).
Reaction SMILES: F[C:2]1[CH:31]=[CH:30][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:24]=[CH:23][C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=3)=[N:11][C:10]=2[C:25](OCC)=[O:26])=[O:7])=[CH:4][CH:3]=1.[NH2:32][CH2:33][CH2:34][OH:35]>CN1C(=O)CCC1.CCOC(C)=O>[OH:35][CH2:34][CH2:33][NH:32][C:25]([C:10]1[N:11]=[C:12]([NH:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)[S:13][C:9]=1[NH:8][C:6](=[O:7])[C:5]1[CH:30]=[CH:31][C:2]([NH:11][CH2:10][CH2:25][OH:26])=[CH:3][CH:4]=1)=[O:26]
Reactant: CCOC(=O)c1nc(Nc2ccc3ccccc3c2)sc1NC(=O)c1ccc(F)cc1
Reactant: NCCO
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C(Nc1sc(Nc2ccc3ccccc3c2)nc1C(=O)NCCO)c1ccc(NCCO)cc1
Yield: 47.5 %

Procedure:
A solution of Ethyl 5-(4-fluorobenzamido)-2-(naphthalen-2-ylamino)thiazole-4-carboxylate (25 mg, 0.06 mmol) and 2-aminoethanol (0.024 mL, 0.40 mmol) in NMP (0.5 mL) was treated using a microwave synthesizer for 70 min (Biotage, 150° C.). The reaction mixture was diluted with EtOAc. The organic layer was washed with H2O, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel chromatography eluted with 2.5% MeOH in DCM to give 7 mg (25% yield) of the titled compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[O:16][C:15]([NH:18][C:19]4[CH:24]=[C:23]([O:25][CH3:26])[C:22]([O:27][CH3:28])=[C:21]([O:29][CH3:30])[CH:20]=4)=[N:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[C:31](Cl)(=[O:33])[CH3:32]>N1C=CC=CC=1>[CH3:26][O:25][C:23]1[CH:24]=[C:19]([NH:18][C:15]2[O:16][C:17]3[C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:31](=[O:33])[CH3:32])=[CH:4][CH:5]=4)=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=2)[CH:20]=[C:21]([O:29][CH3:30])[C:22]=1[O:27][CH3:28]
Reactant: COc1cc(Nc2nc3cccc(-c4ccc(CN)cc4)c3o2)cc(OC)c1OC
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2nc3cccc(-c4ccc(CNC(C)=O)cc4)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.070 g (0.173 mmol) [7-(4-aminomethyl-phenyl)-benzooxazol-2-yl]-(3,4,5-trimethoxy-phenyl)-amine (example 29), 1 ml pyridine and 0.016 g (0.199 mmol) acetyl chloride is stirred for 1.5 h at room temperature. Then the reaction mixture is poured on water and extracted 2× with EtOAc. The combined organic layers are washed with water and 0.1N NaOH solution, dried over MgSO4, filtered and the filtrate is concentrated in vacuo and co-evaporated twice with toluene. The residue is purified by crystallization from dichloromethane/diethyl ether to afford the title compound as a light brown solid. Rt=2.12 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min); MS: 448 (M+1)+; m.p. 237-239° C.
Reaction SMILES: [CH:1](=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[ClH:11].Cl.[F:13][C:14]([F:30])([F:29])[C:15]1[CH:28]=[CH:27][C:18]([CH2:19][NH:20][C:21]([NH:23][C:24]([NH2:26])=[NH:25])=[NH:22])=[CH:17][CH:16]=1>C(O)C>[ClH:11].[NH2:26][C:24]1[NH:23][C:21]([NH:20][CH2:19][C:18]2[CH:27]=[CH:28][C:15]([C:14]([F:13])([F:29])[F:30])=[CH:16][CH:17]=2)=[N:22][CH:1]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[N:25]=1
Reactant: CCCCCCCCC=O
Reactant: N=C(N)NC(=N)NCc1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: CCO
Product: CCCCCCCCC1N=C(N)NC(NCc2ccc(C(F)(F)F)cc2)=N1

Procedure:
100 ml of ethanol, 4.4 ml (25.6 mmol) of 1-nonanal and 0.7 ml of concentrated hydrochloric acid were added to 5.0 g (16.9 mmol) of N1-(4-trifluoromethylbenzyl)-biguanide hydrochloride, and the mixture was refluxed for 26 hours. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (elution with a mixture of chloroform and methanol (9:1.5)) to give a residue, which was dissolved in 80% aqueous ethanol. The solvent was distilled off under reduced pressure, followed by sufficient drying under reduced pressure to obtain 2.3 g of a colorless resinous solid.