Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:61])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:60])[NH:26][C@H:27]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:28][CH2:29][C:30](=[O:52])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][C:39](=[O:51])[NH:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][C:48]([OH:50])=[O:49])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:75]1[C:80](=[O:81])[CH2:79][CH2:78][C:76]1=[O:77])=[N+](C)C)C.CCN(C(C)C)C(C)C>C(#N)C>[C:1]([O:5][C:6](=[O:61])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:60])[NH:26][C@H:27]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:28][CH2:29][C:30](=[O:52])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][C:39](=[O:51])[NH:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][C:48]([O:50][N:75]1[C:80](=[O:81])[CH2:79][CH2:78][C:76]1=[O:77])=[O:49])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCC(=O)NCCOCCOCC(=O)O)C(=O)OC(C)(C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCC(=O)NCCOCCOCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of 19-{(S)-1-tert-Butoxycarbonyl-3-[2-(2-{[2-(2-carboxymethoxyethoxy)ethyl-carbamoyl]methoxy}ethoxy)ethylcarbamoyl]propylcarbamoyl}nonadecanoic acid tert-butyl ester (3.1 g) in acetonitrile (50 ml) was added TSTU (1.39 g) and DIPEA (0.91 ml). The mixture was stirred at room temperature over night and then concentrated in vacuo. To the residue was added aqueous 0.1 N HCl (100 ml) and ethyl acetate (200 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layers were washed with water and brine, dried (magnesium sulphate) and concentrated in vacuo to give an oil. Yield 99% (3.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:13])[C:5](=[CH:11][CH:12]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].C(=O)([O-])[O-].[K+].[K+].Cl[CH:21]([CH3:26])[C:22]([O:24][CH3:25])=[O:23].O>CN(C)C=O>[Cl:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:4]([O:13][CH:21]([C:22]([O:24][CH3:25])=[O:23])[CH3:26])[CH:3]=1
Reactant: COC(=O)C(C)Cl
Reactant: CCOC(=O)c1ccc(Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cl)cc1OC(C)C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
To a solution of ethyl 4-chlorosalicylate (9.45 g) and potassium carbonate (10.3 g) in N,N-dimethylformamide (100 ml) was added methyl 2-chloropropionate (6.9 g), followed by stirring overnight at room temperature. The reaction mixture was poured into water (200 ml) and extracted with ether (200 ml×2). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was subjected to chromatography on silica gel to give ethyl 4-chloro-2-(1(methoxycarbonyl)ethoxy)benzoate (yield, 8.4 g).
Reaction SMILES: CO[CH:3](OC)[N:4]([CH3:6])[CH3:5].[Br:9][C:10]1[CH:11]=[C:12]([C:16](=[O:18])[CH3:17])[CH:13]=[N:14][CH:15]=1>>[Br:9][C:10]1[CH:11]=[C:12]([C:16](=[O:18])[CH:17]=[CH:3][N:4]([CH3:5])[CH3:6])[CH:13]=[N:14][CH:15]=1
Reactant: CC(=O)c1cncc(Br)c1
Reactant: COC(OC)N(C)C
Product: CN(C)C=CC(=O)c1cncc(Br)c1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
An N,N-dimethylformamide dimethylacetal (2 ml) solution containing 1-(5-bromopyridin-3-yl)ethanone (100 mg) (WO2009/87224 A1) was stirred at 100° C. for 5 hours. The solvent was distilled away under reduced pressure, and a yellow solid of 1-(5-bromopyridin-3-yl)-3-(dimethylamino)prop-2-ene-1-one was thus obtained.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[OH:15])[CH3:7]>>[CH2:6]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:1][CH:3]1[O:5][CH2:4]1)[CH3:7]
Reactant: CCOc1ccccc1O
Reactant: ClCC1CO1
Product: CCOc1ccccc1OCC1CO1

