Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([C:16]2([C:19]([O:21]CC)=[O:20])[CH2:18][CH2:17]2)[C@H:13]([F:24])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][C@H:13]([F:24])[C@@H:14]([C:16]2([C:19]([OH:21])=[O:20])[CH2:18][CH2:17]2)[CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1([C@@H]2CN(C(=O)OCc3ccccc3)C[C@H]2F)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(OCc1ccccc1)N1C[C@H](F)[C@@H](C2(C(=O)O)CC2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.3 %

Procedure:
1-Benzyloxycarbonyl-4-(R)-(1-ethoxycarbonylcyclopropyl)-3-(S)-fluoropyrrolidine (3.715 g, 11.08 mmol) was dissolved in ethanol (110 ml), and 10 N sodium hydroxide aqueous solution (11 ml) was added dropwise to the thus prepared solution which was cooled in an ice bath. The reaction solution was stirred at room temperature for 18 hours and then ethanol was evaporated under reduced pressure. The thus obtained residue was mixed with water (50 ml) and washed with dichloromethane (50 ml×2). The thus separated aqueous layer was cooled in an ice bath, acidified by adding dropwise concentrated hydrochloric acid, extracted with diethyl ether (100 ml×5) and then dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was dissolved in benzene (100 ml) and again concentrated under reduced pressure. This azeotropic step with benzene was repeated 3 times to obtain 3.346 g (98.3%) of the title compound as a colorless amorphous substance.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:12]([C:13](Cl)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH2:23][C:24]1[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=1>>[F:1][C:2]([F:22])([F:21])[C:3]1[C:12]([C:13]([NH:23][C:24]2[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=2)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=C(Cl)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Reactant: Cn1ccnc1N
Product: Cn1ccnc1NC(=O)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Yield: 33.9 %

Procedure:
Using the procedure of Example 1, 2,8-bis-(trifluoromethyl)-4-hydroxy-3-quinoline-carboxylic acid chloride and 2-amino-N-methyl-imidazole were reacted to obtain a 33.9% yield of 2,8-bis-(trifluoromethyl)-4-hydroxy-N-(1-methyl-1H-imidazol-2-yl-)-3-quinolinecarboxamide melting at 259° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([OH:34])[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[N:57]1([CH2:63][CH2:64][CH2:65]O)[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([O:35][CH3:36])=[C:31]([O:34][CH2:65][CH2:64][CH2:63][N:57]6[CH2:62][CH2:61][O:60][CH2:59][CH2:58]6)[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:6][CH:7]=1
Reactant: OCCCN1CCOCC1
Reactant: COc1cc2ncnc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)c2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 10.2 %

Procedure:
Crude cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(6-hydroxy-7-methoxy-quinazolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (333 mg, 0.66 mmol), PS-PPh3 resin, (loading=2.33 mmol/g, 797 mg, 1.86 mmol), 3-morpholin-4-yl-propan-1-ol (0.26 ml, 1.88 mmol), and DEAD (0.31 ml, 1.91 mmol) were combined in CH2Cl2 (10 ml) and stirred at room temperature for 1-2 hrs. The reaction mixture was filtered and the resin thoroughly washed with CH2Cl2. The filtrate was concentrated in vacuo and the resulting residue was dissolved in EtOAc and washed with H2O (4×) and sat'd NaCl (1×) and then extracted with 1N HCl (3×). The combined 1N HCl extractions were washed with EtOAc (2×). The acidic aqueous phase was then basified with 1N NaOH and extracted with EtOAc (3×). The combined EtOAc extractions were washed with H2O (1×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by preparative reverse phase HPLC (25 mM NH4OAc/acetonitrile) and the pure fractions were lyophilized to give cyclopropane-1,1-dicarboxylic acid {3-fluoro-4-[7-methoxy-6-(3-morpholin-4-yl-propoxy)-quinazolin-4-yloxy]-phenyl}-amide (4-fluoro-phenyl)-amide (42.6 mg, 10%). 1H NMR (400 MHz, DMSO-d6): δ 10.37 (br s, 1H), 10.05 (br s, 1H), 8.55 (s, 1H), 7.84 (m, 1H), 7.65 (m, 2H), 7.58 (s, 1H), 7.43 (m, 3H), 7.16 (t, 2H), 4.27 (m, 2H), 4.00 (s, 3H), 3.60 (m, 6H), 2.39 (m, 4H), 1.99 (m, 2H), 1.47 (m, 4H). LC/MS Calcd for [M+H]+ 634.2, found 634.1.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.[F:9][C:10]([F:37])([F:36])[C:11]([CH2:31][NH:32][CH2:33][CH2:34][CH3:35])([OH:30])[CH2:12][NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1>>[CH2:33]([N:32]([CH2:31][C:11]([CH2:12][NH:13][C:14]1[CH:22]=[CH:21][CH:20]=[C:19]2[C:15]=1[CH:16]=[N:17][N:18]2[C:23]1[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=1)([OH:30])[C:10]([F:9])([F:36])[F:37])[C:6]([C:3]1[CH:4]=[CH:5][S:1][CH:2]=1)=[O:8])[CH2:34][CH3:35]
Reactant: CCCNCC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F
Reactant: O=C(O)c1ccsc1
Product: CCCN(CC(O)(CNc1cccc2c1cnn2-c1ccc(F)cc1)C(F)(F)F)C(=O)c1ccsc1

