Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[CH2:12]=O.Cl.[CH3:15][NH:16][CH3:17]>CO.O>[CH3:15][N:16]([CH3:12])[CH2:17][CH:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=1)[C:9](=[O:11])[CH3:10]
Reactant: CNC
Reactant: C=O
Reactant: CC(=O)Cc1ccc(C)cc1
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(=O)C(CN(C)C)c1ccc(C)cc1

Procedure:
A mixture of 4-methylphenylacetone (3.01 g), paraformaldehyde (0.489 g) and dimethylamine hydrochloride (1.49 g) in MeOH (2 ml) is stirred under reflux for 3 h. The reaction mixture is diluted with 20 ml of water and the product is extracted with two portions of ether. After addition of 1 M aqueous NaOH solution, the aqueous layer is extracted with two more portions of ether. The combined organic layers are dried (Na2SO4) and the solvent is evaporated to obtain 4-dimethylamino-3-p-tolyl-butan-2-one (compound of formula VI) as a yellowish liquid, MS (ISP) 206.2 (M+H)+. 4-Dimethylamino-3-p-tolyl-butan-2-one is dissolved in AcOEt (17 ml) and iodomethane (1.46) is added. After 1 h the formed solid is collected by filtration, washed with AcOEt and dried on the vacuum. 2.61 g of trimethyl-(3-oxo-2-p-tolyl-butyl)-ammonium iodide are obtained as an off-white solid, MS (ISP) 220.3 M+.
Reaction SMILES: [Na].[CH3:2][N:3]1[CH2:8][CH2:7][CH2:6][CH:5]([OH:9])[CH2:4]1.CCCCCCC.[CH:17]1([C:22]([C:29]#[C:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([OH:28])[C:23](OCC)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1>CCOCC>[CH:17]1([C:22]([C:29]#[C:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)([OH:28])[C:23]([O:9][CH:5]2[CH2:6][CH2:7][CH2:8][N:3]([CH3:2])[CH2:4]2)=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CN1CCCC(O)C1
Reactant: CCOC(=O)C(O)(C#Cc1ccccc1)C1CCCC1
Agent: [Na]
Solvent: CCCCCCC
Solvent: CCOCC
Product: CN1CCCC(OC(=O)C(O)(C#Cc2ccccc2)C2CCCC2)C1
Reaction time: 8 h

Procedure:
Sodium (~0.05 g.) and 1-methyl-3-piperidinol (4.0 g., 0.035 mole) were refluxed in 250 ml. of dry n-heptane in a reaction flask equipped with a Dean-Stark trap until all of the sodium reacted. Then 6.5 g. (0.024 mole) of ethyl α-cyclopentyl-α-phenylethynylglycolate, undiluted, was added dropwise over a 0.25 hour period. The reaction mixture was subsequently refluxed for 20 hours, and about 30 ml. of solvent was collected toward the end of that period. The reaction mixture was kept overnight. No crystallization occurred during that time, but some tarry material was present and was filtered. Ether (acidic) and chloroform (basic) extracts were made of the filtrate as described previously. The chloroform extract yielded, after the solvent was stripped, 6.2 g. of a red-brown oil. The oil was dissolved in ether and petroleum ether (20°-40°) was added until turbidity was produced. The material was then placed in a freezer for four days and the product precipitated. It weighed 3.2 g., (39%) and melted at about 85° after being filtered and dried. The solid was recrystallized from 20°-40° petroleum ether. The first batch yielded off white crystals melting at 112°-113°.
Reaction SMILES: [C-:1]#[N:2].[Na+].Cl[CH2:5][CH2:6][CH2:7][CH:8]1[C:12]2[CH:13]=[C:14]([F:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9]1.CCOCC.O>CS(C)=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]2[O:10][CH2:9][CH:8]([CH2:7][CH2:6][CH2:5][C:1]#[N:2])[C:12]=2[CH:13]=1
Reactant: [C-]#N
Reactant: Fc1ccc2c(c1)C(CCCCl)CO2
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOCC
Product: N#CCCCC1COc2ccc(F)cc21
Temperature: 80 °C
Yield: 49.8 %

