Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([OH:15])=O)[C:8]([Cl:11])=[CH:9][CH:10]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:60][CH2:61][C:62]1[C:63]([CH3:77])=[CH:64][C:65]([NH:69][C:70]([O:72][C:73]([CH3:76])([CH3:75])[CH3:74])=[O:71])=[N:66][C:67]=1[CH3:68]>CN(C=O)C>[F:23][C:2]([F:1])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:3][NH:4][C:5]1[C:6]([F:16])=[C:7]([CH2:12][C:13]([NH:60][CH2:61][C:62]2[C:67]([CH3:68])=[N:66][C:65]([NH:69][C:70]([O:72][C:73]([CH3:75])([CH3:74])[CH3:76])=[O:71])=[CH:64][C:63]=2[CH3:77])=[O:15])[C:8]([Cl:11])=[CH:9][CH:10]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CN
Reactant: O=C(O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)Cc1c(Cl)ccc(NCC(F)(F)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.9 %

Procedure:
To a solution of 2-{3-[(2,2-difluoro-2-phenylethyl)amino]-6-chloro-2-fluorophenyl}acetic acid (25 mg, 73 μmol), as prepared in step 15 of Example 1, in DMF (0.25 mL) was added BOP (52 mg, 116 μmol), a solution of DIEA (38 mg, 295 mol) in DMF (0.1 mL), and N-[5-(aminomethyl)-4,6-dimethyl(2-pyridyl)](tert-butoxy)carboxamide (23 mg, 91 μmol) (Sanderson, P. E., et al. WO 97/01338 (1997)). After stirring at ambient temperature for 2 days, additional amine (7 mg, 28 μmol) BOP (16 mg, 36 μmol), and DIEA (9 mg, 70 μmol) were added, and the mixture was stirred for another 16 hours. The solvents were evaporated, and the resulting residue was partitioned between saturated NaHCO3 and DCM. The organic layer was separated, and the aqueous layer was extracted with DCM. The organic layers were combined, washed with 10% citric acid, H2O, and brine, dried over Na2SO4, concentrated, and flash chromatographed on silica gel eluting with MeOH/DCM (0, 1, 2%) to produce the title compound (18.5 mg, 44% yield) as a pale brown solid. 1H-NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.50-7.41 (m, 5H), 7.24 (s, 1H), 6.98 (dd, J=8.8, 1.1 Hz, 1H), 6.55 (t, J=9.0 Hz, 1H), 5.33 (bs, 1H), 4.40 (d, J=4.7 Hz, 2H), 4.24-4.20 (m, 1H), 3.78-3.70 (m, 4H), 2.39 (s, 3H), 2.28 (s, 3H), 1.50 (s, 9H). Mass spectrum (LCMS, ESI) calcd for C29H33ClF3N4O3 (M+H): 577.0. Found: 577.1.
Reaction SMILES: C([Li])CCC.[CH:6]1([O:11][CH:12]2[NH:16][C:15](=[O:17])[CH2:14][CH2:13]2)[CH2:10][CH2:9][CH2:8][CH2:7]1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CCCCCC.O1CCCC1>[C:18]([N:16]1[CH:12]([O:11][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[CH2:13][CH2:14][C:15]1=[O:17])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCC(OC2CCCC2)N1
Reactant: O=C(Cl)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1CCC(OC2CCCC2)N1C(=O)c1ccccc1
Yield: 70.2 %

