Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[OH:18])[C:13]#[N:14].[CH:19]([O:21][CH2:22][CH3:23])=[CH2:20].O1CCCC1>C(N(CC)CC)C>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[O:18][CH:19]([O:21][CH2:22][CH3:23])[CH3:20])[C:13]#[N:14]
Reactant: COc1cc(C#N)ccc1O
Reactant: C=COCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCOC(C)Oc1ccc(C#N)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2 ml of trifluoroacetic acid was added slowly to a chilled solution of 20 g of 3-methoxy-4-hydroxybenzonitrile, 50.7 ml of ethyl vinyl ether and 50 ml tetrahydrofuran (THF). The mixture was stirred at room temperature overnight. 7.5 ml of triethylamine was added to the mixture and stirring was continued for several minutes until the solvent was evaporated. The residue was partitioned between 400 ml of diethyl ether and 100 ml 1N NaOH. The diethyl ether layer was washed successively with 100 ml H2O and 100 ml brine, dried over MgSO4 and evaporated to yield 31.2 gm of 3-methoxy-4-(2-ethoxy-1-oxapropyl)benzonitrile.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH2:10]([Li])[CH2:11][CH2:12]C.[CH:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1>[CH:11]([O:22][CH:9]([CH3:8])[CH3:4])([CH3:12])[CH3:10].[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[OH:22]
Reactant: c1ccc2scnc2c1
Reactant: O=Cc1ccccc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)OC(C)C
Product: OC(c1ccccc1)c1nc2ccccc2s1
Temperature: -20 °C
Reaction time: 0.25 h

Procedure:
A solution of benzothiazole (1.35 g) in tetrahydrofurane (10 mL) in a dried round bottom balloon is cooled at −70° C. A solution of butyl lithium (4.1 mL) is added and the mixture stirred for 15 minutes. Benzaldehyde (1.03 mL) diluted with tetrahydrofurane (10 mL) is then added. The mixture is stirred at −70° C. for 1 h, allowed to warm to −20° C. and quenched with saturated aqueous ammonium chloride solution. The mixture is extracted with ethyl acetate. Organic extracts are pooled, dried over magnesium sulfate and concentrated under reduced pressure. Trituration of the residue with diisopropyl oxide affords benzothiazol-2-ylphenylmethanol.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[CH3:21][C:22]1[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=1>>[Cl:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]([N:23]3[C:22]([CH3:21])=[CH:26][C:25]([CH3:27])=[N:24]3)[N:11]=2)=[CH:16][CH:15]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1nc(Cl)c2ccccc2n1
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)c3ccccc3n2)n1

Procedure:
Was prepared according to Method B from 2,4-dichloroquinazoline, 4-chloroaniline and 3,5-dimethylpyrazole. Mp. 209.3-211.2° C.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]=[C:4]([CH3:12])[C:3]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(O)C.[CH3:21][N:22]([CH3:27])[CH2:23][CH2:24][CH2:25][NH2:26]>C(N(CC)CC)C>[Cl:11][C:6]1[N:5]=[C:4]([CH3:12])[C:3]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:2]([NH:26][CH2:25][CH2:24][CH2:23][N:22]([CH3:27])[CH3:21])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: CN(C)CCCN
Reactant: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)c1c(C)nc(Cl)c([N+](=O)[O-])c1NCCCN(C)C
Reaction time: 0.17 h

Procedure:
139.5 g. of 4,6-dichloro-2-methyl-5-nitropyridine-3-carboxylic acid, ethyl ester (0.5 ml.) in 500 ml. of ethyl alcohol are heated at reflux temperature. 60 g. of triethylamine are added and then 51 g. of 3-(dimethylamino)propylamine are slowly dropped in with stirring. After the addition is completed, heating is continued for 10 minutes. The solvent is distilled off and the residue is treated with 200 ml. of water and made alkaline (pH 9-10) with sodium hydroxide. This mixture is extracted three times with 150 ml. portions of ether. The organic layers are combined, dried with calcium chloride and evaporated to dryness. The residue is recrystallized from methanol, yield 110 g. (64%); m.p. <20°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][OH:11].C([CH2:14][O:15]C=O)#N.[O:18]1CCC[CH2:19]1>>[CH:14]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][O:11][CH:19]=[O:18])=[O:15]
Reactant: N#CCOC=O
Reactant: COc1ccc(N)c(CO)c1
Reactant: C1CCOC1
Product: COc1ccc(NC=O)c(COC=O)c1
Temperature: 0 °C

