Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[OH:3][CH2:4][C:5]([CH3:12])([CH3:11])[CH2:6][S:7]([NH2:10])(=[O:9])=[O:8].Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2=[N:24][CH:25]=[CH:26][N:16]2[N:15]=1>CN(C)C=O>[CH3:11][C:5]([CH3:12])([CH2:6][S:7](=[O:9])(=[O:8])[NH2:10])[CH2:4][O:3][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]2=[N:24][CH:25]=[CH:26][N:16]2[N:15]=1
Reactant: Clc1nn2ccnc2c2ccccc12
Reactant: CC(C)(CO)CS(N)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(COc1nn2ccnc2c2ccccc12)CS(N)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
0.293 g of 60% oily sodium hydride was suspended in 10 ml of dimethylformamide. To this suspension, 0.577 g of 3-hydroxy-2,2-dimethyl -1-propanesulfonamide was added, followed by stirring at room temperature (15° to 20° C.) under reduced pressure for 30 minutes. To this mixture was added 0.703 g of 6-chloroimidazo[2,1-a]phthalazine, followed by stirring at room temperature for 3 hours. After dimethylformamide was distilled off under reduced pressure, ice water was added to the residue, which was subsequently adjusted to pH 5.0 by the addition of 5 N hydrochloric acid and then extracted with ethyl acetate-tetrahydrofuran (1:1). The extract was washed with 20 ml of saturated saline and then dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography and eluted with dichloromethane-ethyl acetate-methanol (20:20:1). The fraction containing the desired product was concentrated and ethyl ether was added to separate a crystal, which was collected by filtration, to yield 0.769 g of the title compound.
Reaction SMILES: COC1C=CC([CH2:7][N:8](C)[C:9]2[N:10]=[CH:11][CH:12]3[CH:17]([CH:18]=2)[N:16]([CH2:19][CH3:20])[C:15](=[O:21])[C:14]([C:22]2[C:23]([F:41])=[CH:24][C:25]([F:40])=[C:26]([NH:28][C:29]([NH:31][C:32]4[CH:37]=[C:36]([F:38])[CH:35]=[CH:34][C:33]=4[F:39])=[O:30])[CH:27]=2)=[CH:13]3)=CC=1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:39][C:33]1[CH:34]=[CH:35][C:36]([F:38])=[CH:37][C:32]=1[NH:31][C:29]([NH:28][C:26]1[CH:27]=[C:22]([C:14]2[C:15](=[O:21])[N:16]([CH2:19][CH3:20])[CH:17]3[CH:12]([CH:13]=2)[CH:11]=[N:10][C:9]([NH:8][CH3:7])=[CH:18]3)[C:23]([F:41])=[CH:24][C:25]=1[F:40])=[O:30]
Reactant: CCN1C(=O)C(c2cc(NC(=O)Nc3cc(F)ccc3F)c(F)cc2F)=CC2C=NC(N(C)Cc3ccc(OC)cc3)=CC21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCN1C(=O)C(c2cc(NC(=O)Nc3cc(F)ccc3F)c(F)cc2F)=CC2C=NC(NC)=CC21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
A solution of 1-(5-(7-((4-methoxybenzyl)(methyl)amino)-1-ethyl-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)-3-(2,5-difluorophenyl)urea (0.129 g, 0.213 mmol) and anisole (0.233 mL, 2.130 mmol) in DCM (2 mL) was treated with TFA (2 mL, 26.0 mmol) and stirred at RT overnight. The mixture was concentrated to dryness, treated with EtOAc and satd. NaHCO3, stirred for 1 h and the resulting solid collected via filtration and dried to afford 1-(2,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea (84 mg, 81% yield). The material was suspended in MeCN (2 mL), treated with 0.5 N HCl (2.076 mL, 0.208 mmol), diluted with water (2 mL), frozen, lyophilized, triturated with Et2O and the resulting solid was collected via filtration and dried to yield 1-(2,5-difluorophenyl)-3-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2,4a,8a-tetrahydro-1,6-naphthyridin-3-yl)-2,4-difluorophenyl)urea hydrochloride (85 mg, 94% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.24 (s, 1H), 9.18 (s, 1H), 8.53 (s, 1H), 8.18 (t, 1H), 8.02-7.97 (m, 1H), 7.94 (s, 1H), 7.90 (br s, 1H), 7.42 (t, 1H), 7.32-7.26 (m, 1H), 6.84-6.80 (m, 1H), 6.48 (s, 1H), 4.19 (q, 2H), 2.94 (s, 3H), 1.21 (t, 3H); MS (ESI) m/z: 486.2 [M+H]+.
Reaction SMILES: [C:1]1([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[Cl:21])[NH2:17]>>[Cl:13][C:14]1[CH:15]=[C:16]([NH:17][C:11]([NH:10][S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])=[O:12])[CH:18]=[CH:19][C:20]=1[Cl:21]
Reactant: O=C=NS(=O)(=O)c1ccccc1
Reactant: Nc1ccc(Cl)c(Cl)c1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)NS(=O)(=O)c1ccccc1
Yield: 83.5 %