Procedure:
11.8 cm3 of a 1.5M solution of butyllithium in hexane is added at -70° C. to a solution of 3 g of 5-cyclopentyloxy pyrrolidin-2-one in 140 cm3 of tetrahydrofuran. The mixture is maintained at this temperature for 20 minutes, then a solution of 2.49 g of benzoyl chloride in 20 cm3 of tetrahydrofuran is added. The whole is heated gently, then brought to dryness under reduced pressure. After chromatography on silica (eluent: hexane-ethyl acetate 7-3), 3.4 g of expected product is obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[NH:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])([CH3:4])([CH3:3])[CH3:2].[C:26](OC(=O)C)(=[O:28])[CH3:27].N1C=CC=CC=1>N1C=CC=CC=1.O>[C:26]([N:8]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([OH:14])=[O:13])[C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:20]([OH:21])=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)c1cc(Nc2cccc(C(=O)O)c2)cc(C(C)(C)C)c1O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)N(c1cccc(C(=O)O)c1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
A mixture of 5.6 g of 3-(3,5-di-t-butyl-4-hydroxyanilino)benzoic acid (from Example 13) and 15 ml of acetic anhydride was heated under a nitrogen atmosphere at 70°-120° C. for about 90 minutes. The mixture was cooled to 80° C., 5 drops of pyridine were added and the reaction was reheated to 120° C. for 10 minutes. An additional 0.25 ml of pyridine was added at about 80° C., followed by the gradual addition of 10 ml of water to hydrolyze the excess acetic anhydride and the mixed anhydride of the product. Heating was continued until a precipitate formed. The reaction mixture was allowed to cool to room temperature, and the precipitate was then collected, rinsed with a cold mixture of methanol and water, and dried to give 4.3 g of off-white solid m.p. 204°-205.5° C. This material was recrystallized first from a mixture of 30 ml of ethanol and 5 ml of water, and then from a mixture of 30 ml of isopropanol and 5 ml of hexane to give 3.3 g of white solid N-acetyl-3-(3,5-di-t-butyl-4-hydroxyanilino)benzoic acid m.p. 214.5°-215.5° C. Analysis: Calculated for: C23H29NO4 ·1/2(CH3)2CHOH: % C, 71.2; % H, 8.0; % N 3.4. Found: % C, 71.4; % H, 8.1; % N, 3.2.
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]3[C@H:15]4[C@H:25]([CH2:26][CH2:27][C@:10]23[CH3:11])[C@:23]2([CH3:24])[C@H:18]([N:19]([CH3:29])[C:20](=[O:28])[CH2:21][CH2:22]2)[CH2:17][CH2:16]4)=[CH:6][CH:5]=1)([O-])=O.[ClH:32]>CO.C(O)C.O=[Pt]=O>[ClH:32].[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C@H:9]2[CH2:14][CH2:13][C@H:12]3[C@H:15]4[C@H:25]([CH2:26][CH2:27][C@:10]23[CH3:11])[C@:23]2([CH3:24])[C@H:18]([N:19]([CH3:29])[C:20](=[O:28])[CH2:21][CH2:22]2)[CH2:17][CH2:16]4)=[CH:30][CH:31]=1
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](Oc5ccc([N+](=O)[O-])cc5)CC[C@H]4[C@@H]3CC[C@@H]12
Agent: O=[Pt]=O
Agent: Cl
Solvent: CO
Solvent: CCO
Product: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](Oc5ccc(N)cc5)CC[C@H]4[C@@H]3CC[C@@H]12

Procedure:
17β-(4-nitrophenoxy)-4-methyl-5α-4-azaandrostan-3-one (938 mg, 2.2 mmole) in MeOH (70 ml) was hydrogenated at 40 psi in the presence of PtO2 (400 mg) for 90 mins. To the resulting mixture was added 5% conc. HCl in absolute ethanol (4 ml) under N2, and then the mixture was filtered through a pad of celite. The filtrate was concentrated, vacuum dried, and then triturated with CH2Cl2 -hexane to give the title product, mp. 307°-310° C.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[N:6][CH:5]=[CH:4][N:3]=1.O.[NH2:18][NH2:19]>C(O)CCC>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][N:6]=2)[NH:19][N:18]=1
Reactant: Fc1ccccc1C#Cc1nccnc1Cl
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Fc1ccccc1Cc1n[nH]c2nccnc12