Procedure:
3-(2,3-Dihydro-5-fluoro-benzofuran-3-yl)-1-propanol, prepared as described in EXAMPLE 11, (51 g) was dissolved in 300 ml of dichloromethane and 0.5 ml of dimethyl formamide was added. During 20 min 50 ml of thionyl chloride was added dropwise followed by stirring for 3 h. Ice cold water was added, the organic phase separated, dried over magnesium sulfate and concentrated in vacuo giving 46 g of 3-(3-chloro-1-propyl)-2,3-dihydro-5-fluoro-benzofuran as an oil. Sodium cyanide (12 g) was suspended in dimethyl sulfoxide (180 ml) and heated to 80° C. A solution of 3-(3-chloro-1-propyl)-2,3-dihydro-5-fluoro-benzofuran (42 g) in 40 ml of dimethyl sulfoxide was added dropwise followed by heating to 140° C. for 15 min. After cooling ether and water were added, the ether phase separated, washed with water and dried over magnesium sulfate. Removal of solvent in vacuo left a viscous oil which was applied to a silica gel column giving 4-(2,3-dihydro-5-fluoro-benzofuran-3-yl)butyronitrile as an oil (20 g).
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][N:12]3[C:16]([C:17]4[S:18][C:19]5[N:20]=[CH:21][N:22]=[C:23]([NH2:26])[C:24]=5[N:25]=4)=[C:15]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:14]=[CH:13]3)[CH2:7][CH2:6]2)[O:4]CC1.O.C(O)(C(F)(F)F)=O>CC#N>[NH2:26][C:23]1[C:24]2[N:25]=[C:17]([C:16]3[N:12]([CH2:11][CH:8]4[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]4)[CH:13]=[N:14][C:15]=3[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[S:18][C:19]=2[N:20]=[CH:21][N:22]=1
Reactant: Nc1ncnc2sc(-c3c(-c4ccccc4)ncn3CC3CCC4(CC3)OCCO4)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Solvent: CC#N
Product: Nc1ncnc2sc(-c3c(-c4ccccc4)ncn3CC3CCC(=O)CC3)nc12
Reaction time: 48 h

Procedure:
2-[1-(1,4-Dioxaspiro[4,5]dec-8-ylmethyl)-4-phenyl-1H-imidazol-5-yl][1,3]thiazolo[5,4-d]pyrimidin-7-amine (Example 178) (634 mg) was dissolved in MeCN (10 mL) and water (10 mL) and TFA (0.5 mL) was added. After 48 hours at ambient temperature, the title compound was obtained by preparative RPHPLC (eluting with a gradient of water and MeCN containing 0.1% TFA) as a colourless solid (570 mg, 99%);
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH2:15]([NH2:17])[CH3:16].[CH2:18](O)[CH3:19]>>[N+:12]([C:3]1[CH:4]=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[NH:17][CH2:15][CH3:16])([O-:14])=[O:13].[NH2:12][C:3]1[C:4]([NH2:17])=[C:5]([C:8]([F:11])([F:10])[F:9])[CH:6]=[CH:7][C:2]=1[CH2:18][CH3:19]
Reactant: CCN
Reactant: CCO
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Product: CCNc1ccc(C(F)(F)F)cc1[N+](=O)[O-]
Product: CCc1ccc(C(F)(F)F)c(N)c1N

Procedure:
At first, 3-nitro-4-ethylamino-benzotrifluoride is prepared from 4-chloro-3-nitrobenzotrifluoride and ethyl-amine according to Geman Offenlegungsschrift No. 2 018 232, Example 1), and the former product is catalytically reduced in ethanol to give the 3-amino-4-ethyl-amino-benzotrifluoride colorless crystals of a melting point of from 72° to 74° C.
Reaction SMILES: C[O:2][C:3]([C@@:5]12[CH2:14][N:13]([S:15]([C:18]3[CH:19]=[N:20][C:21]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)=[CH:22][CH:23]=3)(=[O:17])=[O:16])[CH2:12][CH2:11][C:10]1=[CH:9][C:8]1[N:30]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=3)[N:31]=[CH:32][C:7]=1[CH2:6]2)=[O:4].O.[OH-].[Li+]>O1CCCC1.O.C(OCC)(=O)C.Cl>[F:39][C:36]1[CH:37]=[CH:38][C:33]([N:30]2[C:8]3[CH:9]=[C:10]4[C@:5]([C:3]([OH:4])=[O:2])([CH2:6][C:7]=3[CH:32]=[N:31]2)[CH2:14][N:13]([S:15]([C:18]2[CH:19]=[N:20][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)(=[O:16])=[O:17])[CH2:12][CH2:11]4)=[CH:34][CH:35]=1
Reactant: COC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Yield: 102.6 %

