Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][CH:5]=1.[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19]C)=[O:17].C[O-].[Na+]>CO>[O:21]=[C:15]([CH2:11][C:10](=[O:12])[C:7]1[CH:6]=[CH:5][C:4]([O:3][C:2]([F:13])([F:14])[F:1])=[CH:9][CH:8]=1)[C:16]([O:18][CH3:19])=[O:17]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(OC(F)(F)F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C(=O)CC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.3 %

Procedure:
To a solution of 1-(4-(trifluoromethoxy)phenyl)ethanone (5.0 g, 24.5 mmol) and diethyl oxalate (4.3 g, 29.4 mmol) in MeOH (60 mL) was added NaOMe (30% in MeOH, 5.3 g, 29.4 mmol). The mixture was stirred at RT for 4 h and then concentrated under reduced pressure. The residue was treated with 2N aq. HCl (15 mL) and extracted with EtOAc (2×100 mL). The organic layer was washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to afford methyl 2,4-dioxo-4-(4-(trifluoromethoxy)phenyl)butanoate as a brown oil (6.85 g, 96%), which was used in the next step without further purification. MS (ES+) C12H9F3O5 requires: 290. found: 291 [M+H]+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[CH3:13][CH:14]([CH3:30])[C:15]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:19]=1)=[O:16]>>[F:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[O:5][CH2:4][CH2:3][CH2:2][N:27]1[CH2:28][CH2:29][CH:24]([C:20]2[CH:19]=[C:18]([NH:17][C:15](=[O:16])[CH:14]([CH3:13])[CH3:30])[CH:23]=[CH:22][CH:21]=2)[CH2:25][CH2:26]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Fc1ccccc1OCCCCl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCOc3ccccc3F)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-(3-chloropropoxy)-2-fluorobenzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 399.2 (M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:21])[CH2:4][CH2:3]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:31]=O)[CH:26]=[N:27][C:28]=1[CH2:29][OH:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:22][C:23]1[CH:24]=[C:25]([CH2:31][NH:1][CH:2]2[CH2:3][CH2:4][N:5]([CH2:8][CH2:9][N:10]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([F:20])[CH:18]=4)[CH:13]=[CH:12][C:11]3=[O:21])[CH2:6][CH2:7]2)[CH:26]=[N:27][C:28]=1[CH2:29][OH:30]
Reactant: O=Cc1cnc(CO)c(Cl)c1
Reactant: NC1CCN(CCn2c(=O)ccc3ncc(F)cc32)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=c1ccc2ncc(F)cc2n1CCN1CCC(NCc2cnc(CO)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 1-[2-(4-amino-1-piperidinyl)ethyl]-7-fluoro-1,5-naphthyridin-2(1H)-one (Intermediate 21: 38.9 mg, 0.134 mmol) and 5-chloro-6-(hydroxymethyl)-3-pyridinecarbaldehyde (Intermediate 39: 23 mg, 0.134 mmol) in 1,2-Dichloroethane (2.5 ml) was stirred under N2 at room temperature for 1 h. Then, sodium triacetoxy borohydride (85 mg, 0.402 mmol) was added and the mixture was stirred at RT overnight. LCMS showed desired compound and imine. An excess of sodium triacetoxy borohydride (85 mg, 0.401 mmol) was added and the mixture was stirred at rt 6 h. LCMS showed desired compound and imine. An excess of sodium triacetoxy borohydride (85 mg, 0.401 mmol) was added. The mixture was stirred at room temperature overnight. LCMS showed desired compound and imine. An excess of sodium triacetoxy borohydride (85 mg, 0.401 mmol) was added and the mixture was stirred at room temperature overnight. LCMS did not show imine and showed desired compound. NaHCO3 sat. was added and the aqueous phase was extracted twice with DCM. The combined organic phases were washed with sat. NaCl, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by Flash-Master chromatography on a 2 g silica gel cartridge using DCM/MeOH 95:5 as eluent to obtain two fractions. The first was 9 mg of white solid consistent with the desired compound by HNMR. The second was 4 mg white solid consistent with desired compound but not enough pure by HNMR and LCMS. This second fraction was discarded.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[CH3:25][O:26][C:27]1[CH:37]=[CH:36][CH:35]=[CH:34][C:28]=1[CH:29]=[CH:30][C:31](O)=[O:32].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:25][O:26][C:27]1[CH:37]=[CH:36][CH:35]=[CH:34][C:28]=1[CH:29]=[CH:30][C:31]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:32]
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Reactant: COc1ccccc1C=CC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccccc1OC
Yield: 87.5 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-tryptophanate hydrochloride (4.0 g), triethylamine (4.8 mL), 2-methoxycinnamic acid (3.1 g), WSC.HCl (3.3 g), and methylene chloride (150 mL), to give the captioned compound (5.2 g, 88%) as an oily product.
Reaction SMILES: [CH2:1]([C:5]1[N:10]=[N:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.FC(F)(F)C(O[C:38]1[C:43]([F:44])=[C:42]([F:45])[C:41]([F:46])=[C:40]([F:47])[C:39]=1[F:48])=O.Cl>C(Cl)Cl>[F:44][C:43]1[C:38]([O:12][C:11]([C:8]2[N:9]=[N:10][C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[C:6]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)=[CH:18][CH:19]=3)[CH:7]=2)=[O:13])=[C:39]([F:48])[C:40]([F:47])=[C:41]([F:46])[C:42]=1[F:45]
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Reactant: CCCCc1nnc(C(=O)O)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1nnc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 70.9 %