Procedure:
A solution of 550 mg (2.36 mmol) of 2-chloro-3-[(2-fluorophenyl)ethynyl]pyrazine from example 13A and 592 mg (11.8 mmol) of hydrazine hydrate in 12 ml of n-butanol is heated in a microwave at 140° C. for 30 min. The solution is then concentrated in vacuo, and the residue is purified by preparative HPLC. 150 mg (26% of theory) of the desired compound are obtained.
Reaction SMILES: [OH:1][C@H:2]1[C@H:7]2[CH2:8][C@H:4]([C@@H:5]([C:16]([O:18]CC)=[O:17])[N:6]2[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.O.[OH-].[Li+]>O1CCOCC1.O>[C:12]([O:11][C:9]([N:6]1[C@H:5]([C:16]([OH:18])=[O:17])[C@H:4]2[CH2:8][C@@H:7]1[C@H:2]([OH:1])[CH2:3]2)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CCOC(=O)[C@@H]1[C@@H]2C[C@@H](O)[C@@H](C2)N1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2O)[C@H]1C(=O)O
Temperature: 43 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
To a solution of 2-tert-butyl 3-ethyl (1R,3S,4S,6R)-6-hydroxy-2-azabicyclo[2.2.1]heptane-2,3-dicarboxylate obtained in Example 5-5 (249 mg) in dioxane (4.5 mL) and water (1.5 mL), was added lithium hydroxide monohydrate (110 mg). The mixture was stirred at 43° C. for 12 hrs and then 60° C. for 3 hrs. The resulting mixture was evaporated in vacuo. 1N Hydrochloric acid (2.7 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The combined organic phase was washed with brine, dried over NaSO4, and evaporated in vacuo. The residue was triturated with ether to give the target compound (164 mg) as a solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([C:13]3[N:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=4)[C:23]#[N:24])[O:15][N:14]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[C:23]([C:22]1[CH:25]=[C:18]([C:16]2[O:15][N:14]=[C:13]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH2:10][CH2:11][CH2:12][C@H:3]4[NH:2][S:31]([CH3:30])(=[O:33])=[O:32])[N:17]=2)[CH:19]=[CH:20][C:21]=1[O:26][CH:27]([CH3:29])[CH3:28])#[N:24]
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4N)no2)cc1C#N
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4NS(C)(=O)=O)no2)cc1C#N
Temperature: 25 °C
Yield: 56.6 %

Procedure:
Prepared using General Procedure 6: To a stirring solution of (R)-5-(3-(5-amino-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride 3 (20 mg, 0.05 mmol) in DCM (1 mL) at 0° C. was added TEA (20 μL, 0.15 mmol) and methanesulfonyl chloride (4.5 μL, 0.06 mmol). The mixture was allowed to warm to room temperature over 2 h. The solvent was evaporated and crude mixture was purified by preparative HPLC to afford 12.8 mg (58%) of (R)-N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)methanesulfonamide 28. LCMS-ESI (m/z) calculated for C23H24N4O4S: 452.5; found 453.1 [M+H]+, tR=3.68 min. 1H NMR (400 MHz, CDCl3) δ 8.40 (t, J=3.5 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 7.96 (dd, J=7.7, 1.1 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.38 (t, J=7.7 Hz, 1H), 7.16-7.07 (m, 1H), 4.88-4.70 (m, 1H), 4.54 (d, J=8.4 Hz, 1H), 3.19 (dt, J=18.0, 5.9 Hz, 1H), 3.10 (d, J=5.0 Hz, 3H), 3.09-2.95 (m, 1H), 2.14 (qt, J=14.5, 7.3 Hz, 1H), 2.06-1.83 (m, 3H), 1.47 (t, J=5.5 Hz, 6H).
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2].[OH-].[K+].[CH3:19][C:20]1[N:25]=[CH:24][C:23]([CH:26]=[CH2:27])=[CH:22][N:21]=1>CN1CCCC1=O.O>[CH2:1]([C:3]1[CH:11]=[CH:10][C:9]2[N:8]([CH2:27][CH2:26][C:23]3[CH:22]=[N:21][C:20]([CH3:19])=[N:25][CH:24]=3)[C:7]3[CH2:12][CH2:13][N:14]([CH3:16])[CH2:15][C:6]=3[C:5]=2[CH:4]=1)[CH3:2]
Reactant: C=Cc1cnc(C)nc1
Reactant: CCc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCc1ccc2c(c1)c1c(n2CCc2cnc(C)nc2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.8 %

