Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([NH:9][C:10]([C:12]1[S:30][C:15]2[N:16]=[C:17]([NH2:29])[N:18]=[C:19]([C:20]3[CH:25]=[C:24]([OH:26])[C:23]([Cl:27])=[CH:22][C:21]=3[Cl:28])[C:14]=2[CH:13]=1)=[O:11])[CH3:8].ClCCl.Br.Br[CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40]>CN(C=O)C>[CH2:7]([NH:9][C:10]([C:12]1[S:30][C:15]2[N:16]=[C:17]([NH2:29])[N:18]=[C:19]([C:20]3[CH:25]=[C:24]([O:26][CH2:36][CH2:37][N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[C:23]([Cl:27])=[CH:22][C:21]=3[Cl:28])[C:14]=2[CH:13]=1)=[O:11])[CH3:8]
Reactant: CCN(CC)CCBr
Reactant: CCNC(=O)c1cc2c(-c3cc(O)c(Cl)cc3Cl)nc(N)nc2s1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCNC(=O)c1cc2c(-c3cc(OCCN(CC)CC)c(Cl)cc3Cl)nc(N)nc2s1
Temperature: -140 °C

Procedure:
Cesium carbonate was added to a solution of 2-Amino-4-(2,4-dichloro-5-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxylic acid ethyl amide in DMF, 2-Bromo-N,N-diethylethylamine hydrobromide was added and the suspension heated, at −140° C., for ˜2 hrs. The resulting suspension was allowed to cool and dichloromethane added. The mixture was washed with water and saturated aqueous sodium chloride solution. The solution was dried over anhydrous sodium sulphate and concentrated to a dark brown gum. The crude product was purified by chromatography on silica eluting with mixtures of dichloromethane and methanol.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH3:6])[C:3](Cl)=[O:4].N1C=CC=CC=1.[Cl:14][C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[C:17]([CH3:25])[C:16]=1[CH:26]([O:29][C:30]([CH3:36])([CH3:35])[C:31]([F:34])([F:33])[F:32])[CH2:27][OH:28]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:3]([O:28][CH2:27][CH:26]([C:16]1[C:17]([CH3:25])=[CH:18][C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]=1[Cl:14])[O:29][C:30]([CH3:36])([CH3:35])[C:31]([F:32])([F:33])[F:34])(=[O:4])[C:2]([CH3:7])([CH3:6])[CH3:1]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc2ccccc2c(Cl)c1C(CO)OC(C)(C)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cc2ccccc2c(Cl)c1C(COC(=O)C(C)(C)C)OC(C)(C)C(F)(F)F
Temperature: 25 °C

