Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH:4]([OH:16])[CH2:5][C:6](=[O:15])[CH2:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])#[N:2].C(O)(=O)C.[BH4-].[Na+].[OH-].[Na+]>O1CCCC1.C(B(CC)CC)C.CO>[C:1]([CH2:3][CH:4]([OH:16])[CH2:5][CH:6]([OH:15])[CH2:7][C:8]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)CC(=O)CC(O)CC#N
Agent: CCB(CC)CC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)CC(O)CC(O)CC#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Crude 5R 1,1-dimethylethyl 6-cyano-5-hydroxy-3-oxohexanoate (about 150 moles) from Step (1) is dissolved in 325 L of tetrahydrofuran containing about 20 kg of triethylborane, stirred for about 2 hours at room temperature, cooled to −75° C.±20° C. and diluted with 25 L of methanol and 8 kg of acetic acid. Sodium borohydride (8 kg) as a solution in methanol and aqueous sodium hydroxide is added slowly. After the addition, the reaction mixture is warmed to 0° C.±25° C. The reaction mixture is optionally quenched by the addition of 3 kg of acetic acid and 10 L of methanol and concentrated by vacuum distillation, saving the distillate. The residue is dissolved in methanol and acetic acid, optionally diluted with water, and concentrated by vacuum distillation, keeping this distillate separate from the first one. The residue is dissolved in methanol and concentrated by vacuum distillation. The residue is dissolved in a mixture of water and ethyl acetate, and the aqueous layer separated. The organic layer is concentrated by vacuum distillation. The residue is dissolved in methanol and acetic acid and concentrated by vacuum distillation. The residue is dissolved in ethyl acetate and concentrated by vacuum distillation affording crude [R-(R*,R*)]-1,1-dimethylethyl 6-cyano-3,5-dihydroxyhexanoate.
Reaction SMILES: [Br-].C1([P+](C2C=CC=CC=2)(C2C=CC=CC=2)[CH2:9][C:10]2[C:15]([CH3:17])([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]=2[CH3:18])C=CC=CC=1.O=C1C2C(=CC=CC=2)C(=O)[N:33]1[CH2:42][CH2:43][CH2:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[CH:48]=O>>[CH3:18][C:11]1[CH2:12][CH2:13][CH2:14][C:15]([CH3:16])([CH3:17])[C:10]=1/[CH:9]=[CH:48]/[C:47]1[CH:46]=[C:45]([CH2:44][CH2:43][CH2:42][NH2:33])[CH:52]=[CH:51][CH:50]=1
Reactant: O=Cc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Reactant: CC1=C(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)C(C)(C)CCC1
Agent: [Br-]
Product: CC1=C(/C=C/c2cccc(CCCN)c2)C(C)(C)CCC1

Procedure:
(E)-3-(3-(2-(2,6,6-Trimethylcyclohex-1-enyl)vinyl)phenyl)propan-1-amine was prepared by coupling triphenyl((2,6,6-trimethylcyclohex-1-enyl)methyl)phosphonium bromide (24) (Scheme 8) with 3-(3-(1,3-dioxoisoindolin-2-yl)propyl)benzaldehyde (29) (Scheme 9).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]#[CH:13])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.I[C:15]1[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])[CH3:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CN(C=O)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([C:12]#[C:13][C:15]3[CH:32]=[CH:31][C:18]([O:19][CH2:20][C@@H:21]([NH:23][C:24](=[O:30])[O:25][C:26]([CH3:27])([CH3:28])[CH3:29])[CH3:22])=[CH:17][CH:16]=3)=[N:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: C[C@@H](COc1ccc(I)cc1)NC(=O)OC(C)(C)C
Reactant: C#Cc1ccc(OCC2CC2)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H](COc1ccc(C#Cc2ccc(OCC3CC3)cn2)cc1)NC(=O)OC(C)(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 97.1 %

Procedure:
A mixture of 5-(cyclopropylmethoxy)-2-ethynylpyridine (591 mg), tert-butyl [(1S)-2-(4-iodophenoxy)-1-methylethyl]carbamate (1.67 g), bis(triphenylphosphine)palladium(II) dichloride (120 mg), copper(I) iodide (32.5 mg), triethylamine (518 mg) and DMF (10 mL) was stirred at 60° C. overnight under an argon atmosphere. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate and water, filtered through celite, and the aqueous layer was separated from the organic layer. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a yellow solid (1.40 g).
Reaction SMILES: C[O-].[Na+].[CH3:4][SH:5].[CH3:6][O:7][C:8]1[N:17]=[C:16](Cl)[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]>CO>[CH3:6][O:7][C:8]1[N:17]=[C:16]([S:5][CH3:4])[CH:15]=[CH:14][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)c1ccc(Cl)nc1OC
Reactant: CS
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(SC)nc1OC

