Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14](Cl)=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1.[NH3:19]>C1COCC1>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[C:13]([C:14]([NH2:19])=[O:15])=[CH:12][S:11][N:10]=2)[CH:4]=1
Reactant: N
Reactant: O=C(Cl)c1csnc1-c1cccc(C(F)(F)F)c1
Solvent: C1CCOC1
Product: NC(=O)c1csnc1-c1cccc(C(F)(F)F)c1

Procedure:
A solution of 2.92 g (0.010 mol) of 3-(α,α,α-trifluoro-m-tolyl)-4-isothiazolecarbonyl chloride in 10 ml of THF was added to a solution of excess ammonia gas in THF stirred in a dry ice acetone bath. The mixture was slowly warmed to 23° with stirring. The solid NH4Cl was removed by filtration, and the filtrate was concentrated to about 20 ml. Then 100 ml of ether was added, and the solution was extracted with two portions of 10% Na2CO3 solution and once with saturated NaCl solution. The ether layer was dried (CaSO4) and concentrated to 2.25 g (83%) of white solid, m.p. 141°-141.5°; infrared (mineral oil mull) 2.92, 3.11, 6.09, 6.11μ.
Reaction SMILES: [C:1]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:15]=[C:16]([CH:20]3[C:29](=O)[C:28]4[C:27]([C:31]([O:33]C)=O)=[CH:26][CH:25]=[CH:24][C:23]=4[NH:22][CH:21]3[C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[CH:17]=[CH:18][CH:19]=2)=[O:13])[CH2:8][CH2:7]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].O.[NH2:42][NH2:43]>CO>[C:1]([N:6]1[CH2:7][CH2:8][N:9]([C:12]([C:14]2[CH:15]=[C:16]([CH:20]3[C:29]4=[N:42][NH:43][C:31](=[O:33])[C:27]5[CH:26]=[CH:25][CH:24]=[C:23]([C:28]=54)[NH:22][CH:21]3[C:35]3[CH:40]=[CH:39][N:38]=[CH:37][CH:36]=3)[CH:17]=[CH:18][CH:19]=2)=[O:13])[CH2:10][CH2:11]1)(=[O:5])[CH:2]([CH3:3])[CH3:4]
Reactant: COC(=O)c1cccc2c1C(=O)C(c1cccc(C(=O)N3CCN(C(=O)C(C)C)CC3)c1)C(c1ccncc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: CC(C)C(=O)N1CCN(C(=O)c2cccc(C3c4n[nH]c(=O)c5cccc(c45)NC3c3ccncc3)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 8 %

Procedure:
A mixture of methyl 3-(3-(4-isobutyryl piperazine-1-carbonyl)phenyl)-4-oxo-2-(pyridin-4-yl)-1,2,3,4-tetrahydroquinoline-5-carboxylate (140 mg, 0.26 mmol) in 85% hydrazine monohydrate (10 mL) and methanol (3 mL) was stirred at 25° C. for 4 hr. The mixture was extracted with ethyl acetate (50 mL×3). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give crude product. The crude product was purified by prep-HPLC to give compound 9-(3-(4-isobutyrylpiperazine-1-carbonyl)phenyl)-8-(pyridin-4-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]phthalazin-3(7H)-one (11 mg, yield 8%) as a white solid. 1H-NMR (400 MHz, CD3OD) δ (ppm): 1.1-1.13 (m, 6H), 2.95-2.98 (m, 1H), 3.26-3.68 (m, 8H), 4.40-4.42 (d, J=8.4 Hz, 1H), 4.82-4.84 (d, J=8.4 Hz, 1H), 7.19-7.32 (m, 4H), 7.36-7.39 (m, 3H), 7.59-7.68 (m, 2H), 8.41-8.42 (d, J=6.0 Hz, 2H); LC-MS (ESI) m/z: 523(M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][NH:11][CH2:10][C:9]2([CH3:15])[CH3:14])=[CH:4][CH:3]=1.[C:17]([NH:24][C@@H:25]([CH2:27][C:28](O)=[O:29])[CH3:26])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@:8]2([OH:16])[CH2:13][CH2:12][N:11]([C:28](=[O:29])[CH2:27][C@H:25]([NH:24][C:17](=[O:18])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH3:26])[CH2:10][C:9]2([CH3:14])[CH3:15])=[CH:4][CH:3]=1
Reactant: CC1(C)CNCC[C@]1(O)c1ccc(Cl)cc1
Reactant: C[C@H](CC(=O)O)NC(=O)OC(C)(C)C
Product: C[C@H](CC(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)NC(=O)OC(C)(C)C

