Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21](Cl)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].[NH2:30][C:31]1[CH:32]=[CH:33][C:34]([N:42]2[CH2:47][CH2:46][O:45][CH2:44][CH2:43]2)=[C:35]2[C:39]=1[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]2>>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17]2[N:22]=[C:21]([NH:30][C:31]3[CH:32]=[CH:33][C:34]([N:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[C:35]4[C:39]=3[C:38](=[O:40])[N:37]([CH3:41])[CH2:36]4)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][N:18]=2)=[C:12]([O:28][CH3:29])[CH:11]=1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Reactant: CN1Cc2c(N3CCOCC3)ccc(N)c2C1=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(N4CCOCC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC

Procedure:
The title compound was prepared according to the procedure for Example 102 using diethyl(4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)phosphonate and 7-Amino-2-methyl-4-(morpholin-4-yl)-2,3-dihydro-1H-isoindol-1-one (Compound 208A). MS (ES+): m/z 665.33 (100) [MH+]; HPLC: tR=1.07 min (UPLC, purity).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:10])=[N:4][C:5](F)=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].O.[OH:14][CH2:15][CH:16]([CH2:18][OH:19])[OH:17]>>[Cl:8][C:6]1[C:5]([O:14][CH2:15][CH:16]([OH:17])[CH2:18][OH:19])=[N:4][C:3]([F:10])=[C:2]([Cl:1])[CH:7]=1
Reactant: Fc1nc(F)c(Cl)cc1Cl
Reactant: OCC(O)CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: OCC(O)COc1nc(F)c(Cl)cc1Cl

Procedure:
To a solution of 12.9 grams (0.07 mole) of 3,5-dichloro-2,6-difluoropyridine in 50 milliliters of glycerol was added over an 8 minute period 2.9 grams of sodium hydroxide in 25 milliliters of glycerol. The mixture was maintained at ~85° C. for ~17 minutes, cooled and poured into 200 milliliters of cold water. The solid which precipitated was air dried and taken up in benzene, dried and most of the benzene was removed by evaporation under reduced pressure. The residue was mixed with hexane and cooled and the crystalline 3-(3,5-dichloro-6-fluoro-2-pyridyloxy)-1,2-propanediol product which precipitated was recovered by filtration. The product was covered in a yield of 10 grams (56 percent of theoretical). The product melted at 78°-80° C. and was found upon analysis to have carbon, hydrogen, chlorine and nitrogen contents of 37.5, 2.9, 27.6 and 5.6 percent, respectively, as compared with the theoretical contents of 37.5, 3.2, 27.7 and 5.5 percent, calculated for the above-named compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:16])[CH2:14][CH3:15].[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]2)=[N:22][CH:23]=1>>[Cl:12][C:9]1[N:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][C:3]([C:13](=[O:16])[CH2:14][CH3:15])=[C:2]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:25]2)=[N:22][CH:23]=1
Reactant: CCC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2ccc(N)cn2)C1
Product: CCC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)nc1
Yield: 84.9 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)propan-1-one (500 mg, 1.96 mmol) was reacted with (R)-tert-butyl (1-(5-aminopyridin-2-yl)piperidin-3-yl)carbamate (860 mg, 2.94 mmol) to afford the desired product (850 mg, 84%) as a light brown solid: ESI MS m/z 511 [M+H]+.
Reaction SMILES: C(S[S:21][CH2:22][CH2:23][CH2:24][CH:25]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[C:26](O)=[O:27])(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[O:27]=[C:26]1[CH:25]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH2:24][CH2:23][CH2:22][S:21]1
Reactant: O=C(O)CCC(CCCSSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCC1CCCSC1=O
Reaction time: 0.5 h
Yield: 37.5 %