Procedure:
To a stirred solution of trimethylacetyl chloride (0.17 mL, 1.36 mmol) and 4-(Dimethylamino)pyridine (55 mg, 0.45 mmol) in pyridine (2.4 mL, 29.48 mmol), 2-(1-chloro-3-methylnaphthalen-2-yl)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)ethanol (157 mg, 0.45 mmol) in CH2Cl2 (2.4 mL) was added at 0° C. The reaction mixture was allowed to warm to room temperature overnight. The mixture was quenched with water and concentrated and purified by flash column chromatography (silica gel, 0 to 20% ethyl acetate/hexanes) to give 2-(1-chloro-3-methylnaphthalen-2-yl)-2-(1,1,1-trifluoro-2-methylpropan-2-yloxy)ethyl pivalate. 1H-NMR: 400 MHz, (CDCl3) δ 8.26 (d, J=8.4 Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 7.58-7.48 (m, 3H), 6.05 (dd, J=8.4, 5.2 Hz, 1H), 4.50 (dd, J=11.2, 8.4 Hz, 1H), 4.21 (dd, J=11.2, 4.8 Hz, 1H), 2.73 (s, 3H), 1.43 (s, 3H), 1.19 (s, 3H), 1.16 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]2[NH:6][C:7](=[O:11])[O:8][C:9](=[O:10])[C:4]=2[CH:3]=1.[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:16]([N:6]1[C:5]2[CH:12]=[CH:13][C:2]([F:1])=[CH:3][C:4]=2[C:9](=[O:10])[O:8][C:7]1=[O:11])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: O=c1[nH]c2ccc(F)cc2c(=O)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1oc(=O)n(Cc2ccccc2)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
A solution of Compound 35 (3 g, 16.57 mmol) in DMF was added slowly to a suspension of NaH (60% in mineral oil, 729 mg, 18.23 mmol) in DMF and further stirred at room temperature for 1 h. Then, neat benzyl bromide (2.17 mL, 18.23 mmol) was added and the solution was further stirred at room temperature for 3 h. The solution was poured into ice water and the solids formed were filtered, washed several times by water, and dried. The solids were suspended in hexane, sonicated briefly, filtered, and washed by hexane to yield 1.88 g (42%) of white solids. M.P. 95° C. 1H NMR (DMSO-d6): δ 5.29 (s, 2H), 7.26 (m, 2H), 7.35 (m, 5H), 7.40 (m, 2H), 7.64 (dt, J=2.9, 8.4 Hz, 1H), 7.82 (dd, J=3.2, 8.0 Hz, 1H). Anal. (C16H13NO3) C, H, N.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:11]([CH:13]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=2)[CH2:14]1)=O.C([BH3-])#N.[Na+]>CO>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:13]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25][CH3:26])=[O:24])=[CH:21][CH:20]=3)[CH2:14]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: COC(=O)c1ccc(CN2CCC(C=O)C2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccccc3)C2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.6 %

Procedure:
A solution of (1R,2S)-2-phenylcyclopropanamine (300 mg, 2.252 mmol) and methyl 4-((3-formylpyrrolidin-1-yl)methyl)benzoate (501 mg, 2.027 mmol) in methanol (50 mL) was heated to reflux for 5 minutes. The reaction mixture was cooled to room temperature and sodium cyanoborohydride (212 mg, 3.38 mmol) was added. The reaction was stirred at room temperature for 16 hours. After concentrating, dichloromethane was added and the solution was washed with water, dried over MgSO4, filtered and concentrated. HPLC purification (reverse phase) was performed with a Gemini NX 5u C18 110A, AXIA. 100×30.00 mm 5 micron column. A 7 minute gradient run (0% AcCN/H2O, 0.1% Formic Acid to 55% ACN/H2O, 0.1% Formic Acid) with UV detection at 214 nm was utilized. Added 1 ml of 1N HCl to fractions containing product and concentrated. Only the desired ester was seen by LC/MS of fractions before concentrating. Obtained 300 mg of a mixture of diastereomers.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[O:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1.[B:17](OC)([O:20]C)[O:18]C>>[F:9][C:6]1[CH:7]=[CH:8][C:3]([B:17]([OH:20])[OH:18])=[C:4]([O:10][CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][O:12]2)[CH:5]=1
Reactant: COB(OC)OC
Reactant: Fc1ccc(Br)c(OC2CCCCO2)c1
Agent: [Mg]
Product: OB(O)c1ccc(F)cc1OC1CCCCO1