Procedure:
To 10 ml of a 1 N methanolic sodium methoxide solution are added dropwise 3 ml of a 3.5 N methanolic methylmercaptan solution. To the resultant methylmercaptide solution is added a solution of 2.01 g (0.01 mole) of methyl 2-methoxy-6-chloronicotinate (cf. Example 6 a)) in 30 ml of methanol. The reaction mixture is refluxed for 5 hours and the solvent is thereafter evaporated in vacuo. The residue is treated with 30 ml of saturated potassium carbonate solution and 150 ml of methylene chloride and separated in a separating funnel. The methylene chloride solution is dried over sodium sulphate and subsequently evaporated to dryness in vacuo. The crystallised residue is recrystallised from pentane and yields the methyl 2-methoxy-6-(methylthio)-nicotinate with a melting point of 71°-75° C.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=[O:14])[CH2:8][CH2:7][CH2:6]2.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[CH3:13])[C:9](=[O:14])[CH2:8][CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1C)C(=O)CCC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2c(cc1O)CCCC2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 80.3 %

Procedure:
A solution of 2.79 g (14.7 mmol) of 6-methoxy-7-methyl-1,2,3,4-tetrahydro-1-naphthalenone in 150 mL of CH2Cl2 was cooled in ice and treated with 20 mL (0.22 mol) of BBr3. After stirring at 0° C. for 0.5 hour, the solution was stirred at room temperature overnight. The solution was poured into ice water and extracted with Et2O. The Et2O was extracted twice with 5% NaOH and the NaOH washed with Et2O. The NaOH solution was acidified to the Congo Red end point with dilute HCl, then extracted with Et2O. The Et2O was washed with saturated NaCl and dried over MgSO4. Removal of the solvent under reduced pressure left the crude product. This was taken up in acetone and treated with charcoal. Filtering through Celite and removal of the solvent under reduced pressure left 2.08 g (80.6% yield) of the product as a brown solid. The structure was confirmed by NMR and mass spectroscopy. MS m/z 177 (M+H+).
Reaction SMILES: [CH2:1]1[O:12][C:11]2[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:13])=[CH:4][C:3]=2[O:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:26][CH2:27][CH:28]([OH:30])[CH3:29]>C(Cl)Cl>[OH:13][C:5]1[CH:4]=[C:3]2[O:2][CH2:1][O:12][C:11]2=[CH:10][C:6]=1[C:7]([NH:26][CH2:27][CH:28]([OH:30])[CH3:29])=[O:9]
Reactant: O=C(O)c1cc2c(cc1O)OCO2
Reactant: CC(O)CN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(O)CNC(=O)c1cc2c(cc1O)OCO2
Yield: 67 %

Procedure:
4,5-Methylenedioxysalicylic acid was activated by carbonyldiimidazole in methylene chloride and combined with 1-amino-2-propanol in essentially an identical manner as for Example 1 above. An acidic quench and subsequent purification by flash chromatography (SiO2) using (1:1) hexane-ethyl acetate gave 1-(2-hydroxy-4,5-methylenedioxybenzamido)-2-propanol as a waxy white solid in 67% yield.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([C:16]([OH:18])=O)=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CN1CCOCC1.[CH3:53][C:54]([NH2:61])([CH2:57][CH:58]([CH3:60])[CH3:59])[CH2:55][NH2:56]>CN(C=O)C.O.C(O)(C(F)(F)F)=O>[NH2:61][C:54]([CH3:53])([CH2:57][CH:58]([CH3:60])[CH3:59])[CH2:55][NH:56][C:16]([C:12]1[N:8]2[CH:9]=[CH:10][CH:11]=[C:6]([O:5][CH2:4][C:3]3[C:19]([F:23])=[CH:20][CH:21]=[CH:22][C:2]=3[F:1])[C:7]2=[N:14][C:13]=1[CH3:15])=[O:18]
Reactant: CC(C)CC(C)(N)CN
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NCC(C)(N)CC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
150 mg (0.47 mmol) of 8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxylic acid Example 3A were initially charged in DMF (1.7 ml), and 159 mg (0.50 mmol) of TBTU and 0.16 ml (1.41 mmol) of 4-methylmorpholine were added. 68 mg (0.52 mmol) of rac-2,4-dimethylpentane-1,2-diamine were then added, and the reaction mixture was stirred at RT overnight. Another 6.1 mg (0.04 mmol) of rac-2,4-dimethylpentane-1,2-diamine were added, and the reaction mixture was stirred at RT for 20 min. The mixture was diluted with water/TFA and purified by prep. RP-HPLC (acetonitrile/water gradient with addition of 0.1% TFA). The product fraction was concentrated. The residue was taken up in dichloromethane and a few drops of methanol and washed twice with saturated aqueous sodium bicarbonate solution, and the aqueous phase was extracted three times with dichloromethane. The organic phase was dried over sodium sulphate, filtered off and concentrated. This gave 126 mg (61% of theory, purity 97%) of the target compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH2:41][C:42]([CH3:46])([CH3:45])[CH2:43][OH:44])=[CH:38][C:37]=1[CH3:50].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]2[C:48]([CH3:49])=[CH:47][C:39]([O:40][CH2:41][C:42]([CH3:45])([CH3:46])[CH2:43][OH:44])=[CH:38][C:37]=2[CH3:50])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: Cc1cc(OCC(C)(C)CO)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OCC(C)(C)CO)cc5C)ccc(F)c43)ccc21
Temperature: 100 °C
Reaction time: 12 h

