Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[F:17][CH:18]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=2[F:42])=[C:30]([CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])[N:29]=1)[CH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=1)[CH:23]=O.O>C1COCC1>[F:17][CH:18]([C:28]1[CH:33]=[CH:32][C:31]([C:34]2[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:35]=2[F:42])=[C:30]([CH2:43][C:44]([CH3:47])([CH3:46])[CH3:45])[N:29]=1)[CH2:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc(F)c(-c2ccc(C(F)Cc3cccc(C=O)c3)nc2CC(C)(C)C)c1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=Cc1cccc(CC(F)c2ccc(-c3cc(OC)ccc3F)c(CC(C)(C)C)n2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under a nitrogen atmosphere, to a suspension of 60% sodium hydride (21 mg) in THF (2.0 mL) was added ethyl diethylphosphonoacetate (117 μL) at 0° C., and the mixture was stirred at room temperature for 5 min. To the obtained colorless solution was added 3-(2-fluoro-2-(5-(2-fluoro-5-methoxyphenyl)-6-neopentylpyridin-2-yl)ethyl)benzaldehyde (entire amount) obtained in Example 36, step 0, at 0° C. and the mixture was stirred at room temperature for 20 min. Water was added to the reaction mixture at room temperature, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (119 mg) as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.Cl[C:14]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[S:21])=[CH:18][N:17]=[C:16]([CH3:25])[N:15]=1>O1CCCC1>[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][O:10][C:18]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[S:21])=[CH:14][N:15]=[C:16]([CH3:25])[N:17]=2)=[CH:7][CH:6]=1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Reactant: COc1ccc(CO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=S)c1cnc(C)nc1OCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.7 %

Procedure:
An ice-cooled suspension of 2.1 g (53 mmol) of sodium hydride (60% w/w dispersion in mineral oil) in 120 ml of tetrahydrofuran was treated dropwise with a solution of 6.5 g (47 mmol) of 4-methoxybenzyl alcohol in 40 ml of tetrahydrofuran. After 30 minutes, a solution of 10 g (43 mmol) of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate was added slowly. After a further 40 minutes the reaction was quenched by the cautious addition of 60 ml of saturated aqueous ammonium chloride. The mixture was separated and the organic phase dried over magnesium sulfate, filtered and evaporated to give 14.2 g (99%) of ethyl 4-(4-methoxy-benzyloxy)-2-methylthiopyrimidine-5-carboxylate as a pale yellow oil. [Mass spectrum (ESI) MH+ =335].
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH:6]1([C:11](O)=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1>O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:11]([CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1)=[O:12]
Reactant: O=C(O)C1CCCC1
Reactant: c1ccsc1
Solvent: O
Product: O=C(c1cccs1)C1CCCC1
Yield: 99 %

Procedure:
A solution of 8.8 g (105 mmol, 1.2 equivs.) of thiophene and 10.0 g (88 mmol) of cyclopentanecarboxylic acid in 20 g of polyphosphoric acid was stirred at 75° C. for 2 hours. The reaction mixture was diluted with water and extracted with o-dichlorobenzene to afford 99% pure product (GC, area % analysis). The mixture was azeotropically dried by stripping a small portion of the solvent. The crude cyclopentyl 2-thienyl ketone solution was then used without purification, for the bromination step of Example 2.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]2[CH:17]=[C:16]([N:18]3[CH2:23][CH2:22][CH:21]([S:24]([CH3:27])(=[O:26])=[O:25])[CH2:20][CH2:19]3)[CH:15]=[CH:14][C:13]=2[NH2:28])=[N:2]1.C(N(CC)CC)C.[CH3:36][C:37]1[CH:41]=[CH:40][S:39][C:38]=1[C:42](Cl)=[O:43].C(=O)([O-])O.[Na+]>C1COCC1>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[C:16]([N:18]3[CH2:19][CH2:20][CH:21]([S:24]([CH3:27])(=[O:25])=[O:26])[CH2:22][CH2:23]3)[CH:15]=[CH:14][C:13]=2[NH:28][C:42]([C:38]2[S:39][CH:40]=[CH:41][C:37]=2[CH3:36])=[O:43])=[N:2]1
Reactant: Cc1ccsc1C(=O)Cl