Procedure:
Procedure analogous to Example 6. Use of 48.6 g (2.00 mol) of magnesium, 510 g (1.85 mol) of 2-bromo-5-fluoro-1-(tetrahydropyran-2-yloxy)benzene and 241.6 ml (2.00 mol) of trimethyl borate. The yield was 434.5 g (1.81 mol), and the product was obtained as a waxy solid which contained varying proportions of boronic anhydrides and borinic acids and was used in the following stage without further purification.
Reaction SMILES: CCCP(O)(O)=O.CCN(C(C)C)C(C)C.[CH2:17]([O:19][P:20]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[N:38]=[C:37]([NH:39][C:40]3[CH:41]=[CH:42][C:43]([C@@H:51]4[CH2:56][CH2:55][C@H:54]([C:57]([OH:59])=O)[CH2:53][CH2:52]4)=[C:44]4[C:48]=3[C:47](=[O:49])[N:46]([CH3:50])[CH2:45]4)[C:36]([C:60]([F:63])([F:62])[F:61])=[CH:35][N:34]=2)=[C:28]([O:64][CH3:65])[CH:27]=1)([O:22][CH2:23][CH3:24])=[O:21])[CH3:18].Cl.[NH2:67][OH:68]>CN(C=O)C>[OH:68][NH:67][C:57]([C@@H:54]1[CH2:55][CH2:56][C@H:51]([C:43]2[CH:42]=[CH:41][C:40]([NH:39][C:37]3[C:36]([C:60]([F:63])([F:61])[F:62])=[CH:35][N:34]=[C:33]([NH:32][C:29]4[CH:30]=[CH:31][C:26]([CH2:25][P:20](=[O:21])([O:19][CH2:17][CH3:18])[O:22][CH2:23][CH3:24])=[CH:27][C:28]=4[O:64][CH3:65])[N:38]=3)=[C:48]3[C:44]=2[CH2:45][N:46]([CH3:50])[C:47]3=[O:49])[CH2:52][CH2:53]1)=[O:59]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](C(=O)O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: NO
Agent: CCCP(=O)(O)O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](C(=O)NO)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 50% 1-propylphosphonic acid cyclic anhydride in DMF (9.9 μL, 0.017 mmol) were added additional DMF (0.5 mL), DIPEA (9.9 μL, 0.0567 mmol) and cis-4-(7-{[2-({4-[(diethoxyphosphoryl)methyl]-2-methoxyphenyl}amino)-5-(trifluoromethyl) pyrimidin-4-yl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylic acid (10.0 mg, 0.0142 mmol). The mixture was stirred at room temperature for 30 minutes. Hydroxylamine hydrochloride (2.0 mg, 0.0283 mmol) was added and the mixture was stirred at room temperature overnight. The crude mixture was purified by MDP to obtain the title compound (5.2 mg, 51% yield). 1H NMR (400 MHz, methanol-d4) d ppm 1.29 (t, J=7.1 Hz, 6 H), 1.68-1.82 (m, 4 H), 2.00-2.16 (m, 4 H), 2.52 (br. s., 1 H), 2.73 (t, J=11.1 Hz, 1 H), 3.19 (s, 3 H), 3.38 (d, J=21.7 Hz, 2 H), 3.90 (s, 3 H), 4.11 (qd, J=7.3, 7.1 Hz, 4 H), 4.55 (s, 2 H), 6.95-7.04 (m, 1 H), 7.14 (s, 1 H), 7.39 (br. s., 1 H), 7.65 (d, J=8.1 Hz, 1 H), 8.33 (br. s., 2 H). MS (ES+): m/z 721.19 (100) [MH+]; HPLC: tR=0.97 min (UPLC, purity).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]1[C:13](O[C:16](=[O:17])[C:5]2=1)=[O:14].[N:18]1C=CC=C[CH:19]=1>>[O:17]=[C:16]1[C:5]2[C:4]3[CH:3]=[C:2]([Br:1])[CH:11]=[CH:10][C:9]=3[N:8]=[C:7]([CH3:12])[C:6]=2[C:13](=[O:14])[N:18]1[CH3:19]
Reactant: c1ccncc1
Reactant: Cc1nc2ccc(Br)cc2c2c1C(=O)OC2=O
Product: Cc1nc2ccc(Br)cc2c2c1C(=O)N(C)C2=O
Temperature: 25 °C

