Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].[NH2:11][CH:12]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[N:14]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13]1=[O:29]>C(O)C>[C:6]([CH:4]([CH:2]([C:1]([OH:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[NH2:11][C@H:12]1[CH2:18][CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[N:14]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:13]1=[O:29]
Reactant: CCOC(=O)CN1C(=O)C(N)CCc2ccccc21
Agent: O=C(O)C(O)C(O)C(=O)O
Solvent: CCO
Product: CCOC(=O)CN1C(=O)[C@@H](N)CCc2ccccc21
Reaction time: 8 h

Procedure:
Tartaric acid (12.6 g) and racemic 3-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (22 g) were dissolved in hot ethanol (200 ml). This solution was cooled and allowed to stand overnight at room temperature. The solid which precepitated was collected by filtration and recrystallized twice from ethanol (200 ml) to give 3-(S)-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one tartrate salt. This was dissolved in H2O (100 ml) and the pH adjusted to 9 with dilute ammonium hydroxide and extracted with methylene chloride (2×50 ml). The combined extracts were washed with water (75 ml), dried (magnesium sulfate) and evaporated to give 3-(S)-amino-1-ethoxycarbonylmethyl-2,3,4,5-tetrahydro-1H -[1]benzazepin-2-one, m.p. 104°-106°, [α]D =-285.5° (c=0.99 in ethanol).
Reaction SMILES: [C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[C@@H:4](O)[C@H:2]1O.P(OCC)(OCC)OCC.[C@@H]1(N2C3N=CN=C(O)C=3N=C2)O[C@H](CO)C=C1>>[C@@H:1]1([N:10]2[C:19]3[N:18]=[CH:17][N:16]=[C:14]([OH:15])[C:13]=3[N:12]=[CH:11]2)[O:9][C@H:6]([CH2:7][OH:8])[CH2:4][CH2:2]1
Reactant: OC[C@H]1O[C@@H](n2cnc3c(O)ncnc32)[C@H](O)[C@@H]1O
Agent: CCOP(OCC)OCC
Agent: OC[C@@H]1C=C[C@H](n2cnc3c(O)ncnc32)O1
Product: OC[C@@H]1CC[C@H](n2cnc3c(O)ncnc32)O1
Yield: 78 %

Procedure:
FIG. 3 is an illustration of Scheme 2 according to the present invention for the synthesis of 2',3'-dideoxyinosine In the case of inosine, the dialkyl xanthate (19) was prepared using β-bromopropionitrile instead of methyl iodide in order to avoid N-methylation as observed in uridine when methyl iodide was employed as the alkylating agent (Scheme 5). The 5'-O-t-butyldimethylsilyl inosine 18 was treated with carbon disulfide in the presence of sodium hydroxide and alkylated in situ with bromopropionitrile to obtain 19 in 61% yield after silica gel chromatography. No nitrogen alkylated product was observed. Even if the alkylation at nitrogen did occur, the cyanoethyl group would be eliminated under the basic conditions used. The dialkyl xanthate 19 was found to undergo facile deoxygenation with tributyltin hydride to give 2',3'-unsaturated nucleoside 21 in 85% yield. The unsaturated inosine derivative 21 was also obtained, although in lower yield (39%), from the thionocarbonate 20 by deoxygenation with triethyl phosphite 5'-Desilylation of 21 to 2',3'-didehydro-2',3'-dideoxyinosine (8) followed by catalytic reduction gave the 2',3'-dideoxyinosine (11) in 78% yield.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1>C1COCC1>[C:1]1([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Clc1ccc2ccccc2n1
Solvent: C1CCOC1
Product: c1ccc(-c2ccc3ccccc3n2)cc1
Reaction time: 0.83 h
Yield: 70.6 %

