Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][OH:24])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[S:14][C:15]=1[CH3:16].O[C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[N:27]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[S:14][C:15]=1[CH3:16])[CH2:23][O:24][C:26]1[C:30]([CH:31]=[O:32])=[CH:29][N:28]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:27]=1
Reactant: COc1cc(CO)ccc1OCc1nc(N2CCOCC2)sc1C
Reactant: O=Cc1cn(-c2ccccc2)nc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(N2CCOCC2)sc1C
Reaction time: 15 h
Yield: 56.5 %

Procedure:
To a mixture of {3-methoxy-4-[(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]phenyl}methanol (2.00 g), 3-hydroxy-1-phenyl-1H-pyrazole-4-carbaldehyde (1.19 g), tributylphosphine (1.74 g) and tetrahydrofuran (100 mL) was added 1,1′-(azodicarbonyl)dipiperidine (2.17 g) at room temperature, and the mixture was stirred for 15 hrs. The precipitated crystals were removed by filtration and the filtrate was concentrated. The residue was subjected to silica gel column chromatography to give 3-({3-methoxy-4-[(5-methyl-2-morpholin-4-yl-1,3-thiazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde as colorless crystals (1.68 g, yield 57%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 149-150° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH2:22]>>[CH3:18][O:19][C:20](=[O:23])[CH2:21][NH:22][C:14](=[O:16])[C@@H:9]([CH2:10][CH2:11][S:12][CH3:13])[NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7]
Reactant: COC(=O)CN
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Product: COC(=O)CNC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C

Procedure:
The title compound was prepared by the general method of Example 1 using 24.9 g (0.1 mole) of t-butoxycarbonyl-D-methionine (BOC-D-Met) and 13.8 g (0.11 mole) of glycine methyl ester hydrochloride. The crude product was recrystallized from ethyl acetate/Skellysolve B to give the title compound, which was used in subsequent reactions without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[NH:15][C:14]2=[O:23])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH3:24][O:25][CH2:26]Cl>CN(C)C=O>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[C:18](=[O:19])[C:17]3[CH2:20][CH2:21][CH2:22][C:16]=3[N:15]([CH2:24][O:25][CH3:26])[C:14]2=[O:23])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)c1cc(-n2c(=O)[nH]c3c(c2=O)CCC3)ccc1Cl
Reactant: COCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-n2c(=O)c3c(n(COC)c2=O)CCC3)ccc1Cl

Procedure:
using ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate and chlorodimethyl ether in dimethylformamide there is obtained ethyl 2-chloro-5-(1,2,4,5,6,7-hexahydro-1-methoxymethyl-2,4-dioxo-3H-cyclopenta[d]pyrimidin-3-yl)-benzoate, m.p. 103°-106° C.,
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([S:36](Cl)(=[O:38])=[O:37])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]>>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([S:36]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]4)=[CH:4][CH:3]=2)(=[O:37])=[O:38])[CH:31]=[CH:32][C:33]=1[O:34][CH3:35]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NS(=O)(=O)c4ccc(OC)c(OC)c4)cc3)ccc2C1=O

Procedure:
The compound of example 292 was prepared analogous to compound of example 284 by reaction of compound of example 223 with 3,4-dimethoxy benzene sulfonyl chloride. The compound of example 292 was used directly without isolation, for the preparation of compound of example 293.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([O:11][CH2:12][CH3:13])[CH:5]=1.[F:15][C:16]([F:20])([F:19])[CH2:17]I.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([O:10][CH2:17][C:16]([F:20])([F:19])[F:15])[CH:7]=[C:6]([O:11][CH2:12][CH3:13])[CH:5]=1
Reactant: CCOc1cc(O)cc(C(=O)OC)c1
Reactant: FC(F)(F)CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCOc1cc(OCC(F)(F)F)cc(C(=O)OC)c1
Temperature: 130 °C
Yield: 41.8 %