Procedure:
tert-Butyl(R)-4-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-4-oxobutan-2-ylcarbamate was prepared from (S)-4-(4-chlorophenyl)-3,3-dimethylpiperidin-4-ol and Boc-D-beta-homoalanine using the conditions described in Example 1, Step 2. MS (ESI+)=425.1 (M+H)+.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[Cl:6][C:7]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:8]=1[C:9](N(OC)C)=[O:10]>C1COCC1.C(OCC)C>[Cl:6][C:7]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][C:8]=1[C:9]([CH:1]1[CH2:3][CH2:2]1)=[O:10]
Reactant: CON(C)C(=O)c1ccc(C)cc1Cl
Reactant: Br[Mg]C1CC1
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.7 ml (7.65 mmol) of a 1N cyclopropylmagnesium bromide solution in THF were added to 1.09 g (5.10 mmol) of the compound from Example 121A in 19 ml of diethyl ether, and the mixture was stirred at RT overnight. A further 7.7 ml (7.65 mmol) of a 1N cyclopropylmagnesium bromide solution in THF were added, and the mixture was stirred at RT overnight. The reaction mixture was added to ice-water and extracted with dichloromethane, the organic phase was dried over magnesium sulfate, filtered and concentrated, and the crude product was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient) to result in 326 mg (33% of theory) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4](Br)[N:3]=1.[NH3:11]>>[Br:1][C:2]1[N:3]=[C:4]([NH2:11])[CH:5]=[C:6]([O:8][CH3:9])[CH:7]=1
Reactant: N
Reactant: COc1cc(Br)nc(Br)c1
Product: COc1cc(N)nc(Br)c1

Procedure:
A solution of 2.00 g 2,6-dibromo-4-methoxy-pyridine in 80 g liquid ammonia under was heated in an autoclave to 140° C. for 4 h. The reaction was cooled to room, evaporated and the residue was purified by silica column chromatography to yield 0.457 g of the title compound as white solid. MS (ISP) M+H+=203.2 205.5
Reaction SMILES: [Br:1][C:2]1[C:10]([Br:11])=[C:9]2[C:5]([CH2:6][C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)([CH2:13][C:14]#[C:15][Si](C)(C)C)[C:8]2=[O:12])=[CH:4][C:3]=1[O:26][CH2:27][C:28]([O:30]CC)=[O:29].[OH-].[Na+]>C(O)C>[Br:1][C:2]1[C:10]([Br:11])=[C:9]2[C:5]([CH2:6][C:7]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)([CH2:13][C:14]#[CH:15])[C:8]2=[O:12])=[CH:4][C:3]=1[O:26][CH2:27][C:28]([OH:30])=[O:29]
Reactant: CCOC(=O)COc1cc2c(c(Br)c1Br)C(=O)C(CC#C[Si](C)(C)C)(c1ccccc1)C2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C#CCC1(c2ccccc2)Cc2cc(OCC(=O)O)c(Br)c(Br)c2C1=O

Procedure:
Desilylation and hydrolysis of ethyl [6,7-dibromo-1-oxo-2-phenyl-2-(3-(trimethylsilyl)-2-propynyl)-5-indanyloxy]acetate with sodium hydroxide in ethanol according to the procedure of Example 1, STEP (c), affords the title comound.
Reaction SMILES: [CH3:1][Li].[Si:3]([O:10][CH:11]1[CH2:15][CH:14]=[C:13](OS(C(F)(F)F)(=O)=O)[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>[Cu]I.C(OCC)C>[Si:3]([O:10][CH:11]1[CH2:15][CH:14]=[C:13]([CH3:1])[CH2:12]1)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)OC1CC=C(OS(=O)(=O)C(F)(F)F)C1
Reactant: [Li]C
Agent: [Cu]I
Solvent: CCOCC
Product: CC1=CCC(O[Si](C)(C)C(C)(C)C)C1
Reaction time: 1 h
Yield: 41 %