Procedure:
In a microwave vial methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate (250 mg), 3-(4-bromo-3,5-dimethylphenoxy)-2,2-dimethylpropan-1-ol (226 mg), K3PO4 (230 mg) are suspended in toluene (2 mL) and water (200 μL) and purged for 10 minutes with argon. Palladium-(II)-acetate (12 mg) and dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (44 mg) are added, the vial is sealed and the mixture is stirred at 100° C. for 12 hours. After cooling to room temperature the mixture is partitioned between ethyl acetate and water. The organic phase is washed with brine, dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 99:1→60:40) to give the title compound. Yield: 99 mg; LC (method 8): tR=0.87 min; Mass spectrum (ESI+): m/z=549 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][C:14](O)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.S(Cl)(Cl)=O>ClCCl.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH:13]=[C:14]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)(c2ccccn2)CC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OCc1ccccc1)N1CC=C(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 63.7 %

Procedure:
A solution of 1-benzyloxycarbonyl-4-hydroxy-4-(2-pyridyl)piperidine (0.8 g) in 20 mL of dichloromethane at 0° C. was treated with pyridine (2 mL) followed by thionyl chloride (0.22 mL). The reaction mixture was allowed to warm to the room temperature and stirred for 16 hours. At the end of this period, the reaction mixture was diluted with water and extracted twice with ethyl acetate. The organic layer was washed with a solution of copper sulfate, dried over magnesium sulfate and concentrated under reduce pressure to obtain the crude material. This material was purified by column chromatography; elution with 1:1 hexane:ethylacetate afforded the named product (0.48 g); MS: 295; NMR: 2.67 (m, 2), 3.74 (m, 2), 4.2 (m, 2), 5.18 (s, 2), 6.6 (m, 1), 7.18 (m, 1), 7.36 (m, 6), 7.68 (m, 1), 8.56 (m, 1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([OH:15])=O)[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:47][C:48]1[CH:49]=[C:50]2[C:54](=[CH:55][CH:56]=1)[NH:53][C:52]([C:57]([CH3:61])([CH3:60])[CH2:58][OH:59])=[CH:51]2>C(#N)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:47][C:48]4[CH:49]=[C:50]5[C:54](=[CH:55][CH:56]=4)[NH:53][C:52]([C:57]([CH3:61])([CH3:60])[CH2:58][OH:59])=[CH:51]5)=[O:15])[CH2:11][CH2:12]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)C1(c2ccc3c(c2)OCO3)CC1
Reactant: CC(C)(CO)c1cc2cc(N)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(CO)c1cc2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.9 %