Reactant: CS(=O)(=O)C1CCN(c2ccc(N)c(C=Cc3n[nH]c4ccccc34)c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccsc1C(=O)Nc1ccc(N2CCC(S(C)(=O)=O)CC2)cc1/C=C/c1n[nH]c2ccccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a similar manner to Example 2, said crude 3-{2-[5-(4-methanesulfonylpiperidin-1-yl)-2-nitrophenyl]vinyl}-1H-indazole (0.23 g, 0.54 mmol) obtained in Step 1 was dissolved in ethanol (7.0 mL) and 2-[2-(1H-indazol-3-yl)vinyl]-4-(4-methanesulfonylpiperidin-1-yl)phenylamine was obtained from tin (0.19 g, 1.6 mmol) and concentrated hydrochloric acid (1.0 mL) at room temperature. In a similar manner to Example 29, a solution of 2-[2-(1H-indazol-3-yl)vinyl]-4-(4-methanesulfonylpiperidin-1-yl)phenylamine (0.22 g, 0.54 mmol) in THF (10 mL) was added with triethylamine (0.23 ml, 1.6 mmol) and 3-methylthiophenecarbonyl chloride (0.09 g, 0.54 mmol), followed by stirring at room temperature for 1 hour. The reaction mixture was added with saturated aqueous sodium hydrogencarbonate solution, extracted with ethyl acetate and the organic layer was concentrated under reduced pressure to obtain crude (E)-N-{2-[2-(1H-indazol-3-yl)vinyl]-4-(4-methanesulfonylpiperidin-1-yl)phenyl}-3-methylthiophene-2-carboxamide. Further, Compound 227 (68 mg, 22%) was obtained using 4 mol/L hydrogen chloride-methanol solution (1.0 mL).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][C:3]=1[NH2:10].Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13]>N1C=CC=CC=1>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][C:3]=1[NH:10][C:12](=[O:13])[O:14][CH2:15][CH3:16]
Reactant: CCOC(=O)Cl
Reactant: COc1cc(C)c(N)cn1
Solvent: c1ccncc1
Product: CCOC(=O)Nc1cnc(OC)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
To a 100 mL flask was added 4-methyl-6-(methyloxy)-3-pyridinamine (850 mg, 6.15 mmol), pyridine (10 mL) and then ethyl chloroformate (0.650 mL, 6.77 mmol) portionwise. The reaction mixture was stirred for 1 h at 0° C. The reaction mixture was then concentrated and partitioned between ammonium chloride and DCM, and the aqueous layer was extracted with DCM (2×). The combined organics layers were washed with brine (1×), eluted through a phase separator then concentrated to afford ethyl [4-methyl-6-(methyloxy)-3-pyridinyl]carbamate (1.223 g, 90% yield).
Reaction SMILES: [C:1]([N:5]([CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C:6](=[O:12])[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].Cl>O1CCOCC1.O>[C:1]([N:5]([CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)[C:6](=[O:12])[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)C(=O)N(CCCC#Cc1cccs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)N(CCCC#Cc1cccs1)C(=O)C(=O)O
Temperature: 50 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a solution of 300 mg of 2d in 6 ml of dioxane was added a solution of 200 mg of KOH in 2 ml of water. The mixture was stirred at 50° C. for 1 hr. After cooling to RT, 25 ml of water was added and the reaction mixture was acidified to pH3 by addition of 0.5N HCl. The product was extracted into ethyl acetate. The organic layer was washed once with water, dried and concentrated, to provide 240 mg of 2e as colorless oil;
Reaction SMILES: [C:1]([N:5]([CH:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[O:11][CH2:10]1)[CH2:6][CH2:7][CH3:8])(=[O:4])[CH2:2][CH3:3].[N+:19]([O-])([OH:21])=[O:20].S(=O)(=O)(O)O>[N+](C)([O-])=O>[N+:19]([C:15]1[CH:16]=[C:17]2[C:12](=[CH:13][CH:14]=1)[O:11][CH2:10][CH:9]([N:5]([C:1](=[O:4])[CH2:2][CH3:3])[CH2:6][CH2:7][CH3:8])[CH2:18]2)([O-:21])=[O:20]
Reactant: CCCN(C(=O)CC)C1COc2ccccc2C1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: C[N+](=O)[O-]
Product: CCCN(C(=O)CC)C1COc2ccc([N+](=O)[O-])cc2C1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
To an ice cool solution of 730 mg (2.96 mmol) 3-(N-propionyl-N-n-propylamino)chroman (16) in nitromethane (15 ml) was a mixture of fuming nitric acid (0.70 ml) and concentrated sulphuric acid (1.42 ml) added. The solution was stirred for 90 min at 0° C. The reaction mixture was poured out on ice and the product was extracted with dichloromethane. The organic layer was washed with water and 5% aqueous Na2CO3. The organic layer was separated, dried (MgSO4) and the solvent was evaporated yielding 700 mg (81%) of 6-nitro-3-(N-propionyl-N-n-propylamino)chroman (17).