Procedure:
To an ether solution of dimethylcopper-lithium obtained by using 8.41 ml of 1.4 M diethyl ether solution of methyllithium, 1.16 g of copper (I) iodide and 15 ml of diethyl ether was added at -30° C. under nitrogen stream 700 mg of 3-trifluoromethanesulfonyloxy-3-cyclopenten-1-yl (t-butyldimethylsilyl) ether and the resulting mixture was stirred for 1 hour. The reaction liquid obtained was after-treated and purified in the same manner as in (1) of the intermediate preparation example 1 to obtain 176 mg of 3-methyl-3-cyclopenten-1-yl (t-butyldimethylsilyl) ether. Yield 41%
Reaction SMILES: [NH2:1][C:2](=[N:16][O:17][C:18]([O:20]CC(CC)CCCC)=O)[C@@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].C1(C)C(C)=CC=CC=1>C(OCC)(=O)C>[O:20]=[C:18]1[O:17][N:16]=[C:2]([C@@H:3]2[CH2:7][CH2:6][CH2:5][C@@H:4]2[NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[NH:1]1
Reactant: CCCCC(CC)COC(=O)ON=C(N)[C@@H]1CCC[C@@H]1NC(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1c1noc(=O)[nH]1
Temperature: 140 °C
Reaction time: 4 h
Yield: 98.9 %

Procedure:
A mixture of tert-butyl [(1S,2R)-2-{amino[({[(2-ethyl hexyl)oxy]carbonyl}oxy)imino]methyl}cyclopentyl]carbamate (492 mg) and xylene (10 ml) was stirred at an outside temperature of 140° C. for 4 hours. The reaction mixture was left to be cooled, ethyl acetate (40 ml) was added, followed by washing with saturated brine. The organic layer was dried over anhydrous magnesium sulfate and the solvent was then removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (1% methanol-chloroform) to obtain tert-butyl [(1S,2R)-2-(5-oxo -4,5-dihydro-1,2,4-oxadiazol-3-yl)cyclopentyl]carbamate (328 mg) as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:13]([OH:15])=O)=[CH:8]2)#[N:2].C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][C:7]([C:13]([Cl:19])=[O:15])=[CH:8]2)#[N:2]
Reactant: N#Cc1cccc2cc(C(=O)O)ccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cccc2cc(C(=O)Cl)ccc12

Procedure:
To a suspension of 5-cyano-naphthalene-2-carboxylic acid, 2, (0.084 g, 0.426 mmol) in CH2Cl2 (2 mL) at room temperature containing 1 drop of DMF is added oxalyl chloride (0.074 mL). Once the solution is homogeneous, the solution is concentrated in vacuo and the crude product is used without further purification.
Reaction SMILES: [F:1][C:2]([F:9])([F:8])[C:3]1[NH:7][N:6]=[N:5][N:4]=1.[C:10](Cl)(=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].N1C=CC=CC=1>C(#N)C>[C:10]([N:4]1[C:3]([C:2]([F:9])([F:8])[F:1])=[N:7][N:6]=[N:5]1)(=[O:26])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: FC(F)(F)c1nnn[nH]1
Solvent: c1ccncc1
Solvent: CC#N
Product: CCCCCCCCCCCCCCCC(=O)n1nnnc1C(F)(F)F
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 43.7 %

Procedure:
6.9 g of 5-trifluoromethyl-1,2,3,4-tetrazole and 13.7 g of palmitoyl chloride were dissolved in 100 ml of acetonitrile while cooling with ice and to the solution was added dropwise 4.5 ml of pyridine over a period of about 10 minutes. After the completion of the dropwise addition, the mixture was stirred at about 5° C. for 30 minutes and then at room temperature for 1 hour, and to the mixture was added dropwise about 100 ml of ice water. The crystals thus-deposited were collected by filtration to obtain 8.2 g of 1-hexadecanoyl-5-trifluoromethyl-1,2,3,4 -tetrazole. A melting point was 66° to 69° C.
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5].[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]>>[C:16]([C:15]1[CH:14]=[C:13]([CH:20]=[CH:19][CH:18]=1)[O:12][C:2]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][C:3]=1[C:4]#[N:5])#[N:17]
Reactant: N#Cc1cc(C=O)ccc1F
Reactant: N#Cc1cccc(O)c1
Product: N#Cc1cccc(Oc2ccc(C=O)cc2C#N)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 2-fluoro-5-formylbenzonitrile and 3-hydroxybenzonitrile.
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[S-:8][C:9]#[N:10].[K+]>C(O)C>[CH2:6]([O:5][C:3](=[O:4])[CH2:2][S:8][C:9]#[N:10])[CH3:7]
Reactant: CCOC(=O)CCl
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCO
Product: CCOC(=O)CSC#N
Yield: 99.1 %