Procedure:
To a solution of 8-Ethyl-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.1 g, 0.00046 mol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.13 g, 0.0023 mol) and allowed to stir for 10 min at RT. 2-methyl-5-vinyl pyrimidine (0.14 g, 0.00116 mol) was added and stirred for further 3 h. At 80 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×50 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure using rotary evaporator. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch) then purified through preparative TLC. to get the desired compound as yellow oil (0.032 g, 20% yield). 8-Ethyl-2-methyl-5-[2-(2-methyl-pyrimidin-5-yl)-ethyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.032 g, 0.000095 mol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.012 g, 0.00 0095 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, Precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.030 g, 75% yield).
Reaction SMILES: [CH2:1]([C:3]1[NH:8][C:7](=O)[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[N:4]=1)[CH3:2].P(Cl)(Cl)([Cl:20])=O>>[Cl:20][C:7]1[CH:6]=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])[N:4]=[C:3]([CH2:1][CH3:2])[N:8]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCc1nc(-c2ccccc2OC)cc(=O)[nH]1
Product: CCc1nc(Cl)cc(-c2ccccc2OC)n1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
A solution of 2-ethyl-6-(2-methoxy-phenyl)-3H-pyrimidin-4-one (1.1 g, 4.9 mmol) and phosphorous oxychloride (3.0 mL, 32 mmol) was refluxed for four hours. After cooling to ambient temperature the reaction mixture was concentrated in vacuo and the resultant residue was diluted with dichloromethane. The organics were washed with ice-water. After extraction of the aqueous layer with dichloromethane the combined organics were washed with brine and dried over sodium sulfate. Following Si gel chromatography (1:5 ethyl acetate:hexanes) 0.91 g (74%) of the title compound was isolated as a pale yellow oil.
Reaction SMILES: CS([C:5]1[N:9]=[C:8]([CH:10]2[CH2:15][CH:14]3[CH2:16][CH:11]2[CH2:12][CH2:13]3)[S:7][N:6]=1)(=O)=O.[CH2:17]([OH:22])[C:18]#[C:19][CH2:20]C.[H-].[Na+]>CN(C)C=O.[Cl-].[Na+].O>[CH:11]12[CH2:16][CH:14]([CH2:13][CH2:12]1)[CH2:15][CH:10]2[C:8]1[S:7][N:6]=[C:5]([O:22][CH2:17][C:18]#[C:19][CH3:20])[N:9]=1
Reactant: CCC#CCO
Reactant: CS(=O)(=O)c1nsc(C2CC3CCC2C3)n1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1nsc(C2CC3CCC2C3)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
300 mg of 3-methylsulfonyl-5-(2-norbornyl)-1,2,4-thiadiazole and 107 mg of 2-pentyn-1-ol were dissolved in 2.5 g of N,N-dimethylformamide, 60 mg of sodium hydride (60% in oil) was added thereto under ice-cooling, and the reaction mixture was stirred for 30 minutes under ice-cooling and for 1 hour under room temperature. Then, the reaction mixture was added to saturated brine, and extracted with t-butyl methyl ether. The organic layer was concentrated under reduced pressure, and the residue obtained was subjected to silica gel column chromatography to give 5-(2-norbornyl)-3-(2-butynyloxy)-1,2,4-thiadiazole. 150 mg of the exo-isomer having low polarity (hereinafter referred to as the present invention compound (9-1)) and 50 mg of the endo-isomer having high polarity (hereinafter referred to as the present invention compound (9-2)) were obtained by using hexane-ethyl acetate system as a carrier solvent.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:14]([CH3:15])=[CH:13][C:8]([O:9][CH2:10][CH2:11][NH2:12])=[C:7]([CH:16]([CH3:18])[CH3:17])[CH:6]=1)(=[O:3])[CH3:2].C(N(CC)CC)C.[OH:26][C:27]1[C:28]([CH3:39])=[C:29]([C:32]([O:37][CH3:38])=[C:33]([CH3:36])[C:34]=1[CH3:35])[CH2:30]Cl>CN(C)C=O>[OH:26][C:27]1[C:28]([CH3:39])=[C:29]([C:32]([O:37][CH3:38])=[C:33]([CH3:36])[C:34]=1[CH3:35])[CH2:30][NH:12][CH2:11][CH2:10][O:9][C:8]1[CH:13]=[C:14]([CH3:15])[C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]=1[CH:16]([CH3:18])[CH3:17]
Reactant: COc1c(C)c(C)c(O)c(C)c1CCl
Reactant: CC(=O)Nc1cc(C(C)C)c(OCCN)cc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1c(C)c(C)c(O)c(C)c1CNCCOc1cc(C)c(NC(C)=O)cc1C(C)C
Temperature: 25 °C
Yield: 5.8 %