Procedure:
The title compound was prepared in 83.5% yield from benzenesulfonyl isocyanate and 3,4-dichloroaniline following the procedure of Example 1, m.p. 194-195° C.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].IC.[C:15](=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:2]=1[NH:1][CH3:15]
Reactant: COC(=O)c1cc(Cl)ccc1N
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CNc1ccc(Cl)cc1C(=O)OC
Reaction time: 48 h
Yield: 12.7 %

Procedure:
A mixture of methyl 2-amino-5-chlorobenzoate (1.0 g, 5.4 mmol), iodomethane (0.75 ml, 12.0 mmol), potassium carbonate (1.7 g, 12.4 mmol), and acetonitrile (20 ml) was stirred for 48 hours. The mixture was filtered through a pad of celite under suction and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica eluting with ethyl acetate-hexane (1:19) to provide 5-chloro-2-methylaminobenzoic acid methyl ester (137 mg, 13% yield) followed by 5-chloro-2-dimethylaminobenzoic acid methyl ester (809 mg, 70% yield).
Reaction SMILES: [Na].[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][OH:21])[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].Cl[CH2:29][C:30]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:31]>>[NH2:2][C:3]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:18][C:19](=[O:22])[NH:20][O:21][CH2:29][C:30](=[O:31])[N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:9]=[CH:10]2)[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)c1c2ccc(CC(=O)NO)ccc-2c(C(=O)OCC)c1N
Reactant: O=C(CCl)N1CCOCC1
Agent: [Na]
Product: CCOC(=O)c1c2ccc(CC(=O)NOCC(=O)N3CCOCC3)ccc-2c(C(=O)OCC)c1N
Yield: 33 %

Procedure:
In an analogous manner to that described in Example 1, from diethyl 2-amino-6-[(hydroxycarbamoyl)-methyl]-azulene-1,3-dicarboxylate sodium and N-chloroacetyl-morpholine the title compound of m.p. 196-198° C. is obtained in 33% yield.
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])=[O:11])=[CH:7][CH:6]=1)[CH2:2][CH2:3]C.[CH2:18](I)CCC>CCOC(C)=O>[CH2:1]([C:5]1[S:9][C:8]([S:10]([NH:13][C:14]([CH3:15])([CH3:16])[CH3:17])(=[O:11])=[O:12])=[CH:7][CH:6]=1)[CH:2]([CH3:3])[CH3:18]
Reactant: CCCCI
Reactant: CCCCc1ccc(S(=O)(=O)NC(C)(C)C)s1
Solvent: CCOC(C)=O
Product: CC(C)Cc1ccc(S(=O)(=O)NC(C)(C)C)s1