Procedure:
A solution of 7.00 g of (2-amino-5-methoxyphenyl)methanol, 9.8 ml of formic acid cyanomethyl ester and 0.05 g of 4-N,N-(dimethylamino)pyridine in 30 ml of anhydrous tetrahydrofuran was heated for 5 hours under reflux. The solution was then concentrated by evaporation in vacuo and the residue was taken up in 100 ml of ethyl acetate. Crystals formed on cooling the solution to 0° C., which were suction filtered, washed with methanol, and dried in vacuo. 7.20 g (75% of theory) of the title compound were thereby obtained.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][C:12]([C:15]2[CH:16]=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=2)=[CH:11][C:10]=1[C:22]([OH:24])=O.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[CH3:39][O:40][C:41]1[CH:42]=[CH:43][C:44]([CH2:49][NH2:50])=[N:45][C:46]=1[O:47][CH3:48].CN1CCOCC1>CN(C)C=O>[CH3:39][O:40][C:41]1[CH:42]=[CH:43][C:44]([CH2:49][NH:50][C:22]([C:10]2[CH:11]=[C:12]([C:15]3[CH:16]=[N:17][CH:18]=[C:19]([CH3:21])[CH:20]=3)[CH:13]=[N:14][C:9]=2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])=[O:24])=[N:45][C:46]=1[O:47][CH3:48]
Reactant: COc1ccc(CN)nc1OC
Reactant: Cc1cncc(-c2cnc(-c3ccccc3F)c(C(=O)O)c2)c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: COc1ccc(CNC(=O)c2cc(-c3cncc(C)c3)cnc2-c2ccccc2F)nc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 6-(2-fluorophenyl)-5′-methyl-3,3′-bipyridine-5-carboxylic acid hydrochloride (3-4, 3.0 g, 8.70 mmol) in dimethylformamide (43 mL) cooled to 0° C., was added EDC (2.67 g, 13.92 mmol) and HOBt (2.13 g, 13.92 mmol) followed by 1-(5,6-dimethoxypyridin-2-yl)methanamine (11-6, 1.90 g, 11.31 mmol) and N-methylmorpholine (5.74 mL, 52.2 mmol). The reaction was allowed to warm to room temperature and stir overnight. The reaction mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organics were washed with water and brine, then stripped to dryness. The crude product was taken up in DMF/DMSO (30 mL, 1:1), filtered and purified via reverse phase chromatography (5→65% acetonitrile in water with 0.1% TFA buffer). The clean fractions were pooled, partitioned between ethyl acetate and 2M sodium carbonate. The organic layer was washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated to afford the title compound (3-5) as a white solid. 1H NMR (500 MHz, CDCl3) δ 8.99 (d, J=2.5 Hz, 1H), 8.74 (d, J=2 Hz, 1H) 8.53 (s, 1H), 8.34 (d, J=2.5 Hz, 1H), 7.77 (s, 1H), 7.66 (m, 1H), 7.31 (m, 1H), 7.21 (t, J=14.6 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.92 (t, J=18.3 Hz, 1H), 6.73 (d, J=7.8 Hz, 1H), 6.46 (m, 1H), 4.44 (d, J=5 Hz, 2H), 3.87 (s, 3H), 3.81(s, 3H), 2.45 (s, 3H). HRMS [M+H] C26H23FN4O3 calc'd 459.1827, found 459.1830.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH2:12]([Mg]Br)[CH2:13][CH3:14].[Cl-].[NH4+].C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>O1CCCC1.C(OC)(C)(C)C.CO>[Cl:1][C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][CH3:14])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: CNC(=O)c1ccc(Cl)nc1
Reactant: CCC[Mg]Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: CCCc1cc(Cl)ncc1C(=O)NC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 0.1 %