Procedure:
In this embodiment of Step 1, illustrated in FIG. 2, Epoxide 1 can be prepared by reacting epichlorohydrin with 2-ethoxyphenol in the presence of a catalytic amount of a phase transfer catalyst without the use of solvents at elevated temperatures in a two-stage process to afford near quantitative yield of 1-(2-ethoxyphenoxy)-2,3-epoxypropane with very few side products. This embodiment of the invention is further illustrated by a non-limiting Example 12. The phase transfer catalyst for this embodiment can be selected from ammonium salts such as benzyltriethylammonium salts, benzyltrimethylammonium salts, tetrabutylammonium salts, etc; phosphonium salts, guanidinium salts, crown ether, polyethylene glycol, polyethylene glycol ether, or polyethylene glycol ester, or other phase transfer catalysts know in the art. The first stage of the process of this embodiment may take place without a solvent in a presence of a large excess of epichlorohydrin. This stage is followed by a de-chlorination stage, before or after removal of excess epichlorohydrin, using a base and a solvent. The reaction produces 1-(2-ethoxyphenoxy)-2,3-epoxypropane in high yield. Example of the bases used herein include but are not limited to NaOH, KOH, LiOH, LiOH/LiCl, K2CO3, Na2CO3, amines such as mono-, di- or tri-substituted amines (such as diethylamine, triethylamine, dibutylamine, tributylamine etc.), DMAP. In one variation of this embodiment of Step 1, the phase transfer catalyst may be used only at the de-chlorination stage of the process. The de-chlorination stage can be carried out in a biphasic system or in a single phase system. For a biphasic system, it can be an organic-aqueous liquid biphasic system, or a liquid-solid biphasic system. Solvents that are useful for the process include but are not limited to non-substituted and substituted aromatic solvents (e.g. toluene, benzene, chlorobenzene, dimethylbenzene, xylene), halo-substituted hydrocarbons (e.g. CH2Cl2, CHCl3), THF, dioxanes, DMF, DMSO, non-substituted and substituted pyridines, ketones, pyrrolidones, ethers, acetonitrile, nitromethane. As mentioned above, this process takes place at the elevated temperature. In one variation of the embodiment, the temperature is above 60° C. In another variation, 2-ethoxyphenol and epichlorohydrin are heated to 60-90° C. for a period of time in the presence of phase transfer catalyst. Excess of epichlorohydrin is removed and the residue is dissolved in a solvent such as toluene or benzene treated with an aqueous base solution, such as NaOH, KOH, LiOH, LiOH/LiCl. In yet another variation of the embodiment, the residue after epichlorohydrin removal can be dissolved in one or more of the said solvent and treated with a base (solid or liquid but not an aqueous solution) and optionally a second phase transfer catalyst, optionally at elevated temperatures.
Reaction SMILES: CN1C2C=CC([C:15]3[CH:16]=[CH:17][C:18]4[N:19]([CH2:42][CH:43]=[CH2:44])[C:20]5[C:25]([C:26]=4[CH:27]=3)=[CH:24][C:23](C3C=CC4N(C)C6C(C=4C=3)=CC=CC=6)=[CH:22][CH:21]=5)=CC=2C2C1=CC=CC=2.C1COCC1.[Cl:50][SiH:51]([Cl:53])[Cl:52]>C1(C)C=CC=CC=1>[Cl:50][Si:51]([Cl:53])([Cl:52])[CH2:44][CH2:43][CH2:42][N:19]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=2[C:26]2[C:18]1=[CH:17][CH:16]=[CH:15][CH:27]=2
Reactant: C=CCn1c2ccc(-c3ccc4c(c3)c3ccccc3n4C)cc2c2cc(-c3ccc4c(c3)c3ccccc3n4C)ccc21
Reactant: Cl[SiH](Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cl[Si](Cl)(Cl)CCCn1c2ccccc2c2ccccc21
Temperature: 60 °C