Procedure:
The titled compound was prepared using the procedure described for the synthesis of 5-butyl-2-(N-t-butylaminosulfonyl)-thiophene by substituting isobutyliodide for butyliodide. Rf=0.37 (6:1 Hex/EtOAc).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[N:8]([CH2:24][CH3:25])[C:9]3[C:14]([C:15]4[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=4)[CH:18]=O)=[CH:13][N:12]=[CH:11][C:10]=3[N:23]=2)=[N:4][O:5][N:6]=1.[CH2:26]([NH2:28])[CH3:27]>>[CH2:24]([N:8]1[C:9]2[C:14]([C:15]3[CH:22]=[CH:21][CH:20]=[C:17]([CH2:18][NH:28][CH2:26][CH3:27])[CH:16]=3)=[CH:13][N:12]=[CH:11][C:10]=2[N:23]=[C:7]1[C:3]1[C:2]([NH2:1])=[N:6][O:5][N:4]=1)[CH3:25]
Reactant: CCN
Reactant: CCn1c(-c2nonc2N)nc2cncc(-c3cccc(C=O)c3)c21
Product: CCNCc1cccc(-c2cncc3nc(-c4nonc4N)n(CC)c23)c1

Procedure:
The product of Step 1 was converted into the title compound by reaction with ethylamine (1M in THF) according to the general method of Example 149. MS (ES+) m/e 364 [M+H]+.
Reaction SMILES: CC(C)(O[C:5]([N:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=[O:6])C.[CH3:14][N:15](C)[C:16](Cl)=O.C(=O)([O-])O.[Na+]>ClCCl.C(N(CC)CC)C>[CH3:14][N:15]([CH3:16])[C:5]([N:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)C(=O)N1CCNCC1

Procedure:
To a solution of 1.92 g 1-(1,1-dimethylethyloxycarbonyl)piperazine in 11 mL of dichloromethane and 1.5 mL of triethylamine at room temperature was added dropwise 1 mL of dimethylcarbamylchloride. After 16 hours 5% aqueous sodium hydrogencarbonate and dichloromethane were added, the organic layer separated, dried over magnesium sulfate and concentrated. Column chromatography on silica gel (dichloromethane/methanol=95/5 v/v) yielded 1.34 g 1-1,1-dimethylethyloxycarbonyl)-4-(dimethylaminocarbonyl)piperazine. This compound was dissolved in a 3N hydrogen chloride solution in methanol at 0° C. After 15 min the reaction mixture was allowed to warm to room temperature and After stirring for 3 days at room temperature the reaction mixture was concentrated to give 1.06 g of 1-(dimethylaminocarbonyl)piperazine hydrochloride. rf=0.29, SiO2: dichloromethane/methanol=4/1 v/v.
Reaction SMILES: [F:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([C:16]4[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=4)=[CH:11][CH:12]=3)[C@@:7]3([CH2:26][O:25][C:24]([NH2:27])=[N:23]3)[C:6]=2[CH:5]=[C:4](/[CH:28]=[CH:29]/[C:30]2([CH3:34])[CH2:33][O:32][CH2:31]2)[CH:3]=1>[Pd].CCO>[F:1][C:2]1[C:15]2[O:14][C:13]3[C:8](=[CH:9][C:10]([C:16]4[C:17]([F:22])=[N:18][CH:19]=[CH:20][CH:21]=4)=[CH:11][CH:12]=3)[C@@:7]3([CH2:26][O:25][C:24]([NH2:27])=[N:23]3)[C:6]=2[CH:5]=[C:4]([CH2:28][CH2:29][C:30]2([CH3:34])[CH2:31][O:32][CH2:33]2)[CH:3]=1
Reactant: CC1(/C=C/c2cc(F)c3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)COC1
Agent: [Pd]
Solvent: CCO
Product: CC1(CCc2cc(F)c3c(c2)[C@]2(COC(N)=N2)c2cc(-c4cccnc4F)ccc2O3)COC1