Reaction SMILES: [C:1]([C@@H:3]1[C@@H:7]([CH2:8][O:9][C:10]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:6][C@@H:5]([N:29]2[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:4]1)#N.[C@@H]1(N2C=C(C)C(=O)NC2=O)O[C@H](CO)[C@@H]([OH:40])C1.CC(C[AlH]CC(C)C)C>C1COCC1.C1(C)C=CC=CC=1>[C:10]([O:9][CH2:8][C@H:7]1[O:6][C@@H:5]([N:29]2[CH:36]=[CH:35][C:33](=[O:34])[NH:32][C:30]2=[O:31])[CH2:4][C@@H:3]1[CH:1]=[O:40])([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: N#C[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C[C@H]1C[C@H](n2ccc(=O)[nH]c2=O)O[C@@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53 %

Procedure:
To a stirred solution of 3'-cyano-2',3'-dideoxy-5' -O-trityl uridine (0.96 g, 2 mmol), (see Tetrahedron Letters 29: 2995 (1988) for synthesis of the thymidine analog) in dry THF (20 ml) under argon was added a solution of DIBAL-H in toluene (Aldrich) (1M, 4 ml) at -10° C. over a period of 10 min. After 30 mins the reaction was quenched with MeOH (5 ml) at -10° C. The mixture was further stirred at ambient temperature for 30 mins and diluted with CH2Cl2 (25 ml) before concentrating under vacuum. This process was repeated with CH2Cl2 (3×25 ml) in order to remove the residual THF. The residue was purified by flash chromatography on silica gel (25 g). Elution with CH2Cl2 (9:1, v/v) and crystallization from CH2Cl2 /MeOH gave 5' -O-trityl-3'-C-formyl-2',3'-dideoxyuridine (0.53 g, 53%); mp 100° C.; 1H NMR (CDCl3) δ2.25-2.8 (m, 2, CH2), 3.4 (m, 1, C3,H), 3.45-3.6 (m, 2, C5,CH2), 4.37 (m, 1, C4, H), 5.4 (d, 1, C5H), 6.1 (m, 1, C1,H), 7.2-7.4 (m, 15, C6H5), 7.81 (d, 1, C6H), 7.95 (brs, 1, NH), 9.61 (s, 1, HC=O).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([F:19])([CH:16]([OH:18])[CH3:17])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>ClCCl>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][C:13]([F:19])([CH:16]([O:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH3:17])[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)C1(F)CCN(C(=O)OCc2ccccc2)C1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(OS(C)(=O)=O)C1(F)CCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a −10° C. solution of 3-fluoro-3-(1-hydroxyethyl)pyrrolidine-1-carboxylic acid benzyl ester (Example A14, 0.267 g, 1.00 mmol), triethylamine (0.4 g, 4 mmol) and dichloromethane (10 mL) is added methanesulfonyl chloride (0.229 g, 2.00 mmol). The mixture is stirred at room temperature for 2 hours and concentrated in vacuo. The residue is partitioned between ethyl acetate and water. The organic layer is dried over Na2SO4 and concentrated to afford the title compound (0.330 g). 1H NMR (200 MHz, CDCl3): δ 7.36 (s, 5H), 5.14 (s, 2H), 4.99-4.81 (m, 1H), 3.76-3.37 (m, 4H), 3.06 (s, 3H), 2.25-1.96 (m, 2H), 1.52-1.47 (m, 3H).