Procedure:
A solution of (R)-1-(4-fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carboxylic acid methyl ester (0.3 g) in tetrahydrofuran (10 mL) and water (10 mL) was treated with lithium hydroxide monohydrate (0.11 g) at 60° C. for 16 hours. The cooled mixture was diluted with ethyl acetate and 1.0 M aqueous hydrochloric acid solution. The aqueous phase was washed with ethyl acetate, the combined organic phases were washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the title compound as a foam (0.3 g). LCMS (Method G): 540.4 (M+H)+, Retention time 3.16 minutes.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:48]([N+:52]1[N:56]=[C:55]([CH3:57])[S:54][C:53]=1[CH3:58])[CH2:49][CH2:50][CH3:51]>>[CH2:48]([N:52]1[N:56]=[C:55]([CH3:57])[S:54]/[C:53]/1=[CH:58]\[C:5]([C:4]1[CH:8]=[CH:9][CH:10]=[C:11]([O:12][CH3:13])[C:3]=1[O:2][CH3:1])=[O:7])[CH2:49][CH2:50][CH3:51]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: COc1cccc(C(=O)O)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cccc(OC)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 2,3-dimethoxybenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ ppm 0.86-0.95 (m, 3 H) 1.27-1.38 (m, 2 H) 1.71-1.77 (m, 2 H) 2.48 (s, 3 H) 3.75 (s, 3 H) 3.80 (s, 3 H) 4.10-4.14 (m, 2 H) 6.45 (s, 1 H) 7.08-7.19 (m, 3 H); MS (ESI) m/z 335 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][C:34]([OH:37])=[C:33]([Br:38])[CH:32]=2)=[CH:27][CH:26]=1)[C:9]([C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]=1[CH2:20][CH2:21][CH2:22][CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:40][C:41]#[N:42].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:1]([N:8]([CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:40][C:41]#[N:42])=[C:33]([Br:38])[CH:32]=2)=[CH:29][CH:30]=1)[C:9]([C:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[O:13][C:12]=1[CH2:20][CH2:21][CH2:22][CH3:23])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCBr
Reactant: CCCCc1oc2ccccc2c1C(=O)N(Cc1ccccc1)Cc1ccc(-c2ccc(O)c(Br)c2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1oc2ccccc2c1C(=O)N(Cc1ccccc1)Cc1ccc(-c2ccc(OCC#N)c(Br)c2)cc1
Temperature: 25 °C
Reaction time: 23 h
Yield: 68.6 %