Procedure:
To a three-neck flask fitted with a reflux condenser and a dropping funnel were added the 3,6-bis(9-methylcarbazol-3-yl)-9-allylcarbazole (10 g), anhydrous THF (100 g), and platinum (0) 1,3-divinyl-1,1,3,3-tetramethyldisiloxane complex (250 mg of a 0.05% solution in anhydrous toluene). Then, trichlorosilane (30 g) was slowly added. When the addition of trichlorosilane was completed, the mixture was heated to 60° C. and maintained at that temperature for two hours. Then, the mixture was distilled at 0.02 torr to remove volatiles and gave 9-(3-trichlorosilylprop-1-yl)carbazole with a yield of about 5.6 g, at a concentration of about 90% by weight. 1 H NMR (CDCl3) δ 8.53 (d, 2 H, J=1.5 Hz); 8.46 (d, 2 H, J=1.2 Hz); 8.21 (d, 2 H, J=7.8 Hz); 7.87 (m, 4 H); 7.48 (m, 8 H); 7.27 (m, 2 H); 6.10 (m, 1 H); 5.40 (d, 1 H, J=9.0 Hz); 5.14 (d, 1 H, J=15.9 Hz); 5.00 (m, 2 H); 3.91 (s, 6 H).
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[S:14][CH:15]=2)=[CH:7][CH:6]=1)([CH3:3])C.[CH2:19](SC1C=CC(B(O)O)=CC=1)[CH2:20][CH2:21][CH2:22]CC>>[CH2:1]([S:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]=[C:13]([C:16]([OH:18])=[O:17])[S:14][CH:15]=2)=[CH:9][CH:10]=1)[CH2:3][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCSc1ccc(B(O)O)cc1
Reactant: CC(C)Sc1ccc(-c2csc(C(=O)O)c2)cc1
Product: CCCCCCSc1ccc(-c2csc(C(=O)O)c2)cc1

Procedure:
The title compound was prepared in a similar manner as described in the preparation of 4-(4-(isopropylthio)phenyl)thiophene-2-carboxylic acid (compound 73, example 12), except 4-(hexylthio)phenylboronic acid (Chemical Communications 2003, 1, 138-139) was used in the place of 4-(isopropylthio)phenylboronic acid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([CH3:15])[C:9]2=[O:16])=[CH:4][CH:3]=1.[C:17]1([C:23]#[CH:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>CN(C=O)C.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.Cl[Pd]Cl.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:15][N:10]1[C:11]([CH3:14])([CH3:13])[CH2:12][N:8]([C:5]2[CH:6]=[N:7][C:2]([C:24]#[C:23][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[CH:3][CH:4]=2)[C:9]1=[O:16]
Reactant: C#Cc1ccccc1
Reactant: CN1C(=O)N(c2ccc(Br)nc2)CC1(C)C
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2ccc(C#Cc3ccccc3)nc2)CC1(C)C
Temperature: 90 °C
Reaction time: 4 h
Yield: 60.4 %

Procedure:
Bis-(triphenylphosphine)-palladium(II)dichloride (6 mg, 8.5 μmol, 0.03 equiv.) was dissolved in 1 ml DMF. (80 mg, 282 μmol) 1-(6-Bromo-pyridin-3-yl)-3,4,4-trimethyl-imidazolidin-2-one (E ample 3, step 2) and phenylacetylene (58 mg, 563 μmol, 2 equiv.) were added at room temperature. Triethylamine (118 μl 0.845 mmol, 3 equiv.), triphenylphosphine (4.4 mg, 16.9 μmol, 0.06 equiv.) and copper(I)iodide (1.6 mg, 8.45 μmol, 0.03 equiv.) were added and the mixture was stirred for 4 hours at 90° C. The reaction mixture was evaporated to dryness with Isolute® and the crude product was purified by flash chromatography by directly loading the solid onto a silica gel column and eluting with an ethyl acetate: heptane gradient 0:100 to 100:0. The desired 3,4,4-trimethyl-1-(6-phenylethynyl-pyridin-3-yl)-imidazolidin-2-one (52 mg, 61% yield) was obtained as a yellow solid, MS: m/e=306.2 (M+H+).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH3:13])([CH3:12])[CH:9]3O[CH:8]3[C:7]=2[CH:15]=1)#[N:2].[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1)#[N:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[C:16]([C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]([C:8]2[C:7]3[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:11][C:10]([CH3:13])([CH3:12])[CH:9]=2)[CH:19]=1)#[N:17]
Reactant: N#Cc1c[nH]c2ccccc12
Reactant: CC1(C)Oc2ccc(C#N)cc2C2OC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(C)C=C(n2cc(C#N)c3ccccc32)c2cc(C#N)ccc2O1
Temperature: 100 °C
Yield: 59.4 %

