Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.[ClH:2].C([S:7][CH2:8][C@@:9]([CH3:14])([C:11]([OH:13])=[O:12])[NH2:10])(C)(C)C>C(O)(C)C>[ClH:2].[CH3:14][C@@:9]([C:11]([OH:13])=[O:12])([CH2:8][SH:7])[NH2:10]
Reactant: CC(C)(C)SC[C@](C)(N)C(=O)O
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: C[C@](N)(CS)C(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
First, water (47.6 g) and conc. hydrochloric acid (177.4 g) were added to S-tert-butyl-α-methyl-L-cysteine (25 g, 131 mmol) produced by the method of EXAMPLE 11, and the resultant mixture was refluxed for 41 hours. Furthermore, conc. hydrochloric acid (47.6 g) was added to the mixture, followed by reflux for 3 hours. After the mixture was allowed to cool down to room temperature, isopropyl alcohol (90 mL) was added to the mixture, followed by vacuum concentration. Then, azeotropic dehydration was performed three times using the same amount of isopropyl alcohol. Finally, isopropyl alcohol was added to the residue, and the resultant mixture was concentrated to a volume of about ⅓. Then, the residue was heated to 60° C., and toluene (90 mL) was added to the residue. After the mixture was allowed to cool down to room temperature under stirring, stirring was continued about 1 hour. Then, the precipitated crystals were filtered off, washed with toluene, and dried under reduced pressure to obtain the title compound as a white solid (13.5 g, yield 60.0%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:15]=2[F:21])=[N:11][C:10]=1[C:22]([O:24]C)=[O:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+].O.Cl>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[S:13][C:12]([C:14]2[C:15]([F:21])=[CH:16][CH:17]=[CH:18][C:19]=2[F:20])=[N:11][C:10]=1[C:22]([OH:24])=[O:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1nc(-c2c(F)cccc2F)sc1NC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)Nc1sc(-c2c(F)cccc2F)nc1C(=O)O
Temperature: 60 °C
Yield: 97.8 %