Procedure:
6-Chloro-N-methylnicotinamide (2.00 g, 11.7 mol) was dissolved in tetrahydrofuran (59 mL), added propylmagnesium bromide (46.9 mL, 46.9 mol) under ice-cold conditions, and stirred at room temperature for 4.5 hours. Then, propylmagnesium bromide (46.9 mL, 46.9 mol) was added under ice-cold conditions and the mixture was further stirred at room temperature for 9 hours. The reaction solution was added methanol (140 mL) and ammonium chloride (7.5 g) under ice-cold conditions, and stirred at room temperature for 0.5 hours. The reaction solution was added DDQ (3.19 g, 14.1 mmol) under ice-cold conditions, and stirred at room temperature for 2 hours. The reaction solution was added tert-butyl methylether, and filtered through a pad of celite, concentrated in vacuo, and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (chloroform/methanol). The title compound (1.88 g (yield 75%)) was obtained as a light brown crystal.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[F:13][C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=1)[O:17][CH:18]1[CH2:22][CH2:21][NH:20][CH2:19]1>>[Cl:12][C:9]1[CH:10]=[N:11][C:2]([N:20]2[CH2:21][CH2:22][CH:18]([O:17][C:16]3[CH:23]=[CH:24][CH:25]=[C:14]([F:13])[CH:15]=3)[CH2:19]2)=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc(Cl)cnc1Cl
Reactant: Fc1cccc(OC2CCNC2)c1
Product: COC(=O)c1cc(Cl)cnc1N1CCC(Oc2cccc(F)c2)C1
Yield: 60.9 %

Procedure:
The title compound (D95) (250 mg) was prepared according to the experimental procedure described in Description 62 starting from methyl 2,5-dichloronicotinate (241.37 mg, 1.17 mmol) and 3-(3-fluorophenoxy)pyrrolidine (D60) (253 mg, 1.39 mmol).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([CH2:6][CH2:7][NH:8][C:9](=[O:27])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][CH2:17]CCN2CCSCC2)=[C:12]([NH2:26])[CH:11]=1)=[O:5].C(O[CH2:32][CH3:33])(=O)C.[CH2:34](O)C>>[CH3:2][O:3][C:4]([CH:6]1[CH2:33][CH2:32][CH2:34][N:8]([C:9](=[O:27])[C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH3:17])=[C:12]([NH2:26])[CH:11]=2)[CH2:7]1)=[O:5]
Reactant: CCOC(C)=O
Reactant: CCO
Reactant: COC(=O)CCNC(=O)c1ccc(NCCCN2CCSCC2)c(N)c1
Agent: Cl
Product: CNc1ccc(C(=O)N2CCCC(C(=O)OC)C2)cc1N

Procedure:
The same procedure is used as in (2). Rf value: 0.48 (silica gel; ethyl acetate/ethanol=7:3)
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21]#[C:22][CH3:23].O.C1(C)C=CC(S(O)(=O)=[O:32])=CC=1.C(=O)([O-])O.[Na+]>C(#N)C>[NH2:1][C:2]1[N:6]([C:7]2[C:8]([Cl:18])=[CH:9][C:10]([C:14]([F:16])([F:15])[F:17])=[CH:11][C:12]=2[Cl:13])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[C:21](=[O:32])[CH2:22][CH3:23]
Reactant: CC#Cc1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CCC(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-(prop-1-ynyl)pyrazole (2.1 g) in acetonitrile (40 ml) was added p-toluenesulphonic acid monohydrate (292 g) and the mixture was stirred at room temperature for 1 hour. p-Toluenesulphonic acid monohydrate (1 g) was then added and stirring continued overnight. Acetonitrile (20 ml) was added p-toluenesulphonic acid monohydrate (1 g) were added and stirring continued for 1 hour and then the reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution (500 ml) and extracted twice with ether (100 ml). The organic layer was separated, washed with brine (100 ml), dried (Na2SO4) and evaporated. The residue was purified by column chromatography on silica gel (70 g) eluted with dichloromethane. Combination and evaporation of suitable fractions gave the title compound as a pale brown solid, m.p. 167-169° C.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]=C)=[O:5].[BH4-].[Na+].OCCCCCCCCCC(OCC)=O.P(Br)(Br)[Br:34]>>[Br:34][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:4]([O:3][CH2:2][CH3:1])=[O:5]
Reactant: BrP(Br)Br
Reactant: C=CCCCCCCCCC(=O)OCC
Agent: CCOC(=O)CCCCCCCCCO
Agent: [BH4-]
Agent: [Na+]
Product: CCOC(=O)CCCCCCCCCBr