Procedure:
To a solution of 2-[3-(tritylthio)mercaptopropyl]pentanedioic acid (150 g, 0.33 mol) in dichloromthane (500 mL) was added dropwise trifluoroacetic acid (110 mL) over 30 minutes. After being stirred for an additional 30 minutes, a solution of triethylsilane (45 mL, 0.33 mol) in dichloromethane (50 mL) was added and the mixture was stirred at 45° C. for 1 hour. The volatiles were removed in vacuo and the residue was triturated with hexanes (500 mL×2). The oily residue was dissolved in toluene (500 mL) containing 10-camphorsulfonic acid (14 g) and refluxed for 6 hours. The liberated water was removed using a Dean-Stork azeotropic adapter. Toluene was then distilled off and the residue was purified by silica gel chromatography (EtOAc/hexanes, 1/4). Subsequent recrystallization from EtOAc/hexanes afforded 23.3 g of 3-(2-oxotetrahydro-2H-thiopyran-3-yl)propanoic acid as a white solid (37% yield): 1H NMR (CD3OD) δ 1.65–1.78 (m, 2 H), 2.05–2.18 (m, 4 H), 2.35–2.48 (m, 2 H), 2.65–2.74 (m, 1 H), 3.13–3.29 (m, 2 H); 13C NMR (CD3OD) δ 23.3, 27.4, 29.3, 31.2, 32.3, 50.0, 177.0, 206.4. Analysis calculated for C8H12O3S: C, 51.04; H, 6.43; S, 17.03. Found: C, 51.08; H, 6.38; S, 17.16.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][N:6]=[C:7]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:32][C:33]([CH3:35])=[CH2:34]>C1COCC1.C(OCC)(=O)C>[C:8]1([C:7](=[N:6][CH:5]([CH2:34][C:33]([CH3:35])=[CH2:32])[C:4]([O:3][CH2:1][CH3:2])=[O:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=C(C)CBr
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=C(C)CC(N=C(c1ccccc1)c1ccccc1)C(=O)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a stirred solution of N-(diphenylmethylene)glycine ethyl ester (available from Aldrich Chemical Co., Milwaukee, Wis.) (50.0 g, 187 mmol) in dry THF (200 mL) at −78° C. under argon was added a 1.0 M solution of lithium bis(trimethylsilyl)amide (Li HMDS; 210 mL, 0.2 mol) in THF over a period of 45 min (“1.A, Scheme A). After 0.5 hour at −78° C., 3-bromo-2-methylpropene (18.91 mL, 187 mmol) was added dropwise to the orange-yellow suspension. After the addition was complete, the reaction mixture was stirred for an additional 0.5 hour at 0° C. and then allowed to warm to room temperature. After 1 hour the reaction mixture was concentrated under reduced pressure to give an orange-colored oil. The crude material was dissolved in ethyl acetate (EA) (600 mL), washed with brine (100 mL), dried over anhydrous MgSO4 and concentrated under reduced pressure to give the desired compound (60 g, 99%), which was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[F:25][C:26]1[CH:31]=[C:30]([O:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:12]3[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]3)[N:9]=[C:10]([C:27]3[CH:28]=[CH:29][C:30]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:31][C:26]=3[F:25])[C:3]=12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(I)c3c(N)ncnc32)C1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1F
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: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@@H](n2nc(-c3ccc(Oc4ccccc4)cc3F)c3c(N)ncnc32)C1
Temperature: 80 °C
Reaction time: 12 h
Yield: 70.5 %

Procedure:
Into a 100 mL 3-necked round-bottom flask purged and maintained under an inert atmosphere of nitrogen, was placed tert-butyl (3R)-3-[4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate (400 mg, 0.90 mmol, 1.00 equiv), (2-fluoro-4-phenoxyphenyl)boronic acid (250 mg, 1.08 mmol, 1.20 equiv), sodium carbonate (190 mg, 1.79 mmol, 1.99 equiv), ethylene glycol dimethyl ether (50 mL), water (15 mL), and Pd(PPh3)4 (52 mg, 0.04 mmol, 0.05 equiv). The resulting solution was stirred for 12 h at 80° C. and then concentrated under vacuum. The residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (100/1) to give 320 mg (70%) of tert-butyl (3R)-3-[4-amino-3-(2-fluoro-4-phenoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]piperidine-1-carboxylate as a yellow solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[OH:11].Br[CH2:13][CH:14]1[CH2:16][CH2:15]1>>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:9])[CH3:10])[CH:5]=[CH:4][C:3]=1[O:11][CH2:13][CH:14]1[CH2:16][CH2:15]1
Reactant: BrCC1CC1
Reactant: CC(C)c1ccc(O)c(Br)c1
Product: CC(C)c1ccc(OCC2CC2)c(Br)c1