Procedure:
The reaction mixture containing 6-cyano-3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-benzopyran (1.5 g, 7.5 mmol) (prepared according to Evans et al., J. Med. Chem., 1983, 26, 1582 and J. Med. Chem., 1986, 29, 2194), 3-cyanoindole (1.46 g, 9.75 mmol) and finely ground potassium carbonate (2.6 g, 18.75 mmol) in dimethylformamide (5.0 mL) was heated at 100° C. for three hours. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and filtered. The filtrate was washed with water, 1N hydrochloric acid, sodium bicarbonate solution and brine. After drying over anhydrous magnesium sulfate, the solvent was evaporated to yield a colorless solid. This material was purified by flash chromatography (20% ethyl acetate in hexanes) to yield 4-(3-cyano-1H-indol-1-yl)-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1.45 g) as a colorless solid, m.p. 192°-193° C. (dichloromethaneisopropyl ether): 1H NMR (CDCl3) δ 7.72 (m, 1 H), 7.6 (s, 1 H), 7.40 (dd, J=8.2 and 1.8 Hz, 1 H), 7.25 (m, 2 H), 7.1 (m, 1 H), 6.90 (d, J=8.7 Hz, 1 H), 6.70 (d, J=2.3 Hz, 1 H), 5.88 (s, 1 H), 1.55 (s, 6 H); 13C NMR (CDCl3) 156.8, 135.6, 135.3, 134.9, 134.4, 129.9, 129.5, 127.3, 126.6, 124.8, 123.0, 120.1, 119.0, 118.2, 114.8, 111.3, 104.5, 88.7, 78.6, 27.9 ppm.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.Cl[C:36]([O:38][CH:39]1[CH:44]([CH:45]([CH3:47])[CH3:46])[CH2:43][CH2:42][CH:41]([CH3:48])[CH2:40]1)=[O:37]>CN(C=O)C>[CH:45]([CH:44]1[CH2:43][CH2:42][CH:41]([CH3:48])[CH2:40][CH:39]1[O:38][C:36]([N:25]1[CH2:26][CH2:27][CH:22]([O:21][C:16]2[C:17]([N+:18]([O-:20])=[O:19])=[C:12]([NH:11][C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)[N:13]=[CH:14][N:15]=2)[CH2:23][CH2:24]1)=[O:37])([CH3:46])[CH3:47]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: CC1CCC(C(C)C)C(OC(=O)Cl)C1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1CCC(C(C)C)C(OC(=O)N2CCC(Oc3ncnc(Nc4ccc(S(C)(=O)=O)cc4)c3[N+](=O)[O-])CC2)C1

Procedure:
Compound A23 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Comound A2) (15 mg, 0.035 mmol), triethylamine (501 μl), menthyl chloroformate (10 mg, 0.046 mmol), DMF (0.6 mL), 1H NMR (CDCl3, 400 MHz) δ 0.81 (d, 3H), 0.92 (d, 6H), 1.06 (m, 1H), 1.10 (m, 1H), 1.41 (m, 1H), 1.51 (m, 1H), 1.67 (m,2H), 1.94 (m, 4H), 2.08 (m, 2H), 3.08 (s, 3H), 3.65 (m, 4H), 4.58 (m, 1H), 5.60 (m, 1H), 7.86 (d, 2H), 7.97 (d, 2H), 8.41 (s, 1H), 10.18 (s, 1H). Exact mass calculated for C27H37N5O7S 575.24, found 576.4 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.[C:13]1([S:19]([O:22][C@@H:23]([CH3:27])[C:24](Cl)=[O:25])(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:24](=[O:25])[C@@H:23]([O:22][S:19]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)(=[O:21])=[O:20])[CH3:27])[CH:7]=[CH:6]2
Reactant: COc1ccc2ccccc2c1
Reactant: C[C@H](OS(=O)(=O)c1ccccc1)C(=O)Cl
Product: COc1ccc2cc(C(=O)[C@H](C)OS(=O)(=O)c3ccccc3)ccc2c1