Procedure:
The order of functionalization and esterification is not critical. For example, rather than performing an ozonolysis of the starting material, for example, 10-undecylenic acid, as described above, the starting material first may be esterified with ethanol or other alcohol to form an ester, for example, ethyl 10-undecylenate. Next, the ester can undergo functionalization by first ozonating the ester and then reducing the ozonide using, for example, sodium borohydride to form a hydroxylated ester, for example, ethyl 10-hydroxydecanoate. The hydroxylated ester finally is converted to the desired functionalized ester using, for example, PBr3 to form ethyl 10-bromodecanoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](N)[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH3:24])[CH:23]=3)[S:18][C:11]=12.[F:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([C:35]2([C:38]([OH:40])=O)[CH2:37][CH2:36]2)=[O:34])=[CH:28][CH:27]=1.CC[N:43](C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:7]=[C:6]([N:32]([C:29]2[CH:28]=[CH:27][C:26]([F:25])=[CH:31][CH:30]=2)[C:33]([C:35]2([C:38]([NH2:43])=[O:40])[CH2:36][CH2:37]2)=[O:34])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][N:13]=[C:12]2[CH:16]=[C:17]([C:19]3[N:20]=[CH:21][N:22]([CH3:24])[CH:23]=3)[S:18][C:11]=12
Reactant: CCN(C(C)C)C(C)C
Reactant: Cn1cnc(-c2cc3nccc(Nc4ccc(N)cc4F)c3s2)c1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1cnc(-c2cc3nccc(Nc4ccc(N(C(=O)C5(C(N)=O)CC5)c5ccc(F)cc5)cc4F)c3s2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a stirred solution of 339 (80 mg, 0.24 mmol) and 1-(4-fluorophenylcarbamoyl) cyclopropanecarboxylic acid (181, 111 mg, 0.50 mmol) in anhydrous DMF were added DIPEA (123 μL, 0.71 mmol) and HATU reagent (256 mg, 0.67 mmol). The reaction mixture was stirred at room temperature overnight under nitrogen, diluted with AcOEt, and successively washed with sat. NaHCO3, water, sat. NH4Cl, water and brine, and concentrated. The crude material was first purified by flash column chromatography (eluents 2% of NH4OH in methanol/CH2Cl2: 10/90) and precipitated in AcOEt (with traces of acetone)/hexanes to afford title compound 336 (75 mg, 58% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 10.32 (s, 1H), 10.04 (s, 1H), 8.65 (bs, 1H), 8.18 (d, J=5.5 Hz, 1H), 7.78 (dd, J=12.9, 2.2 Hz, 1H), 7.77 (d, J=1.8 Hz, 1H), 7.68 (d, J=1.2 Hz, 1H), 7.68-7.60 (m, 2H), 7.50 (s, 1H), 7.44 (dd, J=8.4, 1.8 Hz, 1H), 7.30 (t, J=8.9 Hz, 1H), 7.15 (t, J=9.0 Hz, 2H), 6.36 (dd, J=5.5, 1.6 Hz, 1H), 3.70 (s, 3H), 1.47 (s, 4H). MS (m/z): 545.0 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[CH:17]=[C:16]([C:18]3[S:19][CH:20]=[CH:21][CH:22]=3)[CH:15]=[CH:14][C:13]=2[NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:10])=[CH:5][CH:4]=1.C(O)(=O)C(O)=O.[NH2:37][CH2:38][P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42].CCN(C(C)C)C(C)C.O>CN(C=O)C>[CH3:29][C:26]([O:25][C:24]([NH:23][C:13]1[CH:14]=[CH:15][C:16]([C:18]2[S:19][CH:20]=[CH:21][CH:22]=2)=[CH:17][C:12]=1[NH:11][C:9]([C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:37][CH2:38][P:39](=[O:46])([O:43][CH2:44][CH3:45])[O:40][CH2:41][CH3:42])=[CH:8][CH:7]=1)=[O:10])=[O:30])([CH3:27])[CH3:28]
Reactant: CCOP(=O)(CN)OCC
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1NC(=O)c1ccc(CBr)cc1
Agent: O=C(O)C(=O)O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOP(=O)(CNCc1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1)OCC