Procedure:
To a reaction vessel charged with (S,E)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(2-(3-methyloxetan-3-yl)vinyl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (38 mg, 0.082 mmol) and Pd/C (5%) (30 mg, 0.082 mmol) was added EtOH (1.5 mL). The reaction mixture was purged with hydrogen gas for 5 minutes and then maintained under 1 atm of hydrogen gas for 4 hours. The mixture was filtered through celite and the derived filtrate concentrated to provide (S)-4′-fluoro-7′-(2-fluoropyridin-3-yl)-2′-(2-(3-methyloxetan-3-yl)ethyl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=O)[CH:6]=[C:7]([CH:9]=[O:10])[CH:8]=1.[C:13]([O-])([O-])=O.[K+].[K+].O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[C:5]([CH:11]=[CH2:13])[CH:4]=1)[CH:9]=[O:10]
Reactant: O=C([O-])[O-]
Reactant: COc1cc(C=O)cc(C=O)c1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=Cc1cc(C=O)cc(OC)c1
Yield: 47.9 %

Procedure:
A mixture of the 5-methoxy-benzene-1,3-dicarbaldehyde (3.68 g, 22.4 mmol) obtained in Example 198.1, methyl-triphenylphosphonium bromide (8.17 g, 22.4 mmol), K2CO3 (3.10 g, 22.4 mmol), water (0.68 ml) and dioxan (51 ml) was heated for 2 h. to 90° C. The reaction mixture was concentrated and the product was purified by chromatography (SiO2, hexane/CH2Cl2 4:1). There were obtained 1.74 g (48%) of 3-methoxy-5-vinyl-benzaldehyde as a colorless oil; MS: 162 ([M]+).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:26](=[O:27])[C:23]1[CH:22]=[CH:21][C:20]([CH2:19][C:18]2[CH:29]=[CH:30][CH:31]=[C:16]([F:15])[CH:17]=2)=[CH:25][N:24]=1
Reactant: O=C(O)c1ccc(Cc2cccc(F)c2)cn1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(Cc2cccc(F)c2)cn1
Yield: 23.1 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-5-(3-fluorobenzyl)picolinamide was prepared according to Method A starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.140 g; 0.605 mmol), 5-(3-fluorobenzyl)picolinic acid (0.139 g; 0.605 mmol), HATU (0.254 g; 0.668 mmol) and N,N-diisopropylethylamine (0.262 mL; 1.52 mmol) in DMF (5 mL). Flash chromatography on silica gel (eluent 20 to 100% ethyl acetate in heptane) furnished 0.057 g (23%) of the title compound as a white solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:15])[CH:12]([CH3:14])[CH3:13])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][O:30][C:31]2[CH:32]=[N:33][C:34](Cl)=[CH:35][CH:36]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([CH2:29][O:30][C:31]2[CH:32]=[N:33][C:34]([N:1]3[C:9]4[C:4](=[CH:5][C:6]([NH:10][C:11](=[O:15])[CH:12]([CH3:13])[CH3:14])=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)=[CH:35][CH:36]=2)[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(Cl)nc2)CC1
Reactant: CC(C)C(=O)Nc1ccc2[nH]ccc2c1
Product: CC(C)C(=O)Nc1ccc2c(ccn2-c2ccc(OCC3CCN(C(=O)OC(C)(C)C)CC3)cn2)c1