Procedure:
A solution of phenylmagnesium bromide (1M in THF, 4.2 mL, 4.2 mmol) is added to a solution of 2-chloro-quinoline (300 mg, 1.83 mmol)) and Fe(acac)3 (32 mg, 0.09 mmol) in THF (10 mL) at −30° C. After stirring for 50 min at that temperature, the reaction is quenched with brine, the aqueous layer is extracted with Et2O, the combined organic phases are dried over Na2SO4 and evaporated, and the residue is purified by flash chromatography (hexane/ethyl acetate, 15:1). After eluting a first fraction containing biphenyl (44 mg), one obtains 2-phenyl-quinoline as a colorless solid (265 mg, 71%). 1H NMR (300 MHz, CD2Cl2) δ8.22–8.25 (m, 3H), 8.16 (d, 1H), 7.92 (d, 1H), 7.86 (d, 1H), 7.75 (m, 1H), 7.46–7.57 (m, 4H); 13C NMR (75 MHz, CD2Cl2) δ 157.3, 148.7, 139.9, 137.0, 130.0, 129.7, 129.1, 127.8, 127.7, 127.6, 127.3, 126.8, 119.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:30][C:11]3=[N:12][CH:13]=[C:14]([Cl:29])[C:15]([C:16]4[S:20][C:19]([C:21]5([O:25]COC)[CH2:24][CH2:23][CH2:22]5)=[N:18][CH:17]=4)=[C:10]3[CH:9]=2)[CH:5]=[CH:4][C:3]=1[NH:31][C:32](=[O:37])[CH2:33][N:34]([CH3:36])[CH3:35].ClC1C(C2SC(C3(OCOC)CCC3)=NC=2)=C2C=C(C3N=C(C4CCCN(C(OC(C)(C)C)=O)C4)ON=3)NC2=NC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:30][C:11]3=[N:12][CH:13]=[C:14]([Cl:29])[C:15]([C:16]4[S:20][C:19]([C:21]5([OH:25])[CH2:24][CH2:23][CH2:22]5)=[N:18][CH:17]=4)=[C:10]3[CH:9]=2)[CH:5]=[CH:4][C:3]=1[NH:31][C:32](=[O:37])[CH2:33][N:34]([CH3:35])[CH3:36]
Reactant: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5ccc(NC(=O)CN(C)C)c(Cl)c5)cc34)s2)CCC1
Agent: COCOC1(c2ncc(-c3c(Cl)cnc4[nH]c(-c5noc(C6CCCN(C(=O)OC(C)(C)C)C6)n5)cc34)s2)CCC1
Product: CN(C)CC(=O)Nc1ccc(-c2cc3c(-c4cnc(C5(O)CCC5)s4)c(Cl)cnc3[nH]2)cc1Cl