Procedure:
1,1-dimethylethyl [2-({[4-(bromomethyl)phenyl]carbonyl}amino)-4-(2-thienyl)phenyl]carbamate (500 mg, 1.026 mmol), diethyl (aminomethyl)phosphonate oxalate (791 mg, 3.08 mmol), and DIPEA (1.254 mL, 7.18 mmol) were stirred in DMF (6 mL) at 50° C. overnight. Room temperature was attained, H2O: was added and the products extracted into EtOAc (×2). The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by MPLC (0-10% MeOH-EtOAc) gave diethyl [({[4-({[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-5-(2-thienyl)phenyl]amino}carbonyl)phenyl]methyl}amino)methyl)phosphonate as a colourless gum. MS: cal'd 574 (MH+), exp 574.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.Cl.[CH2:31]([O:33][C:34](=[O:38])[CH2:35][CH2:36][NH2:37])[CH3:32].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl>[CH2:31]([O:33][C:34](=[O:38])[CH2:35][CH2:36][NH:37][C:16]([C:13]1[CH:12]=[C:11]([CH3:19])[C:10]([CH:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])[S:20]([C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)(=[O:21])=[O:22])=[CH:15][N:14]=1)=[O:17])[CH3:32]
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: CCOC(=O)CCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CCOC(=O)CCNC(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 96 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (106 mg, 0.252 mmol) obtained in Example 12 in methylene chloride (3 ml), β-alanine ethyl ester hydrochloride (46 mg, 0.302 mmol), 1-hydroxybenzotriazole (34 mg, 0.252 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride mg, 0.302 mmol) and 4-methylmorpholine (66 μl, 0.604 mmol) were added. The reaction solution was stirred for 15 hours at room temperature, and was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with hexane:ethyl acetate (=1:1) was concentrated under reduced pressure, to obtain the title compound (126 mg, 0.242 mmol, 96%) as an amorphous substance.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2=[N:6][CH:7]=1.CO[CH:30]([OH:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[H-].[Na+].CN(C)[CH:42]=[O:43]>>[Br:1][C:2]1[C:3]([O:37][CH2:30][C:31]2[CH:32]=[CH:33][C:34]([O:43][CH3:42])=[CH:35][CH:36]=2)=[C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[CH:9][N:8]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[C:5]2=[N:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: COC(O)c1ccccc1
Reactant: COc1ccccc1-c1cn(COCC[Si](C)(C)C)c2ncc(Br)c(Cl)c12
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(COc2c(Br)cnc3c2c(-c2ccccc2OC)cn3COCC[Si](C)(C)C)cc1
Yield: 74 %