Procedure:
Prepared similarly to Example 1 from 3-thiophenecarboxylic acid and 1,1,1-trifluoro-3-{[1-(4-fluorophenyl)-1H-indazol-4-yl]amino}-2-[(propylamino)methyl]-2-propanol.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([NH:21][CH2:22][C:23]3([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:20])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1.C([Si]([O:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH:60]2[CH2:62][O:61]2)=[CH:54][CH:53]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>>[C:28]1([C:23]2([CH2:22][NH:21][C:19]([N:16]3[CH2:15][CH2:14][CH:13]([S:10]([C:7]4[CH:6]=[CH:5][C:4]([CH2:3][CH2:2][NH:1][CH2:62][C@H:60]([OH:61])[CH2:59][O:58][C:55]5[CH:56]=[CH:57][C:52]([OH:51])=[CH:53][CH:54]=5)=[CH:9][CH:8]=4)(=[O:12])=[O:11])[CH2:18][CH2:17]3)=[O:20])[CH2:27][CH2:26][CH2:25][CH2:24]2)[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(S(=O)(=O)C2CCN(C(=O)NCC3(c4ccccc4)CCCC3)CC2)cc1
Product: O=C(NCC1(c2ccccc2)CCCC1)N1CCC(S(=O)(=O)c2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 33.1 %

Procedure:
4-{[4-(2-Aminoethyl)phenyl]sulfonyl}-N-[(1-phenylcyclopentyl)methyl]-1-piperidinecarboxamide (0.570 g, 1.20 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenylsilane (0.417 g, 1.03 mmol) according to Procedure G to give the title compound (eluant: 20:1 chloroform-methanol) (0.298 g, 0.341 mmol).
Reaction SMILES: [CH:1]1([N:7]2[C:10](=[O:11])[C:9]([CH3:13])([CH3:12])[NH:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br>>[Cl:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][N:8]1[C:9]([CH3:13])([CH3:12])[C:10](=[O:11])[N:7]1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Clc1ccccc1CBr
Reactant: CC1(C)NN(C2CCCCC2)C1=O
Product: CC1(C)C(=O)N(C2CCCCC2)N1Cc1ccccc1Cl

Procedure:
2-Cyclohexyl-4,4-dimethyl-1,2-diazetidin-3-one and 2-chlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a pale yellow oil.
Reaction SMILES: [O:1]=[C:2]1[C:10](=[CH:11][C:12]2[NH:13][CH:14]=[CH:15][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:17]2[CH:18]=[C:19]([NH:23][C:24]([C:26]3[CH:31]=[CH:30][C:29]([O:32]C(=O)OC)=[CH:28][CH:27]=3)=[O:25])[CH:20]=[CH:21][CH:22]=2)[NH:3]1.O.[OH-].[K+]>O1CCOCC1>[O:1]=[C:2]1[NH:3][C:4]2[C:9](/[C:10]/1=[CH:11]/[C:12]1[NH:13][CH:14]=[CH:15][CH:16]=1)=[C:8]([C:17]1[CH:18]=[C:19]([NH:23][C:24](=[O:25])[C:26]3[CH:27]=[CH:28][C:29]([OH:32])=[CH:30][CH:31]=3)[CH:20]=[CH:21][CH:22]=1)[CH:7]=[CH:6][CH:5]=2
Reactant: COC(=O)Oc1ccc(C(=O)Nc2cccc(-c3cccc4c3C(=Cc3ccc[nH]3)C(=O)N4)c2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C1Nc2cccc(-c3cccc(NC(=O)c4ccc(O)cc4)c3)c2/C1=C/c1ccc[nH]1
Temperature: 90 °C