Procedure:
The title compound was prepared as described in Example 22E, substituting N-(2-chloro-4-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)phenyl)-2-(dimethylamino)acetamide (Example 63D) for 1 tert-butyl 3-(3-(5-chloro-4-(2-(1-(methoxymethoxy)cyclobutyl)thiazol-5-yl)-1H-pyrrolo[2,3-b]pyridin-2-yl)-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate (Example 22D). 1H NMR (400 MHz, DMSO-d6) ppm 12.59 (s, 1H) 9.86 (s, 1H) 8.33 (s, 1H) 8.29 (s, 1H) 8.27 (s, 1H) 8.26 (d, 1H) 8.00 (dd, 1H) 7.17 (s, 1H) 6.69 (s, 1H) 3.15 (s, 2H) 2.63 (m, 2H) 2.42 (m, 2H) 2.36 (s, 6H) 1.99 (m, 2H); MS ESI(+) m/z 516.1 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]([CH:5]1[CH2:10][CH2:9][N:8]([O:11][CH3:12])[CH2:7][CH2:6]1)[C:3]#[N:4].CCN(CC)CC.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[C:22]=1[CH2:29][C:30](Cl)=[O:31].O>C1COCC1>[C:3]([CH:2]([CH:5]1[CH2:6][CH2:7][N:8]([O:11][CH3:12])[CH2:9][CH2:10]1)[NH:1][C:30](=[O:31])[CH2:29][C:22]1[C:21]([CH3:20])=[CH:26][C:25]([CH3:27])=[CH:24][C:23]=1[CH3:28])#[N:4]
Reactant: CON1CCC(C(N)C#N)CC1
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CON1CCC(C(C#N)NC(=O)Cc2c(C)cc(C)cc2C)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred mixture of amino-(1-methoxy-piperidin-4-yl)-acetonitrile (500 mg, 2.95 mmol) and Et3N (610 mg, 6.02 mmol) in THF (15 ml), was added (2,4,6-trimethyl-phenyl)-acetyl chloride (581 mg, 2.95 mmol). After the addition, the mixture was stirred at room temperature for 0.5 h. Then, the mixture was poured into water (100 ml) and extracted with CH2Cl2 (3×50 ml). The combined organic layers were dried over Na2SO4, filtered and evaporated under vacuum. The residue was purified by chromatography on silica gel. Yield: 700 mg of N-[cyano-(1-methoxy-piperidin-4-yl)-methyl]-2-(2,4,6-trimethyl-phenyl)-acetamide as a solid.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][O:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23].[C:25](Cl)([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)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:18]([O:19][CH2:20][CH:21]([CH2:22][O:23][C:25]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)([C:38]1[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[OH:24])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCCCOCC(O)CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCCCOCC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 70 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
51.69 Grams (150 mmol) of batylalcohol and 62.73 g (225 mmol) freshly recrystallized tritylchloride are dissolved at 35° C. in 350 ml methylene chloride. (Note: It is recommended that the tritylchloride be freshly recrystallized from halpasol, trademark for a petroleum ether fraction, b.p. 100°-120° C.). During 15 minutes, 22.77 g (225 mmol; 31.38 ml) triethylamine is added dropwise to the stirred solution at 30°-35° C. (cooling with a water bath). The reaction is continued for six hours at ambient temperature. (Note: It is recommended that a control TLC be done to make sure that the reaction is complete). The solution is then washed with 300 ml of a NaHCO3 solution (1%), dried over anhydrous sodium sulfate, filtered and evaporated under vacuum. The oily residue (155 g) is dissolved in 660 ml acetonitrile by warming up to 70° C. with stirring. After cooling to room temperature the title product crystallizes (preferentially after adding a few seed crystals). Crystallization is completed by standing overnight at ambient temperature. The crystallizate is filtered off to yield 82.5 g (93.7%) of crude product (m.p. 53°-55° C.) which can be used for the following step without purification. Recrystallization from halpasol (310 ml) yields 71 g (80%) of pure tritylbatylalcohol. B. In a similar way, introduction of the 3-O-trityl function is accomplished for each 1-O-R-glycerol of Example 2-B.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](NCC)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[NH2:45][C:46]1[CH:59]=[CH:58][C:49]([C:50]([NH:52][N:53]2[CH2:57][CH2:56][CH2:55][CH2:54]2)=[O:51])=[CH:48][CH:47]=1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26](=[O:27])[NH:45][C:46]4[CH:59]=[CH:58][C:49]([C:50]([NH:52][N:53]5[CH2:54][CH2:55][CH2:56][CH2:57]5)=[O:51])=[CH:48][CH:47]=4)=[CH:23][CH:24]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: Nc1ccc(C(=O)NN2CCCC2)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(C(=O)NN5CCCC5)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-amino-N-(pyrrolidin-1-yl)benzamide as the aniline component. (8%, MS=582.3 (M+H))
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[C:30]1([CH2:36][CH:37]=O)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C(Cl)Cl>[CH2:37]([N:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]3[C:15]([C:20]4[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=4)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:13])[CH:6]=2)[CH2:1]1)[CH2:36][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: O=C(Nc1ccc2c(c1)CCNC2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=CCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: O=C(Nc1ccc2c(c1)CCN(CCc1ccccc1)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1

Procedure:
A 400 mg (1.01 mmole) sample of compound (II), phenylacetaldehyde (121 mg, 1.01 mmole), sodium triacetoxyborohydride (320 mg, 1.52 mmole) and acetic acid (61 mg, 1.01 mmole) were stirred in 10 mL of 1,2-dichloroethane for 12 hrs. at ambient temperature. The reaction was diluted with methylene chloride, washed with 1N NaOH, water and brine. Purification was carried out with silica gel chromatography using 50% ethyl acetate/hexanes as the eluent.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=O)[CH3:10])=[CH:4][CH:3]=1.[OH:12][CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=1)[CH2:14][NH2:15].O>C1C=CC=CC=1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:15][CH2:14][CH:13]([OH:12])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=2)[CH3:10])=[CH:4][CH:3]=1
Reactant: NCC(O)c1cccc(Cl)c1
Reactant: CC(=O)Cc1ccc(O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC(Cc1ccc(O)cc1)NCC(O)c1cccc(Cl)c1
Reaction time: 0.67 h