Procedure:
To a stirred solution of the carboxylic acid (24.4 mmol, 8.6 g) in DCM (100 mL) was added pyridine (81 mmol, 6.4 g) followed pentafluorophenyl trifluoroacetate (40.52 mmol, 11.3 g) drop-wise. The reaction was stirred at 0° C. for 30 min and then at room temperature for 8 h. The reaction was added to 1N HCl (100 mL), and the product was extracted with ethyl acetate. The crude product was purified using a mixture of hexanes in ethyl acetate on a 330 g silica gel ISCO column to provide 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester (9.0 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[Br:9][C:10]([CH3:15])([CH3:14])[C:11](Br)=[O:12].C(N(CC)CC)C>C(Cl)Cl>[Br:9][C:10]([CH3:15])([CH3:14])[C:11]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])=[O:12]
Reactant: CC(C)(Br)C(=O)Br
Reactant: Nc1ccccc1O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(Br)C(=O)Nc1ccccc1O
Temperature: 0 °C
Reaction time: 4 h
Yield: 921 %

Procedure:
To a stirred solution of 2-aminophenol (10 g, 9.2 mmol) in DCM (92 mL) at 0° C. was added 2-bromoisobutyryl bromide (11.4 mL, 9.17 mmol) followed by triethyl amine (12.7 mL, 9.2 mmol) and stirred the reaction mixture at 0° C. for 4 h. Reaction mixture was diluted with DCM 100 mL and then washed with water 100 mL dried over sodium sulfate, concentrated on rotavap to give 2-Bromo-N-(2-hydroxy-phenyl)-2-methyl-propionamide (21.8 g) brown solid which was used for next reaction without purification
Reaction SMILES: C1(N[C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)CCCC1.Cl.[F:24][C:25]1[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=1>>[F:24][C:25]1[CH:26]=[C:27]([NH:31][C:7]2[C:12]([CH3:13])=[C:11]([CH3:14])[N:10]=[C:9]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[N:8]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Nc1cccc(F)c1
Reactant: Cc1nc(NCc2ccccn2)nc(NC2CCCC2)c1C
Agent: Cl
Product: Cc1nc(NCc2ccccn2)nc(Nc2cccc(F)c2)c1C

Procedure:
The titled compound was synthesized according to the procedure described for preparation of N4-cyclopentyl-5,6-dimethyl-N2-(pyridin-2-ylmethyl)pyrimidine-2,4-diamine (Example 29) using (3-fluorophenyl)amine hydrochloride instead of cyclopentanamine. The crude material was purified by column chromatography eluting with mixture of chloroform/ethanol/20% water solution of ammonia (200:10:1), and then the final product was washed with diethyl ether to afford the titled compound as a white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.04 (s, 3H), 2.20 (s, 3H), 4.51 (d, J=5.6 Hz, 2H), 6.67 (t, J=5.9 Hz, 1H), 7.05-7.29 (m, 4H), 7.60 (bs, 1H), 7.69 (t, J=8.1 Hz, 1H), 8.08 (s, 1H), 8.48 (d, J=4.0 Hz, 1H); MS (ESI) m/z 324.4 (M+1)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]4[C:33]5[C:28](=[CH:29][C:30]([OH:36])=[C:31]([O:34][CH3:35])[CH:32]=5)[N:27]=[CH:26][N:25]=4)=[C:19]([F:37])[CH:18]=3)=[O:15])[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([CH2:51]OS(C)(=O)=O)[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:40])[CH3:39].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[C:38]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH:48]([CH2:51][O:36][C:30]2[CH:29]=[C:28]3[C:33]([C:24]([O:23][C:20]4[CH:21]=[CH:22][C:17]([NH:16][C:14]([C:11]5([C:9](=[O:10])[NH:8][C:5]6[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=6)[CH2:13][CH2:12]5)=[O:15])=[CH:18][C:19]=4[F:37])=[N:25][CH:26]=[N:27]3)=[CH:32][C:31]=2[O:34][CH3:35])[CH2:47][CH2:46]1)=[O:44])([CH3:41])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC(COS(C)(=O)=O)CC1
Reactant: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ncnc2cc1OCC1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Yield: 60.6 %