Procedure:
The title compound was prepared by following the similar procedure as described in Example-1 using N-(1H-indol-5-yl)isobutyramide (intermediate 10) and tert-butyl 4-(((6-chloropyridin-3-yl)oxy)methyl)piperidine-1-carboxylate (intermediate 29).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:37]([CH3:38])=[N:36][C:35]2=[CH:39][C:32]3=[N:33][N:34]2[C:11]=1[N:12]1[CH2:44][CH2:43][C:15]([CH3:45])([O:16][CH2:17][CH:18]=[CH:19][CH2:20][C@H:21]([CH3:42])[O:22][C:23]2[C:28]([CH2:29][O:30][CH2:31]3)=[C:27]([F:40])[CH:26]=[C:25]([F:41])[CH:24]=2)[CH2:14][CH2:13]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>C(O)C.CC1C=C(C)C(N2C(=[Ru](Cl)(Cl)=CC3C=CC=CC=3OC(C)C)N(C3C(C)=CC(C)=CC=3C)CC2)=C(C)C=1>[C:1]([O:5][C@@H:6]([C:10]1[C:37]([CH3:38])=[N:36][C:35]2=[CH:39][C:32]3=[N:33][N:34]2[C:11]=1[N:12]1[CH2:44][CH2:43][C:15]([CH3:45])([O:16][CH2:17][CH2:18][CH2:19][CH2:20][C@H:21]([CH3:42])[O:22][C:23]2[C:28]([CH2:29][O:30][CH2:31]3)=[C:27]([F:40])[CH:26]=[C:25]([F:41])[CH:24]=2)[CH2:14][CH2:13]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCC=CC[C@H](C)Oc1cc(F)cc(F)c1COC3
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru](Cl)(Cl)=Cc2ccccc2OC(C)C)c(C)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1nc2cc3nn2c(c1[C@H](OC(C)(C)C)C(=O)O)N1CCC(C)(CC1)OCCCC[C@H](C)Oc1cc(F)cc(F)c1COC3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.3 %

Procedure:
To a solution of (2S)-2-(tert-butoxy)-2-[(20S)-14,16-difluoro-4,20,26-trimethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13,15,17,22-octaen-3-yl]acetic acid (0.020 g, 0.032 mmol) in ethanol (0.5 mL) were added Hoveyda-Grubbs catalyst 2nd generation (3.99 mg, 6.36 μmol) and sodium borohydride (6.02 mg, 0.159 mmol) and the mixture was stirred at rt. After 30 min, the mixture was quenched with water and the product was extracted with EtOAc. The organic phase was dried (Na2SO4), filtered and concentrated. The crude material was purified via preparative HPLC to afford (2S)-2-(tert-Butoxy)-2-[(20S)-14,16-difluoro-4,20,26-trimethyl-11,19,25-trioxa-1,5,7,8-tetraazapentacyclo[24.2.2.16,9.02,7.013,18]hentriaconta-2,4,6(31),8,13,15,17-heptaen-3-yl]acetic acid (3.9 mg, 12.83% yield). 1H NMR (500 MHz, DMSO-d6) δ: 6.92 (d, J=11.7 Hz, 1H), 6.77 (t, J=9.0 Hz, 1H), 6.42 (s, 1H), 4.83-4.54 (m, 4H), 4.49-4.24 (m, 2H), 3.61 (dd, J=10.5, 4.6 Hz, 2H), 3.37 (br. s., 2H), 2.59 (d, J=9.9 Hz, 1H), 2.33-1.97 (m, 4H), 1.93 (br. s., 1H), 1.88-1.41 (m, 9H), 1.31-1.06 (m, 15H). LCMS (M+H) calcd for C33H45F2N4O6: 631.33. found: 631.4.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[CH2:16][CH2:15][N:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:13](=[O:24])[C:12]=2[C:11]([CH3:25])=[C:10]1[C:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1.[F:33][C:34]([F:42])([F:41])[CH2:35][CH2:36][S:37](Cl)(=[O:39])=[O:38]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17]2[CH2:16][CH2:15][N:14]([N:18]3[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[C:13](=[O:24])[C:12]=2[C:11]([CH3:25])=[C:10]1[C:26]1[CH:27]=[CH:28][C:29]([O:32][S:37]([CH2:36][CH2:35][C:34]([F:42])([F:41])[F:33])(=[O:39])=[O:38])=[CH:30][CH:31]=1
Reactant: Cc1c2c(n(-c3ccc(F)cc3Cl)c1-c1ccc(O)cc1)CCN(N1CCCCC1)C2=O
Reactant: O=S(=O)(Cl)CCC(F)(F)F
Solvent: c1ccncc1
Product: Cc1c2c(n(-c3ccc(F)cc3Cl)c1-c1ccc(OS(=O)(=O)CCC(F)(F)F)cc1)CCN(N1CCCCC1)C2=O
Temperature: 0 °C
Reaction time: 3 h

