Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12].[Li]C(C)(C)C.CN([CH:24]=[O:25])C>C1COCC1>[F:8][C:5]1[CH:6]=[CH:7][C:2]([CH:24]=[O:25])=[C:3]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:4]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)C(=O)Nc1cc(F)ccc1Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1cc(F)ccc1C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
N-(2-bromo-5-fluorophenyl)pivalamide(2.4 g, 8.75 mmol)) was dissolved in THF(30 mL) at room temperature, and the colorless solution was cooled to −78° C., followed by fast dropwise addition of t-BuLi (10.3 mL, 1.7M in heptane, 17.4 mmol) under N2 over 10 min. The resulting yellow solution was continued stirring at −78° C. for 1 hr, followed by dropwise addition of DMF(2.7 mL, 35.0 mmol) over 5 min. The light yellow solution was stirred for additional 30 min at −78° C. Thus the mixture was quenched with saturated NH4Cl (30 mL), extracted with Et2O (2×150 mL). The combined organic phase was washed with brine(30 mL), dried over MgSO4, concentrated on rotary vacuum, and purified on flash chromatography eluting with 25˜50% EtOAc/hexanes (1400 mL) to afford an expected product, as a white solids(1.03 g, 53% yield); 1H NMR (400 MHz, CDCl3) δppm 1.30 (s, 9H), 6.80-6.86 (m, 1H), 7.63 (dd, J=8.56, 6.04 Hz, 1H), 8.53 (dd, J=12.21, 2.39 Hz, 1H), 9.83 (s, 1H), 11.54 (s, 1H); Mass spec. 224.16 (MH+), Calc. for C12H14FNO2 223.1.
Reaction SMILES: [OH-].[NH4+:2].[CH3:3][O:4][C:5]([C:7]1[S:11][C:10]2[S:12][C:13]([S:15](Cl)(=[O:17])=[O:16])=[CH:14][C:9]=2[CH:8]=1)=[O:6]>CC(C)=O>[CH3:3][O:4][C:5]([C:7]1[S:11][C:10]2[S:12][C:13]([S:15]([NH2:2])(=[O:17])=[O:16])=[CH:14][C:9]=2[CH:8]=1)=[O:6]
Reactant: COC(=O)c1cc2cc(S(=O)(=O)Cl)sc2s1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)=O
Product: COC(=O)c1cc2cc(S(N)(=O)=O)sc2s1
Reaction time: 0.5 h

Procedure:
To stirred ammonium hydroxide (150 ml) was added dropwise 5-methoxycarbonylthieno[2,3-b]thiophene-2-sulfonyl chloride (11.58 g. 39.02 mmoles) dissolved in acetone (140 ml). After the addition was complete, the solution was stirred for 30 minutes. The reaction was worked up by evaporating the ammonia and acetone in vacuo. The crystals were collected and dried (9.66 g.) (89%). Recrystallization from nitromethane gave 7.02 g. mp 219°-220° C.
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[I:17])=[CH:14][C:13]([F:18])=[CH:12][CH:11]=2)=[O:7].[C:19]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1>[CH2:22]([O:21][C:19](=[O:20])[CH:24]=[CH:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[I:17])=[CH:14][C:13]([F:18])=[CH:12][CH:11]=2)=[O:7])[CH3:23]
Reactant: O=CCCNC(=O)c1[nH]c2ccc(F)cc2c1I
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C=CCCNC(=O)c1[nH]c2ccc(F)cc2c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-fluoro-3-iodo-1H-indole-2-carboxylic acid (3-oxo-propyl)-amide, prepared as in reference 13, (5.86 g, 16.3 mmol) in THF (200 mL) is added (carbethoxymethylene) triphenylphosphorane (18 g, 51.7 mmol) at 0° C. The reaction is stirred at room temperature overnight. It is washed with saturated NH4Cl (200 mL) and extracted with Et2O (200 mL×2). The combined organic layers are washed with brine and dried. It is concentrated and purified by silica gel column chromatography and eluted with EtOAc-Hexanes to give 5-[(5-fluoro-3-iodo-1H-indole-2-carbonyl)-amino]-pent-2-enoic acid ethyl ester as the trans isomer; 1H NMR (DMSO-d6) δ 1.25 (t, 3H, J=6.8 Hz), 2.52 (t, 2H, J=6.8 Hz), 3.48 (q, 2H, J=5.6 Hz), 4.10 (q, 2H, 6.8 Hz), 5.96 (d, 1H, J=15.6 Hz), 6.96 (dt, 1H, J1=5.8 Hz, J2=15.6 Hz), 7.06-7.18 (m, 2H), 7.46 (dd, 1H, J1=4.0 Hz, J2=8.8 Hz), 8.11 (t, 1H, J=6.4 Hz), 12.10 (s, 1H); m/z [M++1] 431.0.
Reaction SMILES: CO.Cl[Si:4](Cl)(Cl)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1>O>[SiH3:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1
Reactant: Cl[Si](Cl)(Cl)CCc1ccccn1
Solvent: CO
Solvent: O
Product: [SiH3]CCc1ccccn1
Reaction time: 1 h