Procedure:
A mixture of 1-(4-hydroxyphenyl)propan-2-one (4.6 g) and 2-hydroxy-2-(3-chlorophenyl)ethanamine (5.2 g) in dry benzene (150 ml) was heated under reflux using a Dean and Stark head until the required amount of water had been collected. The solution was cooled, the solvent evaporated, the residue dissolved in methanol (20 ml), cooled in ice and treated portionwise with sodium borohyride (6.1 g) over 30 minutes. The mixture was stirred for 40 minutes, and the solvent removed under reduced pressure. Water was added to the residue and the mixture adjusted to pH 5 by addition of acetic acid followed by extraction with ethyl acetate. The extracts were washed with water, aqueous sodium bicarbonate and brine, dried (magnesium sulphate), filtered and evaporated to dryness. Chromatography of the residue on silica gel in 5% methanoldichloromethane gave N-[2-(4-hydroxyphenyl)-1-methylethyl]-2-hydroxy-2-(3-chlorophenyl)ethanamine mp 50°-5° C., of analytical purity as a 53:47 mixture of diastereoisomers.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[CH2:9][S:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[OH:19]O.CSC>C(O)(=O)C>[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:18])[CH2:9][S:10]([C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)=[O:19]
Reactant: OO
Reactant: O=C(CSc1ccc(O)cc1)c1ccccc1O
Solvent: CSC
Solvent: CC(=O)O
Product: O=C(CS(=O)c1ccc(O)cc1)c1ccccc1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 71 %

Procedure:
6.0 g (23.1 mmol) of 2′-hydroxy-2-(4-hydroxyphenylthio) acetophenone and 50 mL of acetic acid were added under a room temperature into a 100 mL flask with four inlets and attached with a stirrer and a thermometer. To the resultant solution, 2.8 g (24.7 mmol) of 30% aqueous solution of hydrogen peroxide was added, and the solution was stirred for 12 hours at a room temperature. Following to the completion of the reaction, 0.5 g of dimethyl sulfide was added into the solution, and then, the solution was extracted with MIBK. The MIBK layer was washed several times with water, and followed by washing with sodium hydrogencarbonate. The MIBK in the solution was distilled out under reduced pressure, and the resultant residue was subjected to recrystallization with ethyl acetate to obtain 4.5 g of 2′-hydroxy-2-(4-hydroxyphenylsulfinyl) acetophenone. The yield was 71% and the melting point of the compound was in a range of 166 to 167° C.
Reaction SMILES: C1C=C(O[C:8](OC2N=CC=CC=2)=[S:9])N=CC=1.[NH2:17][C:18]1[C:27]([CH3:28])=[C:26]2[C:21]([CH:22]=[CH:23][CH:24]=[N:25]2)=[C:20]([C:29]#[N:30])[CH:19]=1>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:29]([C:20]1[CH:19]=[C:18]([N:17]=[C:8]=[S:9])[C:27]([CH3:28])=[C:26]2[C:21]=1[CH:22]=[CH:23][CH:24]=[N:25]2)#[N:30]
Reactant: Cc1c(N)cc(C#N)c2cccnc12
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1c(N=C=S)cc(C#N)c2cccnc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of di-2-pyridyl thionocarbonate (1.22 g) and 4-dimethylaminopyridine (0.08 g) in methylene chloride (60 mL) is added dropwise a solution of 7-amino-5-cyano-8-methylquinoline (1.22 g) in methylene chloride (80 mL). The mixture is stirred for 4 hours at room temperature then rotary evaporated. The residue is purified by flash chromatography on silica gel, eluting with 25% ethyl acetate/hexane to afford 5-cyano-8-methyl-7-quinolinylisothiocyanate as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[I:14].CO>C1COCC1>[NH2:7][CH2:6][C:5]1[CH:8]=[C:9]([C:10]([F:12])([F:13])[F:11])[C:2]([NH2:1])=[C:3]([I:14])[CH:4]=1
Reactant: N#Cc1cc(I)c(N)c(C(F)(F)F)c1
Solvent: C1CCOC1
Solvent: CO
Product: NCc1cc(I)c(N)c(C(F)(F)F)c1
Reaction time: 12 h
Yield: 3.4 %