Procedure:
A mixture of 3-ethoxy-5-hydroxy-benzoic acid methyl ester (1.5 g, 7.65 mmol, 1.0 equiv; prepared as described in WO 99/05123 A1, Astra Pharmaceuticals Ltd.), 2,2,2-trifluoroethyl iodide (2.25 mL, 4.82 g, 22.94 mmol, 3.0 equiv) and cesium carbonate (4.98 g, 15.29 mmol, 2.0 equiv) was heated to 130° C. under microwave irradiation for 20 min. The crude reaction mixture was filtered over Hyflo Super Cel and extracted with dichloromethane (3×50 mL). The combined organic phases were dried over MgSO4, the solvent removed by evaporation under reduced pressure and the crude material purified by flash column chromatography on silica eluting with a gradient of heptane/dichloromethane (1:1→0:1) yielding 0.89 g (42%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.35 (t, J=7.0 Hz, 3H), 3.84 (s, 3H), 4.00 (q, J=7.0 Hz, 2H), 4.30 (q, J=8.1 Hz, 2H), 6.62-6.63 (m, 1H), 7.10-7.11 (m, 1H), 7.19-7.21 (m, 1H). MS (ISP): 279.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH:13]([OH:16])[CH2:14][OH:15])=[CH:9][CH:8]=1.N1C=CN=C1.[C:26]([Si:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)Cl)([CH3:29])([CH3:28])[CH3:27]>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:26]([Si:30]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[O:15][CH2:14][CH:13]([C:10]1[CH:9]=[CH:8][C:7]([O:6][CH2:5][C:4]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:2]([Cl:1])[CH:3]=2)=[CH:12][CH:11]=1)[OH:16])([CH3:29])([CH3:27])[CH3:28]
Reactant: OCC(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OCC(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1-[4-(3,4-Dichloro-benzyloxy)-phenyl]-ethane-1,2-diol (18.8 g), imidazole (8.17 g), and a catalytic amount of DMAP were dissolved in 60 mL of anhydrous DMF. tert-Butyldiphenylchlorosilane (18.7 mL) was added drop-wise and the mixture stirred at rt for 16 h. The reaction mixture was poured into 1 L of a mixture of water-ethyl acetate-hexanes (2:2:1) and the layers were separated. After an additional extraction with 0.5 L 3:1 EtOAc/hexanes, the organic extracts were dried over sodium sulfate and concentrated. The yellow oil was purified by silica gel flash chromatography (ethyl acetate/hexanes) to give 14.0 g of the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][CH3:18])=[O:5])[CH3:2].[CH:19]1([NH2:24])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:17][CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(CC)cccc2c1Cl
Reactant: NC1CCCC1
Product: CCOC(=O)c1cnc2c(CC)cccc2c1NC1CCCC1

Procedure:
4-Chloro-8-ethyl-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.95 mmol) was treated with cyclopentylamine following general procedure B to afford 4-cyclopentylamino-8-ethyl-quinoline-3-carboxylic acid ethyl ester (250 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid in quantitative yield using general procedure D and then transformed into the corresponding ethylamide (180 mg) following general procedure E.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:37]([O:38][CH2:39][CH:40]([F:42])[F:41])=[CH:36][C:14]3[N:15]([CH3:35])[C:16]([NH:18][C:19]4[CH:24]=[C:23]([CH2:25][NH:26]C(OC(C)(C)C)=O)[CH:22]=[CH:21][C:20]=4[Cl:34])=[N:17][C:13]=3[CH:12]=2)=[O:10])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[C:37]([O:38][CH2:39][CH:40]([F:42])[F:41])=[CH:36][C:14]3[N:15]([CH3:35])[C:16]([NH:18][C:19]4[CH:24]=[C:23]([CH2:25][NH2:26])[CH:22]=[CH:21][C:20]=4[Cl:34])=[N:17][C:13]=3[CH:12]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: Cn1c(Nc2cc(CNC(=O)OC(C)(C)C)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(Nc2cc(CN)ccc2Cl)nc2cc(C(=O)Nc3ccc(Br)cc3)c(OCC(F)F)cc21
Temperature: 25 °C