Procedure:
1-(2-Chloro-4-fluorophenyl)-2-(4-hydroxyphenyl)-3-methyl-5-piperidin-1-yl-1,5,6,7-tetrahydropyrrolo[3,2-c]pyridin-4-one (0.223 g, 0.49 mmol) was co-concentrated with pyridine twice and put under nitrogen. Pyridine (2.5 ml) was added and the reaction mixture cooled to 0° C. with an ice-bath followed by addition of 3,3,3-trifluoropropane-1-sulfonyl chloride (0.153 g, 0.78 mmol). The reaction mixture was stirred at 0° C. for 3 h adding more 3,3,3-trifluoropropane-1-sulfonyl chloride (0.171 g, 0.87 mmol) after 1 h 10 min. The ice bath was removed and the reaction mixture evaporated. The crude product was purified by hplc to yield the product as a beige solid after freeze-drying (0.19 g, 63%).
Reaction SMILES: C([O:4][C:5]1[CH:45]=[CH:44][C:8]([CH2:9][O:10][CH:11]2[CH:16]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=4[O:35][CH3:36])=[CH:19][CH:18]=3)[CH2:15][CH2:14][N:13]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:12]2)=[CH:7][C:6]=1[N+:46]([O-])=O)C=C.[BH4-].[Li+].C(=O)([O-])O.[Na+]>O1CCCC1.CC([O-])=O.CC([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd+2]>[NH2:46][C:6]1[CH:7]=[C:8]([CH:44]=[CH:45][C:5]=1[OH:4])[CH2:9][O:10][CH:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][O:27][CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[CH:19][CH:18]=2)[CH2:15][CH2:14][N:13]([C:37]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:38])[CH2:12]1
Reactant: C=CCOc1ccc(COC2CN(C(=O)OC(C)(C)C)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)cc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc(O)c(N)c2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The solution of 2.16 g of tert-butyl 3-(4-allyloxy-3-nitrobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 15 ml of tetrahydrofuran is admixed with stirring at room temperature with 0.025 g of bis(triphenylphosphine)palladium(II) acetate and 0.075 g of lithium borohydride and stirred at room temperature for 2.5 hours. The reaction mixture is poured onto 1M sodium hydrogencarbonate (50 ml) and extracted with tert-butyl methyl ether (2×50 ml). The organic phases are washed with water (50 ml) and brine (50 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.38 (1:1 EtOAc-heptane); Rt=6.02.
Reaction SMILES: FC(F)(F)[C:3]([NH:5][C:6]1[CH2:10][CH:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[N:7]=1)=[O:4].C(O)=O.ClC1C=C(N2CC(C)C(NC=O)=N2)C=CC=1Cl>O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([N:8]2[CH:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:10][C:6]([NH:5][CH:3]=[O:4])=[N:7]2)=[CH:22][CH:21]=1
Reactant: O=C(NC1=NN(c2ccc(F)cc2)C(c2ccccc2)C1)C(F)(F)F
Agent: CC1CN(c2ccc(Cl)c(Cl)c2)N=C1NC=O
Solvent: O=CO
Solvent: O
Product: O=CNC1=NN(c2ccc(F)cc2)C(c2ccccc2)C1
Reaction time: 2 h