Procedure:
4-Amino-3-iodo-5-trifluoromethylbenzonitrile (1805.2 mg, 5.19 mmol) was dissolved in THF at 0° C. After Borane-THF complex (3 eq, 17.36 mmol, 17.36 ml) was slowly added into the reaction mixture, A reaction temperature was heated to reflux. The reaction mixture was stirred for 12 hr with reflux. After confirming the completion of the reaction, MeOH was added. The mixture was stirred for 4 hr. The reaction solvent was removed in vacuo. A residue was extracted with Ethyl acetate, washed with H2O and brine, dried with Na2SO4 and concentrated in vacuo to yield 4-Aminomethyl-2-iodo-6-trifluoromethylphenylamine (55.1 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:25])[CH2:11][CH:12]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:6][CH:5]=1)([O-])=O>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([C:10](=[O:25])[CH2:11][CH:12]([CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:8][CH:9]=1
Reactant: CCOC(=O)CCC(CC(=O)c1ccc([N+](=O)[O-])cc1)C(=O)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC(CC(=O)c1ccc(N)cc1)C(=O)OCC
Yield: 79.3 %

Procedure:
A solution of diethyl (RS)-2-(2-(4-nitrophenyl)-2-oxoethyl)glutarate (1.48 g, 4.2 mmol) and 10% palladium on carbon (0.23 g) in ethanol (100 ml) was shaken under hydrogen (30-35 psi) for 40 minutes. The catalyst was filtered off and the filtrate concentrated in vacuo. Purification by chromatography on silica gel eluting with ethyl acetate:hexane (1:1) gave diethyl (RS)-2-(2-(4-aminophenyl)-2-oxoethyl)glutarate (1.07 g) as an oil that solidified on standing. M.P. 58°-61° C. 1H NMR (DMSO-d6), 200 MHz) δ: 1.13 (t, J=7 Hz, 3H, CH3), 1.16 (t, J=7 Hz, 3H, CH3), 1.67-1.87 (m, 2H, CH2), 2.28-2.40 (m, 2H, CH2CO2), 2.72-2.88 (m, 1H, CH), 2.99 (ABX, apparent JAB =17.5 Hz, JAX =4.5 Hz, 1H, COCH--H), 3.19 (ABX, apparent JAB =17.5 Hz, JBX =9.5 Hz, 1H, COCH--H), 4.00 (q, J=7 Hz, 2H, ester CH2), 4.03 (q, J=7 Hz, 2H, ester CH2), 6.04 (br s, 2H, NH2), 6.53 (d, J=9 Hz, 2H, Ar), 7.66 (d, J=9 Hz, 2H Ar). Mass spectrum (CI-CH4): 322 (M+1, 94.4%), 276 (100%). Anal. Calculated for C17H23NO5.0.15 H2O: C, 63.01; H, 7.25; N, 4.32. Found: C, 62.98; H, 7.24; N, 4.28.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[CH:20][C:21]([C:23]3[S:24][C:25]([N:33]([CH3:43])[CH2:34][CH2:35][O:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[C:26]([C:28]([O:30]CC)=[O:29])[N:27]=3)=[CH:22][C:14]1=2)=[O:12].[OH-].[K+].CO>O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([N:13]1[CH2:18][CH2:17][O:16][C:15]2[CH:19]=[CH:20][C:21]([C:23]3[S:24][C:25]([N:33]([CH3:43])[CH2:34][CH2:35][O:36][C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=3)=[CH:22][C:14]1=2)=[O:12]
Reactant: CCOC(=O)c1nc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCO3)sc1N(C)CCOc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(CCOc1ccccc1)c1sc(-c2ccc3c(c2)N(C(=O)Nc2nc4ccccc4s2)CCO3)nc1C(=O)O
Temperature: 55 °C
Reaction time: 24 h
Yield: 7.5 %