Procedure:
To 350 ml of dry pyridine was added 14.7 g of the anhydride (ix) in a 3-neck flask with reflux condenser, drying tube, magnetic stirrer and a thermometer. The flask was cooled with an ice/H2O bath and dry reagent grade CH3NH2 was passed into the mixture. The flask was then allowed to warm up to room temperature and refluxed for 20 hours.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)(=[O:9])=[O:8])=[CH:4][CH:3]=1.CCOC(OC(OCC)=O)=O.[CH:30]1([N:36]2[CH2:41][CH2:40][N:39]([C:42]3[CH:47]=[C:46]([CH2:48][NH2:49])[CH:45]=[C:44]([C:50]4[CH:55]=[CH:54][C:53]([C:56]([F:59])([F:58])[F:57])=[CH:52][CH:51]=4)[N:43]=3)[CH2:38][CH2:37]2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C1COCC1>[Cl:1][C:2]1[S:6][C:5]([S:7]([N:10]([CH2:17][CH3:18])[C:11]2([C:14]([NH:49][CH2:48][C:46]3[CH:45]=[C:44]([C:50]4[CH:51]=[CH:52][C:53]([C:56]([F:59])([F:57])[F:58])=[CH:54][CH:55]=4)[N:43]=[C:42]([N:39]4[CH2:38][CH2:37][N:36]([CH:30]5[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]5)[CH2:41][CH2:40]4)[CH:47]=3)=[O:16])[CH2:12][CH2:13]2)(=[O:8])=[O:9])=[CH:4][CH:3]=1
Reactant: NCc1cc(-c2ccc(C(F)(F)F)cc2)nc(N2CCN(C3CCCCC3)CC2)c1
Reactant: CCN(C1(C(=O)O)CC1)S(=O)(=O)c1ccc(Cl)s1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: CCN(C1(C(=O)NCc2cc(-c3ccc(C(F)(F)F)cc3)nc(N3CCN(C4CCCCC4)CC3)c2)CC1)S(=O)(=O)c1ccc(Cl)s1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 10.3 %

Procedure:
A solution of acid 18 (463 mg, 1.5 mmol) in THF (30 mL) was added with DEPC (0.23 mL, 1.0 mol eq) and the mixture was stirred at room temperature for about 5 minutes. Then [2-[4-(cyclopropylmethyl)piperazin-1-yl]-6-[4-(trifluoromethyl)phenyl]-4-pyridyl]methanamine 27E (628 mg, 1.04 mol eq) and a catalytic amount of TEA were added, then the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure, the residue was suspended in EtOAc (40 mL) and washed with water (50 mL) and brine. The separated organic phase was dried over Na2SO4 and evaporated under reduced pressure and the residue was purified by flash chromatography (9:1 EtOAc:methanol) to afford a white solid (110 mg) after crystallization from diethyl ether. Yield=10%, 1HNMR (DMSO, 200 MHz) δ 1.15 (bm, 9H), 1.80 (bm, 4H), 2.35 (bm, 1H), 2.59 (bm, 4H), 3.37 (bm, 2H), 3.65 (bm, 4H), 4.45 (bd, 2H), 6.89 (s, 1H), 7.35 (m, 2H), 7.60 (d, 1H, J=3.4), 7.82 (d, 2H, J=8), 8.25 (bm, 3H). [M+1] 711.65 (C33H39ClF3N5O3S2 requires 710.27).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28]Br)=[CH:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=2)=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(O)cc1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccc(C(F)(F)F)cc2)cc1
Yield: 59.8 %

Procedure:
Followed the same procedure as that of step 2 in Example 91 with the use of (R)-2-(4-hydroxy-phenoxymethyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (150 mg, 0.5 mmol) and 4-trifluoromethyl-benzyl bromide (145 mg, 0.6 mmol) to afford title product (135 mg, 60% yield); LCMS; 100% APCI+, Calcd: +451.49. Found m/z: 452.3 (M+1). 1H NMR (400 MHz, CDCl3); δ 1.47 (s, 9H), 1.80-2.09 (m, 4H), 3.28-3.46 (m, 2H), 3.69-3.91 (m, 1H), 4.02-4.18 (m 2H), 5.07 (s, 2H), 6.87 (s, 4H), 7.53 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.0 Hz, 2H).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[Na+].[Na+].[C:16]1(B(O)O)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1.O.O.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>[C:16]1([C:2]2[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(Cl)cn1
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-c2ccccc2)cn1
Yield: 24.5 %