Procedure:
In the same manner as described in Example 10 but using β-methoxynaphthalene and (S)-2-(benzenesulfonyloxy)-propionyl chloride, (S)-1-(6-methoxy-2-naphthyl)-2-benzenesulfonyloxy-1-propanone was obtained as colorless crystals.
Reaction SMILES: [CH2:1]([N:3]([C:31](=O)[C:32]1[CH:37]=[CH:36][C:35]([OH:38])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH: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].Cl[CH2:42][C:43]([N:45]([CH2:47][CH:48]([CH3:50])[CH3:49])[CH3:46])=O>>[CH2:1]([N:3]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([O:38][CH2:42][CH2:43][N:45]([CH2:47][CH:48]([CH3:50])[CH3:49])[CH3:46])=[C:34]([F:39])[CH:33]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CC(C)CN(C)C(=O)CCl
Reactant: CCN(C(=O)c1ccc(O)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Product: CCN(Cc1ccc(OCCN(C)CC(C)C)c(F)c1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 7.7 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(3-fluoro-4-hydroxybenzoyl)amino]-4,5-dimethoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 2-chloro-N-isobutyl-N-methylacetamide (12 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (1.5 mg) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][CH:12]=C)[C:6]=2[CH:14]=1.I([O-])(=O)(=O)=[O:16].[Na+]>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8](=[O:10])[N:7]([CH2:11][CH:12]=[O:16])[C:6]=2[CH:14]=1
Reactant: C=CCn1c(=O)sc2ccc(Cl)cc21
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: O=CCn1c(=O)sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5-chloro-3-(2-propen-1-yl)-1,3-benzothiazol-2(3H)-one (0.43 g, 1.9 mmol) (0.43 g, 1.9 mmole) was dissolved in 1,4-dioxane (20 ml) and water (22 ml) was added. Sodium periodate (0.94 g, 4.4 mmol) was added followed by 4% osmium tetroxide in water (2.1 ml) and stirred at rt for 30 mins after which time a heavy precipitate had formed. Water (20 ml) was added followed by more sodium periodate (1.9 g, 8.9 mmol) and the mixture stirred at rt for 18 h. The mixture was concentrated in-vacuo to a small volume and partitioned between water (50 ml) and DCM (2×50 ml). The organics were separated and dried. Chromatography on silica gel eluting with a gradient of 25-100% ethyl acetate/40-60 petroleum ether gave 0.21 g, 48%) of the title compound.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18](/[CH:21]=[CH:22]\[CH3:23])=[C:17]([C:24]([F:27])([F:26])[F:25])[CH:16]=2)=[O:13])=[CH:4][CH:3]=1.[H][H]>CO.[Pt]>[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[CH:31]=[CH:30][CH:29]=[CH:28][C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH3:23])=[C:17]([C:24]([F:25])([F:26])[F:27])[CH:16]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: C/C=C\c1ccc(NC(=O)c2ccccc2NCc2ccncc2)cc1C(F)(F)F
Reactant: [H][H]
Agent: [Pt]
Agent: Cl
Solvent: CO
Product: CCCc1ccc(NC(=O)c2ccccc2NCc2ccncc2)cc1C(F)(F)F

Procedure:
A solution of 2-[4-pyridinylmethyl]amino-N-[4-[(Z)-1-propenyl]-3-(trifluoromethyl)phenyl]benzamide (Example 8; 0.80 g, 1.75 mmol) in methanol (25 mL) is hydrogenated at atmospheric pressure over 5% platinum on carbon (0.2 g) at 22° C. The calculated amount of hydrogen is taken up after 12 hours. The mixture is then filtered and the solvent is evaporated under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent 20% dichloromethane in EtOAc and recrystallised from diethylether-hexane to give the title compound as a colourless crystalline solid; m.p. 134–135° C.
Reaction SMILES: ON1C2C=CC=CC=2N=N1.[Cl:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[C:21]([O:23][CH3:24])=[O:22])[C:15]([OH:17])=O.[C:25]1([C@H:35]([NH2:37])[CH3:36])[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1>CN(C)C=O>[CH3:24][O:23][C:21](=[O:22])[C:20]1[CH:19]=[CH:18][C:14]([C:15]([NH:37][C@@H:35]([C:25]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]=[CH:27][CH:26]=2)[CH3:36])=[O:17])=[CH:13][C:12]=1[Cl:11]
Reactant: COC(=O)c1ccc(C(=O)O)cc1Cl
Reactant: C[C@@H](N)c1cccc2ccccc12
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)N[C@H](C)c2cccc3ccccc23)cc1Cl
Temperature: 25 °C
Reaction time: 6 h
Yield: 116.2 %