Procedure:
A solution of 2-(2-silylethyl)pyridine oligosilsesquioxane pillar material was prepared from a methanol solution of 2-(2-trichlorosilylethyl)pyridine (24 grams of 2-(2-trichlorosilylethyl)pyridine in 175 ml of methanol) by adding 10.5 ml of water. The mixture was stirred for 1 hour while maintaining the temperature below 30° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:7])[CH2:3][CH2:4][CH2:5][OH:6].[ClH:8].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14](O)=[O:15]>>[ClH:8].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([O:6][CH2:5][CH2:4][CH2:3][CH:2]([CH3:7])[CH3:1])=[O:15]
Reactant: NCC(=O)CCC(=O)O
Reactant: CC(C)CCCO
Agent: Cl
Product: CC(C)CCCOC(=O)CCC(=O)CN
Reaction time: 2 h

Procedure:
From 4-methyl-1-pentanol (6.0 ml) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 70° C. The reaction was complete after 2 h. The yield was 1.32 g (87%).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([C:4](=[O:7])[CH2:5]Cl)[CH3:3].[F:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C:2]([CH3:8])([C:4](=[O:7])[CH2:5][O:16][C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1)[CH3:3]
Reactant: CC(C)(C)C(=O)CCl
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)COc1ccc(F)cc1
Temperature: 25 °C
Yield: 17.2 %

Procedure:
418.3 g (3.11 mols) of 2,2-dimethyl-4-chloro-butan-3-one were added dropwise to a suspension, heated to the boiling point, of 315 g (2.8 mols) of 4-fluorophenol and 386.4 g (2.8 mols) of potassium carbonate in 1,500 ml of acetone. The mixture was stirred under reflux for 4 hours. After cooling to room temperature, the salt which had separated out was filtered off and the filtrate was concentrated in vacuo. The oil which remained was distilled in vacuo. 101.5 g (86.2% of theory) of 2,2-dimethyl-4-(4-fluorophenoxy)-butan-3-one of boiling point 83°-84° C./0.05 mm Hg (nD20 =1.4919) were obtained. ##STR49##
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:11][C:10]2[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:9]=2[C:8]=1[Br:17].O>CCOCC>[Br:17][C:8]1[C:9]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:10]=2[S:11][CH:7]=1
Reactant: Cc1ccc2c(Br)c(Br)sc2c1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: Cc1ccc2c(Br)csc2c1
Reaction time: 1 h
Yield: 66.5 %