Procedure:
Cyclopropane-1,1-dicarboxylic acid [3-fluoro-4-(7-hydroxy-6-methoxy-quinazolin-4-yloxy)-phenyl]-amide (4-fluoro-phenyl)-amide (325 mg, 0.64 mmol), 4-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester (193 mg, 0.66 mmol), K2CO3 (181 mg, 1.31 mmol) were combined in DMF (5 ml) and heated to 80° C. overnight. The reaction was not complete and more 4-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester (90 mg, 0.31 mmol) and K2CO3 (90 mg, 0.65 mmol) were added and heating at 80° C. continued for another night. The reaction mixture was allowed to cool to room temperature, then diluted with EtOAc and washed with H2O (3×), sat'd NaCl (1×), dried (Na2SO4) and concentrated in vacuo. The resulting crude material was purified by flash chromatography (1:1 hexanes:EtOAc, followed by 1:3 hexanes:EtOAc) to give 4-[4-(2-fluoro-4-{[1-(4-fluoro-phenylcarbamoyl)-cyclopropanecarbonyl]-amino}-phenoxy)-6-methoxy-quinazolin-7-yloxymethyl]-piperidine-1-carboxylic acid tert-butyl ester (273 mg, 60%). LC/S Calcd for [M+H]+ 704.3, found 704.4.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14]O)[CH:6]=1)(=[O:3])[CH3:2].C(Br)(Br)(Br)[Br:17].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[C:1]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][CH2:12][CH2:13][CH2:14][Br:17])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccc(CCCCO)c1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)Oc1cccc(CCCCBr)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 3-(4-hydroxybutyl)phenyl acetate (416 mg) in DCM (10 mL) was treated with carbon tetrabromide (1.16 g) and triphenylphosphine (791 mg) and stirred at room temperature for 15 min prior to concentration in vacuo. The residue was purified by chromatography (SPE, DCM-petrol 1:1) to give the title compound. LCMS RT=3.58 min
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:24][C:25](=[O:38])[C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[CH:28][CH:27]=2)=[CH:17][CH:16]=1)[C:10]([O:12]C)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>>[CH2:1]([O:8][CH:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][NH:24][C:25](=[O:38])[C:26]2[CH:31]=[CH:30][C:29]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=3)=[CH:28][CH:27]=2)=[CH:17][CH:16]=1)[C:10]([OH:12])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccn3)cc2)cc1)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCOc1ccc(CC(OCc2ccccc2)C(=O)O)cc1)c1ccc(-c2ccccn2)cc1
Yield: 94.1 %