Procedure:
N,N-dicyclohexylcarbodiimide (5.12 g, 24.84 mmol) and 1-hydroxybenzotriazole (3.08 g, 24.84 mol) were added to a solution of 3-chloro-4-(methoxycarbonyl)benzoic acid (Example 72; 5.0 g, 23.7 mmol) and (R)-(+)-1-(naphthalen-1-yl)ethylamine (3.45 g, 20.7 mmol) in N,N-dimethylformamide (10 mL). The solution was stirred for 6 h at room temperature, then after the volatiles were removed in vacuo, the residual material was partitioned between ethyl acetate and water. The separated aqueous phase was extracted with three portions of ethyl acetate , then the combined ethyl acetate layers were washed with brine, dried (Na2SO4) and evaporated under reduced pressure. The resulting colorless solid was crystallized from dichloromethane/hexane to yield 8.85 g of (R)-2-chloro-4-[[1-(naphthalen-1-yl)ethylamino]carbonyl]benzoic acid methyl ester (over theory; material 94% pure by analytical HPLC).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:36][CH2:35][C:34]1=[O:37]>>[O:37]=[C:34]1[CH2:35][CH2:36][N:33]1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[CH2:26][NH:25][C:22]([C:10]1[N:11]=[C:12]2[N:17]([C:18](=[O:19])[C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:16][CH2:15][O:14][C:13]2([CH3:21])[CH3:20])=[O:23]
Reactant: NCc1ccccc1N1CCC1=O
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Product: CC1(C)OCCn2c1nc(C(=O)NCc1ccccc1N1CCC1=O)c(OCc1ccccc1)c2=O

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and 1-(2-(aminomethyl)phenyl)azetidin-2-one, derived from reduction of intermediate 115, 2-(2-oxoazetidin-1-yl)benzonitrile. 1H NMR (400 MHz, CDCl3) δ ppm: 8.67 (1H, brt, J=6.3 Hz), 7.60 (1H, dd, J=1.3, 7.6 Hz), 7.53-7.50 (1H, dd, m), 7.34-7.24 (5H, m), 7.18 (1H, ddd(dt), J=1.2, 7.4 Hz), 7.10 (1H, dd, J=1.2, 8.0 Hz), 5.27 (2H, s), 4.60 (2H, d, J=6.3 Hz), 4.01-3.95 (4H, m), 3.71 (2H, t, J=4.5 Hz), 3.10 (2H, t, J=4.5 Hz), 1.60 (6H, s); LCMS (+ESI, M+H+) m/z 489.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[C:23](=O)([O-:25])[NH2:24].C(N(CC)C(C)C)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:23](=[O:25])[NH2:24])[CH:20]=[CH:21][CH:22]=1
Reactant: NC(=O)[O-]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(N)=O)c3)c2cc1OC
Yield: 45 %

Procedure:
Using the procedure described in Example 113C, 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (104 mg, 0.35 mmol) and the carbamate from the previous step (124 mg, 0.45 mmol) were reacted in the presence of N,N-diisopropylethylamine (73 μl, 0.42 mmol) to give 143-cyclopentylisoxazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (75.22 mg, 45%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.05 (s, 1H), 8.56 (s, 1H) 7.57 (s, 2H), 7.56-7.39 (t, 2H) 7.29 (d, 1H), 6.98 (d, 1H), 5.95 (s, 1H), 4.00 (s, 6H), 3.04-3.01 (m, 1H), 1.99-1.93 (m, 2H), 1.69-1.61 (m, 6H)); LC-MS (ESI) m/z 476 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH:15]=O)=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2].[CH3:29][NH:30][CH3:31]>>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[C:8]2[C:13]([C:14]=1[CH2:15][N:30]([CH3:31])[CH3:29])=[CH:12][C:11]([F:17])=[CH:10][CH:9]=2)=[O:5])[CH3:2]
Reactant: CNC
Reactant: CCOC(=O)c1c(C=O)c2cc(F)ccc2n1Cc1cccc2ccccc12
Product: CCOC(=O)c1c(CN(C)C)c2cc(F)ccc2n1Cc1cccc2ccccc12

Procedure:
5-Fluoro-3-formyl-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester (from Example 76.1.) was reacted with dimethyl amine as described in Example 86.1. to give 3-dimethylaminomethyl-5-fluoro-1-naphthalen-1-ylmethyl-1H-indole-2-carboxylic acid ethyl ester which was hydrolyzed as described in the general procedure B (Exp. 2.2) to give the title compound as a colorless solid. MS: 375.5 ([M−H]−).