Procedure:
A solution of ethyl chloroacetate (20 g, 0.16 mol) and potassium thiocyanate (12.7 g, 0.13 mol) in ethanol (100 ml) was refluxed for 3 h. The solution was filtered and concentrated under reduced pressure to afford 18.7 g of thiocyanato-acetic acid ethyl ester (97%). A mixture of cyclopropylammonium acetate (0.50 g, 4.27 mmol) and thiocyanato-acetic acid ethyl ester (0.62 g, 4.27 mmol) was heated to 90° C. for 3 h, and left at rt overnight. The reaction mixture was partitioned between 6N HCl and dichloromethane. The layers were separated. The aqueous layer was made basic by the addition of 6N ammonium hydroxide, and then concentrated to dryness. The crude was triturated with dichloromethane and the solution separated from the solid by filtration. This solution was dried over sodium sulfate and concentrated to dryness. The crude was purified on a silica gel column with 100% ethyl acetate to afford 2-cyclopropylamino-thiazol-4-one (244 mg, 37%).
Reaction SMILES: [F:1][C:2]([F:55])([F:54])[C:3]1[CH:4]=[C:5]([CH:13]([N:15]([CH2:29][C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[CH:32][C:31]=2[N:40]([CH2:43][C@H:44]2[CH2:49][CH2:48][C@H:47]([CH2:50][C:51]([OH:53])=[O:52])[CH2:46][CH2:45]2)[CH2:41][CH3:42])[C:16]2[N:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:27])=[O:26])=[CH:18][N:17]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH2:56](O)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1.CCN=C=NCCCN(C)C.Cl.O>ClCCl.CN(C1C=CN=CC=1)C>[CH2:56]([O:52][C:51](=[O:53])[CH2:50][C@H:47]1[CH2:48][CH2:49][C@H:44]([CH2:43][N:40]([C:31]2[CH:32]=[CH:33][C:34]([C:36]([F:39])([F:37])[F:38])=[CH:35][C:30]=2[CH2:29][N:15]([CH:13]([C:5]2[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=[C:3]([C:2]([F:1])([F:54])[F:55])[CH:4]=2)[CH3:14])[C:16]2[N:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][S:25]([CH3:28])(=[O:26])=[O:27])=[CH:18][N:17]=2)[CH2:41][CH3:42])[CH2:45][CH2:46]1)[C:57]1[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=1
Reactant: CCN(C[C@H]1CC[C@H](CC(=O)O)CC1)c1ccc(C(F)(F)F)cc1CN(c1ncc(OCCS(C)(=O)=O)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CCN(C[C@H]1CC[C@H](CC(=O)OCc2ccccc2)CC1)c1ccc(C(F)(F)F)cc1CN(c1ncc(OCCS(C)(=O)=O)cn1)C(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid (racemate compound (I), 20 g, 24.61 mmol) synthesized by the method described in Patent document 2 (International Patent Publication WO2008/129951), Example 45 in anhydrous dichloromethane (200 mL) was added with benzyl alcohol (2.93 g, 27.07 mmol), DMAP (300 mg, 2.46 mmol) and WSC.HCl (5.19 g, 27.07 mmol) under ice cooling, and the mixture was warmed to room temperature, and stirred for 16 hours. The reaction mixture was added with water (100 mL), and the mixture was extracted with chloroform (500 mL). The organic layer was washed with 2 M aqueous hydrochloric acid (100 mL) and saturated brine (100 mL), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure, and the resulting residue was purified by column chromatography (silica gel: 350 g, developing solvent: N-hexane/ethyl acetate=3/1→1/1) to obtain trans-{4-[({2-[({1-[3,5-bis(trifluoromethyl)phenyl]ethyl}{5-[2-(methylsulfonyl)ethoxy]pyrimidin-2-yl}amino)methyl]-4-(trifluoromethyl)phenyl}(ethyl)amino)methyl]cyclohexyl}acetic acid benzyl ester (21.15 g, yield: 95.2%) as white amorphous.
Reaction SMILES: C[O:2][CH:3]=[C:4]1[CH2:16][CH2:15][CH2:14][C:6]2([CH:11]=[CH:10][CH2:9][CH2:8][C:7]2([CH3:13])[CH3:12])[CH2:5]1.Cl>C(#N)C.[Cl-].[Na+].O>[CH3:12][C:7]1([CH3:13])[C:6]2([CH2:5][CH:4]([CH:3]=[O:2])[CH2:16][CH2:15][CH2:14]2)[CH:11]=[CH:10][CH2:9][CH2:8]1
Reactant: COC=C1CCCC2(C=CCCC2(C)C)C1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC1(C)CCC=CC12CCCC(C=O)C2
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a solution of 8-(1-methoxymethylidene)-5,5-dimethyl-spiro[5.5]undec-1-ene (240 mg) obtained in Step 6 in acetonitrile (6 mL) was added 1N aqueous hydrochloric acid solution (1.1 mL), followed by stirring the reaction mixture at room temperature for 3 hours. Then, after addition of saturated brine, the reaction mixture was extracted with diethyl ether. The organic layer was washed with water, dried and concentrated. The resulting residue was dissolved in a mixed solution of methanol (5.4 mL)-water (0.6 mL). To the solution was added potassium carbonate (150 mg), followed by stirring the reaction mixture at room temperature for 2 hours. Then, after addition of water, the reaction mixture was extracted with diethyl ether. The organic layer was washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (hexane:ethyl acetate (volume ratio)=40:1) to give 11,11-dimethyl-spiro[5.5]undec-7-ene-2-carbaldehyde (195 mg).
Reaction SMILES: O=[C:2]([CH2:8][C:9](=O)[C:10]1[CH:14]=[CH:13][S:12][CH:11]=1)[C:3]([O:5][CH2:6][CH3:7])=[O:4].C1C=CC=CC=1.[CH3:22][CH:23]([N:25]1[C:29]([NH2:30])=[CH:28][CH:27]=[N:26]1)[CH3:24]>C(O)(=O)C>[CH3:22][CH:23]([N:25]1[C:29]2[N:30]=[C:9]([C:10]3[CH:14]=[CH:13][S:12][CH:11]=3)[CH:8]=[C:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:28]=2[CH:27]=[N:26]1)[CH3:24]
Reactant: CC(C)n1nccc1N
Reactant: CCOC(=O)C(=O)CC(=O)c1ccsc1
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: CCOC(=O)c1cc(-c2ccsc2)nc2c1cnn2C(C)C