Reaction SMILES: Cl[CH2:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4].[CH3:18][NH:19][CH3:20]>CCOCC>[CH3:18][N:19]([CH2:2][C:3]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:4])[CH3:20]
Reactant: CCCCCCCCCCCCOC(=O)CCl
Reactant: CNC
Solvent: CCOCC
Product: CCCCCCCCCCCCOC(=O)CN(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
Dodecyl chloroacetate (5.5 g, 0.021 mol) was dissolved in 20 ml of ether and the resultant solution was cooled in an ice-bath. Dimethylamine (40 ml, 0.1 M in ether) was added to the cooled solution of dodecyl chloroacetate. The reaction mixture was stirred at room temperature for two hours, then filtered through a filter paper to remove the white solid which formed. The filtrate was concentrated to give a liquid product which was chromatographed through a column of silica gel (60-200 mesh) using ethyl acetate as the eluent. The purity of the fractions was checked by thin layer chromatography. The pure fractions were combined and the solvent was removed by a rotary evaporator under reduced pressure to afford 5.8 g (100% yield) of dodecyl (N,N-dimethylamino)acetate. 1HNMR(CCl4) δ0.83(3H, t, CH3); 1.20[20 H, s, broad, --(CH2)10 ]; 2.23[6H, s, (CH3)2N--]; 3.0 (2H, s, --CH2 --N); 3.93 (2H, t, J=6 Hz, --OCH2 --) νmax (film): 2940,2870,2790 (CH); 1760, 1740(C=O); 1200, 1170 (--C--O--C) cm-1. m/e 271; C16H33NO2 requires 271.
Reaction SMILES: Br[C:2]1[N:3]([CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][C@@H:13]([CH3:17])[CH2:14][CH2:15][CH3:16])[N:5]=2.[CH3:24][O-:25].[Na+]>CO>[CH3:17][C@H:13]([O:12][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([O:25][CH3:24])[N:3]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[C:8]([NH2:11])[N:7]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCC[C@H](C)Oc1nc(N)c2nc(Br)n(C3CCCCO3)c2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCC[C@H](C)Oc1nc(N)c2nc(OC)n(C3CCCCO3)c2n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
8-Bromo-2-{[(1S)-1-methylbutyl]oxy}-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (7.1 g, 18.48 mmol) was dissolved in anhydrous methanol (70 ml) and a solution of sodium methoxide (25%) in methanol (8 ml) was added dropwise under an atmosphere of nitrogen. The solution was heated to reflux at 90° C. for 4 hours under an atmosphere of nitrogen. Additional sodium methoxide in methanol (25% solution, 3 ml) was added and the reaction was stirred at 60° C. for a further 16 hours. An additional portion of sodium methoxide in methanol (25% solution, 5 ml) was added and the reaction was stirred at 90° C. for a further 7 hours. The solvent was removed on the rotary evaporator and the crude product was partitioned between EtOAc (75 ml) and saturated ammonium chloride solution (75 ml). The organic layer was washed with brine (75 ml). The solvent was removed on the rotary evaporator to yield the title compound as a pale orange foam (6 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:9])[C:5]([I:8])=[N:6][CH:7]=1.C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>ClCCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][Br:17])[C:5]([I:8])=[N:6][CH:7]=1
Reactant: Cc1cc(Br)cnc1I
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: BrCc1cc(Br)cnc1I
Temperature: 80 °C

Procedure:
To a stirred solution of 5-bromo-2-iodo-3-methyl-pyridine (22.5 g, 75.5 mmol, 1 eq) in 1,2-dichloroethane (200 mL) was added NBS (20.16 g, 113.255 mmol, 1.5 eq) followed by addition of AIBN (4.96 g, 30.2 mmol, 0.4 eq) at room temperature in dark. Resulting reaction mixture was heated at 80° C. for 16 hours. After maximum consumption of starting material, reaction mixture was cooled to room temperature and quenched with water (150 mL), extracted with DCM (2×150 mL). Combined organic phase was washed with brine (200 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to get dark brownish semi solid (25 g, crude). Crude of title compound was used as such for next reaction. 1H NMR (400 MHz, CDCl3) δ: (Mixture of starting with product): 4.45 (s, 2H), 7.81 (d, J=2.36 Hz, 1H), 8.31 (d, J=2.36 Hz, 1H). LC-MS (m/z): No ionization.