Procedure:
To a solution of 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid (0.075 g, 0.36 mmol) in acetonitrile (1.5 mL) were added HBTU (0.138 g, 0.36 mmol) and Et3N (152 μL, 1.09 mmol) at room temperature. The mixture was stirred at room temperature for 10 minutes before a solution of 2-(5-amino-1H-indol-2-yl)-2-methylpropan-1-ol (0.074 g, 0.36 mmol) in acetonitrile (1.94 mL) was added. After addition, the reaction mixture was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure and the residue was dissolved in dichloromethane. The organic layer washed with 1 N HCl (1×3 mL) and saturated aqueous NaHCO3 (1×3 mL). The organic layer was dried over Na2SO4, filtered and evaporated under reduced pressure. The crude material was purified by column chromatography on silica gel (ethyl acetate/hexane=1/1) to give 1-(benzo[d][1,3]dioxol-5-yl)-N-(2-(1-hydroxy-2-methylpropan-2-yl)-1H-indol-5-yl)cyclopropanecarboxamide (0.11 g, 75%). 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.38 (s, 1H), 7.55 (s, 1H), 7.15 (d, J=8.6 Hz, 1H), 7.04-6.90 (m, 4H), 6.06 (s, 1H), 6.03 (s, 2H), 4.79 (t, J=2.7 Hz, 1H), 3.46 (d, J=0.0 Hz, 2H), 1.41-1.39 (m, 2H), 1.26 (s, 6H), 1.05-1.02 (m, 2H).
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[N:7]1[C:15]2[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=2[C:9]2[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]1=2.[F:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].O>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>[F:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH2:6][CH2:5][CH2:4][C:3]=2[N:7]2[C:15]3[CH:14]=[CH:13][C:12]([CH3:16])=[CH:11][C:10]=3[C:9]3[CH2:17][N:18]([CH3:21])[CH2:19][CH2:20][C:8]2=3)=[CH:25][CH:24]=1
Reactant: Cc1ccc2c(c1)c1c(n2C2=C(Br)CCC2)CCN(C)C1
Reactant: OB(O)c1ccc(F)cc1
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+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccc2c(c1)c1c(n2C2=C(c3ccc(F)cc3)CCC2)CCN(C)C1
Temperature: 90 °C
Reaction time: 0.75 h

Procedure:
To a degassed stirred solution of 5-(2-bromocyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.29 mmol), 4-fluorophenylboronic acid (81 mg, 0.578 mmol) and potassium carbonate (120 mg, 0.87 mmol) in 1,2-dimethoxyethane (4 mL)-water (2 mL) was added Pd(PPh3)4 (17 mg, 0.0147 mmol). The reaction mixture was stirred at 90° C. for 45 min. The reaction mixture concentrated to dryness, residue diluted with water (20 mL) and extracted with EtOAc (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue was purified by reverse phase HPLC to yield 5-(2-(4-fluorophenyl)cyclopent-1-enyl)-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole. 1H NMR (CD3OD, TFA salt) δ (ppm): 7.3 (s, 1H), 7.17 (d, 1H), 7.02 (d, 1H), 6.8-6.98 (m, 4H), 4.7 (d, 1H), 4.3 (d, 1H), 3.65 (m, 1H), 3.41 (m, 1H), 2.9-3.18 (m, 7H), 2.52-2.77 (m, 2H), 2.45 (s, 3H), 2.21 (m, 2H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[H][H]>CO>[C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[CH2:19][CH2:18]1)[CH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1CCC(=O)O1
Reactant: [H][H]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H]1CCC(=O)O1

Procedure:
15 g (49.12 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]dihydrofuran-2-(3H)-one [Example 2b)] are dissolved in 150 ml of methanol, and this solution is treated with 0.75 g of Nishimura catalyst and hydrogenated (RT, standard pressure) until there is no further uptake of hydrogen. The catalyst is filtered off, the solvent is removed, and the residue is chromatographed on silica gel (toluene/ethyl acetate, 5:1). The title compound is obtained as a thick, viscous oil. IR (CH2Cl2) inter alia: 3431, 1774, 1711, 1501 und 1170 cm-1. FAB-MS (M+1)+ =312. 1H-NMR (DMSO-d6) inter alia: 6.80 (d, 1H); 4.40 (m, 1H); 3.66 (m, 1H); 2.58-2.43 (m, 2H); 2.37 (dxq, 1H); 2.14 (m, 1H) and 1.39 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([O:24][CH2:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]4)=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:34])[NH:6]2.ClC(Cl)(Cl)[C:37]([N:39]=C=O)=[O:38]>N1C=CC=CC=1.CO>[C:37]([N:31]1[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][CH2:25][O:24][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:10]4[C:2]([F:1])=[C:3]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([CH3:34])=[CH:4]5)=[N:13][CH:14]=[N:15]3)=[CH:20][C:19]=2[O:22][CH3:23])[CH2:29][CH2:30]1)(=[O:38])[NH2:39]
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCNCC1
Reactant: O=C=NC(=O)C(Cl)(Cl)Cl
Solvent: CO
Solvent: c1ccncc1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(C(N)=O)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.4 %