Procedure:
The title compound was prepared in the same manner as described for intermediate 61 using ethyl 2,4-dioxo-4-(3-thienyl)butanoate (542 mg, 2.397 mmol), benzene (5 mL), 1-(1-methylethyl)-1H-pyrazol-5-amine (300 mg, 2.397 mmol), and acetic acid (5 ml). The crude product was purified using column chromatography (silica gel, eluent: 0 to 100% EtOAc/hexanes) to afford the product as 590 mg (78%). LCMS E-S (M+H)=315.8. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.53 (t, J=6.8 Hz, 3 H), 1.66 (d, J=6.8 Hz, 6 H), 4.56 (q, J=7.1 Hz, 2 H), 5.43 (spt, J=6.7 Hz, 1 H), 7.47 (dd, J=5.1, 3.0 Hz, 1 H), 7.84-7.95 (m, 1 H), 8.08-8.18 (m, 2 H), 8.32-8.43 (m, 1 H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([OH:13])=O)=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:14][CH2:15][CH3:16])[CH2:10][C:11]([NH:27][CH2:26][C:25]2[CH:28]=[CH:29][C:22]([F:21])=[CH:23][CH:24]=2)=[O:13])=[CH:5][C:4]=1[C:17]([F:20])([F:19])[F:18])#[N:2]
Reactant: NCc1ccc(F)cc1
Reactant: CCCN(CC(=O)O)c1ccc(C#N)c(C(F)(F)F)c1
Product: CCCN(CC(=O)NCc1ccc(F)cc1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described in Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-propylglycine and 4-fluorobenzyl amine: MS (APCI) m/z 394 (M+1).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:20][CH3:21].S(Cl)([Cl:25])(=O)=O>C(O)(=O)C>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH2:20][CH3:21])[Cl:25]
Reactant: CCC1Cc2cc(OCCCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Product: CCC1(Cl)Cc2cc(OCCCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
By following the method of Example 12, Step B, 4-(1-oxo-2ethyl-6,7-dichloro-5-indanyloxy)butyric acid (13.24 g., 0.04 mole) is treated with sulfuryl chloride (3.6 ml., 0.044 mole) in acetic acid (100 ml.) to obtain 9.33 g. of 4-(1-oxo-2-ethyl-2,6,7-trichloro-5-indanyloxy)butyric acid, m.p. 123°-124° C. after recrystallization from ethanol.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[CH2:16]([O:23][CH2:24][C@H:25]([NH:29]C(OC(C)(C)C)=O)[C:26](O)=[O:27])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[NH2:29][C@@H:25]([CH2:24][O:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:26]([NH:11][C:10]1[CH:12]=[CH:13][C:7]([O:6][C:5]2[CH:14]=[CH:15][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1)=[O:27]
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Reactant: Nc1ccc(Oc2ccc(F)cc2)cc1
Product: N[C@@H](COCc1ccccc1)C(=O)Nc1ccc(Oc2ccc(F)cc2)cc1
Yield: 69 %