Procedure:
A solution of the crude carbonic acid methyl ester 4-[3-[2-oxo-3-[(1H-pyrrol-2-yl)methylene]-2,3-dihydro-1H-indol-4-yl]-phenylcarbamoyl]-phenyl ester (90 mg, 0.194 mmol) in 2 mL of 1,4-dioxane (Aldrich) was treated with 1.5 mL of distilled water and then powdered potassium hydroxide (25 mg, 0.445 mmol) . The reaction mixture was heated at 90° C. for 1 h. The reaction mixture was then allowed to cool to room temperature and directly purified by flash chromatography (Merck Silica gel 60, 230-400 mesh, 45% ethyl acetate-hexanes elution) to provide a crude yellow solid containing the desired product and a 1,3-dicyclohexylcarbodiimide derivative. Most of the 1,3-dicyclohexylcarbodiimide derivative was removed by precipitation from an ethanolic solution through the slow addition of distilled water. The precipitated solid was collected by suction filtration. The filtrate was concentrated in vacuo and then directly purified by column chromatography. Two additional rounds of flash chromatography (Merck Silica gel 60, 230-400 mesh, 25% ethyl acetate-hexanes elution each) provided pure (Z)-N-[3-[2,3-dihydro-2-oxo-3-[(1H-pyrrol-2-yl)methylene]-1H-indol-4-yl]-phenyl]-4-hydroxybenzamide (yield: 49 mg, 60%) as a yellow solid (mp 236-238° C.).
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@@H:26]([OH:29])[CH2:27][OH:28])=[CH:20][CH:19]=2)[C:13]([C:30]#[N:31])=[C:12]([S:32][CH2:33][C:34]2[N:35]=[C:36]([C:39]3[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][CH:40]=3)[O:37][CH:38]=2)[N:11]=1.[ClH:46]>C(#N)C.[Cu](Cl)Cl>[Cl:46][C:10]1[C:15]([C:16]#[N:17])=[C:14]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C@@H:26]([OH:29])[CH2:27][OH:28])=[CH:20][CH:19]=2)[C:13]([C:30]#[N:31])=[C:12]([S:32][CH2:33][C:34]2[N:35]=[C:36]([C:39]3[CH:40]=[CH:41][C:42]([Cl:45])=[CH:43][CH:44]=3)[O:37][CH:38]=2)[N:11]=1
Reactant: Cl
Reactant: N#Cc1c(N)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@@H](O)CO)cc1
Agent: Cl[Cu]Cl
Agent: CC(C)CCON=O
Solvent: CC#N
Product: N#Cc1c(Cl)nc(SCc2coc(-c3ccc(Cl)cc3)n2)c(C#N)c1-c1ccc(OC[C@@H](O)CO)cc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
171 mg (1.46 mmol) of isopentyl nitrite and 196 mg (1.46 mmol) of copper(II) chloride were initially charged in 18 ml of acetonitrile. 389 mg (0.73 mmol) of the compound from Example 40A were added, and the mixture was then stirred at 60° C. for 3 h. After cooling to RT, 20 ml of 1N hydrochloric acid were added. The aqueous phase was extracted twice with in each case 30 ml of ethyl acetate. The combined organic phases were dried over magnesium sulfate. The solvent was removed, and the product was then used without further purification for the subsequent reaction.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.CC(C)([O-])C.[K+].Cl[CH2:23][C:24]1[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=1)[C:27]([O:29][CH3:30])=[O:28]>O1CCCC1>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[N:6]([CH2:23][C:24]3[CH:25]=[C:26]([CH:31]=[CH:32][CH:33]=3)[C:27]([O:29][CH3:30])=[O:28])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)c1cccc(CCl)c1
Reactant: c1ccc2c(c1)CCc1ccccc1N2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cccc(CN2c3ccccc3CCc3ccccc32)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25.6 %