Reaction SMILES: C([NH:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[CH:11]=2)[CH2:6]1)(=O)C.Cl.[CH3:29]O>>[NH2:4][CH:5]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:14]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)=[CH:15][CH2:16][CH2:17][CH2:18][C:19]([O:21][CH3:29])=[O:20])[CH:11]=2)[CH2:6]1
Reactant: CC(=O)NC1Cc2ccc(C(=CCCCC(=O)O)c3cccnc3)cc2C1
Reactant: CO
Agent: Cl
Product: COC(=O)CCCC=C(c1cccnc1)c1ccc2c(c1)CC(N)C2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3.1 g of 6-(2-acetylaminoindan-5-yl)-6-(3-pyridyl)hex-5-enoic acid are refluxed for 15 hours with 20 ml of half concentrated hydrochloric acid and then rotary evaporated. The residue is then added to 50 ml of methanol saturated with dry hydrogen chloride. After 30 minutes stirring at ambient temperature the reaction mixture is rotary evaporated to dryness. The residue is taken up in 1N sodium hydroxide solution and adjusted to pH 10. It is then extracted 3 times with 50 ml of methylene chloride, the organic phase is dried and rotary evaporated.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([OH:23])[CH:15]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:37]([CH:39]1[O:41][CH2:40]1)Cl>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:24]=[CH:25][C:26]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:12]1[O:13][C:14]2[C:19]([C:20](=[O:22])[CH:21]=1)=[CH:18][CH:17]=[C:16]([O:23][CH2:37][CH:39]1[O:41][CH2:40]1)[CH:15]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2cc(O)ccc12
Reactant: ClCC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccc(OCc3ccccc3)c(OCc3ccccc3)c2)oc2cc(OCC3CO3)ccc12

Procedure:
Reaction of 3′,4′-dibenzyloxy-7-hydroxy-flavone, 23 (10 g, 22.2 mmol), 50% sodium hydride (3 g, 125 mmol) and epichlorohydrin (6.9 mL, 88 mmol) in dry dimethyl formamide (160 mL) using identical procedure as described for 28 furnished 29. Yield 9.7 g (86%); mp 168-170° C.; MS (FAB) 507 (M++1); IR (KBr) 1639; 1H NMR (200 MHz, CDCl3) δ 8.12 (d, J=8.7 Hz, 1H), 7.50-7.32 (m, 12H), 7.04-6.93 (m, 3H), 6.61 (s, 1H), 5.24 (s, 4H), 4.38 (dd, J=11.1 Hz, 2.9 Hz, 1H), 4.05 (dd, J=11.1 Hz, 5.8 Hz, 1H), 3.42-3.40 (m, 1H), 2.96 (t, J=4.5 Hz, 4.5 Hz, 1H), 2.80 (dd, J=4.8 Hz, 2.6 Hz, 1H).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[NH:2][NH2:3].[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH2:19][CH:20]=O>C1(C)C=CC=CC=1>[O:8]=[C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11](=[O:18])[N:10]1[CH2:19]/[CH:20]=[N:3]/[NH:2][C:1]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)NN
Solvent: Cc1ccccc1
Product: CCOC(=O)N/N=C/CN1C(=O)c2ccccc2C1=O
Temperature: 75 °C
Reaction time: 3 h

Procedure:
A solution of ethyl carbazate (435 mg, 4.18 mmol) in toluene (6 ml) was slowly added dropwise to a solution of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetaldehyde (719 mg, 3.80 mmol) in toluene (12 ml), and the mixture was stirred at 75° C. for 3 hours. Crystals were collected by filtration and washed with diethyl ether to give 612 mg (58.5% (2 steps)) of the desired product as a solid.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[CH:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[CH2:3][CH2:2]1.[CH:21]1([CH2:24][C@H:25]([NH2:31])[C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][C@H:25]([NH:31][C:12]([C:10]2[CH:9]=[CH:8][C:7]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[C:6]([O:5][CH2:4][CH:1]3[CH2:2][CH2:3]3)[N:11]=2)=[O:14])[C:26]2[S:27][CH:28]=[CH:29][N:30]=2)[CH2:23][CH2:22]1
Reactant: N[C@@H](CC1CC1)c1nccs1
Reactant: O=C(O)c1ccc(C2CCOCC2)c(OCC2CC2)n1