Procedure:
To a stirred solution of 5-chloro-2-cyanopyridine (300 mg, 2.17 mmol) in toluene: H2O (7:3) (10 mL) was added Na2CO3 (459 mg, 4.33 mmol) followed by Pd(PPh3)4 (500 mg, 0.43 mmol) and phenylboronic acid (337 mg, 2.60 mmol) at room temperature. The resulting mixture was heated to reflux for 3 hrs. The reaction mixture was then diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated brine solution, dried over sodium sulphate and concentrated. The resulting residue was purified by column chromatography (using silica gel 60-120 mesh and 4% ethylacetate in hexane as eluent) to afford 96 mg (24.6% yield) of 5-phenyl-pyridine-2-carbonitrile. LCMS Purity: 97.5%
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[N:26]=[N:25][C:24]([N:27]2[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1>CC#N>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:33][CH:30]2[CH2:31][CH2:32][N:27]([C:24]3[N:25]=[N:26][C:21]([Cl:20])=[CH:22][CH:23]=3)[CH2:28][CH2:29]2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NC1CCN(c2ccc(Cl)nn2)CC1
Solvent: CC#N
Product: CC(C)(C)N1C(=O)C(NC2CCN(c3ccc(Cl)nn3)CC2)=C(c2ccccc2)S1(=O)=O
Temperature: 120 °C
Yield: 26.8 %

Procedure:
2-tert-Butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.450 g, 1.50 mmol), 1-(6-chloropyridazin-3-yl)piperidin-4-amine (0.487 g, 1.95 mmol) and TEA (0.456 g, 4.50 mmol) was dissolved in dry MeCN (15 ml) and heated in a microwave reactor at 120° C. for 30 mins. The reaction mixture was evaporated and the residue was diluted with EtOAc (150 ml) and washed with water (500 ml). The organic phase was dried over MgSO4, filtered and evaporated. The residue was purified by silica gel column chromatography using a 60:40→50:50 mixture of heptane and EtOAc as eluant, to give the title compound (0.191 g, 27%). 1H NMR (500 MHz, CDCl3): δ 7.55-7.50 (m, 2H), 7.47-7.43 (m, 3H), 7.15 (d, 1H), 6.81 (d, 1H), 5.20 (d, 1H), 4.11-4.05 (m, 2H), 3.22-3.13 (m, 1H), 2.60-2.52 (m, 2H), 1.80-1.73 (m, 2H), 1.72 (s, 9H), 1.41-1.32 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 159.5, 158.6, 147, 133.8, 131.6, 130, 128.8, 128.7, 125, 115.4, 107.3, 61.6, 50, 43.8, 31.6, 27.6.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[CH:7][C:8]([OH:11])=[CH:9][CH:10]=1.N1C=CC=CC=1.[C:18](Cl)(=[O:20])[CH3:19]>ClCCl>[CH3:1][CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:18]([CH3:19])=[O:20])=[CH:7][CH:6]=1
Reactant: CC(=O)Cl
Reactant: CCCCc1ccc(O)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCc1ccc(OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
4-n-Butylphenol (1.00 g) was dissolved in dichloromethane (10 ml) to prepare a solution. Pyridine (783 mg) and acetyl chloride (675 mg) were added to the solution, and the mixture was stirred at room temperature overnight. The solvent was removed by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure. The residue was purified by column chromatography using chloroform to give 4-n-butylphenyl acetate (1.03 g, yield 80%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][NH:29][CH3:30])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:32]([O:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)=[O:33].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[N:15]([CH2:27][CH2:28][N:29]([C:32]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[O:33])[CH3:30])[CH:16]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=3)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CNCCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(CCn1cc(-c2ccc(F)c(Cl)c2)nc1C1CCN(C(=O)OC(C)(C)C)CC1)C(=O)OCc1ccccc1
Reaction time: 0.25 h
Yield: 83.2 %