Procedure:
To a solution of 10,11-dihydro-5H-dibenz[b,f]azepine (2.44 g) in tetrahydrofuran (25 ml) was added potassium tert-butoxide (2.02 g) at 0° C. The mixture was stirred at 0° C. for 15 minutes, and then a solution of methyl 3-(chloromethyl)benzoate (3.57 g) in tetrahydrofuran (15 ml) was added. The mixture was stirred at 25° C. for 1 hour, and then evaporated. The residue was partitioned between ethyl acetate and 0.1N hydrochloric acid. The organic layer was washed with water and brine, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel eluting with a mixture of hexane and ethyl acetate (40:1) to give methyl 3-(10,11-dihydro-5H-dibenz[b,f]azepin-5-ylmethyl)benzoate (1.10 g) as an oil.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:13][CH2:14][CH3:15])=[CH:9][CH:10]=2)[C:5]1=O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O.[NH2:29][CH2:30][C@H:31]([OH:33])[CH3:32]>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:29]([CH2:30][C@H:31]([OH:33])[CH3:32])[C:5]=32)=[CH:10][CH:9]=1)[CH3:15]
Reactant: C[C@@H](O)CN
Reactant: CCOc1ccc2c(c1)C(=O)C(CC=O)C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOc1ccc2c(c1)-c1c(ccn1C[C@@H](C)O)C2
Reaction time: 0.75 h
Yield: 54.6 %

Procedure:
A solution of 1.6 g of (RS)-2-(2-oxoethyl)-6-ethoxy-1-indanone and 70 mg of p-toluenesulfonic acid in 70 ml of anhydrous toluene was heated on a water separator. A solution of 2.2 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 45 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/hexane 4:1). 1.03 g (52%) of (R)-1-(7-ethoxy-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[CH:5][C:4]=1[Cl:12].[CH3:13][C:14]1[N:19]=[C:18]([SH:20])[N:17]=[C:16]([OH:21])[CH:15]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:12][C:4]1[CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[CH:7]=[CH:8][C:3]=1[CH2:2][S:20][C:18]1[N:17]=[C:16]([OH:21])[CH:15]=[C:14]([CH3:13])[N:19]=1
Reactant: Cc1cc(O)nc(S)n1
Reactant: O=[N+]([O-])c1ccc(CBr)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(O)nc(SCc2ccc([N+](=O)[O-])cc2Cl)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
1-(bromomethyl)-2-chloro-4-nitrobenzene, 6-methyl-2-sulfanylpyrimidin-4-ol (425 mg, 3 mmol), and potassium carbonate (420 mg, 3 mmol) were mixed in DMF (10 mL). The mixture was stirred at room temperature for 2 hours. To the mixture, water (100 mL) was added. The suspension was filtered and washed with water and ethyl acetate to provide pure titled product (500 mg, 54% yield); 1H NMR (400 MHz, DMSO-d6): δ 2.20 (s, 3H), 4.55 (s, 2H), 6.03 (s, 1H), 7.92 (d, 1H), 8.19 (d, 1H), 8.31 (s, 1H); M+ 312.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][O:48][CH2:49][C:50](Cl)=[O:51].C(N(CC)CC)C>O1CCCC1>[CH3:47][O:48][CH2:49][C:50]([NH:46][C:42]1[CH:43]=[CH:44][CH:45]=[C:40]([C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[C:12]([C:16]4[N:20]=[CH:19][N:18]([C:21]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:34]5[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=5)[N:17]=4)[CH:11]=3)[N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[N:8]=2)[CH:41]=1)=[O:51]
Reactant: COCC(=O)Cl
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(=O)Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5[-1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.125 g, 0.207 mmol), in tetrahydrofuran (5 mL), were added, 2-methoxy acetyl chloride (0.034 g, 0.315 mmol, 0.025 mL) and triethylamine (0.107 g, 1.06 mmol, 0.147 mL). The reaction mixture was stirred at room temperature for 12 hours. After evaporation of the solvent, the residue was dissolved in 10 mL of ethyl acetate and was washed 3 times with water (5 mL). The crude was used without further purification (0.141 g, 99% yield): ES-MS (m/z) 675 [M+1]+.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([OH:17])(=[O:16])[C@@H:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[OH:11].C(N(CC)CC)C>C(OCC)(=O)C>[CH2:1]([O:17][C:9](=[O:16])[C@@H:10]([CH2:12][CH:13]([CH3:15])[CH3:14])[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](O)C(=O)O
Reactant: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)C[C@@H](O)C(=O)OCc1ccccc1
Yield: 62.3 %