Procedure:
To a suspension of methyl 5-[(tert-butoxycarbonyl)amino]-2-(2,6-difluorophenyl)-1,3-thiazole-4-carboxylate (6.99 g, 18.9 mmol) in MeOH (50.0 mL), lithium hydroxide monohydrate (5.24 g, 125 mmol) was added, followed by water (50.0 mL). The mixture was heated at 60° C. for 5 h. The reaction mixture was then cooled to 0° C., and 6 M HCl was added slowly until the pH reached 2. The resulting solid was collected by filtration and the filter cake was washed with water (50 mL) and MeOH/water (1:1, 50 mL) to provide the sub-title compound as a yellow solid (6.59 g, 98%). LCMS calc. for C15H15F2N2O4S (M+H)+: m/z=357.1. found 357.0.
Reaction SMILES: [NH2:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(O[CH:16]1[CH2:20][CH2:19][CH:18](OCC)O1)C>O1CCOCC1>[C:3]1(=[O:12])[N:2]([N:1]2[CH:16]=[CH:20][CH:19]=[CH:18]2)[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]12
Reactant: NN1C(=O)c2ccccc2C1=O
Reactant: CCOC1CCC(OCC)O1
Solvent: C1COCCO1
Product: O=C1c2ccccc2C(=O)N1n1cccc1
Temperature: 5 °C
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To 10.0 g(61.7 mmol) of N-aminophthalimide was added a solution of 12 ml(72.4 mmol) of 2,5-diethoxytetrahydrofuran in 100 ml of dioxane and 10 ml of 5 N hydrohloric acid was added thereto. The reaction mixture was stirred for 1 hour and cooled to 5° C. The resulting precipitate was filtered, recrystallized from dioxane:water(1:3), washed with ethanol and dried to give 10.3 g of 1-phthalimidopyrrole. This product was dissolved in 60 ml of methanol and 3 ml of 82% hydrazine hydrate was slowly added thereto. After refluxing the reaction mixture for 30 min, cooled to 0°~5° C. and 1.5 ml of glacial acetic acid was added thereto. The resulting precipitate was filtered off and the filtrate was concentrated under the reduced pressure to remove methanol. The concentrate was washed with diethyl ether and vacuum-distilled to give 2.4 g of the desired compound(47.3%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.C(N(CC)CC)C.[Cl:29][CH2:30][CH2:31][CH2:32][C:33](Cl)=[O:34]>C1COCC1>[Cl:29][CH2:30][CH2:31][CH2:32][C:33]([NH:21][C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)=[O:34]
Reactant: O=C(Cl)CCCCl
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1COc1ccc(NC(=O)CCCCl)nn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.7 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (1.0 g, 3.5 mmol) in THF (15 ml) was added triethylamine (0.59 mL, 4.3 mmol). The mixture was cooled in an ice bath and a solution of 4-chlorobutyryl chloride (0.48 mL, 4.3 mmol) in THF (5 mL) was added dropwise. After stirring for 1 h at room temperature the precipitate was filtered and the organic phase was evaporated. The residue was dissolved in methanol (20 mL), sodium bicarbonate (1 spatula) was added and the mixture was stirred at room temperature for 1 h. The solvent was evaporated and the residue was extracted (dichloromethane/water). Then the organic phase was dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane/ethyl acetate=100:0 to 60:40) afforded the title compound (740 mg, 54%) (as the least polar component of two formed in the reaction) which was obtained as a white solid. MS: m/e=387.3 [M+H]+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:9]([Cl:17])=[N:10][CH:11]=[C:12]([CH:16]=1)[C:13]([OH:15])=O.Cl.O1CCOCC1.Cl.[CH:26]12[NH:32][CH:29]([CH2:30][CH2:31]1)[CH2:28][CH2:27]2.C(N(CC)CC)C>C(Cl)Cl>[Cl:7][C:8]1[CH:16]=[C:12]([C:13]([N:32]2[CH:26]3[CH2:31][CH2:30][CH:29]2[CH2:28][CH2:27]3)=[O:15])[CH:11]=[N:10][C:9]=1[Cl:17]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: C1CC2CCC1N2
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cnc(Cl)c(Cl)c1)N1C2CCC1CC2
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
Oxalyl chloride (3.2 mL; 36.0 mmol) was added to a solution of 5,6 dichloronicotinic acid (5.76 g, 30.0 mmol) and 4M hydrogen chloride in dioxane (7.5 mL; 30.0 mmol) in DCM (50 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo, the residue azeotroped with toluene (2×15 mL) and added to a solution of 7-azabicyclo[2.2.1]heptane hydrochloride (4.75 g; 36.0 mmol) and triethylamine (15.1 mL; 108 mmol) in DCM (150 mL). The mixture was stirred at RT for 18 hours, the DCM evaporated in vacuo and the residue partitioned between water (75 mL) and ethyl acetate (150 mL). The organic layer was washed with brine, dried (MgSO4) and evaporated to give a solid which was crystallised from ethyl acetate to give the desired compound (5.45 g).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].Br[CH2:10][CH2:11][CH2:12][Cl:13]>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][CH2:10][CH2:11][CH2:12][Cl:13]
Reactant: Sc1ccccc1Br
Reactant: ClCCCBr
Product: ClCCCSc1ccccc1Br

Procedure:
Prepared by Procedure R and Scheme Z using 2-bromobenzenethiol and 1-bromo-3-chloropropane.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:23][N:24](C)[C:25](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:39]>CC(O)C>[ClH:39].[F:1][C:2]1[C:3]([CH2:23][NH:24][CH3:25])=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cnn(C)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cnn(C)c2)c(-c2cccnc2F)c1F
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 72 %

Procedure:
tert-Butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (460 mg) was dissolved in 2-propanol (5 mL), 4 mol/L hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was stirred at 50° C. for 20 min. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethanol to give the title compound as colorless crystals (yield 285 mg, 72%).
Reaction SMILES: O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[NH:15]([C:22]1[CH:30]=[C:29]([C:31](O)=[O:32])[C:28]([NH:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:27][C:23]=1[C:24](O)=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH:38]1[CH:39]=[C:40]2[C:31]([C:29]3[C:28]([NH:34][C:35]2=[CH:36][CH:37]=1)=[CH:27][C:23]1[C:24]([C:21]2[C:16]([NH:15][C:22]=1[CH:30]=3)=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:25])=[O:32]
Reactant: O=C(O)c1cc(Nc2ccccc2)c(C(=O)O)cc1Nc1ccccc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: O=c1c2ccccc2[nH]c2cc3c(=O)c4ccccc4[nH]c3cc12
Temperature: 85 °C