Procedure:
A mixture of N-benzyl-N-[(3′-bromo-4′-hydroxy-1,1′-biphenyl-4-yl)methyl]-2-butyl-1-benzofuran-3-carboxamide (1.5 g, 2.64 mmol), prepared in the previous step, bromoacetonitrile (220 μL, 3.16 mmol) and potassium carbonate (1.862 g, 13.5 mmol) in 75 mL of DMF was stirred under nitrogen at room temperature for 23 h. The reaction was partitioned between methylene chloride and water. If an emulsion forms saturated NaCl can be added to separate it. The organic layer was separated, extracted multiple times with water, dried (MgSO4), and the solvent removed under reduced pressure to give N-benzyl-N-{[3′-bromo-4′-(cyanomethoxy)-1,1′-biphenyl-4-yl]methyl}-2-butyl-1-benzofuran-3-carboxamide (1.1 g, 69%) as a yellow oily solid, MS (ESI) m/z 607 [M+H]+. Elemental Analysis for C35H31BrN2O3: Calc'd: C, 69.19; H, 5.14; N, 4.61; Found: C, 67.76; H, 5.44; N, 4.29
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:20])([CH3:19])[C@@H:11]([O:15][C:16](=[O:18])[CH3:17])[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.CN(C)C=O.[N:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH2:38]O)[CH:33]=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:20])([CH3:19])[C@@H:11]([O:15][C:16](=[O:18])[CH3:17])[C:12]([O:14][CH2:38][C:34]1[CH:33]=[N:32][CH:37]=[CH:36][CH:35]=1)=[O:13])(=[O:6])=[O:7]
Reactant: OCc1cccnc1
Reactant: CC(=O)O[C@@H](C(=O)O)C(C)(C)COS(=O)(=O)CCCCl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)O[C@@H](C(=O)OCc1cccnc1)C(C)(C)COS(=O)(=O)CCCCl
Yield: 55.5 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-2-acetyloxy-3,3-dimethylbutanoic acid (16) (0.31 g, 0.94 mmol) dissolved in 10 mL of anhydrous dichloromethane (DCM) was reacted with 0.56 mL (1.1 mmol) of oxalyl chloride (2.0 M in DCM) in the presence of a catalytic amount of N,N-dimethylformamide (DMF). After completion of the reaction, a solution of 0.28 mL of 3-pyridylmethanol (0.26 g, 2.3 mmol) in dichloromethane was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) as eluent (EtOAc/Hxn=2:1) to provide 0.22 g (54% yield) of the title compound (38a) as a colorless oil. Rf=0.55 (EtOAc). 1H NMR (400 MHz, CDCl3):): δ=1.03 (s, 3H), 1.05 (s, 3H), 2.10 (s, 3H), 2.22-2.30 (m, 2H), 3.24-3.28 (m, 2H), 3.62-3.66 (m, 2H), 3.92 (d, J=9.2 Hz, 1H), 4.12 (d, J=9.6 Hz, 1H), 4.77 (s, 1H), 5.15-5.22 (m, 2H), 7.30-7.34 (m, 1H), 7.70-7.73 (m, 1H), 8.54-8.59 (m, 2H) ppm. MS (ESI) m/z 422.00 (M+H)+. The analytical data was consistent with proposed structure.
Reaction SMILES: Cl.NO.C([N:7](CC)C(C)C)(C)C.[Br:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([NH:23]C(OCC)=O)=S)=[N:18][CH:19]=1>CCO.CO>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[N:18]([N:7]=[C:21]([NH2:23])[N:20]=2)[CH:19]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCOC(=O)NC(=S)Nc1ccc(Br)cn1
Agent: Cl
Agent: NO
Solvent: CO
Solvent: CCO
Product: Nc1nc2ccc(Br)cn2n1
Temperature: 20 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
To a suspension of hydroxylamine hydrochloride (409.2 g, 5.888 mol) in EtOH/MeOH (1:1, 2.5 L) was added N,N-diisopropylethylamine (606.1 mL, 3.480 mol), the mixture was stirred at room temperature (20° C.) for 1 h. 1-(6-Bromo-pyridin-2-yl)-3-carboethoxy-thiourea (2) (352.8 g, 1.160 mol) was then added and the mixture slowly heated to reflux (Note: bleach scrubber required to quench H2S evolved). After 2 h at reflux the mixture was allowed to cool and filtered to collect the precipitated solid. The collected solid was washed successively with water (1.0 L), EtOH/MeOH (1:1, 1.0 L) and diethyl ether (500 mL) then air-dried to afford the title compound as a white solid (169.2 g, 69%). No further purification was required.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.C1COCC1.[F:16][C:17]([F:35])([F:34])[C:18]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:20]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[N:19]=1.C(N(CC)CC)C>O>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:31][C:30]2[CH:29]=[CH:28][C:27]([N:20]3[C:21]([C:23]([F:24])([F:25])[F:26])=[CH:22][C:18]([C:17]([F:35])([F:34])[F:16])=[N:19]3)=[CH:33][CH:32]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-n2nc(C(F)(F)F)cc2C(F)(F)F)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 48.1 %

Procedure:
4-Chlorobenzoyl chloride (88 mg) and THF (2 ml) were added to a mixture of 4-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]aniline (150 mg), triethylamine (57 mg) and THF (2 ml) under ice-cooling, followed by stirring at room temperature for 4 hours. Water was added to the reaction solution, the thus formed product was extracted with ethyl acetate and then the extract was washed with 1-N-hydrochloric acid aqueous solution, saturated sodium bicarbonate aqueous solution and saturated brine in that order. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under a reduced pressure. By recrystallizing the resulting residue from a mixed solvent of ethyl acetate and n-hexane, 4-chloro-4′-[3,5-bis(trifluoromethyl)-1H-pyrazol-1-yl]benzanilide (105 mg) was obtained as colorless powder crystals.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]([F:21])([F:20])[C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](Cl)=[O:14]>N1C=CC=CC=1>[Cl:8][C:3]1[C:2]([NH:1][C:13](=[O:14])[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[C:10]([F:9])([F:20])[F:21])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Reactant: Nc1cccnc1Cl
Solvent: c1ccncc1
Product: O=C(Nc1cccnc1Cl)c1ccccc1C(F)(F)F
Yield: 91.5 %