Procedure:
4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-piperazin-1-ylpropoxy)quinazoline (240 mg, 0.52 mmol), (prepared as described for the starting material in Example 15), was dissolved in pyridine (5 ml) and cooled to 0° C. Trichloroacetyl isocyanate (61 μl, 0.52 mmol) was added and the mixture stirred at ambient temperature for 1 hour. The mixture was concentrated under reduced pressure and the residue dissolved in 7N ammonia in methanol and stirred at 45° C. for 2.5 hours. Aqueous ammonia (1 ml) was added and the mixture was stirred at 60° C. for 1.5 hours and then at ambient temperature overnight. The solvent was removed under reduced pressure. Column chromatography of the residue using methylne chloride/methanol (90/10) followed by methylene chloride/methanol (saturated with ammonia) (90/10) gave a solid which was suspended in methanol and filtered to give 7-(3-[4-carbamoylpiperazin-1-yl]propoxy)-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (120 mg, 46%) as a pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].Cl.[CH3:20][NH:21][CH3:22]>C(N(CC)CC)C>[CH3:20][N:21]([CH3:22])[C:16]([C:14]1[S:15][C:11]([C:3]2[C:2]([CH3:1])=[C:6]([C:7]([F:10])([F:9])[F:8])[O:5][N:4]=2)=[CH:12][CH:13]=1)=[O:18]
Reactant: CNC
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(C(=O)N(C)C)s2)noc1C(F)(F)F
Yield: 72 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and dimethylamine hydrochloride by the method described in Example 2 Method B utilizing an additional equivalent of triethylamine. The reaction mixture was evaporated to a solid then triturated and filtered with the aid of water to afford product as a colorless solid (110 mg, 72%). 1H NMR (CDCl3) 2.37 (s, 3 H), 3.22 (br s, 6 H), 7.41 (d, J=4.0, 1 H), 7.47 (d, J=4.0, 1 H). 13C NMR 7.9, 37.0 (br), 39.8 (br), 114.7, 118.8 (q, J=271), 128.0, 129.7, 131.6, 140.9, 155.7 (q, J=41), 158.0, 163.7. 19F NMR −63.2. LC/MS 6.03 min, [M+1]+ 305.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[CH3:15]OS(OC)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:1]([C:5]1[C:6]([O:12][CH3:15])=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cccc(C(C)(C)C)c1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1c(C)cccc1C(C)(C)C
Temperature: 95 °C
Reaction time: 15 h

Procedure:
A mixture of 0.12 mole of 2-t-butyl-6-methylphenol and 12.0 ml. of 10.0 N sodium hydroxide solution is stirred and heated on the steam bath for 1 hour. The water is evaporated in vacuo. The residue is added portion-wise with stirring to 0.24 mole of dimethylsulfate and the mixture is stirred at 95° C. for 6 hours and at room temperature for 15 hours. Sodium carbonate (0.25 mole) in 100 ml. of water is added and stirring is continued for 5 hours. The mixture is extracted with 3 × 100 ml. of ether and the extract is dried and concentrated to dryness to give 3-t-butyl-2-methoxytoluene.
Reaction SMILES: [SH:1][CH:2]([CH2:6][C:7]([OH:9])=[O:8])[C:3]([OH:5])=[O:4].[CH2:10]([C:13]([F:31])([F:30])[C:14]([F:29])([F:28])[C:15]([F:27])([F:26])[C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:11]O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:30][C:13]([F:31])([C:14]([F:29])([F:28])[C:15]([F:27])([F:26])[C:16]([F:25])([F:24])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])[CH2:10][CH2:11][O:4][C:3](=[O:5])[CH:2]([SH:1])[CH2:6][C:7]([O:9][CH2:11][CH2:10][C:13]([F:30])([F:31])[C:14]([F:28])([F:29])[C:15]([F:26])([F:27])[C:16]([F:24])([F:25])[C:17]([F:23])([F:22])[C:18]([F:21])([F:20])[F:19])=[O:8]
Reactant: OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: O=C(O)CC(S)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C(CC(S)C(=O)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)OCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Yield: 94.7 %

Procedure:
Mercaptosuccinic acid (Aldrich) (12.5 g, 0.083 mole) and 1H,1H,2H,2H-perfluorooctan-1-ol (Fluorochem Ltd.) (60.6 g, 0.166 mole) were suspended in toluene (400 ml). p-Toluene sulfonic acid hydrate (Aldrich) (0.36 g) was added and the mixture refluxed under argon atmosphere for 72 hours in a flask equipped with a Dean & Stark reflux condenser. The solution was allowed to cool and the toluene was removed by evaporation under reduced pressure. The resulting oil was redissolved in ethyl acetate (1000 ml) and washed with saturated aqueous sodium hydrogen carbonate (800 ml). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and evaporated to give 2-mercaptosuccinic acid bis-(3,3,4,4,5,5,6,6,7,7,8,8,8-tridecafluorooctyl) ester as a pale yellow oil (66.2 g, 100% yield).