Procedure:
2-(4-Acetylamino-2-isopropyl-5-methylphenoxy)ethylamine (1.0 g) and triethylamine (0.50 g) were dissolved in N,N-dimethylformamide (20 ml), and 3-hydroxy-6-methoxy-2,4,5-trimethylbenzyl chloride (0.86 g) dissolved in N,N-dimethylformamide (10 ml) was added dropwise while stirring the mixture at room temperature. The mixture was stirred for 5 hours. After the completion of the reaction, the solvent was distilled off, and water and ethyl acetate were added. The mixture was stirred and an insoluble matter was collected by filtration. The obtained solid was recrystallized from ethyl acetate to give 100 mg of the title compound.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)=[CH:8]2)(=[O:4])=[O:3].[H-].[Na+].[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27]Br)=[CH:25][CH:24]=1.O>CN(C)C=O>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:10]2[C:11]3[C:7](=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:13][CH:12]=3)[CH:8]=[C:9]2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:25][CH:24]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: CS(=O)(=O)c1ccc2[nH]c(-c3ccncc3)cc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CS(=O)(=O)c1ccc2c(c1)cc(-c1ccncc1)n2Cc1ccc(F)cc1
Reaction time: 0.33 h

Procedure:
To a solution of the compound obtained in Example 31 (1) (0.4 g) in N,N-dimethylformamide (160 ml), 60% sodium hydride (0.065 g) was added at 0° C. under nitrogen atmosphere and the mixture was stirred for 20 minutes, followed by addition of 4-fluorobenzyl bromide (0.2 ml), and the mixture was stirred at 15 to 30° C. for 15 hours. The reaction solution was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was separated using silica gel column chromatography (hexane:ethyl acetate=1:3) to obtain 0.3882 g of the desired product.
Reaction SMILES: [C:1]1([C:7]2([OH:20])[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][O:22][C:23](=[O:45])[C@H:24]([CH2:43]O)[NH:25][C:26]([O:28][CH2:29][CH:30]1[C:42]2[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=2[C:36]2[C:31]1=[CH:32][CH:33]=[CH:34][CH:35]=2)=[O:27]>C1C=CC=CC=1.S(=O)(=O)(O)O>[CH3:21][O:22][C:23](=[O:45])[C@H:24]([CH2:43][O:20][C:7]1([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[C:19]1=[CH:18][CH:17]=[CH:16][CH:15]=2)[NH:25][C:26]([O:28][CH2:29][CH:30]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:36]=2[C:37]2[C:42]1=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:27]
Reactant: OC1(c2ccccc2)c2ccccc2-c2ccccc21
Reactant: COC(=O)[C@H](CO)NC(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Solvent: c1ccccc1
Product: COC(=O)[C@H](COC1(c2ccccc2)c2ccccc2-c2ccccc21)NC(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 1 h

Procedure:
A solution of 6.2 g (24 mmol) of 9-phenyl-9H-fluoren-9-ol (Example 1b) and 6.8 g (20 mmol) of Nα -(9-fluorenylmethoxycarbonyl)-L-serine methyl ester in benzene (150 mL) was placed in a round bottomed flask fitted with a Dean-Stark trap. Two drops of concentrated sulfuric acid were added and the mixture heated under reflux with stirring for 1 h. Removal of the solvent under vacuo gave the crude Nα -(9-fluorenylmethoxycarbonyl)--O--(9-phenyl-9H-fluoren-9-yl)-L-serine methyl ester which was subjected to the Fmoc deprotection in Step 2 without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][C:3]1=[O:9].[Cl:11][C:12]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:13]=1[C:14](C#N)=[O:15].C(N(CC)CC)C.Cl>C(Cl)Cl.[Cl-].[Zn+2].[Cl-]>[CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=[O:8])[CH:4]([C:14](=[O:15])[C:13]2[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:12]=2[Cl:11])[C:3]1=[O:9]
Reactant: N#CC(=O)c1ccc(Cl)cc1Cl
Reactant: CC1(C)CCC(=O)CC1=O
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)CCC(=O)C(C(=O)c2ccc(Cl)cc2Cl)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 40 %