Procedure:
Starting from 2-bromo-4-isopropyl-phenol (example B.a6) and commercially available bromomethyl-cyclopropane the title compound is obtained as colorless solid after short path distillation at 2×10−3 mbar.
Reaction SMILES: [CH3:1][C:2]1[O:7][C:6](=O)[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([Br:13])[C:4]=2[N:3]=1.C([O-])(=O)C.[NH4+:18]>O>[CH3:1][C:2]1[N:18]=[C:6]([OH:7])[C:5]2[C:4](=[C:12]([Br:13])[CH:11]=[CH:10][CH:9]=2)[N:3]=1
Reactant: [NH4+]
Reactant: Cc1nc2c(Br)cccc2c(=O)o1
Agent: CC(=O)[O-]
Solvent: O
Product: Cc1nc(O)c2cccc(Br)c2n1
Temperature: 140 °C
Reaction time: 2 h
Yield: 83.7 %

Procedure:
Part B: A mixture of 17.0 g (71 mmol) of 2-methyl-8-bromo-3,1-benzoxazin4-one and 84.8 g (1.1 mol) of ammonium acetate was heated to 140° C. while stirring for 2 hours. After cooling to room temperature 250 ml of water was added under intensive stirring to the mixture. The resulting precipitate was collected by filtration and washed three times with 50 ml of water. The product was dried in vacuo, suspended in 150 ml of diisopropylether, stirred for 30 minutes and collected by filtration. The product was washed three times with diisopropylether and dried in vacuo resulting in a total of 14.2 g of 2-methyl-4-hydroxy-8-bromo-quinazoline (84% yield).
Reaction SMILES: [NH2:1][C:2]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[CH:8]=1)([CH2:5][OH:6])[CH2:3][OH:4].C1COCC1.C([O-])([O-])=O.[Na+].[Na+].[Cl:25][CH2:26][C:27](Cl)=[O:28]>O>[Br:13][C:9]1[CH:8]=[C:7]([C:2]([NH:1][C:27](=[O:28])[CH2:26][Cl:25])([CH2:5][OH:6])[CH2:3][OH:4])[CH:12]=[CH:11][CH:10]=1
Reactant: NC(CO)(CO)c1cccc(Br)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=C(CCl)NC(CO)(CO)c1cccc(Br)c1
Reaction time: 1 h

Procedure:
To a stirred suspension of 2-amino-2-(3-bromo-phenyl)-propane-1,3-diol (3.5 g, 14.22 mmol), 30 ml of THF and 30 ml of 10% aqueous Na2CO3 solution was added dropwise chloroacetyl chloride (1.472 ml, 18.5 mmol) at 0° C. over a period of 10 min. The mixture was stirred for 1 h, diluted with water and extracted with EtOAc. The organic phase was washed with 1N aqueous NaOH solution, 10% aqueous Na2CO3 solution and brine. Chromatography on silica gel (EtOAc/hexane 50-30%) gave the title compound in the form of a colourless solid. TLC (hexane/EtOAc=1:1): Rf=0.21; HPLC: RtH2=2.926 min; 1H-NMR (400 MHz, CD3OD): 7.58 (s, 1H), 7.44 (d, 1H), 7.37 (d, 1H), 7.29 (t, 1H), 4.91 (s, 2H), 4.07 (d, 2H), 4.00 (d, 2H); MS: 322, 324, 326 [(M+H)+].
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:47][CH:48]([C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C:49]1[CH:54]=[CH:53][C:52]([P:55]([CH2:60][CH2:61][CH3:62])(=[O:59])[O:56][CH2:57][CH3:58])=[CH:51][CH:50]=1>CC#N>[OH:1][C:2]1[C:7]([C:8]([NH:47][CH:48]([C:63]2[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=2)[C:49]2[CH:50]=[CH:51][C:52]([P:55]([CH2:60][CH2:61][CH3:62])(=[O:59])[O:56][CH2:57][CH3:58])=[CH:53][CH:54]=2)=[O:10])=[CH:6][N:5]=[C:4]([N:11]2[CH:15]=[CH:14][CH:13]=[N:12]2)[N:3]=1
Reactant: O=C(O)c1cnc(-n2cccn2)nc1O
Reactant: CCCP(=O)(OCC)c1ccc(C(N)c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCP(=O)(OCC)c1ccc(C(NC(=O)c2cnc(-n3cccn3)nc2O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 4-hydroxy-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid (8-b, 526 mg, 2.56 mmol) in MeCN (10 ml) was added Et3N (645 mg, 6.39 mmol), then added HATU (1068 mg, 2.81 mmol). After 5 mins, ethyl 4-(amino(phenyl)methyl)phenyl(propyl)phosphinate, 16-e, (810 mg, 2.56 mmol) was added and the resulting mixture was stirred at rt for 2 hours. The mixture was then evaporated and the residue was diluted with ethyl acetate followed by washing with brine. The organic layer was dried and concentrated under vacuo to give the title compound, 16-f, (crude product, 2.1 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:27])[CH2:7][CH:6]([CH:8]2[CH2:17][C:16](=O)[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:19]4[CH:20]=[C:21]([CH:24]=[CH:25][CH:26]=4)[C:22]#[N:23])[CH:14]=3)[O:9]2)[CH2:5][CH2:4][O:3]1.C[Si]([N:32]=[C:33]=[N:34][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[C:22]([C:21]1[CH:20]=[C:19]([C:13]2[CH:14]=[C:15]3[C:10](=[CH:11][CH:12]=2)[O:9][CH:8]([CH:6]2[CH2:5][CH2:4][O:3][C:2]([CH3:27])([CH3:1])[CH2:7]2)[CH2:17]/[C:16]/3=[N:34]\[C:33]#[N:32])[CH:26]=[CH:25][CH:24]=1)#[N:23]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: CC1(C)CC(C2CC(=O)c3cc(-c4cccc(C#N)c4)ccc3O2)CCO1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1(C)CC(C2C/C(=N\C#N)c3cc(-c4cccc(C#N)c4)ccc3O2)CCO1
Temperature: 0 °C
Reaction time: 1 h
Yield: 103.8 %

