Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:17]1([C:26]([OH:28])=O)[CH2:22][CH2:21][CH2:20][CH:19]([C:23]([OH:25])=O)[CH2:18]1>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:23]([CH:19]1[CH2:20][CH2:21][CH2:22][CH:17]([C:26]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:28])[CH2:18]1)=[O:25])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Reactant: O=C(O)C1CCCC(C(=O)O)C1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)C1CCCC(C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)C1
Yield: 69.4 %

Procedure:
Using General Procedure A with 5.6 g (23.2 mmol) D-Proline benzyl ester hydrochloride and 2.0 g (11.6 mmol) cyclohexane-1,3-dicarboxylic acid afforded, after flash chromatography (EtOAc), 4.4 g (70%) of the title compound as a colorless oil. MS m/e (%): 547 (M+H+, 100).
Reaction SMILES: [CH3:1][NH:2][C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:19]([O:55][CH3:56])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:53][CH3:54])[C@@H:29]([CH3:52])[C:30]([NH:32][C@@H:33]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)=[O:35])=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:8])[CH:4]([CH3:6])[CH3:5].O=[CH:62][CH2:63][CH2:64][C:65]([OH:67])=[O:66].C(O)(=O)C>CO>[C:65]([CH2:64][CH2:63][CH2:62][N:2]([CH3:1])[C@H:3]([C:7]([NH:9][C@H:10]([C:14]([N:16]([C@@H:18]([C@@H:57]([CH3:60])[CH2:58][CH3:59])[C@H:19]([O:55][CH3:56])[CH2:20][C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@H:24]1[C@H:28]([O:53][CH3:54])[C@@H:29]([CH3:52])[C:30]([NH:32][C@@H:33]([CH2:42][C:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[NH:45][CH:44]=1)[C:34]([N:36]1[CH2:41][CH2:40][CH2:39][CH2:38][O:37]1)=[O:35])=[O:31])=[O:22])[CH3:17])=[O:15])[CH:11]([CH3:12])[CH3:13])=[O:8])[CH:4]([CH3:5])[CH3:6])([OH:67])=[O:66]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@@H](NC)C(C)C)C(C)C
Reactant: O=CCCC(=O)O
Solvent: CO
Solvent: CC(=O)O
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N1CCCCO1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)CCCC(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.052 mmol) of N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-3-(1H-indol-3-yl)-1-(1,2-oxazinan-2-yl)-1-oxopropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide (Intermediate 192) and 204 μl einer of a 15% aqueous solution of 4-oxobutanoic acid were combined in 2 ml of methanol and admixed with 23.4 mg (0.252 mmol) of borane-pyridine complex and 6 μl of acetic acid. The reaction mixture was stirred at RT overnight. This was followed by concentration under reduced pressure, and the residue was purified by means of preparative HPLC. After concentration of the corresponding fractions, 38 mg (78% of theory) of the title compound were obtained.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Br:20][C:21]1[CH:28]=[C:27]([F:29])[C:24]([CH:25]=O)=[C:23]([F:30])[CH:22]=1.O>ClCCl>[Br:20][C:21]1[CH:28]=[C:27]([F:29])[C:24]([CH2:25][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)=[C:23]([F:30])[CH:22]=1
Reactant: C1CCNC1
Reactant: O=Cc1c(F)cc(Br)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Fc1cc(Br)cc(F)c1CN1CCCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.2 %