Procedure:
A solution of n-butyl lithium (22.3 ml. of 1.6M solution in hexane) was added dropwise to a stirred solution of 2,3-dibromo-6-methylbenzo[b]thiophene (11.76 g.) in dry ether (150 ml.) at 0° under an atmosphere of dry nitrogen. The resulting solution was stirred at 0° for 1 hour and then water (50 ml.) was added. The mixture was stirred for a few minutes and then the ether layer was separated, dried (Na2SO4) and evaporated to give an oil. The oil was distilled to give 3-bromo-6-methylbenzo[b]thiophene (5.80 g.), b.p. 112°-114° C. @ 0.2 m.m., m.p. 51°-53° C. (from methanol).
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:22])=[CH:17][N:16]=2)[CH2:11][CH2:10]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([N:23]3[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]3)=[O:22])=[CH:17][N:16]=2)[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(C(=O)N3CCCCC3)cn2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1CCN(c2ccc(C(=O)N3CCCCC3)cn2)CC1

Procedure:
A solution of 0.475 g of 4-tert-butoxycarbonylamino-1-(5-piperid-1-ylcarbonyl-2-pyridyl)piperidine (1.24 mmol) and 5 ml of trifluoroacetic acid in 20 ml of dichloromethane is stirred for 1 hour. The reaction medium is concentrated under reduced pressure and then taken up in dichloromethane. The solution is basified (pH=9) using saturated aqueous sodium carbonate solution. The aqueous phase is extracted five times with dichloromethane. The organic phases are dried over magnesium sulfate and concentrated under reduced ressure. The 4-amino-1-(5-piperid-1-ylcarbonyl-2-pyridyl)piperidine is obtained in the form of an oil (0.310 g, 88%). [M+H+]=289.4
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:14][CH:15]=2)=[CH:2]1.[H-].[Na+].[C:35](Cl)(=[O:37])[CH3:36]>CN(C)C=O.O1CCOCC1>[C:35]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[C:27]5[CH:28]=[CH:29][CH:30]=[C:21]([C:22]=45)[S:20]3(=[O:32])=[O:31])[CH2:12][CH:11]=2)=[CH:2]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: O=S1(=O)c2cccc3cccc(c23)N1CCCN1CC=C(c2c[nH]c3ccccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CC(=O)n1cc(C2=CCN(CCCN3c4cccc5cccc(c45)S3(=O)=O)CC2)c2ccccc21
Temperature: 20 °C
Reaction time: 15 h