Procedure:
Proceeding as in Reference 5, but substituting 4-(4-fluorophenoxy)aniline and (S)-3-(benzyloxy)-2-(tert-butoxycarbonylamino)propanoic acid, gave (S)-2-amino-3-(benzyloxy)-N-(4-(4-fluorophenoxy)phenyl)propanamide (443 mg, 69%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH2:7])[CH:2]=1.[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[C:13]([CH:17]=1)[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C=O)C>[Br:8][C:9]1[CH:10]=[CH:11][C:12]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[C:26]#[N:27])=[C:13]([CH:17]=1)[C:14]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)=[O:15]
Reactant: Nc1cccnc1
Reactant: N#Cc1ccccc1COc1ccc(Br)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: N#Cc1ccccc1COc1ccc(Br)cc1C(=O)Nc1cccnc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Solid pyridin-3-amine (91 mg, 0.96 mmol) was added in one charge to a stirred solution of 5-bromo-2-{[(2-cyanophenyl)methyl]oxy}benzoic acid (may be prepared as described in Description 34; 160 mg, 0.48 mmol), 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (111 mg, 0.58 mmol) and 1-Hydroxybenzotriazole (78 mg, 0.58 mmol) in DMF (15 ml) under nitrogen at 20° C. The reaction mixture was stirred at 20° C. for 16 h. The organic phase was washed with water (25 ml), and extracted with ethyl acetate (3×30 ml), dried over sodium sulphate, evaporated in vacuo and purified by column chromatography (petroleum ether:ethyl acetate=2:1) to yield the title compound as a white solid. 180 mg.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([C:6]2[N:14]=[C:13]3[C:9]([N:10]=[CH:11][N:12]3[CH:15]([CH3:17])[CH3:16])=[C:8]([NH:18][CH2:19][CH2:20][C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([OH:30])[CH:28]=4)[NH:23][CH:22]=3)[N:7]=2)[C:3]2[CH:31]=[CH:32][CH:33]=[CH:34][C:2]1=2.[C:35]([O:39][C:40]([NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48](O)=[O:49])=[O:41])([CH3:38])([CH3:37])[CH3:36].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:35]([O:39][C:40]([NH:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][C:48]([O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[NH:23][CH:22]=[C:21]2[CH2:20][CH2:19][NH:18][C:8]1[N:7]=[C:6]([C:4]2[C:3]3[CH:31]=[CH:32][CH:33]=[CH:34][C:2]=3[S:1][CH:5]=2)[N:14]=[C:13]2[C:9]=1[N:10]=[CH:11][N:12]2[CH:15]([CH3:17])[CH3:16])=[O:49])=[O:41])([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)n1cnc2c(NCCc3c[nH]c4ccc(O)cc34)nc(-c3csc4ccccc34)nc21
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)n1cnc2c(NCCc3c[nH]c4ccc(OC(=O)CCCCCNC(=O)OC(C)(C)C)cc34)nc(-c3csc4ccccc34)nc21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(2-(2-(benzo[b]thiophen-3-yl)-9-isopropyl-9H-purin-6-ylamino)ethyl)-1H-indol-5-ol (55.5 mg, 0.119 mmol) and 6-(tert-butoxycarbonylamino)hexanoic acid (30 mg, 0.113 mmol) in DMF (3 ml) was added Et3N (24 mg, 0.237 mmol) and HATU (90 mg, 0.237 mmol). The mixture was stirred at rt for 16 hr, and then was concentrated. Water was added and the reaction mixture was extracted with ethyl acetate. The organic fractions were combined, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography (0 to 5% MeOH in DCM eluant) to afford the title compound as an off-white solid.