Procedure:
To a solution of 3-(2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-4-oxochroman-6-yl)benzonitrile (251 mg, 0.69 mmol) in anhydrous DCM (15 mL) under N2 atmosphere was added 1 M TiCl4 (in DCM, 1.4 mL, 1.4 mmol) dropwise within 5 min at room temperature. It was stirred another 1 h after the addition. To this mixture was added Bis-trimethylsilylcarbodiimide (283 mg, 340 μL 1.52 mmol) dropwise. The resulting mixture was stirred for another 20 h after the addition. The reaction mixture was poured into ice-water (20 g), It was transferred to a separating funnel after stirred for 30. The separated aqueous phase was extracted with DCM (2×20 mL). The combined organic phases were dried over anhydrous Na2SO4, and filtered, and concentrated to give yellowish gel like solid (E)-N-(6-(3-cyanophenyl)-2-(2,2-dimethyltetrahydro-2H-pyran-4-yl)chroman-4-ylidene)cyanamide (276 mg), which was used for next step without further purification. MS ESI+ve m/z 386 (M+H)+.
Reaction SMILES: [CH:1]1[C:13]2[C:12](=O)[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[C:4](C(Cl)=O)=[CH:3][CH:2]=1.C1C2C(C3C=CC(OCCO)=CC=3)(C3C=CC([O:35]CCO)=CC=3)C3C(=CC=CC=3)C=2C=CC=1.C(N(CC)CC)C>O1CCCC1>[C:1]1(=[O:35])[C:13]2[C:5]([C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)=[CH:4][CH:3]=[CH:2]1
Reactant: O=C(Cl)c1cccc2c1-c1ccccc1C2=O
Reactant: OCCOc1ccc(C2(c3ccc(OCCO)cc3)c3ccccc3-c3ccccc32)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1C=CC=C2C1=Cc1ccccc12
Reaction time: 0.5 h