Procedure:
In a similar manner to that described in Example 2, methyl 2-benzyloxy-3-[4-[2-(4-pyridine-2-ylbenzoylamino)ethoxy]phenyl]propionate (94 mg), which is the product of Example 158, was reacted with aqueous sodium hydroxide solution (1N, 0.36 ml) and the reaction mixture was treated to give the title compound (86 mg) as colorless crystals.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2].C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.ClC(Cl)(Cl)C(=N)O[CH2:76][CH:77]=[CH:78][C:79]1[CH:84]=[CH:83][C:82]([O:85][Si:86]([C:89]([CH3:92])([CH3:91])[CH3:90])([CH3:88])[CH3:87])=[CH:81][CH:80]=1>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:76][CH:77]=[CH:78][C:79]3[CH:84]=[CH:83][C:82]([O:85][Si:86]([C:89]([CH3:90])([CH3:92])[CH3:91])([CH3:88])[CH3:87])=[CH:81][CH:80]=3)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH:6]([OH:55])[CH2:5][C:4]1=[O:56])[CH3:2]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C=CCOC(=N)C(Cl)(Cl)Cl)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccc(O[Si](C)(C)C(C)(C)C)cc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (700 mg in 12 ml methylene chloride)4-t-butyldimethylsiloxycinnamyl trichloroacetimidate (550 μl neat) was added and the reagents allowed to mix for 5 minutes. Camphorsulfonic acid (35 mg) was added and the mixture stirred at room temperature. After 5 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×15 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification oof the concentrate by flash chromatography on silica gel (ethyl acetate:hexane (1:2)+1% methanol) gave the title compound (190 mg).
Reaction SMILES: C(OC([N:8](C(OC(C)(C)C)=O)[C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]2)=[CH:11][C:10]=1[Cl:28])=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:28][C:10]1[CH:11]=[C:12]([N:15]2[CH2:16][CH2:17][NH:18][CH2:19][CH2:20]2)[CH:13]=[CH:14][C:9]=1[NH2:8]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c(Cl)c2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(N2CCNCC2)cc1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of the product of EXAMPLE 42B (320 mg, 0.63 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (1 mL) dropwise and the mixture was stirred at ambient temperature for 4 hours. The solvent was removed and the crude title compound was used in the next step without further purification. MS: 212 (M+H+).
Reaction SMILES: Cl[CH:2]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4](=[O:11])[N:3]1[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[F:19].[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>ClCCl>[Cl:18][C:15]1[CH:16]=[CH:17][C:12]([N:3]2[CH:2]([S:26][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:10]3[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=3[C:4]2=[O:11])=[C:13]([F:19])[CH:14]=1
Reactant: O=C1C2=C(CCCC2)C(Cl)N1c1ccc(Cl)cc1F
Reactant: Sc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1C2=C(CCCC2)C(Sc2ccccc2)N1c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
In 30 ml of dichloromethane were dissolved 3.0 g of 3-chloro-2-(4-chloro-2-fluorophenyl)-2,3,4,5,6,7-hexahydro-1H-isoindol-1-one and 1.1 g of thiophenol, and 1.0 g of triethylamine was added to the solution over a 10-minute period, followed by stirring at room temperature for 2 hours. The reaction mixture was washed with water, dried over anhydrous sodium sulfate and freed of the dichloromethane under reduced pressure. The residue was purified by means of column chromatography with the use of silica gel (developing solvent of dichloromethaneacetone), thereby producing 3.2 g (yield of 86%) of the subject compound in white crystals, m.p. 86°-87° C.
Reaction SMILES: [CH2:1]([C@@H:8]([NH:12]C(=O)OC(C)(C)C)[CH:9]([OH:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O>[NH2:12][C@H:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:9]([OH:11])[CH3:10]
Reactant: CC(O)[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(O)[C@H](N)Cc1ccccc1

Procedure:
A solution of 19.3 g of tert-butyl (1R)-1-benzyl-2-hydroxypropylcarbamate in 160 cm3 of dioxane and 67 cm3 of 6.5N hydrochloric dioxane is stirred at room temperature for 5 hours and is then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. A yellow oil is obtained, and is taken up in 50 cm3 of water and basified to a pH in the region of 10 with potassium carbonate. This mixture is extracted with 3 times l1o cm3 of ethyl acetate and the combined organic phases are then dried over sodium sulfate, filtered and evaporated under reduced pressure (2 kPa) at a temperature in the region of 40° C. 12.9 g of a 75%/25% mixture of the two diastereoisomers A and B of (3R)-3-amino-4-phenyl-2-butanol are obtained in the form of an orange-colored oil. 1H NMR spectrum (300 MHz, (CD3)2SO-d6, δ in ppm). A mixture of diastereoisomers is observed: from 0.70 to 1.50 (broad unres. mult.: 2H); 1.08 (d, J=6Hz: 3H); from 2.25 to 2.45 (mt: 1H); from 2.70 to 2.85 (mt: 2H); 3.44 (mt: 1H); from 4.25 to 4.75 (unres. mult.: 1H); from 7.10 to 7.35 (mt: 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[CH2:21][C:22]([C:24]1[CH:25]=[CH:26][C:27]2[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=2[CH:34]=1)=[O:23].CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([CH:14]3[CH2:19][CH2:18][N:17]([CH2:21][C:22]([C:24]4[CH:25]=[CH:26][C:27]5[S:32][CH2:31][C:30](=[O:33])[NH:29][C:28]=5[CH:34]=4)=[O:23])[CH2:16][CH2:15]3)=[O:13])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2sc(C(=O)C3CCNCC3)nc12
Reactant: O=C1CSc2ccc(C(=O)CCl)cc2N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2sc(C(=O)C3CCN(CC(=O)c4ccc5c(c4)NC(=O)CS5)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 45 %