Procedure:
Pyrrolidine (25 mL, 0.30 mol) and sodium triacetoxyborohydride (64 g, 0.30 mol) were added in portions to a stirred solution of Intermediate 18a, 4-Bromo-2,6-difluorobenzaldehyde (53.5 g, 0.24 mol) in dichloromethane (500 mL) on ice bath. The reaction mixture was intensively stirred for 12 h at RT. Water (400 mL) was added followed by addition of 5M aq. NaNSO4 to attain pH ˜2. The organic layer was separated. The aqueous one was extracted with CH2Cl2 (2×200 mL). The organic layers were discarded. The aqueous fraction was alkalized with K2CO3 to pH ˜10, and extracted with CHCl3 (2×300 mL). The organic extract was washed with brine, dried over anhydrous Na2SO4 (100 g) and evaporated in vacuo to give the title compound (52.5 g, 79%, 0.19 mol). LC/MS data: 275.9 and 277.9 (M+H)+ (calculated for C11H12BrF2N, 276.13). 1H NMR data (DMSO-d6): 7.40-7.48 (m, 2H, Ar—H), 3.66 (s, 2H, Ar—CH2), 2.38-2.46 (m, 4H pyrrolidine (CH2)2N), 1.61-1.71 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C:10]32[O:12][CH2:11]3)[CH:5]=[CH:6][C:7]=1[Cl:8].[N-:25]=[N+:26]=[N-:27].[Na+].O>CN(C=O)C>[N:25]([CH2:11][C:10]1([OH:12])[CH:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1)=[N+:26]=[N-:27]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C2(CO2)C1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(O)(CN=[N+]=[N-])C1
Temperature: 80 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To a solution of tert-butyl (3RS,4SR)-4-(3,4-dichlorophenyl)-1,5-dioxa-8-azaspiro[2.6]nonane-8-carboxylate (460 mg) in DMF (5 ml) was added sodium azide (240 mg), and the mixture was stirred at 80° C. overnight. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (232 mg).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([O-:5])=O.[K+].[Mg+2].[Cl-].[Cl-].[F:14][C:15]1[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[CH:20][C:16]=1C(Cl)=O>C(#N)C>[CH2:8]([O:7][C:1](=[O:6])[CH2:2][C:3](=[O:5])[C:20]1[CH:16]=[C:15]([F:14])[C:23]([F:24])=[C:22]([F:25])[C:21]=1[F:26])[CH3:9]
Reactant: O=C(Cl)c1cc(F)c(F)c(F)c1F
Reactant: CCOC(=O)CC(=O)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium ethyl malonate (3.66 g, 21.5 mmol), MgCl2 (2.44 g, 25.7 mmol) and TEA (2.05 g, 20.3 mmol) were mixed in acetonitrile (70 ml) at 10–15° C. for 2.5 hr. 2,3,4,5-tetrafluorobenzoyl chloride (2.00 g, 10.3 mmol) in acetonitrile (10 ml) was added at 0° C. over 15 min followed by a second addition of TEA (0.23 g, 2.3 mmol). After allowing to warm to RT, the mixture was stirred for 16 hr. After removal of volatiles in vaccuo Toluene (30 ml) was added and removed in vacuo. Following the addition of toluene (60 ml), HCl 1.5 M (40 ml) was added cautiously, ensuring the temperature did not exceed 25° C. The organic fraction was washed with HCl 1.5 M (2×25 ml) and water (2×25 ml), dried over MgSO4 and reduced to a light orange oil in vacuo ([M+1]+ 265, 98%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[C:7](Cl)(=[O:10])[CH:8]=[CH2:9]>>[C:7]([N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6])(=[O:10])[CH:8]=[CH2:9]
Reactant: O=C1CCCN1
Reactant: C=CC(=O)Cl
Product: C=CC(=O)N1CCCC1=O
Yield: 70 %

Procedure:
The title compound was synthesized by using the similar procedure as described in Reference Example 1 except that 2-pyrrolidone and acryloyl chloride were used. The yield was 70%.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[C:10]1(C)[C:11](S(O)(=O)=O)=CC=C[CH:15]=1>COC(OC)(C)C.C1C=CC=CC=1>[OH:2][C:1]1[C:3]2[O:4][C:10]([CH3:11])([CH3:15])[O:6][C:5]=2[CH:7]=[CH:8][CH:9]=1
Reactant: Oc1cccc(O)c1O
Reactant: Cc1ccccc1S(=O)(=O)O
Solvent: COC(C)(C)OC
Solvent: c1ccccc1
Product: CC1(C)Oc2cccc(O)c2O1