Procedure:
A mixture of N-(4-bromo-phenyl)-2-(2-chloro-5-{[(tert-butoxycarbonyl)-amino]-methyl}-phenylamino)-6-(2,2-difluoro-ethoxy)-1-methyl-1H-benzimidazole-5-carboxylic acid amide (1.35 g; 2.03 mmol) and TFA (3.47 g; 30.5 mmol) in DCM (75 mL) was stirred over night at rt. The mixture was cooled to 0° C. and basicified to pH ˜10 and extracted with DCM. The organic extracts were dried over Na2SO4, filtered and concentrated. The residue was washed with a mixture of Et2O and petroleum ether to give the sub-title compound.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](N1C=CN=C1)=[O:11])[CH2:2]2.[F:17][C:18]1[CH:19]=[C:20]([CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[OH:26])[CH:21]=[CH:22][C:23]=1[F:24]>>[F:17][C:18]1[CH:19]=[C:20]([CH:25]([O:26][C:10](=[O:11])[O:9][C@@H:3]2[CH:4]3[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]3)[CH2:2]2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=[CH:22][C:23]=1[F:24]
Reactant: OC(c1ccccc1)c1ccc(F)c(F)c1
Reactant: O=C(O[C@H]1CN2CCC1CC2)n1ccnc1
Product: O=C(OC(c1ccccc1)c1ccc(F)c(F)c1)O[C@H]1CN2CCC1CC2

Procedure:
The desired product was prepared by reacting imidazole-1-carboxylic acid (R)-1-aza-bicyclo[2.2.2]oct-3-yl ester with (3,4-difluoro-phenyl)-phenyl-methanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=2)=[C:4]([F:15])[C:3]=1[O:16][CH3:17].[F:18][C:19]([F:30])([F:29])[C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[F:15][C:4]1[C:3]([O:16][CH3:17])=[C:2]([C:23]2[CH:24]=[CH:25][C:20]([C:19]([F:30])([F:29])[F:18])=[CH:21][CH:22]=2)[CH:7]=[CH:6][C:5]=1[C:8]1[N:9]=[CH:10][C:11]([NH2:14])=[N:12][CH:13]=1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Reactant: COc1c(Br)ccc(-c2cnc(N)cn2)c1F
Product: COc1c(-c2ccc(C(F)(F)F)cc2)ccc(-c2cnc(N)cn2)c1F

Procedure:
The title compound was prepared in a manner similar to that described for Example 850 using 5-(4-bromo-2-fluoro-3-methoxyphenyl)pyrazin-2-amine and 4-(trifluoromethyl)phenylboronic acid. MS (ESI): mass calcd. for C18H13F4N3O, 363.10; m/z found, 363.9 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.61-8.56 (m, 1H), 8.12 (d, J=1.5, 1H), 7.72-7.66 (m, 4H), 7.22 (dd, J=8.3, 1.4, 1H), 7.28-7.24 (m, 1H), 4.73 (s, 2H), 3.77 (d, J=1.2, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[Al+3].[Cl-].[Cl-].[Cl-].Br[C:18]([CH3:21])([CH3:20])[CH3:19]>C(Cl)Cl>[C:18]([C:7]1[C:6]2[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[NH:9][CH:8]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: CC(C)(C)Br
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(C)(C)c1c[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 15 °C
Reaction time: 8 h
Yield: 31.1 %