Procedure:
5-Bromo-4-chloro-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (245 mg, 0.52 mmol) and methoxybenzyl alcohol (723 mg, 5.2 mmol) were dissolved in dimethylformamide (0.25 mL). Sodium hydride (167 mg, 4.2 mmol) was added and the mixture was irradiated in a Personal Chemistry Optimizer at 120° C. for 5 min. The reaction was quenched with water, applied to a Varian chemelut cartridge and eluted with ethyl acetate. The crude product was purified by flash silica gel chromatography using a gradient of (ethyl acetate and methanol 9:1) in hexanes to afford 5-Bromo-4-(4-methoxy-benzyloxy)-3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (220 mg, 0.38 mmol, 74% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.39 (s, 1H), 7.66 (s, 1H), 7.40 (m, 1H), 7.35 (dd, J=7 Hz, J2=2 Hz, 1H), 7.08 (d, J=8 Hz, 1H), 7.01 (td, J1=7 Hz, J2=1 Hz, 1H), 6.77 (m, 4H), 5.63 (s, 2H), 4.37 (s, 2H), 3.71 (s, 3H), 3.64 (s, 3H), 3.58 (t, J=8 Hz, 1H), 0.83 (t, J=8 Hz, 1H), −0.08 (s, 9H). MS: m/z 569.4/571.3 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.[Br:12]Br.C(N(CC)CC)C.[C:21]([O:25][C:26]([O:28]C(OC(C)(C)C)=O)=O)([CH3:24])([CH3:23])[CH3:22]>CN(C)C=O.CN(C)C1C=CN=CC=1>[C:21]([O:25][C:26]([N:8]1[C:9]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2)[C:6]([Br:12])=[CH:7]1)=[O:28])([CH3:24])([CH3:23])[CH3:22]
Reactant: COc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: BrBr
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)c(Br)cn2C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
A solution of 5-methoxyindole (10 g) in dry dimethylformamide (150 mL) at ambient temperature was treated with bromine (4 mL) dropwise ensuring the temperature did not rise above 30° C. The mixture was treated immediately with triethylamine (28 mL) and 4-dimethylaminopyridine (0.5 g) followed by a solution of di-tert-butyldicarbonate (18 g) in dry dimethylformamide (80 mL) and stirring was continued for a further 4 hours. The reaction mixture was evaporated and the residue was partitioned between ethyl acetate (250 mL) and water (200 mL). The aqueous layer was extracted with ethyl acetate (100 mL). The combined organic phases were washed with water (100 mL), then with brine (100 mL), then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of pentane and ethyl acetate (19/1, v/v) to give the title compound (23.4 g) as a colourless solid, m.p. 111-112° C.
Reaction SMILES: [Cl:1][C:2]1[N:10](CC=C)[C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=2[N:3]=1.CS(C)=O.N1CCOCC1>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[NH:10][C:9]2[C:8](=[O:14])[N:7]([CH3:15])[C:6](=[O:16])[N:5]([CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[C:4]=2[N:3]=1
Reactant: C=CCn1c(Cl)nc2c1c(=O)n(C)c(=O)n2CCCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCN1
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: CCCCCn1c(=O)n(C)c(=O)c2[nH]c(Cl)nc21
Reaction time: 5 h

Procedure:
Tetrakis(triphenylphosphine)palladium (1.0, 0.90 mmol) was placed in a flask which was evacuated and then filled with nitrogen (×3). A solution of 8-chloro-1-methyl-3-pentyl-7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (2.78 g, 8.96 mmol) in 50 ml of THF was added and the flask evacuated once more and nitrogen introduced. DMSO (4.5 ml) and morpholine (7.8 ml, 89.6 mmol) was added and the solution stirred for 5 h. The solution was partitioned between ethyl acetate and 2N HCl solution and the organic fraction washed with brine, dried (MgSO4) and concentrated. The crude was purified with an aminopropyl SPE eluting with first methanol then methanol containing 0-15% acetic acid to provide the title compound as a white solid, 1.12 g, 46%. NMR δH (400 MHz, d6-DMSO) 0.86 (t, 3H, J=7 Hz), 1.21-1.35 (m, 4H), 1.59-1.68 (m, 2H), 3.22 (s, 3H), 3.91 (t, 2H, J=7.5 Hz), NH not observed; m/z 271 [MH+].
Reaction SMILES: CS(O)(=O)=[O:3].[NH2:6][C@H:7]([CH3:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10].C(N([CH2:19][CH3:20])CC)C>>[C:19]([NH:6][C@H:7]([CH3:13])[CH2:8][C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:20].[C:9]([O:11][C:19](=[O:3])[CH3:20])(=[O:10])[CH3:8]
Reactant: COC(=O)C[C@@H](C)N
Reactant: CS(=O)(=O)O
Reactant: CCN(CC)CC
Product: CC(=O)OC(C)=O
Product: COC(=O)C[C@@H](C)NC(C)=O

Procedure:
The enantiomeric excess was measured after conversion of the methyl (R)-3-aminobutanoate methanesulfonate obtained into methyl (R)-3-acetamidobutanoate by acetylation with acetic anhydride in the presence of triethylamine, and was found to be 85.0% ee.