Procedure:
A 10.0 g quantity of 9-fluorenone-4-carbonyl chloride (0.04 mole, obtained from Aldrich Chemicals Co, Milwaukee, Wis. 53201, USA) and 100 ml of tetrahydrofuran (obtained from Aldrich) were added to a 250 ml, 3-neck round bottom flask equipped with a reflux condenser and a mechanical stirrer. The solution was stirred for about ½ hour, and then 9.04 g of 4.4′-(9-fluorenylidene)-bis(2-phenoxyethanol) (0.02 mole, obtained from Aldrich) in 50 ml of tetrahydrofuran were added, followed by the addition of 4.17 g of triethylamine (0.04 mole, obtained from Aldrich). The solution was refluxed for 6 hours, filtered hot to remove triethylamine hydrochloride salt byproduct, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was recrystallized from tetrahydrofuran with activated charcoal. The product was dried at 60° C. in a vacuum oven for 6 hours to yield a fourth dimeric fluorenone derivative, which was a yellow solid (9.0 g, 51% yield). The product had a melting point of 137–138° C. A 1H-NMR (300 MHz) spectrum in CDCl3 yielded chemical shifts (ppm) of: 4.25–4.34 (t, 4H); 4.67–4.77 (t, 4H); 6.71–6.86 (m, 4H); 7.06–7.17 (m, 4H); 7.19–7.48 (m, 12H); 7.65–7.72 (td, 2H); 7.72–7.79 (d, 2H); 7.78–7.84 (dd, 2H); 7.86–7.95 (dd, 2H); 8.22–8.33 (d, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].[OH-].[K+].C(O)C>O>[CH2:16]([O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C(O)c1ccc2cc(O)ccc2c1
Reactant: CCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCOc1ccc2cc(C(=O)O)ccc2c1
Reaction time: 2 h

Procedure:
6-Hydroxynaphthalene-2-carboxylic acid (39.8 g), 1-bromooctane (61.3 g), potassium hydroxide (23.7 g), ethanol (900 ml) and water (120 ml) were stirred and refluxed for 16 hours. 10% Aqueous potassium hydroxide (200 ml) was added and refluxing was continued for a further 2 hours, when the solution was poured into water (5 liter) and acidified to ph 1. The solid was filtered, washed with water, dried and recrystallised from acetic acid to give the product (49.0 g, 77.2% theory) as a white crystalline solid, mpt 150°-153° C. (98.2% pure by hplc).
Reaction SMILES: [CH2:1](O)[C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1.C(N(CC)CC)C.S(Cl)([Cl:21])=O>C1C=CC=CC=1>[Cl:21][CH2:1][C:2]1[CH:10]=[CH:9][C:8]2[O:7][CH2:6][O:5][C:4]=2[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2c(c1)OCO2
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: ClCc1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 24 h
Yield: 99.9 %

Procedure:
Piperonyl alcohol (10 g, 65.7 mmol) was dissolved in benzene. Triethylamine (11 ml, 78.8 mmol) and thionyl chloride (11 ml, 131.4 mmol) were added dropwise thereto and was stirred for 24 hours at 0° C. The reaction mixture was extracted with sodium bicarbonate and ethyl acetate, the organic layer was separated, and dried over anhydrous magnesium sulfate to obtain 5-chloromethyl benzo[1,3]dioxol (11.2 g, yield 100%).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([C:10]2[CH:14]=[CH:13][NH:12][N:11]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].Br[CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]>>[O:28]=[C:19]1[C:20]2[C:21](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22](=[O:23])[N:18]1[CH2:17][CH2:16][N:12]1[CH:13]=[CH:14][C:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([CH3:1])[CH:9]=2)=[N:11]1
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Cc1cc(-c2cc[nH]n2)ccc1C#N
Product: Cc1cc(-c2ccn(CCN3C(=O)c4ccccc4C3=O)n2)ccc1C#N
Yield: 31.8 %

Procedure:
2-Methyl-4-(1H-pyrazol-3-yl)benzonitrile (0.949 g, 5.2 mmol) was reacted with N-(2-bromoethyl)phthalimide (1.58 g, 6.2 mmol) using the method of Example 27(a). Crude product was purified by chromatography (CombiFlash, silica column, eluent: 0-100% EtOAc/heptane) to yield 0.590 g (32%) of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 2.36 (s, 3H), 3.99 (t, 2H), 4.44 (t, 2H), 6.76 (d, 1H), 7.44 (s, 1H), 7.46 (m, 1H), 7.62 (d, 1H), 7.83 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH3:15])[CH2:9]2)=[CH:4][CH:3]=1.[F:16][CH:17]([F:30])[C@H:18]([C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)[CH3:19]>>[F:30][CH:17]([F:16])[C@H:18]([C:20]1[CH:21]=[C:22]([S:26]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C@@H:8]3[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH3:15])[CH2:9]3)=[CH:6][CH:7]=2)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1)[CH3:19]
Reactant: C[C@@H](c1cccc(S(=O)(=O)Cl)c1)C(F)F
Reactant: CCCN1CC[C@@H](c2ccc(N)cc2)C1
Product: CCCN1CC[C@@H](c2ccc(NS(=O)(=O)c3cccc([C@H](C)C(F)F)c3)cc2)C1