Procedure:
A solution of pyrogallol (63 parts) in 2,2-dimethoxypropane (100 parts) and benzene (100 parts) containing toluenesulphonic acid (0.01 parts) was slowly distilled through a fractionating column during 4 hours, removing liquid (150 parts), boiling point 57°-64° C. A few drops of triethylamine were then added and the mixture thoroughly washed with water, dried and evaporated. Distillation gave 4-hydroxy-2,2-dimethyl-1,3-benzodioxole (36 parts), boiling point 110° C/0.7 mm., which was purified by recrystallisation from carbon tetrachloride. Melting point 88°-90° C.
Reaction SMILES: [CH2:1]1[O:9][CH:2]1[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[NH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17]>CO>[OH:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][NH:10][CH2:1][CH:2]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:9]
Reactant: c1ccc(C2CO2)cc1
Reactant: NCCCCCCO
Solvent: CO
Product: OCCCCCCNCC(O)c1ccccc1

Procedure:
From styrene oxide and 6-amino-1-hexanol. Yield after chromatography (methanol): 30% (oil).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C@@H:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].[N:31]1([CH2:38][CH2:39][C:40]2[S:44][C:43]([C:45]([O-])=O)=[CH:42][CH:41]=2)[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.[Li+]>>[N:31]1([CH2:38][CH2:39][C:40]2[S:44][C:43]([CH2:45][N:3]([CH2:1][CH3:2])[C:4]3[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=3[C@@H:14]3[CH2:23][CH2:22][C:21]4[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=4[CH2:15]3)=[CH:42][CH:41]=2)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]1
Reactant: CCNc1cc(OC)c(OC)cc1[C@@H]1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: O=C([O-])c1ccc(CCN2CCCCCC2)s1
Agent: [Li+]
Product: CCN(Cc1ccc(CCN2CCCCCC2)s1)c1cc(OC)c(OC)cc1[C@@H]1CCc2cc(O)ccc2C1
Yield: 97.5 %

Procedure:
Synthesized from pivalic acid (R)-6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (30 mg) and lithium 5-(2-azepan-1-ylethyl)thiophene-2-carboxylate (60 mg) according to an analogous synthetic method to Example 152 and purified by LC-MS, the title compound (39 mg) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:28]=[C:27]([CH2:29][CH3:30])[CH:26]=[CH:25][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][O:20]C2=O)=[CH:14][C:13]=1[F:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Ba+2].[OH-]>CO.O>[CH2:1]([O:8][C:9]1[CH:28]=[C:27]([CH2:29][CH3:30])[CH:26]=[CH:25][C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][CH2:22][CH2:21][OH:20])=[CH:14][C:13]=1[F:24])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCc1ccc(Oc2ccc(N3CCOC3=O)cc2F)c(OCc2ccccc2)c1
Agent: [Ba+2]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCc1ccc(Oc2ccc(NCCO)cc2F)c(OCc2ccccc2)c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a solution of 3-[4-(2-Benzyloxy-4-ethylphenoxy)-3-fluorophenyl]oxazolidin-2-one (350 mg, 0.85 mmol) in 5 ml of methanol was added barium hydroxide (245 mg, 1.28 mmol) taken in 5 ml of water. The reaction mixture was warmed to 65° C. and stirred overnight (reaction was complete on TLC). The reaction mixture concentrated in vacuo to remove methanol, diluted with water and the aqueous layer was extracted with ethyl acetate. The combined organic fraction was washed with brine, dried over anhydrous Na2SO4 and concentrated to get 300 mg, 91.57% of the title compound as a brown oil, used as such in the next step.
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]([CH:18]3[CH2:23][CH2:22][N:21](C)[CH2:20][CH2:19]3)[N:8]=2)=[CH:4][CH:3]=1.[CH2:27]([O:29][C:30](Cl)=[O:31])[CH3:28]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10](=[O:17])[N:9]([CH:18]3[CH2:19][CH2:20][N:21]([C:30]([O:29][CH2:27][CH3:28])=[O:31])[CH2:22][CH2:23]3)[N:8]=2)=[CH:25][CH:26]=1
Reactant: CCOC(=O)Cl
Reactant: CN1CCC(n2nc(Cc3ccc(F)cc3)c3ccccc3c2=O)CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(n2nc(Cc3ccc(F)cc3)c3ccccc3c2=O)CC1
Reaction time: 4 h