Procedure:
The experiment is carried out as in Example 44, starting with 2-{3-[4-(3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8-cd]isothiazole 1,1-dioxide (11 g) in dimethylformamide (150 cc), acetyl chloride (1.95 cc) in dioxane (50 cc) and sodium hydride (1.3 g as a 50% dispersion in vaseline oil). The mixture is stirred for 15 hours at a temperature of about 20° C. After purification by flash-chromatography on a silica column, under a current of argon at medium pressure (0.5-1.5 bar), firstly with dichloromethane as eluant and then with ethyl acetate as eluant, then recrystallization from boiling acetonitrile (45 cc), 2-{3-[4-(1-acetyl-3-indolyl)-1,2,3,6-tetrahydro-1-pyridyl]propyl}naphtho[1,8cd]isothiazole 1,1-dioxide (1.3 g) is obtained, m.p. 163° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH2:16]Br)[CH:9]=[N:10]2.[CH3:19][NH:20][CH3:21].C(O)C>CN(C=O)C>[CH3:1][O:2][C:3](=[O:18])[CH2:4][C:5]1[C:14]([Cl:15])=[CH:13][CH:12]=[C:11]2[C:6]=1[CH:7]=[C:8]([CH2:16][N:20]([CH3:21])[CH3:19])[CH:9]=[N:10]2
Reactant: COC(=O)Cc1c(Cl)ccc2ncc(CBr)cc12
Reactant: CNC
Solvent: CCO
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(Cl)ccc2ncc(CN(C)C)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
To a solution of (3-bromomethyl-6-chloro-quinolin-5-yl)-acetic acid methyl ester (500 mg, 1.52 mmol) in DMF (10 mL) was added a 33% solution of dimethylamine in ethanol (547 μL, 3.04 mmol). The reaction mixture was stirred for 16 h at room temperature, followed by removal of the solvents in vacuo. The residue was purified by flash column chromatography (silica gel, gradient of CH2Cl2/MeOH 100:0 to 90:10) to afford the title compound as a violet solid (424 mg, 1.45 mmol, 95%). %). 1H NMR (400 MHz, DMSO-d6, 298 K): δ=8.89 (d, J=2.0 Hz, 1H), 8.38 (bs, 1H), 8.00 (d, J=9.1 Hz, 1H), 7.80 (d, J=9.1 Hz, 1H), 4.36 (s, 2H), 3.69 (bs, 2H), 3.63 (s, 3H), 2.24 (bs, 6H). MS (ES+): 293 (M(C15H735ClN2O2)+H)+.
Reaction SMILES: C1(C[O:8][C:9](=[O:63])[CH2:10][N:11]([C:23]2[CH:28]=[C:27]([C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:30])[CH:26]=[C:25]([C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])=[O:47])[CH:24]=2)[CH2:12][C:13]([O:15]CC2C=CC=CC=2)=[O:14])C=CC=CC=1>[Pd].C(OCC)(=O)C.C1COCC1>[C:9]([CH2:10][N:11]([C:23]1[CH:28]=[C:27]([C:29]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:30])[CH:26]=[C:25]([C:46]([O:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])=[O:47])[CH:24]=1)[CH2:12][C:13]([OH:15])=[O:14])([OH:63])=[O:8]
Reactant: CCCCCCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCCCCCC)cc(N(CC(=O)OCc2ccccc2)CC(=O)OCc2ccccc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCOC(=O)c1cc(C(=O)OCCCCCCCCCCCCCC)cc(N(CC(=O)O)CC(=O)O)c1
Reaction time: 2 h
Yield: 82.1 %

Procedure:
A mixture of 0.43 g of N-[3,5-bis[(tetradecyloxy)carbonyl]phenyl]-N-[2-(phenylmethoxy)-2-oxoethyl]glycine phenylmethyl ester and 0.2 g of 10% palladium on carbon in 30 ml of ethyl acetate and 20 ml of THF was shaken under an initial hydrogen pressure of 51 psi for 2 hours. The catalyst was removed by filtration and the filtrate was concentrated at reduced pressure to a solid which was recrystallized from methanol-water to give 0.28 g (82% yield, mp 84°-87°) of N-(carboxy-methyl)-N-[3,5-bis[(tetradecyloxy)carbonyl]phenyl]glycine.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]([NH:12][NH2:13])=[N:4][N:3]=1.C([O-])(=O)C.[Na+].[N:19]#[C:20]Br>CO>[NH2:19][C:20]1[N:4]2[N:3]=[C:2]([Cl:1])[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]2=[N:12][N:13]=1
Reactant: N#CBr
Reactant: NNc1nnc(Cl)c2c1CCCC2
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1nnc2c3c(c(Cl)nn12)CCCC3
Reaction time: 0.5 h

Procedure:
A 46.88 gm (0.236 mole) quantity of 1-chloro-4-hydrazino5,6,7,8-tetrahydrophthalazine was added to 450 ml of methanol. A 40.8 gm quantity of sodium acetate and 25.0 gm of cyanogen bromide was added and the mixture was stirred on a warm plate for 30 minutes. Yellow crystals appeared immediately. The mixture was allowed to sit for 3 days. The resulting solid was filtered, washed with ether, and dried, yielding 44.85 gm of 3-amino-6-chloro-7,8,9,10-tetrahydro-1,2,4-triazolo[3,4-a]phthalazine; mp 224-225° C. (ethanol).
Reaction SMILES: [C:1]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][C:16](=O)[NH2:17])(=[O:12])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(N(CC)C(C)C)(C)C.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)(Cl)Cl>[C:1]([NH:13][C@H:14]([C:19]([OH:21])=[O:20])[CH2:15][C:16]#[N:17])(=[O:12])[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: NC(=O)C[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: N#CC[C@H](NC(=O)c1ccc2ccccc2n1)C(=O)O
Reaction time: 24 h
Yield: 32.3 %