Procedure:
Following the same procedure as described in Example 1.7, (S)-3-(4-amino-phenyl)-1-propyl-pyrrolidine was coupled with (S)-3-(1,1-difluoropropan-2-yl)benzene-1-sulfonyl chloride to give the title compound.
Reaction SMILES: [F:1][C:2]([F:17])([C:6]1([OH:16])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7]1)[C:3]([O-:5])=O.CCN(CC)CC.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[O:30][CH2:31][C:32]1[O:36][N:35]=[C:34]([C@@H:37]2[CH2:41][CH2:40][CH2:39][NH:38]2)[CH:33]=1>C1COCC1.ClC(OCC)=O>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[O:30][CH2:31][C:32]1[O:36][N:35]=[C:34]([C@@H:37]2[CH2:41][CH2:40][CH2:39][N:38]2[C:3](=[O:5])[C:2]([F:1])([F:17])[C:6]2([OH:16])[CH2:11][C:10]([CH3:13])([CH3:12])[CH2:9][C:8]([CH3:15])([CH3:14])[CH2:7]2)[CH:33]=1
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)[O-])C1
Reactant: COc1ccc(OCc2cc([C@@H]3CCCN3)no2)cc1OC
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(OCc2cc([C@@H]3CCCN3C(=O)C(F)(F)C3(O)CC(C)(C)CC(C)(C)C3)no2)cc1OC
Reaction time: 0.5 h
Yield: 217 %

Procedure:
To a solution of 2,2-difluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexyl)acetate (87.83 g) and Et3N (122 mL) in THF (2000 mL), ethyl chloroformate (30.8 mL) was added at room temperature and the mixture was stirred for 30 minutes. To the reaction mixture, a THF (500 mL) solution of the compound (89.00 g) obtained in Example 1-(1) was added dropwise at room temperature over an hour and the mixture was stirred at room temperature for 20 hours. The reaction mixture was concentrated and AcOEt (2 L) and a saturated aqueous solution of NH4Cl (2 L) were added; after filtering the insoluble matter, the organic layer was separated and washed with saturated aqueous sodium bicarbonate (2 L), dried (MgSO4), filtered and concentrated to give a crude product (165.0 g). A similar method was applied using 2,2-difluoro-2-(1-hydroxy-3,3,5,5-tetramethylcyclohexyl)acetate (34.64 g) and (S)-5-((3,4-dimethoxyphenoxy)methyl)-3-(pyrrolidin-2-yl)isoxazole (35.10 g) to give a crude product (60.10 g), which was combined with the first crude product and further purified by silica gel chromatography (AcOEt/hexane) and NH-form silica gel chromatography (AcOEt/hexane); the purified product was recrystallized (Et2O/pentane) to give the titled compound (134.30 g, colorless powder.)
Reaction SMILES: Cl.[N:2]1([CH2:7][C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([C:24]([OH:26])=O)=[CH:18]3)=[O:14])[CH2:6][CH2:5][CH2:4][CH2:3]1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.[F:49][C:50]1([F:56])[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[F:49][C:50]1([F:56])[CH2:55][CH2:54][N:53]([C:24]([C:19]2[NH:20][C:21]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:13]([N:9]2[CH2:10][CH2:11][CH2:12][C@@H:8]2[CH2:7][N:2]2[CH2:3][CH2:4][CH2:5][CH2:6]2)=[O:14])=[CH:23][CH:22]=3)=[O:26])[CH2:52][CH2:51]1
Reactant: FC1(F)CCNCC1
Reactant: O=C(O)c1cc2cc(C(=O)N3CCC[C@@H]3CN3CCCC3)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc2cc(C(=O)N3CCC[C@@H]3CN3CCCC3)ccc2[nH]1)N1CCC(F)(F)CC1
Yield: 74 %

Procedure:
The title compound was synthesized in analogy to example 1, from 5-((R)-2-pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-1H-indole-2-carboxylic acid hydrochloride, O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (commercially available), 4,4-difluoropiperidine (commercially available) and N,N-diisopropylethylamine in N,N-dimethylformamide, to give the desired product as a colorless solid (74%).