Procedure:
366.5 g (1.043 mol) 4-(4-Fluorobenzyl)-2-(N-methyl-piperidin-4-yl)-1-(2H)-phtalazinone are dissolved in 1100 ml toluene which had been dried over K2CO3. Any water present in azeotropically distilled off using a water separator. 390 g (3.59 mol) ethylchloroformate are added dropwise over 11/2 hours and the mixture stirred for 4 hours under reflux. A precipitate separated out and is suction filtered. The filtrate is evaporated on a rotary evaporator, the residue is taken up in 400 ml ether, stirred briefly and suction filtered. After washing with ether, the substance is dried in a drying cupboard. (M.p. 151°-152° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][N:35]([CH:47]2[CH2:49][CH2:48]2)[C:36]([O:38][CH2:39][C:40]([C:43]([O:45]C)=[O:44])([CH3:42])[CH3:41])=[O:37])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O[Li].O>O.C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][N:35]([C:36]([O:38][CH2:39][C:40]([C:43]([OH:45])=[O:44])([CH3:42])[CH3:41])=[O:37])[CH:47]2[CH2:48][CH2:49]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)OCC(C)(C)C(=O)OC)C2CC2)C(C)C)ccc1OC
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN(C(=O)OCC(C)(C)C(=O)O)C2CC2)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of (3S*,4R*)-3-{[cyclopropyl-(2-methoxycarbonyl-2-methyl-propoxycarbonyl)-amino]-methyl}-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (290 mg, 0.42 mmol) and LiOH•H2O (44 mg, 1.05 mmol) in H2O (2 mL) and THF (6 mL) is stirred at RT for 3 d. After evaporation of the solvent 1N HCl is added and the mixture is extracted with ethyl acetate. Drying (Na2SO4) of the combined extracts, filtration and evaporation of the solvent affords the title compound which is used without further purification. MS (LC-MS): 578.0 [M+H-Boc]+; tR (HPLC, Macherey-Nagel Nucleosil C18 column, 10-100% CH3CN/H20/5 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA, flow: 1.5 ml/min): 5.44 min.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[CH:12]=O.[CH:14]([CH:16]=[CH2:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.ClCCl>[O:9]1[C:4]2=[C:3]3[C:2](=[CH:11][CH:10]=[C:5]2[O:6][CH2:7][CH2:8]1)[O:1][CH2:17][C:16]([CH:14]=[O:15])=[CH:12]3
Reactant: O=Cc1c(O)ccc2c1OCCO2
Reactant: C=CC=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: O=CC1=Cc2c(ccc3c2OCCO3)OC1

Procedure:
3 g (16.6 mmol) of the compound obtained in Step B and 1.4 g (25 mmol) of acrolein are added to a suspension of 3.48 g (25 mmol) of potassium carbonate in 40 ml of 1,4-dioxane; the medium is then heated at reflux under argon for 3 hours. After cooling and filtering off the salts, the solvent is evaporated in vacuo. The residue obtained is taken up in dichloromethane and then washed with water. The organic phase is dried over magnesium sulphate and then concentrated in vacuo. Chromatography on a silica column (eluant:ethyl acetate/petroleum ether 10/90) allows the title compound to be obtained in the form of a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1Cl.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10]>>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][N:19]([C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[Cl:1])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Clc1ccncc1Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ccncc2Cl)CC1