Procedure:
To a mixture of 5-nitro-1H-indole (6 g, 36.8 mmol) and AlCl3 (24 g, 0.18 mol) in CH2Cl2 (100 mL) was added 2-bromo-2-methyl-propane (8.1 g, 36.8 mmol) dropwise at 0° C. After being stirred at 15° C. overnight, the reaction mixture was poured into ice (100 mL). The precipitated salts were removed by filtration and the aqueous layer was extracted with CH2Cl2 (30 mL×3). The combined organic layers were washed with water, brine, dried over Na2SO4 and concentrated under vacuum to obtain the crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 20:1) to give 3-tert-butyl-5-nitro-1H-indole (2.5 g, 31%). 1H NMR (CDCl3, 400 MHz) δ 8.49 (d, J=1.6 Hz, 1H), 8.31 (brs, 1H), 8.05 (dd, J=2.0, 8.8 Hz, 1H), 7.33 (d, J=8.8 Hz, 1H), 6.42 (d, J=1.6 Hz, 1H), 1.42 (s, 9H).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:15])([CH2:13][OH:14])[C:10]([OH:12])=[O:11].[C:16](Cl)(=[O:20])[C:17]([CH3:19])=[CH2:18]>ClCCl>[F:8][C:9]([F:15])([CH2:13][O:14][C:16](=[O:20])[C:17]([CH3:19])=[CH2:18])[C:10]([OH:12])=[O:11]
Reactant: O=C(O)C(F)(F)CO
Reactant: C=C(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCC(F)(F)C(=O)O
Reaction time: 8 h

Procedure:
To a mixture of 250 mL dichloromethane with 10.1 g (100 mmol) of triethylamine is added 12.6 g (100 mmol) of 2,2-difluoro-3-hydroxypropanoic acid and the resulting mixture is placed into an ice bath. 10.5 g (100 mmol) of methacryloyl chloride is added slowly into the flask and reaction is kept stirring for overnight. The resulting mixture is then washed with 200 mL of 1% NaHCO3 solution and the solvent is then subsequently removed. The product is then recrystallized from methanol to provide 2,2-difluoro-3-(methacryloyloxy)propanoic acid, in expected good yield, which is used for following synthesis without further purifications.
Reaction SMILES: [CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:24]([CH2:34][C:35](=O)[CH2:36][CH2:37][N:38]1[C:46](=[O:47])[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]1=[O:48])[C:25](=O)[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:54]>C(O)(=O)C>[CH2:1]([N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][C:13]([Cl:19])=[CH:14][CH:15]=2)[N:10]=[C:9]1[CH:20]([N:24]1[CH:34]=[C:35]([CH2:36][CH2:37][N:38]2[C:46](=[O:47])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[C:39]2=[O:48])[N:54]=[C:25]1[C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)[CH:21]([CH3:23])[CH3:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)N(CC(=O)CCN2C(=O)c3ccccc3C2=O)C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: Cc1ccc(-c2nc(CCN3C(=O)c4ccccc4C3=O)cn2C(c2nc3cc(Cl)ccc3c(=O)n2Cc2ccccc2)C(C)C)cc1
Yield: 4.9 %

Procedure:
A solution of N-[1-(3-benzyl-7-chloro-4-oxo-3,4-dihydro-quinazolin-2-yl)-2-methyl-propyl]-N-[4-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2-oxo-butyl]-4-methyl-benzamide (641 mg, 9.948 mmol) and ammonium acetate (3.65 g, 47.4 mmol) in acetic acid (30 mL) was refluxed for 6.0 h using a Dean-Stark trap and condenser. The reaction was concentrated in vacuo and the residue was triturated with water, dried in a Buchner funnel, and recrystallized from ethanol to provide the title compound as a white solid (320 mg, 51%). MS(ES+) m/e 656 [M+H]+.
Reaction SMILES: C(O)(=O)C.[CH3:5][O:6][C:7]([C:9]1[N:10]=[CH:11][C:12]([CH:21]=O)=[C:13]2[CH2:18][O:17][C:16]([CH3:20])([CH3:19])[O:15][C:14]=12)=[O:8].[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][CH:25]=1.C([BH3-])#N.[Na+]>CO>[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][CH2:21][C:12]2[CH:11]=[N:10][C:9]([C:7]([O:6][CH3:5])=[O:8])=[C:14]3[O:15][C:16]([CH3:19])([CH3:20])[O:17][CH2:18][C:13]=23)=[CH:26][CH:25]=1
Reactant: COC(=O)c1ncc(C=O)c2c1OC(C)(C)OC2
Reactant: Nc1ccc(F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ncc(CNc2ccc(F)cc2)c2c1OC(C)(C)OC2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 96.2 %