Procedure:
Dissolve 4-[4-(3-chloro-4-fluoro-phenyl)-1-(2-methylamino-ethyl)-1H-imidazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.56 mmol; 680 mg) in DCM (10 mL) and add benzyl chloroformate (1.56 mmol; 0.23 mL) and DIPEA (3.11 mmol; 0.54 mL). Stir 15 min and evaporate. Purify the residue on 120 g silica gel with DCM to 20% EA/DCM to provide the title compound (741 mg; 83%). MS (ES): m/z=571 (M+H).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:10]=[C:11]([CH:15]=[C:16]([Cl:18])[N:17]=2)[C:12]([NH2:14])=[O:13])[CH2:5][CH2:4]1.[CH2:19]([C:21]1[C:25]([CH2:26][CH3:27])=[C:24]([CH3:28])[NH:23][C:22]=1[C:29](O)=[O:30])[CH3:20]>>[Cl:18][C:16]1[CH:15]=[C:11]([CH:10]=[C:9]([N:6]2[CH2:5][CH2:4][CH:3]([NH:2][C:29]([C:22]3[NH:23][C:24]([CH3:28])=[C:25]([CH2:26][CH3:27])[C:21]=3[CH2:19][CH3:20])=[O:30])[CH2:8][CH2:7]2)[N:17]=1)[C:12]([NH2:14])=[O:13]
Reactant: NC(=O)c1cc(Cl)nc(N2CCC(N)CC2)c1
Reactant: CCc1c(C)[nH]c(C(=O)O)c1CC
Agent: Cl
Product: CCc1c(C)[nH]c(C(=O)NC2CCN(c3cc(C(N)=O)cc(Cl)n3)CC2)c1CC

Procedure:
Title compound was synthesized by an analogous method to Example 18 by coupling 2-(4-aminopiperidin-1-yl)-6-chloroisonicotinamide hydrochloride (Intermediate 70) with 3,4-diethyl-5-methyl-1H-pyrrole-2-carboxylic acid (commercially available).
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=[C:9]([OH:17])[CH:8]=1)=[O:6].[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)=[O:24])([CH3:21])([CH3:20])[CH3:19].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>O>[C:18]([O:22][C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:5](=[O:6])[NH:4][CH2:3][CH2:2][OH:1])=[CH:8][C:9]1=[O:17])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: O=C(NCCO)c1cc(O)nc2ccccc12
Reactant: CC(C)(C)OC(=O)NCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCCCn1c(=O)cc(C(=O)NCCO)c2ccccc21
Temperature: 60 °C
Reaction time: 6 h

Procedure:
A mixture of 4-(2-hydroxy-1-ethylcarbamoyl)-2-hydroxyquinoline (1.2 g), N-(tert-butoxycarbonyl)-6-bromo-hexylamine (2.2 g), cesium carbonate (4 g) and N,N-dimethylformamide (50 ml) was stirred for 6 hours at 60° C. followed by stirring overnight at room temperature. Ice and water were added and the mixture was extracted three times with ethyl acetate. The organic phases were washed with saturated sodium chloride, dried and evaporated to leave a yellow oil which after purification by chromatography on silica gel with ethyl acetate/methanol/aqueous ammonia (45:5:1.5) as eluent gave the desired compound as a light brown solid.
Reaction SMILES: [CH2:1]([N:13]1[CH2:17][C@@H:16]([O:18][C:19]2[CH:24]=[CH:23][C:22](I)=[CH:21][CH:20]=2)[CH2:15][C@H:14]1[C:26]([O:28][CH3:29])=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[F:30][C:31]([F:37])([F:36])[CH:32]([OH:35])[CH:33]=[CH2:34].C(N(CCCC(OCC)=O)CCOC1C=CC(/C=C/C(O)C(F)(F)F)=CC=1)CCCCCCCCCCC>>[CH2:1]([N:13]1[CH2:17][C@@H:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:34][CH2:33][C:32](=[O:35])[C:31]([F:37])([F:36])[F:30])=[CH:21][CH:20]=2)[CH2:15][C@H:14]1[C:26]([O:28][CH3:29])=[O:27])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(I)cc2)C[C@H]1C(=O)OC
Reactant: C=CC(O)C(F)(F)F
Agent: CCCCCCCCCCCCN(CCCC(=O)OCC)CCOc1ccc(/C=C/C(O)C(F)(F)F)cc1
Product: CCCCCCCCCCCCN1C[C@@H](Oc2ccc(CCC(=O)C(F)(F)F)cc2)C[C@H]1C(=O)OC
Yield: 8.5 %