Procedure:
The pyridine from step (a) above (5 g, 3.38 mmol) and tert-butylpiperazinecarboxylate (6.29 g, 3.38 mmol, Aldrich) reacted under the conditions of Example 3a to give the title compound as an orange oil. MS (ESI, pos. ion) m/z: 298 (M+1).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:18]1.C([O-])(=O)C.[K+].O1CCOCC1>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CN(C=O)C>[NH:13]1[CH2:14][CH2:15][N:16]=[C:12]1[CH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]([OH:18])[C:3]=2[CH2:4][CH2:5][O:6]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Brc1cccc2c1CCOC2C1=NCCN1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: Oc1cccc2c1CCOC2C1=NCCN1
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-(5-bromoisochroman-1-yl)-4,5-dihydro-1H-imidazole (720 mg), bis(pinacolato)diboron (715 mg) bis(tri-t-butylphosphine)palladium(0) (39 mg), potassiumacetate (503 mg), dioxane (9 ml) and DMF (0.75 ml) was stirred under inert atmosphere in microwave reactor at 160° C. for 30 minutes. Additional bis(tri-t-butylphosphine)palladium(0) (21 mg) was added and heating continued for 15 minutes. The intermediate 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-1-yl)-4,5-dihydro-1H-imidazole (680 mg) was purified with separation method A and stirred with EtOAc (2 ml), water (2 mil) and hydrogen peroxide (35%, 0.07 ml) at ice bath temperature for 2 hrs. The title compound was purified with separation methods A and E. (Yield 45 mg).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18](O)=[O:19])[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[CH3:23][N:24]([C@@H:28]1[CH2:32][CH2:31][NH:30][CH2:29]1)[C:25](=[O:27])[CH3:26]>>[CH3:23][N:24]([C@@H:28]1[CH2:32][CH2:31][N:30]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:3]=[N:2][NH:1][CH:5]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:19])[CH2:29]1)[C:25](=[O:27])[CH3:26]
Reactant: CC(=O)N(C)[C@@H]1CCNC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: CC(=O)N(C)[C@@H]1CCN(C(=O)c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)—N-methyl-N-(pyrrolidin-3-yl)acetamide (1.2 equiv) to give 180 (24.3 mg, M+1 438.1)
Reaction SMILES: [C:1](Cl)(Cl)=[S:2].[NH2:5][C:6]1[CH:21]=[CH:20][C:9]2[N:10]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:12][C:8]=2[CH:7]=1.O>O1CCOCC1>[N:5]([C:6]1[CH:21]=[CH:20][C:9]2[N:10]=[C:11]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[S:12][C:8]=2[CH:7]=1)=[C:1]=[S:2]
Reactant: S=C(Cl)Cl
Reactant: Nc1ccc2nc(Oc3ccccc3)sc2c1
Solvent: C1COCCO1
Solvent: O
Product: S=C=Nc1ccc2nc(Oc3ccccc3)sc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
An amount of 8.46 g of thiophosgene in a sulphonating flask is stirred into 500 ml of ice water. An addition is then made dropwise, in the course of 10 minutes, of a solution of 18 g of 6-amino-2-phenoxybenzothiazole in 100 ml of dioxane as well as 10 ml of water. The suspension is further stirred overnight at room temperature. The formed precipitate is separated and washed with water; the residue is dissolved in 100 ml of methylene chloride, and the solution dried over sodium sulphate. After chromatography with methylene chloride through aluminium oxide (neutral, activity stage III), an amount of 12.5 g. of 6-isothiocyano-2-phenoxybenzothiazole, M.P. 118° to 119°C, is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:17]=[CH:18]/[C:19]([O:21]CC)=[O:20])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[OH-].[Li+].Cl>O1CCCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH:15]=3)[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)/C=C/c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)/C=C/c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 476.1 %