Procedure:
Acetic acid (50 μL, 0.87 mmol) was added to a mixture of 5-Formyl-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylic acid methyl ester [J. Org. Chem. 1999, 64, 4537] (220 mg, 0.87 mmol) and 4-fluoroaniline (125 μL, 1.3 mmol) in dry methanol (4 mL) and stirred at room temperature for 15 min. and sodium cyanoborohydride (72 mg, 1.3 mmol) was added. This mixture was stirred at room temperature for 3 h followed by evaporation of 90% of the methanol volume under reduced pressure. The residue was extracted with dichloromethane (3×25 mL) and the combined organic layers were dried (anh. Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by silica gel (methanol/dichloromethane, 0 to 10% methanol) to give 0.290 g of methyl 5-((4-fluorophenylamino)methyl)-2,2-dimethyl-4H-[1,3]dioxino[4,5-c]pyridine-8-carboxylate (compound 21a) (96%) as a white solid MS-ESI m/z 347 [MI-1]+.
Reaction SMILES: [CH3:1][O:2][C:3](Cl)=[O:4].[CH3:6][C:7]([CH3:51])([CH2:49][CH3:50])[CH2:8][C:9]1[N:10]=[C:11]([CH2:33][CH:34]([C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)=[CH:38][CH:37]=2)[NH2:35])[N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:13]=1.C(N(CC)CC)C>ClCCl>[CH3:6][C:7]([CH3:51])([CH2:49][CH3:50])[CH2:8][C:9]1[N:10]=[C:11]([CH2:33][CH:34]([NH:35][C:3](=[O:4])[O:2][CH3:1])[C:36]2[CH:37]=[CH:38][C:39]([C:42]3[CH:47]=[CH:46][C:45]([F:48])=[CH:44][N:43]=3)=[CH:40][CH:41]=2)[N:12]([C:14]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:13]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(N)c2ccc(-c3ccc(F)cn3)cc2)n1
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(NC(=O)OC)c2ccc(-c3ccc(F)cn3)cc2)n1
Reaction time: 2 h

Procedure:
Methylchoroformate (16 μL, 0.21 mmol) was added to a solution of 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethanamine (64 mg, 0.11 μmol) and triethylamine (31 μL, 0.22 mmol) in dichloromethane (5 mL) at ambient temperature. After stirring for 2 hr, the reaction mixture concentrated in vacuo to afford methyl {2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethyl}carbamate which was used without further purification.
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@H:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([C:39]3([C:42]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:43])[CH2:41][CH2:40]3)=[CH:35][CH:34]=2)O1>>[CH2:1]([S:8][CH2:9][C@H:10]([C:12]1[C:13]([CH3:24])=[N:14][O:15][C:16]=1[C:17]1[CH:22]=[CH:21][C:20]([C:33]2[CH:34]=[CH:35][C:36]([C:39]3([C:42]([NH:44][S:45]([CH3:48])(=[O:47])=[O:46])=[O:43])[CH2:41][CH2:40]3)=[CH:37][CH:38]=2)=[CH:19][CH:18]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)OB(c2ccc(C3(C(=O)NS(C)(=O)=O)CC3)cc2)OC1(C)C
Reactant: Cc1noc(-c2ccc(Br)cc2)c1[C@H](O)CSCc1ccccc1
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1[C@H](O)CSCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 2, using (S)-2-benzylsulfanyl-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-ethanol and N-{1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarbonyl}-methanesulfonamide.
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=2[CH2:3]1.[N:19]1([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)(Cl)Cl>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:14]=[CH:15][C:16]([CH3:18])=[CH:17][C:4]=3[CH2:3][CH:2]([N:22]3[CH2:23][CH2:24][N:19]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH2:20][CH2:21]3)[C:8]=2[CH:9]=1
Reactant: O=C1OCCN1CCN1CCNCC1
Reactant: Cc1ccc2c(c1)CC(Cl)c1cc(F)ccc1S2
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)CC(N1CCN(CCN3CCOC3=O)CC1)c1cc(F)ccc1S2