Procedure:
278 g of benzyl bromide were added to a stirred solution of 215 g of D-leucic acid and 246 g of triethylamine in 2.5 l of ethy acetate. The mixture was then heated under reflux for 5 hours, cooled and filtered to remove triethylamine hydrobromide. The filtrate was washed twice with 2M hydrochloric acid, water, saturated sodium bicarbonate solution and then saturated sodium chloride solution. The organic extract was dried over magnesium sulfate and evaporated to give 225 g of D-leucic acid benzyl ester as a yellow liquid.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].FC(F)(F)C(O)=O.[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46](=[O:53])[N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1.[F:55][C:56]1[CH:64]=[C:63]([F:65])[CH:62]=[CH:61][C:57]=1[C:58](Cl)=[O:59]>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([OH:12])=[O:11].[Cl:22][C:23]1[CH:24]=[N:25][C:26]2[NH:27][C:28]3[CH:29]=[N:30][CH:31]=[C:32]([CH:54]=3)[CH2:33][CH2:34][C:35]3[CH:43]=[C:39]([NH:40][C:41]=1[N:42]=2)[CH:38]=[CH:37][C:36]=3[O:44][CH2:45][C:46]([N:47]1[CH2:52][CH2:51][N:50]([C:58](=[O:59])[C:57]2[CH:61]=[CH:62][C:63]([F:65])=[CH:64][C:56]=2[F:55])[CH2:49][CH2:48]1)=[O:53]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(COc1ccc2cc1CCc1cncc(c1)Nc1ncc(Cl)c(n1)N2)N1CCN(C(=O)c2ccc(F)cc2F)CC1
Yield: 30 %

Procedure:
The desired compound was prepared according to the procedure of Example D94 using 6-chloro-12-(2-oxo-2-piperazin-1-ylethoxy)-2,4,8,18,22-pentaazatetracyclo[14.3.1.1(3,7).1(9,13)]docosa-1(20),3(22),4,6,9(21),10,12,16,18-nonaene tris(trifluoroacetate) and 2,4-difluorobenzoyl chloride as the starting materials in 30% yield. LCMS for C30H27ClF2N7O3 (M+H)+: m/z=606.0.
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][S:5][C:6](SC)=[CH:7][C:8]([C:10]1[C:15]([Cl:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][C:11]=1[Cl:21])=O>C(O)C>[Cl:21][C:11]1[CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=[C:15]([Cl:16])[C:10]=1[C:8]1[CH:7]=[C:6]([S:5][CH3:4])[NH:3][N:2]=1
Reactant: CSC(=CC(=O)c1c(Cl)cc(C(F)(F)F)cc1Cl)SC
Reactant: NN
Solvent: O
Solvent: CCO
Product: CSc1cc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)n[nH]1
Reaction time: 0.75 h

Procedure:
Hydrazine monohydrate (0.51 ml) was added dropwise to a solution of 3.6 g of 3,3-bis[methylthio]-1-(2,6-dichloro-4-trifluoromethylphenyl)-2-propen-1-one (17) in 40 ml of ethanol at room temperature, and the mixture was stirred for 45 minutes and then refluxed for 4 hours. The reaction mixture was concentrated under reduced pressure to obtain a residue, which was purified by column chromatography on silica gel (eluent: ether/hexane=2/5) to afford 3.3 g of the desired compound in the form of white crystals.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][S:13](Cl)(=[O:15])=[O:14].[CH:17]1([NH2:20])[CH2:19][CH2:18]1>>[CH:17]1([NH:20][S:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])(=[O:15])=[O:14])[CH2:19][CH2:18]1
Reactant: O=S(=O)(Cl)CCCCCCCCCCCBr
Reactant: NC1CC1
Product: O=S(=O)(CCCCCCCCCCCBr)NC1CC1
Yield: 96 %