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione [14.0 grams (g), 0.1 mole], 20.0 g (0.1 mole) 2,4-dichlorobenzoyl cyanide and 13.6 (0.11 mole) anhydrous, powdered zinc chloride were combined in 100 milliliters (ml) methylene chloride. Triethylamine (10.1 g, 0.12 mole) was slowly added with cooling. The reaction mixture was stirred at room temperature for 5 hours and then poured into 2N hydrochloric acid. The aqueous phase was discarded and the organic phase was washed with 150 ml 5% Na2CO3 four times. The aqueous washings were combined and acidified with HCl, extracted with methylene chloride, dried and concentrated to yield 25.3 g of crude product. The crude product was chromatographed (2% AcOH/CH2Cl2) in 5 g aliquots then reduced on rotavap under reduced pressure at 50° C. for 30 minutes to remove AcOH. This yielded an oil (40% yield). The structure was confirmed by instrumental analysis.
Reaction SMILES: [CH3:1][CH:2]([C:4]([OH:6])=[O:5])[Cl:3].[CH2:7]=[CH:8][CH2:9][CH2:10]O.S(=O)(=O)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COC(C)(C)C.O>[CH3:1][CH:2]([C:4]([O:6][CH2:10][CH2:9][CH:8]=[CH2:7])=[O:5])[Cl:3]
Reactant: C=CCCO
Reactant: CC(Cl)C(=O)O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: C=CCCOC(=O)C(C)Cl
Reaction time: 0.17 h

Procedure:
CH3CHClCOOH (50 g)and CH2═CH(CH2)2OH (75 ml) were put into a flask and stirred and 10 ml of concentrated sulfuric acid was added dropwise thereto over period of 10 minutes at room temperature. The resulting reaction solution was added to 250 ml of a saturated sodium carbonate aqueous solution. Water (150 ml) and tert-butyl methyl ether (150 ml) were added thereto, followed by liquid separation to obtain a tert-butyl methyl ether layer as an organic layer. Further, the organic layer was washed with 150 ml of water, dried over magnesium sulfate and then subjected to filtration to obtain a crude liquid. The crude liquid was concentrated to obtain CH3CHClCOO(CH2)2CH═CH2.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18])([O-])=O>>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[NH2:8])(=[O:19])=[O:18])[CH2:4][CH2:3]1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CN1CCNCC1
Product: CN1CCN(S(=O)(=O)c2ccccc2N)CC1
Yield: 80 %

Procedure:
The title compound (2.1 g, 80%) was obtained as a white solid from N-methylpiperazine and 2-nitrobenzenesulfonyl chloride following the same procedure as described in Preparation 2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH2:23][CH2:22]2)[CH:18]=[C:17]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:16]=1)([CH3:14])([CH3:13])[CH3:12].C(N(C(C)C)CC)(C)C.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[C:11]([C:15]1[N:20]=[C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][NH:31][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=3)[CH2:25][CH2:26]2)[CH:18]=[C:17]([CH:32]2[CH2:35][CH2:34][CH2:33]2)[N:16]=1)([CH3:14])([CH3:12])[CH3:13]
Reactant: O=C(O)c1cccc(F)c1
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3cccc(F)c3)CC2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
0.29 g of 3-fluoro-benzoic acid (2.03 mmol) and 0.7 g of 4-[4-(2-tert-Butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (2.03 mmol) were dissolved in 25 ml of dichloromethane. Addition of 1.04 g of diisopropylethylamine (8.04 mmol), 0.19 g of hydroxybenzotriazole (HOBt, 1.4 mmol), and 0.46 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 2.4 mmol) at 0° C. was followed by stirring the reaction mixture for 16 h at room temperature. 30 ml of dichloromethane were added, the organic layer was washed with aqueous saturated sodium chloride. The aqueous phase was re-extracted once with dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using ethyl acetate and ethyl acetate-methanol (15:1). Fractions containing the product were combined, the solvent was evaporated to yield 0.88 g of the title compound as a white solid.