Procedure:
424 parts of polyphosphoric acid, containing 85.0% P2O5, are introduced into a pressure vessel. Then 84.7 parts of 2,5-dianilinoterephthalic acid are introduced with stirring at from 80 to 90° C. and the mixture is heated at 125° C. for 1 hour during which ring closure takes place to form the quinacridone. The reaction mixture is then introduced into a second pressure vessel where it is hydrolyzed under pressure and with stirring with 1906 parts of 30.9% phosphoric acid at 140° C. During this hydrolysis the temperature rises to 155° C. The mixture is stirred at 155° C. for 0.5 hour. Then it is cooled to 60° C. and the pigment is filtered off with suction, washed to neutrality with water and dried at 80° C.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:37]([NH2:43])[C:38]1[O:42][CH:41]=[CH:40][CH:39]=1>>[O:42]1[CH:41]=[CH:40][CH:39]=[C:38]1[CH2:37][NH:43][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[S:27][CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: NCc1ccco1
Product: O=C(NCc1ccco1)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 93.5 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and furfurylamine (29 mg, 0.30 mmol, 0.6M in DMF) were combined to give 54 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 578 [M+H]+.
Reaction SMILES: [CH2:1]([N:3](CC)[C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=O)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2].C([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][C:31]1=O)(OC(C)(C)C)=O>>[CH2:1]([NH:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]2[C:10](=[C:33]3[CH2:32][CH2:31][NH:30][CH2:35][CH2:34]3)[C:11]3[C:16]([O:17][C:18]=2[CH:19]=1)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:5])[CH3:2]
Reactant: CCN(CC)C(=O)c1ccc2c(=O)c3ccccc3oc2c1
Reactant: CC(C)(C)OC(=O)N1CCCCC1=O
Product: CCNC(=O)c1ccc2c(c1)Oc1ccccc1C2=C1CCNCC1

Procedure:
Following Procedure 7, substituting compound 7a for compound 6a and substituting N-Boc-piperidone for N-carbethoxynortropinone, the title compound 2b was synthesized. MS m/z (MH+) 334.8.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]3[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=3[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:27][C:28]1[CH:29]=[C:30]([C:35]2[CH:40]=[CH:39][C:38](B(O)O)=[C:37]([O:44][CH3:45])[CH:36]=2)[CH:31]=[C:32]([F:34])[CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:27][C:28]1[CH:29]=[C:30]([C:35]2[CH:40]=[CH:39][C:38]([C:2]3[C:11]4[C:6](=[CH:7][C:8]([S:12]([O:15][C:16]5[C:21]([F:22])=[C:20]([F:23])[C:19]([F:24])=[C:18]([F:25])[C:17]=5[F:26])(=[O:14])=[O:13])=[CH:9][CH:10]=4)[CH:5]=[CH:4][N:3]=3)=[C:37]([O:44][CH3:45])[CH:36]=2)[CH:31]=[C:32]([F:34])[CH:33]=1
Reactant: COc1cc(-c2cc(F)cc(F)c2)ccc1B(O)O
Reactant: O=S(=O)(Oc1c(F)c(F)c(F)c(F)c1F)c1ccc2c(Cl)nccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cc(-c2cc(F)cc(F)c2)ccc1-c1nccc2cc(S(=O)(=O)Oc3c(F)c(F)c(F)c(F)c3F)ccc12
Yield: 65.5 %