Procedure:
To a mixture of 0.198 g (0.69 mmol) of N-quinaldoyl-L-asparagine and 0.24 ml (1.38 mmol) of N,N-diisopropylethylamine in 1 ml of chloroform was added 0.146 g (0.71 mmol) of dicyclohexylcarbodiimide. The reaction mixture was stirred for 24 hr. at room terperature, then partitioned between 10ml of 5% sodium bicarbonate and 10 ml of ether. The aqueous phase was acidified to pH2 and the acid was taken up by extraction with chloroform (3×10ml). The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated to give 0.101 g of crude product. This was recrystallized from a small portion of methylene chloride to give 0.06 g of the title compound melting at 144°-146° C.; NMR (5% DMSO-d6 in CDCl3): 3.22 (d, 2H, ala CH2); 4.95 (m, 1H, ala CH); 7.2-8.57 (m, 7H, aromatic, OH); 9.19(d, 1H, NH).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Br:6][C:7]1[CH:8]=[CH:9][C:10]2[N:14]=[C:13](C(Cl)(Cl)Cl)[N:12]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([NH2:25])[N:20]=3)[C:11]=2[CH:26]=1>>[NH2:25][C:21]1[N:20]=[C:19]([N:12]2[C:11]3[CH:26]=[C:7]([Br:6])[CH:8]=[CH:9][C:10]=3[N:14]=[C:13]2[NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH:24]=[CH:23][N:22]=1
Reactant: COCCN
Reactant: Nc1nccc(-n2c(C(Cl)(Cl)Cl)nc3ccc(Br)cc32)n1
Product: COCCNc1nc2ccc(Br)cc2n1-c1ccnc(N)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45 %

Procedure:
A mixture of 2-methoxyethanamine (5 mL) and 4-[6-bromo-2-(trichloromethyl)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine (500 mg, 1.23 mmol) were stirred at RT for 3 days. The reaction mixture was then concentrated in vacuo and EtOAc/heptane (2:1) added. The solvent was removed in vacuo and this was repeated (×2). The resulting solid was then triturated from EtOAc:heptane (1:2). The solid was then dissolved in DCM (5 ml) and washed with water (2×2 ml). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo to give the title compound (145 mg, 45% yield): 1H NMR (500 MHz, DMSO) delta 3.28 (3H, s), 3.71-3.53 (4H, m), 6.93 (1H, d, J=5.5), 7.14 (2H, s), 7.31-7.20 (2H, m), 7.67 (1H, d, J=1.6), 8.13 (1H, t, J=5.3), 8.41 (1H, d, J=5.5); LC-MS: m/z+363/365 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[CH3:9][O:10][C:11]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:16][C:12]=1[C:13](O)=O>P(Cl)(Cl)(Cl)=O>[CH3:9][O:10][C:11]1[CH:19]=[C:18]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:17]=[CH:16][C:12]=1[C:13]1[NH:8][C:7]2[CH:6]=[CH:5][N:4]=[CH:3][C:2]=2[N:1]=1
Reactant: COc1cc(NS(C)(=O)=O)ccc1C(=O)O
Reactant: Nc1ccncc1N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(NS(C)(=O)=O)ccc1-c1nc2cnccc2[nH]1