Procedure:
(2S, 4S)-1-N-Dodecyl-4-(4-iodophenoxy)pyrrolidine-2-carboxylic acid, methyl ester (800 mg, 1.55 mmol) and 4,4,4-trifluorobut-1-en-3-ol (complex with 1 tetrahydrofuran, 620 mg, 3.1 mmol) were reacted by the general procedure as described in the preparation of 4-[N-dodecyl-N-2-[4-(E)-[3-hydroxy-4,4,4-trifluorobut-1-en-1-yl]phenoxy]ethylamino]butanoic acid, ethyl ester and afforded the title compound (575 mg, 72%) as a colorless oil [[a]D=−28.7° (c 0.8, CHCl3)] and (2S, 4S)-1-N-dodecyl-4-[4-(3-oxo-4,4,4-trifluorobut-1-yl)phenoxy]pyrrolidine-2-carboxylic acid, methyl ester (68 mg, 9%) as a pale yellow oil.
Reaction SMILES: [C:1](=O)([O:21]N1C(=O)CCC1=O)[O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:20])[NH:16][CH:17]3[CH2:19][CH2:18]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH3:30][NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:44]=[CH:43][N:42]=[CH:41][CH:40]=2)[CH:34]=1.C(N(CC)CC)C>ClCCl>[CH3:30][N:31]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]2[CH:40]=[CH:41][N:42]=[CH:43][CH:44]=2)[CH:34]=1)[C:1](=[O:21])[O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:20])[NH:16][CH:17]3[CH2:19][CH2:18]3)=[CH:11][CH:10]=2)=[CH:7][CH:8]=1
Reactant: O=C(Oc1ccc(-c2ccc(C(=O)NC3CC3)cc2)cc1)ON1C(=O)CCC1=O
Reactant: CNCc1cccc(-c2ccncc2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(Cc1cccc(-c2ccncc2)c1)C(=O)Oc1ccc(-c2ccc(C(=O)NC3CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 100-mL round-bottom flask was placed a solution of 4-[4-(cyclopropylcarbamoyl)phenyl]phenyl 2,5-dioxopyrrolidin-1-yl carbonate (600 mg, 1.52 mmol, 1.00 equiv) in dichloromethane (40 mL), N-methyl([[3-(pyridin-4-yl)phenyl]methyl])amine (301 mg, 1.52 mmol, 1.00 equiv) and triethylamine (153 mg, 1.51 mmol, 0.99 equiv). The resulting solution was stirred overnight at room temperature. The reaction mixture was washed with 2×20 mL of water and dried over anhydrous sodium sulfate. The resulting mixture was concentrated under vacuum. The crude product (650 mg) was purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-002(Agilent)): Column, SunFire Prep C18, 19*150 mm 5 um; mobile phase, water and acetonitrile (10.0% acetonitrile up to 80.0% in 10 min, up to 100.0% in 1 min, down to 10.0% in 2 min); Detector, uv 220 & 254 nm. The title compound was obtained as a white solid.