Procedure:
A round-bottom flask was charged with perfluorophenyl 1-chloroisoquinoline-6-sulfonate (see EXAMPLE 73, STEP 1, 4.40 g, 10.74 mmol), (3′,5′-difluoro-3-methoxy-[1,1′-biphenyl]-4-yl)boronic acid (INTERMEDIATE JJJJJ; 3.40 g, 12.89 mmol), potassium carbonate (4.45 g, 32.2 mmol), and Pd(Ph3P)4 (1.241 g, 1.074 mmol). The flask was flushed with Ar (g), then 1,4-dioxane (40.3 ml) and water (13.42 ml) were added in sequence. The flask was fitted with a reflux condenser and lowered into a 50° C. heating bath for 1 h. The mixture was diluted with water and extracted with EtOAc (2×). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated. TLC showed two major spots. The residue was purified by chromatography on silica gel (100-g SNAP Ultra column, 0-50% EtOAc/Heptane). Fractions containing the desired product were combined and concentrated to give perfluorophenyl 1-(3′,5′-difluoro-3-methoxy-[1,1′-biphenyl]-4-yl)isoquinoline-6-sulfonate (4.179 g, 7.04 mmol, 65.6% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.93 (d, J=1.6 Hz, 1H), 8.84 (d, J=5.6 Hz, 1H), 8.20 (d, J=5.7 Hz, 1H), 8.07 (dd, J=1.9, 9.0 Hz, 1H), 7.95 (d, J=8.9 Hz, 1H), 7.70-7.62 (m, 2H), 7.59-7.50 (m, 3H), 7.36-7.27 (m, 1H), 3.79 (s, 3H). m/z (ESI) 594.0 (M+H)+.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.FC(F)(F)S(O[C:13]1[CH:26]=[C:25]2[C:16]([O:17][C:18]3[CH:19]=[CH:20][C:21]([NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=4)=[CH:22][C:23]=3[C@:24]32[CH2:30][O:29][C:28]([NH2:31])=[N:27]3)=[C:15]([F:41])[CH:14]=1)(=O)=O.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>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:41][C:15]1[C:16]2[O:17][C:18]3[C:23](=[CH:22][C:21]([NH:32][C:33]4[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=4)=[CH:20][CH:19]=3)[C@@:24]3([CH2:30][O:29][C:28]([NH2:31])=[N:27]3)[C:25]=2[CH:26]=[C:13]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)[CH:14]=1
Reactant: C1COCCN1
Reactant: COc1cccc(Nc2ccc3c(c2)[C@@]2(COC(N)=N2)c2cc(OS(=O)(=O)C(F)(F)F)cc(F)c2O3)c1
Agent: [Pd]
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COc1cccc(Nc2ccc3c(c2)[C@@]2(COC(N)=N2)c2cc(N4CCOCC4)cc(F)c2O3)c1
Temperature: 110 °C

Procedure:
A vial was charged with morpholine (0.062 mL, 0.706 mmol), (S)-2-amino-5′-fluoro-2′-(3-methoxyphenylamino)-5H-spiro[oxazole-4,9′-xanthene]-7′-yl trifluoromethanesulfonate (127 mg, 0.235 mmol), Pd2 dba3 (10.78 mg, 0.012 mmol), (8.43 mg, 0.028 mmol). The tube was flushed with argon and LiHMDS (1M in THF) (0.942 mL, 0.942 mmol) was added and the vial sealed and heated at 110° C. in microwave reactor for 1 hr. The mixture was quenched with 1 ml of water, diluted with EtOAc, and loaded onto 2 g SCX-2 column. The column was washed with EtOAc and MeOH. The material was flushed from the column using 2M ammonia in MeOH. The derived solution was purified by silica gel chromatography to afford (S)-4′-fluoro-N7′-(3-methoxyphenyl)-2′-morpholino-5H-spiro[oxazole-4,9′-xanthene]-2,7′-diamine MS m/z=477.0 [M+H].
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]2=[C:8]([CH3:14])[N:9]=[C:10]([CH2:11][CH2:12][CH3:13])[N:4]2[N:3]=1.[CH3:15][C:16]1([CH3:24])[CH2:21][C:20](=[O:22])[CH2:19][C:18](=[O:23])[CH2:17]1>C(O)C>[NH2:1][C:2]1[NH:7][CH:6]([CH:19]2[C:20](=[O:22])[CH2:21][C:16]([CH3:24])([CH3:15])[CH2:17][C:18]2=[O:23])[C:5]2=[C:8]([CH3:14])[N:9]=[C:10]([CH2:11][CH2:12][CH3:13])[N:4]2[N:3]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CCCc1nc(C)c2cnc(N)nn12
Solvent: CCO
Product: CCCc1nc(C)c2n1N=C(N)NC2C1C(=O)CC(C)(C)CC1=O