Product: O=C(N[C@@H](CC1CC1)c1nccs1)c1ccc(C2CCOCC2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carboxylic acid (Example 9 f) and (S)-2-cyclopropyl-1-thiazol-2-yl-ethylamine as starting materials, MS (LC/MS): 428.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:32])[C:19]([CH3:31])([S:21]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)(=[O:23])=[O:22])[CH3:20])[O:14][N:13]=1)([CH3:11])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1.[CH2:33]([Li])CCC.CI>C1COCC1>[CH3:11][C:2]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:32])[C:19]([CH3:31])([S:21]([CH:24]([CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[CH3:33])(=[O:23])=[O:22])[CH3:20])[O:14][N:13]=1)([CH3:1])[CH2:3][O:4][CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][O:6]1
Reactant: CC(C)(COC1CCCCO1)c1cc(NC(=O)C(C)(C)S(=O)(=O)CC2CCOCC2)on1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: CC(C1CCOCC1)S(=O)(=O)C(C)(C)C(=O)Nc1cc(C(C)(C)COC2CCCCO2)no1
Temperature: -78 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
A solution of 0.4 g (0.85 mmol) of N-{3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-2-methyl-2-(tetrahydro-pyran-4-ylmethanesulfonyl)-propionamide (synthesized according to method B, step 1) in anhydrous THF (5 mL) under nitrogen is cooled to −78° C. A 2.5 M solution of n-butyl lithium in hexanes (1 mL) is added dropwise. The reaction mixture is stirred at −78° C. for 1 h, followed by addition of 0.11 mL (1.69 mmol) of methyl iodide. The reaction is allowed to warm to room temperature and stirred for 18 h. The mixture is quenched by addition of water (5 mL) and the organic solvent is removed under reduced pressure. The aqueous residue is extracted with DCM (2×10 mL). The combined organic extracts are washed with brine (10 mL), dried (Na2SO4) and filtered. The filtrate is concentrated under reduced pressure and the residue is purified by mass-triggered preparative LC (neutral method) to afford 0.1 g of N-{3-[1,1-dimethyl-2-(tetrahydro-pyran-2-yloxy)-ethyl]-isoxazol-5-yl}-2-methyl-2-[1-(tetrahydro-pyran-4-yl)-ethanesulfonyl]-propionamide. Yield: 24%, ES-MS: 403 [M+H].
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:10]2[CH:11]=[N:12][C:13]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:14][CH:15]=2)=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].Cl[C:23]1[N:28]=[C:27]([CH3:29])[C:26]([CH:30]([OH:35])[C:31]([F:34])([F:33])[F:32])=[CH:25][CH:24]=1>>[CH3:29][C:27]1[N:28]=[C:23]([NH:1][C:2]2[S:3][C:4]([C:10]3[CH:11]=[N:12][C:13]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)=[CH:14][CH:15]=3)=[CH:5][C:6]=2[C:7]([NH2:9])=[O:8])[CH:24]=[CH:25][C:26]=1[CH:30]([OH:35])[C:31]([F:34])([F:32])[F:33]
Reactant: Cc1nc(Cl)ccc1C(O)C(F)(F)F
Reactant: NC(=O)c1cc(-c2ccc(N3CCOCC3)nc2)sc1N
Product: Cc1nc(Nc2sc(-c3ccc(N4CCOCC4)nc3)cc2C(N)=O)ccc1C(O)C(F)(F)F

Procedure:
The title compound was prepared as described in Example 1 using 2-amino-5-(6-morpholin-4-ylpyridin-3-yl)thiophene-3-carboxamide (150 mg, 0.49 mmol) and 1-(6-chloro-2-methylpyridin-3-yl)-2,2,2-trifluoroethanol (111 mg, 0.49 mmol) as starting materials.
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:17][C:18]([O:20]C)=[O:19])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=O)C.[H][H].C(O)(=O)C>CO.[OH-].[Na+]>[C:18]([CH2:17][CH:6]([CH2:5][SH:4])[C:7]([N:9]1[CH2:16][CH2:15][CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])([OH:20])=[O:19]
Reactant: [H][H]
Reactant: COC(=O)CC(CSC(C)=O)C(=O)N1CCC[C@H]1C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 4 h

Procedure:
To a solution of the product from Example 81 (3.0 g.) in methanol (60 ml.), 1N sodium hydroxide (60 ml.) is added. After 4 hours, the solution is applied to a column of Dowex 50 ion exchange resin in the hydrogen cycle, and the desired material is eluted with water to yield 2.3 g. of the named product Rf 0.2 (silica gel-benzene:acetic acid, 75:25).