Procedure:
4.57 g 3-amino-2-chloropyridine (36 mmol) and 30 mL pyridine were mixed in an ice bath. 8.24 g 2-trifluoromethyl benzoyl chloride (40 mol) was then added. After return to room temperature and reaction for 4 hr, the reaction was quenched by water. After extraction three times by ethyl acetate, an ethyl acetate layer was collected and washed by 1M HCl solution. After drying, filtration, concentration, and purification by silicon-gel column, 9.9 g solid was obtained, with a yield of 92%.
Reaction SMILES: C1(C[CH2:8][CH2:9][NH2:10])C=CC=CC=1.[CH:11]1([CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:29]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[C:34]([C:38](O)=[O:39])[CH:35]=4)[CH2:30]3)=[O:28])=[CH:22][CH:21]=2)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1.C1C2C(=CC=CC=2)CN1[C:50](NC1C=CC(C(O)=O)=CC=1)=[O:51]>>[CH:11]1([CH2:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27]([N:29]3[CH2:37][C:36]4[C:31](=[CH:32][CH:33]=[C:34]([C:38]([NH:10][CH2:9][CH2:8][O:51][CH3:50])=[O:39])[CH:35]=4)[CH2:30]3)=[O:28])=[CH:22][CH:21]=2)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: NCCCc1ccccc1
Reactant: O=C(CC1CCCC1)Nc1ccc(NC(=O)N2Cc3ccc(C(=O)O)cc3C2)cc1
Reactant: O=C(O)c1ccc(NC(=O)N2Cc3ccccc3C2)cc1
Product: COCCNC(=O)c1ccc2c(c1)CN(C(=O)Nc1ccc(NC(=O)CC3CCCC3)cc1)C2

Procedure:
The title compound was prepared as described in Example 1C, substituting 2-methoxyethanamine for 3-phenylpropan-1-amine and 2-({4-[(cyclopentylacetyl)amino]phenyl}carbamoyl)isoindoline-5-carboxylic acid for 4-(isoindoline-2-carboxamido)benzoic acid. 1H NMR (300 MHz, DMSO-d6) δ ppm 9.69 (s, 1H), 8.56-8.49 (m, 1H), 8.31 (s, 1H), 7.84-7.77 (m, 2H), 7.50-7.40 (m, 5H), 4.78 (bs, 4H), 3.50-3.39 (m, 4H), 3.27 (s, 3H), 2.31-2.18 (m, 3H), 1.81-1.68 (m, 2H), 1.66-1.43 (m, 4H), 1.26-1.12 (m, 2H); MS (ESI(+)) m/e 465 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][O:10][C:11](=[O:24])[C@H:12]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[NH2:13].[CH3:25][O:26][C:27](=[O:30])[CH2:28]Br>C1COCC1>[CH3:9][O:10][C:11](=[O:24])[C@H:12]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)[NH:13][CH2:28][C:27]([O:26][CH3:25])=[O:30]
Reactant: COC(=O)[C@@H](N)Cc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)CBr
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CN[C@@H](Cc1ccc([N+](=O)[O-])cc1)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
Triethylamine (22 mmol) was added to a suspension of 4-Nitrophenylalanine methyl ester hydrochloride (2) (21 mmol) in THF (50 ml). The mixture was stirred at room temperature for one hour, the triethylamine hydrochloride was filtered off, and the filtrate concentrated to yellow oil. The oil was dissolved in dry THF (50 ml) and to this solution was added triethylamine (60 mmol) and methylbromoacetate (60 mmol), the solution was stirred at room temperature under nitrogen atmosphere for 3 hours, after which the precipitate was filtered off and the filtrate concentrated on vacuum. The residue was dissolved in ethylacetate, washed with H2O, dried (MgSO4) and concentrated on vacuum to give yellow oil. The yield was 92%.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=[O:18].[Na+].N([O-])=O>S(=O)(=O)(O)O.O>[OH:18][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([S:11]([F:16])([F:15])([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=N[O-]
Reactant: Nc1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(O)cc(S(F)(F)(F)(F)F)c1
Temperature: -5 °C
Reaction time: 0.67 h
Yield: 92 %