Procedure:
2-Amino-5-methyl-7-propylimidazo[5,1-f]-as-triazine (Example 4) (1 g.) in aqueous ethanol (20 ml., 1:1) and 5,5-dimethylcyclohexane-1,3-dione (1 g.) in aqueous ethanol (20 ml., 1:1) were mixed. The solid was collected and dried and had m.p. 243°.
Reaction SMILES: [Cl:1][CH2:2][C@@H:3]([OH:21])[CH2:4][C@@H:5]([OH:20])[CH2:6][C:7]([O:9][C:10]([CH3:19])([CH3:18])[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:8].CO[C:24](OC)([CH3:26])[CH3:25].CS(O)(=O)=O>CC(C)=O.C(OCC)(=O)C>[Cl:1][CH2:2][C@H:3]1[O:21][C:24]([CH3:26])([CH3:25])[O:20][C@@H:5]([CH2:6][C:7]([O:9][C:10]([CH3:18])([CH3:19])[CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:8])[CH2:4]1
Reactant: COC(C)(C)OC
Reactant: CC(C)(Cc1ccccc1)OC(=O)C[C@H](O)C[C@H](O)CCl
Agent: CS(=O)(=O)O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C)(Cc1ccccc1)OC(=O)C[C@H]1C[C@@H](CCl)OC(C)(C)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The crude compound (3R,5S)-2-methyl-1-phenylpropan-2-yl 6-chloro-3,5-dihydroxy-hexanoate (21.1 g) prepared in Example 3 was dissolved in acetone (210 ml), and 2,2-dimethoxypropane (65.6 ml) and methanesulfonic acid (0.2 ml) were added dropwise thereto, followed by stirring at room temperature for 2 hours. The reaction liquid was diluted with ethyl acetate (320 ml) and washed successively with a saturated sodium bicarbonate aqueous solution (320 ml), a saturated sodium chloride aqueous solution (320 ml) and purified water (320 ml). The separated organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the crude title compound (23.7 g).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[N:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[N:22]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[C:30]([Si](C)(C)C)([F:33])([F:32])[F:31].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>CCOC(C)=O>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][S:10]([C:7]2[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:2])[C:30]([F:33])([F:32])[F:31])=[CH:9][CH:8]=2)(=[O:12])=[O:11])=[C:15]([N:21]2[C:29]3[C:24](=[N:25][CH:26]=[CH:27][CH:28]=3)[N:23]=[N:22]2)[CH:16]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Product: CC(O)(c1ccc(S(=O)(=O)Nc2ccc(Cl)cc2-n2nnc3ncccc32)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To 4-acetyl-N-(4-chloro-2-[1,2,3]triazolo[4,5-b]pyridin-1-yl-phenyl)-benzene-sulfonamide (synthesized according to general procedures F and G, 500 mg, 1.17 mmol) was added CF3-TMS (trifluoromethyl-trimethylsilane) (4.7 mL, 0.5 M solution in THF), followed by TBAF (tetra-n-butylammonium fluoride)(2.34 mL, 1.0 M solution in THF) at 0° C., and the solution was stirred at room temperature for 16 hours. Both TLC and LCMS analysis indicated ˜10-15% completion of reaction. The reaction mixture was diluted with EtOAc (50 mL) and the organics were washed with washed with 2 N HCl (2×25 mL), water (25 mL), and brine (25 mL). The organics were subsequently dried (Na2SO4), concentrated in vacuo, and purified by automated flash chromatography followed by preparative HPLC to afford the title compound as a white powder: MS (ES) M+H expected 498.1, found 498.0.
Reaction SMILES: C[O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH2:20][C:21]([NH2:23])=[O:22])=[C:6]([CH3:19])[N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH2:20][C:21]([NH2:23])=[O:22])=[C:6]([CH3:19])[N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc2c1c(CC(N)=O)c(C)n2Cc1ccccc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(CC(N)=O)c2c(O)cccc2n1Cc1ccccc1
Yield: 65.6 %