Procedure:
To a solution of ethyl (2E)-3-[3-(4-fluorophenyl)-1H-indazol-5-yl]prop-2-enoate (0.10 g, 0.32 mmol) in tetrahydrofuran (10 mL) was added a solution of lithium hydroxide (0.032 mg, 1.6 mmol) in water (5 mL) and the mixture was stirred at ambient temperature overnight. The reaction mixture was acidified with 6 N hydrochloric acid solution to give a white solid. It was then purified by HPLC to provide the title compound (0.43 g, 48% yield): 1H NMR (DMSO-d6) δ 13.45 (br s, 1H), 12.28 (br s, 1H), 8.39 (s, 1H), 8.11 (d, 1H), 8.10 (d, 1H), 7.83 (d, 1H), 7.79 (d, 1H), 7.60 (d, 1H), 7.35 (t, 2H), 6.57 (d, 1H); ES-MS (m/z) 283 [M+1]+.
Reaction SMILES: C(O[C:4]([C:6]1[NH:23][C:9]2[N:10]=[CH:11][N:12]=[C:13]([NH:14][C@@H:15]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH3:16])[C:8]=2[CH:7]=1)=[O:5])C.[C-:24]#[N:25].[Na+].O>CN.C1COCC1>[CH3:24][NH:25][C:4]([C:6]1[NH:23][C:9]2[N:10]=[CH:11][N:12]=[C:13]([NH:14][C@@H:15]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH3:16])[C:8]=2[CH:7]=1)=[O:5]
Reactant: [C-]#N
Reactant: CCOC(=O)c1cc2c(N[C@H](C)c3ccccc3)ncnc2[nH]1
Agent: CN
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1cc2c(N[C@H](C)c3ccccc3)ncnc2[nH]1

Procedure:
In a bomb tube, 155 mg (0.50 mmol) of 6-ethoxycarbonyl-4-[1(R)-phenyl-ethylamino]-7H-pyrrolo[2,3-d]pyrimidine and 2.5 mg (0.05 mmol) of NaCN in 4 ml of methylamine (33% in ethanol) are heated at 50° C. for 30 hours. The reaction mixture is dissolved in THF, 25 ml of water are added thereto and concentration by evaporation is carried out to a residual volume of =25 ml. The resulting crystals are filtered off and washed with water. Recrystallization from hot THF and ethyl acetate yields the title compound; HPLC: tRet (Grad20)=8.3; TLC-Rf =0.31 (CH2Cl2 /methanol [10:1]); FAB-MS: (M+H)+ =296.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:4]=1[OH:10].C(N(CC)CC)C.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([O:10][C:4]1[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=1[O:2][CH3:1])(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc(C)ccc1O
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Product: COc1cc(C)ccc1OC(=O)c1ccccc1

Procedure:
The synthesis of this compound proceeded in the same fashion as in Example 1 using 27.63 g (0.20 mol) of 2-methoxy-4-methyl phenol, 22.26 g (0.22 mol) of triethylamine and 28.11 g (0.20 mol) of benzoyl chloride. The product amounted to 46.78 g, m.p. 73°-75° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[C:11](Br)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][O:30][C:31]1[C:38](B2OC(C)(C)C(C)(C)O2)=[CH:37][CH:36]=[CH:35][C:32]=1[CH:33]=[O:34]>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][C:9]1[CH:10]=[C:11]([C:38]2[CH:37]=[CH:36][CH:35]=[C:32]([CH:33]=[O:34])[C:31]=2[O:30][CH2:29][O:28][CH2:27][CH2:26][O:25][CH3:24])[C:12]([O:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])=[CH:13][CH:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOCOc1ccc(CNC(=O)OC(C)(C)C)cc1Br
Reactant: COCCOCOc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Product: COCCOCOc1ccc(CNC(=O)OC(C)(C)C)cc1-c1cccc(C=O)c1OCOCCOC

Procedure:
Proceeding as in Reference 19, but substituting tert-butyl[3-bromo-4-(2-methoxyethoxymethoxy)-benzyl]carbamate (2.3 g, 5.9 mmol) and 2-(2-methoxyethoxymethoxy)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (60 mL, 0.1 M in toluene), gave tert-butyl[3′-formyl-6,2′-bis(2-methoxyethoxymethoxy)biphenyl-3-ylmethyl]carbamate (2.96 g).