Procedure:
3-Amino-5-pentafluorosulfanylbenzoic acid (O6.007; 3.9 g) was dissolved in 35% sulfuric acid (120 ml) and cooled to −5° C., and a solution of sodium nitrite (1.1 g) in water (100 ml) was added dropwise within 10 min. After 40 min, further nitrite solution was added (2 ml), and another 2 ml and 1 ml after a further 20 min in each case. Then the cooling bath was removed and the mixture was heated to 100° C. After 5 h, the mixture was cooled and the solution was decanted. The clear, acidic solution was extracted five times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. The crude product was recrystallized from ethyl acetate/heptane. 3.6 g of the desired compound were obtained.
Reaction SMILES: C([O:4][CH2:5][CH2:6][O:7][C:8]1[C:12](I)=[C:11]([N:14]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])C(OCC(C)C)=O)[O:10][N:9]=1)(=O)C.[CH2:35]1[O:43][C:42]2[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][C:37]=2[O:36]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1>[O:36]1[C:37]2[CH:38]=[CH:39][C:40]([C:12]3[C:8]([O:7][CH2:6][CH2:5][OH:4])=[N:9][O:10][C:11]=3[NH:14][S:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([CH3:34])([CH3:32])[CH3:33])=[CH:27][CH:26]=3)(=[O:23])=[O:24])=[CH:41][C:42]=2[O:43][CH2:35]1
Reactant: CC(=O)OCCOc1noc(N(C(=O)OCC(C)C)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1I
Reactant: OB(O)c1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2onc(OCCO)c2-c2ccc3c(c2)OCO3)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.2 %

Procedure:
To a stirring solution of 2-({5-[{[4-(tert-butyl)phenyl]sulfonyl}(isobutoxycarbonyl)amino]-4-iodo-3-isoxazolyl}oxy)ethyl Acetate (Preparation 5) (2.41 g) in dioxane (25 mL) was added 3,4-methylenedioxybenzeneboronic acid (0.72 g) followed by cesium carbonate (5.15 g) and water (3 mL). The reaction mixture was purged with nitrogen three times, after which time tetrakis(triphenylphosphine)-palladium(O) (140 mg). The reaction mixture was heated to reflux for about 2 hours. Ethanol (50 mL) and sodium hydroxide (2M, 50 mL) were added to the reaction mixture and then this was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the solid residue was partitioned between saturated ammonium chloride solution (100 mL) and ethyl acetate (100 mL). The organics were washed with brine (50 mL), dried over sodium, sulfate and concentrated under reduced pressure to yield the crude material as a brown oil. The crude material was purified by column chromatography (100 g silica) using a gradient elution of hexane (50% to 0%) and ethyl acetate (50% to 100%) and also with methanol (5% in ethyl acetate) to yield the product as a light brown foam (770 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[CH:8]=[CH:9][NH:10]2)=[CH:5][C:4]=1[C:14]([O:16][CH3:17])=[O:15].S(Cl)([Cl:20])=O>CN(C=O)C>[Cl:20][C:7]1[C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([C:14]([O:16][CH3:17])=[O:15])[CH:5]=2)[N:10]=[CH:9][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cc2c(=O)cc[nH]c2cc1OC
Solvent: CN(C)C=O
Product: COC(=O)c1cc2c(Cl)ccnc2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A mixture of 7-methoxy-6-methoxycarbonyl-1,4-dihydroquinolin-4-one (5.4 g, 23 mmol), DMF (0.4 ml) and thionyl chloride (75 ml) was heated at reflux for 2 hours and then stirred at ambient temperature for a further 2 hours. The excess thionyl chloride was removed by evaporation and by azeotroping with toluene. The residue was suspended in methylene chloride and washed with saturated aqueous sodium hydrogen carbonate solution. The organic layer was separated, dried by passing through phase separating paper and the solvent was removed by evaporation. The residue was suspended in ether, collected by filtration, washed with hexane and dried to give 4-chloro-7-methoxy-6-methoxycarbonylquinoline (4.06 g, 70%) as an orange solid.