Procedure:
The reaction was carried out in the same manner as in Preparation Example 3 except for using 11-bromoundecanesulfonyl chloride (2.29g, 6.85 mmol) in place of 6-bromohexanesulfonyl chloride, and cyclopropylamine (860 mg, 15.1 mmol), to give N-cyclopropyl-11-bromoundecanesulfonamide (2.33 g) as colorless crystals.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:10][C@H:9]([OH:11])[CH2:8][C@H:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:6]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:53](O)(=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55]>C1COCC1>[C:1]([O:4][C@H:5]1[CH2:6][C@H:7]([O:12][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])[CH2:8][C@H:9]([O:11][C:53](=[O:58])[C:54]([CH3:57])([CH3:56])[CH3:55])[CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(C)(C)C(=O)O
Reactant: CC(=O)O[C@@H]1C[C@H](O)C[C@H](O[Si](C)(C)C(C)(C)C)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(=O)O[C@@H]1C[C@@H](OC(=O)C(C)(C)C)C[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reaction time: 1 h

Procedure:
To a solution of 10.67 g of (1R,3S,5S)-3-(tert-butyl-dimethyl-silanoxy)-5-hydroxycyclohex-1-yl acetate in 107 ml of THF was added at 22° 14.55 g of triphenylphosphine, the solution was cooled to 0° and treated dropwise with a solution of 11.81 g of diisopropyl azodicarboxylate and 5.67 g of pivalic acid in 85 ml of THF over 1 h and the solution was stirred at 0° for 1 h after which time t.l.c. showed completion of the reaction. The solution was evaporated, the residue triturated with 130 ml of hexane/AcOEt 9:1, the suspension was filtered and the filtrate evaporated. The residue was chromatographed on silica with hexane/AcOEt 30:1 to give 12.63 g of the pure (t.l.c.) title compound as a colorless oil. IR (neat): 1733s (C═O); MS (EI): 371/1 (M−H).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[C:9]([OH:12])[CH:10]=[CH:11][N:5]2[N:4]=1.[H-].[Na+].[CH3:15][Si:16]([CH3:23])([CH3:22])[CH2:17][CH2:18][O:19][CH2:20]Cl>CN(C=O)C>[CH3:1][S:2][C:3]1[N:8]=[CH:7][C:6]2=[C:9]([O:12][CH2:20][O:19][CH2:18][CH2:17][Si:16]([CH3:23])([CH3:22])[CH3:15])[CH:10]=[CH:11][N:5]2[N:4]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: CSc1ncc2c(O)ccn2n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ncc2c(OCOCC[Si](C)(C)C)ccn2n1
Reaction time: 0.5 h

Procedure:
Into a 1-Neck round-bottom flask, 2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazin-5-ol (0.810 g, 4.47 mmol) and N,N-Dimethylformamide (35.00 mL, 452.0 mmol) were added. Sodium Hydride (60% dispersion mineral oil)(6:4, Sodium hydride:Mineral Oil, 0.214 g, 5.36 mmol) was added portion wise at room temperature and stirred for 30 minutes. [β-(Trimethylsilyl)ethoxy]methyl chloride (0.745 g, 4.47 mmol) in DMF (5 mL) was added dropwise over 10 minutes. The reaction mixture was stirred at room temperature for 1 hour. The reaction was partitioned with water and Et2O. The organic was separated, washed with Brine and dried over Na2SO4. The solid was filtered and washed with DCM. The solvent was removed under vacuum. The reaction mixture was purified via ISCO column chromatography with Hexane and EtOAc as eluant (0 to 40% EtOAc). The collected fractions afforded 2-Methylsulfanyl-5-(2-trimethylsilanyl-ethoxymethoxy)-pyrrolo[2,1-f][1,2,4]triazine as a yellow solid (1.05, 75%).