Procedure:
17.6 g of 10-chloro-8-fluoro-10,11-dihydro-2-methyldibenzo[b,f]thiepin are heated for 20 hours under reflux conditions together with 27.3 g of 3-[2-(1-piperazinyl)-ethyl] -2-oxazolidinone in 10 ml of chloroform. After evaporation of the chloroform, the residue is mixed with ice, benzene and aqueous sodium hydroxide solution and again mixed well. The benzene phase is acidified with 6 N aqueous hydrochloric acid and maintained in an ice bath for 30 minutes. The precipitate, which is formed, is filtered, made alkaline with aqueous sodium hydroxide solution and taken up in benzene. The benzene phase is dried over sodium sulphate and evaporated, whereby 3-{2-[4-(8-fluoro-10,11-dihydro-2-methyl-dibenzo [b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone is obtained, which is converted into the corresponding dihydrochloride by reaction with ethanolic hydrochloric acid. The dihydrochloride melts at 210°(dec;).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].[CH3:6][CH2:7][CH2:8][CH2:9][SnH:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14]>CC(N=NC(C#N)(C)C)(C#N)C.CCOC(C)=O>[CH2:15]([Sn:10]([CH2:9][CH2:8][CH2:7][CH3:6])([CH2:11][CH2:12][CH2:13][CH3:14])[CH:4]=[CH:3][CH2:2][CH2:1][OH:5])[CH2:16][CH2:17][CH3:18]
Reactant: CCCC[SnH](CCCC)CCCC
Reactant: C#CCCO
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: CCCC[Sn](C=CCCO)(CCCC)CCCC
Temperature: 90 °C
Reaction time: 16 h
Yield: 41.6 %

Procedure:
A stirred mixture of but-3-yn-1-ol (7.00 g, 99.87 mmol) and AIBN (0.50 g, 2.81 mmol), contained in large round-bottomed flask equipped with a reflux condenser, was degassed with N2 at 25° C. and treated with Bu3SnH (40.4 mL, 150 mmol). The mixture was slowly heated to 90° C. and stirred at 100° C. for 16 hours. The solution was cooled and the crude product was subjected to chromatography on Al2O3 gel with a 1-10% gradient of EtOAc in PE. The mixture of E-isomer and Z-isomer were obtained as colorless oil (15 g, 40.9%).
Reaction SMILES: [C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[OH:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([C@@H:17]1[CH2:21][CH2:20][N:19]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([OH:22])=[CH:24][CH:25]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: Oc1ccc(CCBr)cc1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@@H]1CCN(CCc2ccc(O)cc2)C1

Procedure:
A mixture containing 3-(S)-(1-carbamoyl-1,1-diphenylmethyl)pyrrolidine (0.1 g--see Preparation 10B), 4-hydroxyphenethyl bromide (0.072 g), anhydrous potassium carbonate (0.15 g) and acetonitrile (2 ml) was heated under reflux for 45 minutes. On cooling, the mixture was partitioned between dichloromethane (5 ml) and 10% aqueous potassium carbonate (10 ml). The layers were separated, and the aqueous layer was further extracted with dichloromethane (2×5 m]). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a foam which was purified by column chromatography on silica eluting with dichloromethane containing methanol (5%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless foam, yield 0.035 g.