Procedure:
Quantities of 5.45 gm (50 mmol) of 3,4-diaminopyridine and 12.25 gm (50 mmol) of 2-methoxy-4-methanesulfonylaminobenzoic acid were triturated together and refluxed for four hours in 300 ml of phosphorus oxychloride. Excess phosphorus oxychloride was then distilled off, and the residue was mixed with 500 ml of water and adjusted to a pH of 8 with concentrated ammonia. The insoluble components were filtered off, the filtrate was saturated with sodium chloride, and the crude product precipitated. After purification by chromatography (800 gm of aluminum oxide: eluant: dichloromethane with 5 to 10% of ethanol), 4.8 gm (25.2% of theory) were obtained.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:11])=[C:4]([C:8](=O)[CH3:9])[CH:5]=[CH:6][CH:7]=1.[O:12]1[CH2:17][CH2:16][N:15]([S:18]([C:21]2[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=2)[C:24]([NH:26][NH2:27])=[O:25])(=[O:20])=[O:19])[CH2:14][CH2:13]1>CO.C(O)(=O)C>[Cl:1][C:2]1[C:3]([F:11])=[C:4](/[C:8](=[N:27]/[NH:26][C:24](=[O:25])[C:23]2[CH:28]=[CH:29][CH:30]=[C:21]([S:18]([N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)(=[O:19])=[O:20])[CH:22]=2)/[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Cl)c1F
Reactant: NNC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1
Solvent: CC(=O)O
Solvent: CO
Product: C/C(=N\NC(=O)c1cccc(S(=O)(=O)N2CCOCC2)c1)c1cccc(Cl)c1F
Temperature: 120 °C
Yield: 43.1 %

Procedure:
1-(3-Chloro-2-fluorophenyl)ethanone (20 mg, 0.116 mmol) and 3-(morpholinosulfonyl)benzohydrazide (33.1 mg, 0.116 mmol) were dissolved in methanol (4 mL) in the presence of acetic acid as a catalyst, and the reaction mixture was heated via microwave irradiation to 120° C. for 30 min. Following cooling, the solvent was removed by vacuum and the resulting crude material was purified by flash column chromatography (2% CH3OH/CH2Cl2) affording the title compound (22 mg) as a solid. 1H NMR (400 MHz, CDCl3): δ 9.43 (s, 1H), 8.37 (m, 1H), 8.16 (m, 1H), 7.87 (d, 1H, J=7.2 Hz), 7.65 (m, 1H), 7.41 (m, 1H), 7.10 (t, 1H, J=8.0 Hz), 3.71 (m, 4H), 2.95 (m, 4H), 2.38 (s, 3H). ESI-MS: 440.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([N+:10]([O-])=O)=[CH:8][N:7]=[C:6]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:5]=1>CCO>[CH3:1][O:2][C:3](=[O:22])[C:4]1[C:9]([NH2:10])=[CH:8][N:7]=[C:6]([O:13][C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])[CH:5]=1
Reactant: COC(=O)c1cc(Oc2ccc(F)cc2F)ncc1[N+](=O)[O-]
Solvent: CCO
Product: COC(=O)c1cc(Oc2ccc(F)cc2F)ncc1N
Reaction time: 4 h
Yield: 58.9 %