Procedure:
A solution of 1.45 g (4.7 mmol) of 4-methoxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide and 14.1 mL (14.1 mmol) of 1M BBr3 in methylene chloride was reacted as described in Example 2, Part C to give after chromatography on silica (eluted with EtOAc/hexane, then EtOAc) 908 mg (66% yield) of 4-hydroxy-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 200°-208° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][NH2:20])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4].[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C@H:25]1[O:27][CH2:26]1>[N+](C)([O-])=O>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH2:18][CH2:19][NH:20][CH2:26][C@@H:25]([C:24]3[CH:28]=[CH:29][CH:30]=[C:22]([Cl:21])[CH:23]=3)[OH:27])[CH:12]=2)[CH:8]=[CH:9][CH:10]=1)=[O:4]
Reactant: COC(=O)c1cccc(-c2cccc(OCCN)c2)c1
Reactant: Clc1cccc([C@@H]2CO2)c1
Solvent: C[N+](=O)[O-]
Product: COC(=O)c1cccc(-c2cccc(OCCNC[C@H](O)c3cccc(Cl)c3)c2)c1
Yield: 55.8 %

Procedure:
A solution of methyl-3′-[(2-amino)ethoxy]-[1,1′-biphenyl]-3-carboxylate (284.5 mg) and (R)-(-)-3-chlorostyrene oxide (124 mg) in nitromethane (4.0 mL) was heated at 70-75° C. for 20 h. The mixture was concentrated with a rotary evaporator to afford the crude product. Purification by silica gel chromatography (eluting with ethyl acetate followed by 10:1 ethyl acetate: methanol followed by 3:1 ethyl acetate: methanol) afforded the title compound (190.6 mg) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:31]=[CH:30][C:5]([C:6]([N:8]([CH2:22][CH2:23][CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:9]2[CH:10]=[CH:11][C:12]3[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14][C:13]=3[CH:21]=2)=[O:7])=[CH:4][CH:3]=1.[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[CH:40])=[CH:35][CH:34]=1>>[Cl:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[C:40][C:2]2[CH:3]=[CH:4][C:5]([C:6]([N:8]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:9]3[CH:10]=[CH:11][C:12]4[C:17](=[O:18])[O:16][C:15]([CH3:20])([CH3:19])[O:14][C:13]=4[CH:21]=3)=[O:7])=[CH:30][CH:31]=2)=[CH:35][CH:34]=1
Reactant: C#Cc1ccc(Cl)cc1
Reactant: CC1(C)OC(=O)c2ccc(N(CCCC3CCCC3)C(=O)c3ccc(Br)cc3)cc2O1
Product: CC1(C)OC(=O)c2ccc(N(CCCC3CCCC3)C(=O)c3ccc(C#Cc4ccc(Cl)cc4)cc3)cc2O1
Yield: 80 %

Procedure:
The title compound was prepared following procedure described in example 26, step d) from 4-bromo-N-(3-cyclopentylpropyl)-N-(2,2-dimethyl-4-oxo-4H-1,3-benzodioxin-7-yl)benzamide (437 mg, 0.90 mmol) and 4-chlorophenylacetylene (Apollo, 118 mg, 0.86 mmol). Purification by flash chromatography on silicagel (EtOAc/c-Hex 20:80) gave 373 mg (80%) of the title compound as a white foam. HPLC, Rt: 6.03 min (purity: 93.6%). LC/MS, M+(ESI): 541.9. 1H NMR (CDCl3) δ: 7.78 (d, J=8.3 Hz, 1H), 7.24-7.45 (m, 8H), 6.74 (dd, J=8.4, 2.0 Hz, 1H), 6.58 (d, J=1.9 Hz, 1H), 3.90 (t, J=7.6 Hz, 2H), 1.46-1.86 (m, 9H), 1.40 (s, 6H), 1.36 (m, 2H), 1.03 (m, 2H).