Procedure:
The title compound 2-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(methyl(2-phenoxyethyl)amino)thiazole-4-carboxylic acid (20) was prepared by the following procedure: To ethyl 2-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(methyl(2-phenoxyethyl)amino)thiazole-4-carboxylate (20C) (0.210 g, 0.34 mmol) and KOH (0.1 g, 1.8 mmol) was added MeOH (2 mL) and water (5 mL). The reaction mixture was allowed to heat to 55° C. and stirred 24 hours. The reaction was monitored by LCMS. To the reaction mixture was added (0.1 g, 1.8 mmol). The reaction mixture was allowed to heat to 55° C. and stirred for 24 hours. The reaction mixture was cooled to rt and concentrated under reduced pressure. To the crude residue was added EtOAc and water. The layers were separated and extracted with EtOAc and the combined organic extracts were washed sequentially with water, brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude residue was purified by reverse phase HPLC to provide 0.015 g (8%) of the desired product 2-(4-(benzo[d]thiazol-2-ylcarbamoyl)-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-(methyl(2-phenoxyethyl)amino)thiazole-4-carboxylic acid (20): LC/MS (APCI): m/z 588.1 (M+H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[OH:22]>>[OH:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1
Reactant: Oc1ccccc1I
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Product: COC(=O)CCc1ccc(C#Cc2ccccc2O)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (102 mg, 0.53 mmol) and 2-iodophenol (130 mg, 0.58 mmol) according to the general procedure IF to give 19 mg (13%) of a white solid after purification by flash chromatography (SiO2, EtOAc:PE, 1:10). Rf=0.28 (EtOAc:PE, 1:5); 1H NMR (CDCl3): δ 7.79 (dt, J=8.3 Hz, 2.0 Hz, 2H), 7.56 (d, J=1.0 Hz, 1H), 7.50 (d, J=1.0 Hz, 1H), 7.29-7.21 (m, 3H), 6.98 (d, J=1.0 Hz, 1H), 3.68 (s, 3H), 2.99 (t, J=7.8 Hz, 2H), 2.60 (t, J=7.8 Hz, 2H); 13C NMR (CDCl3): δ 173.2, 155.9, 154.8, 141.1, 129.3, 128.7, 128.8, 125.1, 124.1, 122.9, 120.9, 111.1, 100.9, 51.6, 35.5, 30.7; ESI-MS m/z 303.1 (M+Na+).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28](=[O:43])[NH:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=1[CH2:38][CH:39]([OH:42])[CH2:40][CH3:41])([CH3:26])([CH3:25])[CH3:24]>C1COCC1>[C:23]([O:27][C:28](=[O:43])[NH:29][C:30]1[CH:35]=[C:34]([O:36][CH3:37])[CH:33]=[CH:32][C:31]=1[CH2:38][C:39](=[O:42])[CH2:40][CH3:41])([CH3:25])([CH3:24])[CH3:26]
Reactant: CCC(O)Cc1ccc(OC)cc1NC(=O)OC(C)(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: C1CCOC1
Product: CCC(=O)Cc1ccc(OC)cc1NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 83.2 %

Procedure:
To a solution of Dess-Martin reagent (2.82 g, 6.68 mmole) in 80 ml THF cooled at 0° C. was added [2-(2-hydroxy-butyl)-5-methoxy-phenyl]-carbamic acid t-butyl ester 73a (1.64 g, 5.57 mmole) in 20 ml THF. The reaction mixture was stirred and warmed to room temperature for 2 h, quenched with half saturated NaHCO3, extracted with EtOAc. The organic layer was dried over MgSO4 and concentrated. The residue was purified by flash column chromatography (10–15% EtOAc in hexane) to give colorless oil (1.36 g, 84%). 1H NMR (CDCl3) δ 7.67 (1H, bs), 7.48 (1H, s), 6.99–7.03 (1H, m), 6.56–6.60 (1H, m), 3.79 (3H, s), 3.59 (2H, s), 2.53–2.61 (2H, q, J=7.2 Hz), 1.51 (9H, s), 1.02 (3H, t, J=7.2 Hz). ESIMS (MNa+): 316.10.