Procedure:
A mixture of (4-methoxy-benzothiazol-2-yl)-piperidin-4-yl-methanone (83 mg, 0.3 mmol) and 6-(2-chloro-acetyl)-4H-benzo[1,4]thiazin-3-one (72.5 mg, 0.3 mmol, prepared as described in WO 02/096907) in DMF (1 ml) was treated with DIPEA (50 μl, 0.3 mmol) and the mixture was stirred at RT overnight. The mixture was poured on water and extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated. Crystallisation from ether and MeOH gave 65 mg (45%) of title compound as a beige solid.
Reaction SMILES: Cl[C:2]1[N:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[N:9]([N:10]=[C:11]([CH3:13])[CH:12]=3)[C:4]=2[CH:3]=1.CN(C)C=O.[H][H]>[Pd].C(N(CC)CC)C>[CH3:13][C:11]1[CH:12]=[C:8]2[NH:7][C:6](=[O:14])[C:5]3[CH:15]=[N:16][CH:2]=[CH:3][C:4]=3[N:9]2[N:10]=1
Reactant: Cc1cc2[nH]c(=O)c3cnc(Cl)cc3n2n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc2[nH]c(=O)c3cnccc3n2n1

Procedure:
2.3 g. of 8-chloro-2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-5(4H)-one are hydrogenated in 50 ml. of dimethylformamide in the presence of 10% palladium on charcoal and 2 g. of triethylamine at 80° and 3 atmospheres hydrogen pressure. When the hydrogen absorption ceases, the solution is heated to reflux temperature and then filtered. After addition of 20 ml. of water, 2-methylpyrazolo[1,5-a]pyrido[3,4-e]pyrimidin-5(4H)-one crystallizes, yield: 1.8 g. (90%); m.p. > 300°.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1.[CH:16]([C:18]1[CH:19]=[CH:20][C:21]([OH:27])=[C:22]([CH:26]=1)[C:23]([OH:25])=[O:24])=[O:17]>CN(C)C=O>[F:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][O:27][C:21]2[CH:20]=[CH:19][C:18]([CH:16]=[O:17])=[CH:26][C:22]=2[C:23]([O:25][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[O:24])=[CH:10][CH:11]=1
Reactant: O=Cc1ccc(O)c(C(=O)O)c1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccc(F)cc2)c(C(=O)OCc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cesium carbonate (11.77 g, 36.1 mmol) and 1-(bromomethyl)-4-fluorobenzene (1.50 ml, 12.04 mmol) were added to a solution of 5-formyl-2-hydroxybenzoic acid (2 g, 12.04 mmol) in dimethylformamide (100 m) at room temperature. The mixture was stirred at room temperature overnight. The mixture was filtered, the dimethylformamide was evaporated and the residue was diluted with ethyl acetate (100 ml) and washed with water (3×50 ml). The organic layer was dried (MgSO4) and evaporated under reduced pressure to give an oil which solidified on standing. The solid was triturated with an 8:1 mixture of hexane/ethyl acetate. The solid was filtered and dried in air under vacuum to yield the title compound as a white solid. 4.09 g.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:12]=1)[C:8]#[N:9])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[C:13]([C:11]1[CH:10]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:12]=1)[CH2:8][NH2:9])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)c1cc(C#N)cc(C(C)(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CN)cc(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3, 5-di-tert-butylbenzonitrile (863 mg, 4.02 mmol) in dry THF (10 mL) at 0° C. was added lithium aluminum hydride (304 mg, 8.0 mmol) in one portion. The reaction mixture was allowed to warm to rt for 2 h, whereupon the reaction was quenched (0.2 mL water, followed by 0.2 mL 15% potassium hydroxide solution and 0.6 mL water). The reaction mixture was stirred at rt for 1 h, then filtered through diatomaceous earth (CH2Cl2 elution). The filtrate was then concentrated and used in the next reaction without further purification: 1H NMR (300 MHz, CDCl3) δ 7.33 (s, 1H), 7.16 (d, J=1.8 Hz, 2H), 3.86 (s, 2H), 1.33 (s, 18H); mass spec (CI): 203.2 (M−NH2).