Procedure:
A mixture of 5.0 g. of 3-amino-1-(p-fluorophenyl)-5-phenyl-2-pyrazoline (prepared as described in Example 43) and 85.0 ml. of a mixture of formic acid and acetic anhydride (Example 15) is allowed to remain at room temperature for 2 hours. The solvent is evaporated in vacuo to give an oil. Water is added to separate a solid. The solid is dissolved in dichloromethane and is columnized and recrystallized twice as described in Example 26 (A) to give 3.55 g. of the desired product as colorless crystals, m.p. 158.5°-160.5° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:14])[CH3:2].[CH3:19][C:20]1[N:21]=[C:22]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[S:23][C:24]=1[CH2:25]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>>[CH2:1]([O:3][C:4](=[O:18])[CH:5]([O:15][CH2:16][CH3:17])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:25][C:24]2[S:23][C:22]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[N:21][C:20]=2[CH3:19])=[CH:9][C:8]=1[CH3:14])[CH3:2]
Reactant: Cc1nc(-c2ccccc2)sc1CO
Reactant: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)C(Cc1ccc(OCc2sc(-c3ccccc3)nc2C)cc1C)OCC

Procedure:
In analogy to the procedure described in example 10 c], [rac]-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid ethyl ester (example 10 b]) was reacted with (4-methyl-2-phenyl-thiazol-5-yl)-methanol [PCT Int. Appl. (2002), WO 02/80899 A1] in the presence of triphenylphosphine and diethyl azodicarboxylate to yield [rac]-2-ethoxy-3-[2-methyl-4-(4-methyl-2-phenyl-thiazol-5-ylmethoxy)-phenyl]-propionic acid ethyl ester as colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][O:5][CH2:4]1.[N-:15]=[N+:16]=[N-:17].[Na+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)(O)[O-].[Na+].O>[N:15]([CH2:2][C:3]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:6][O:5][CH2:4]1)=[N+:16]=[N-:17]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCC1(COc2ccccc2)COC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Product: [N-]=[N+]=NCC1(COc2ccccc2)COC1
Yield: 185.6 %

Procedure:
A mixture of 3-chloromethyl-3-phenoxymethyloxetane (20.0 g, 44 mmol), sodium azide (7.35 g, 113 mmol), sodium bicarbonate (0.53 g, 6.3 mmol), tetra-n-butylammonium bromide (0.653 g, 2.0 mmol) and water (41 mL) was heated at about 109° C. to about 113° C. for 16 h. The mixture was cooled and separated. The organic layer was washed with brine solution, diluted with methylene chloride and filtered through a pad of alumina. The solvent was evaporated to give 17.9 g (87%) of 3-azidomethyl-3-phenoxymethyloxetane as an oil that was pure by glc and NMR analysis. NMR: 1H NMR: d 3.71 (s, 2H), 4.07 (s, 2H), 4.42 & 4.46 (AB, J=6.2 Hz, 4H), 6.83-7.21(m, 5H); 13C NMR: d 43.36,53.88, 68.84, 76.18, 114.47, 121.31, 129.50, 158.45; glc Rt=8.13 min.
Reaction SMILES: [N:1]1[C:6](=[O:7])[NH:5][C:4](=[O:8])[N:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]=12.[CH2:13]([CH:15]1[O:17][CH2:16]1)Br.[H-].[Na+]>CN(C)C=O>[O:17]1[CH2:16][CH:15]1[CH2:13][N:5]1[C:4](=[O:8])[N:3]2[CH2:9][CH2:10][CH2:11][CH2:12][C:2]2=[N:1][C:6]1=[O:7]
Reactant: O=c1nc2n(c(=O)[nH]1)CCCC2
Reactant: BrCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1nc2n(c(=O)n1CC1CO1)CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.6 %

Procedure:
After dissolving 6,7,8,9-tetrahydropyrido[1,2-a][1,3,5]triazine-2,4-dione (CAS 133365-43-2) (195 mg) and epibromohydrin (321 mg) in N,N-dimethylformamide (1 ml), sodium hydride (60% in oil) (52 mg) was added and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by NH silica gel column chromatography. The title compound (189 mg) was thus obtained.