Procedure:
Compound (1B) (7.99 g, 25.6 mmol) was taken up in EtOH (350 mL), and nitrogen gas was bubbled through the solution for five minutes before 10% Pd/C (1.6 g) was carefully added. The resulting mixture was put on the Parr Shaker under 60 psi hydrogen gas for 4 hours. By TLC, there was no starting material remaining. The reaction mixture was filtered through a 3 cm bed of celite, and the filtrate was concentrated to give 7.0 g of crude product. Purification by column chromatography eluting on 130 g of silica gel with a gradient of 5% EtOAc in hexanes through 10% EtOAc in hexanes afforded the titled compound (1C) as an off-white powder (4.223 g, (M+H)+=281, Mp=102.0–103.9° C.).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][S:5][CH3:6].S(Cl)(Cl)=O.[CH3:14]O>>[NH2:1][C@H:2]([C:7]([O:9][CH3:14])=[O:8])[CH2:3][CH2:4][S:5][CH3:6]
Reactant: CO
Reactant: CSCC[C@H](N)C(=O)O
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H](N)CCSC
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of methionine (30.0 g, 201 mmol) in methanol (500 mL) was added dropwise thionyl chloride (36 g, 0.30 mol) at 0° C. The reaction mixture was heated to 80° C. After 2 hours, the reaction mixture was concentrated under reduced pressure to give methyl methioninate. The material was used without purification. MS ESI calc'd. for C6H14NO2S [M+H]+ 164. found 164. 1H NMR (300 MHz, CD3OD) δ 4.19 (t, J=6.6 Hz, 1H), 3.84 (s, 3H), 2.64 (t, J=6.6 Hz, 2H), 2.24-2.12 (m, 2H), 2.10 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[CH:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[C:10]=1/[CH:29]=[CH:30]/[C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:36])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:23])[CH3:24])[C:10]=1[CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:2]
Reactant: CCOC(=O)/C=C/c1c(C=CCCCCO[Si](C)(C)C(C)(C)C)cccc1OCCCC(=O)OCC
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCO[Si](C)(C)C(C)(C)C)c1CCC(=O)OCC
Yield: 85.8 %

Procedure:
To a solution of 4-[3-[6-(tert-butyl-dimethyl-silanyloxy)-hex-1-enyl]-2-((E)-2-ethoxycarbonyl-vinyl)-phenoxy]-butyric acid ethyl ester (0.977 mmol, 507 mg) in ethyl acetate (10 mL) was added 10% palladium on carbon (350 mg) at room temperature. The resulting black mixture was stirred in the presence of atmospheric hydrogen gas in a balloon for 36 h at room temperature. Then, the catalyst was removed by filtration using a filter paper and the residue was washed with hot ethyl acetate (˜60 mL). The filtrate was concentrated in vacuo and the resulting residue was dried under high vacuum to obtain 4-[3-[6-(tert-butyl-dimethyl-silanyloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (438 mg, 86%) as a colorless oil: ES(+)-HRMS m/e calculated for C29H50O6Si (M+Na)+ 545.3269, found 545.3267.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([S:18]([N:8]2[C:5]3=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:10]([I:11])=[CH:9]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Clc1cnc2[nH]cc(I)c2c1
Reactant: O=S(=O)(Cl)c1ccccc1
Product: O=S(=O)(c1ccccc1)n1cc(I)c2cc(Cl)cnc21

Procedure:
1-Benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 12 was prepared in 1 step from 5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 2 and benzenesulfonyl chloride 11 as shown in Scheme 5.
Reaction SMILES: CS(O[CH:6](C)[C:7]([C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=1)(OC)OC)(=O)=O.[C:23](=[O:26])(O)[O-:24].[Na+].CO>O>[CH2:18]([C:15]1[CH:14]=[CH:13][C:12]([CH:7]([CH3:6])[C:23]([OH:24])=[O:26])=[CH:17][CH:16]=1)[CH:19]([CH3:21])[CH3:20]
Reactant: COC(OC)(c1ccc(CC(C)C)cc1)C(C)OS(C)(=O)=O
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)Cc1ccc(C(C)C(=O)O)cc1
Yield: 72.3 %

Procedure:
A mixture of 17 g of 1-(4-isobutylphenyl)-1,1-dimethoxyprop-2-yl methanesulfonate from Example 21, 16.5 g of sodium bicarbonate, 170 ml of methanol and 135 ml of water is heated to 67°-70° C. and held at reflux for 23 hours. Then the methanol is distilled from the reaction mixture and the aqueous phase remaining is extracted with 150 ml of methylene chloride. The aqueous phase is acidified with concentrated hydrochloric acid and extracted with 150 ml of methylene chloride. The organic phase is dried over magnesium sulfate, and the solvent evaporated to yield 7.67 g of 2-(4-isobutylphenyl)propionic acid (melting point: 73°-75° C.).