Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][NH:9][S:10]([CH3:13])(=[O:12])=[O:11])=[C:6]([CH:14]2[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]2)[CH:5]=[C:4]([C:27]2[C:32]([OH:33])=[CH:31][CH:30]=[CH:29][C:28]=2[O:34][CH2:35][CH:36]2[CH2:38][CH2:37]2)[N:3]=1.C(N(CC)CC)C.Cl[C:47](Cl)([O:49]C(=O)OC(Cl)(Cl)Cl)Cl>O1CCCC1>[CH:36]1([CH2:35][O:34][C:28]2[CH:29]=[CH:30][CH:31]=[C:32]([OH:33])[C:27]=2[C:4]2[CH:5]=[C:6]([CH:14]3[CH2:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]3)[C:7]3[CH2:8][N:9]([S:10]([CH3:13])(=[O:11])=[O:12])[C:47](=[O:49])[NH:1][C:2]=3[N:3]=2)[CH2:37][CH2:38]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3OCC3CC3)nc(N)c2CNS(C)(=O)=O)C1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3OCC3CC3)nc3c2CN(S(C)(=O)=O)C(=O)N3)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.7 %

Procedure:
To a cooled (0° C.) solution of tert-butyl 3-(2-amino-6-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-3-{[(methylsulfonyl)amino]methyl}-4-pyridinyl)-1-piperidinecarboxylate (0.050 g, 0.091 mmol) and triethylamine (0.077 mL, 0.549 mmol) in tetrahydrofuran (15 mL) was added to a solution of triphosgene (0.027 g, 0.091 mmol) in tetrahydrofuran (5 mL) under an argon atmosphere. The mixture was allowed to warm to room temperature, and the stirring was continued for 3 hrs under an argon atmosphere. After quenched by water, the mixture was extracted with ethyl acetate. The separated organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting yellow solid was triturated with diisopropyl ether and collected by filtration to give tert-butyl 3-[7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-3-(methylsulfonyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-5-yl]-1-piperidinecarboxylate as a yellow solid (0.028 g, yield; 55%).
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:28]([O:30][C:31]1[CH:36]=[CH:35][C:34]([N+:37]([O-:39])=[O:38])=[CH:33][CH:32]=1)=[O:29]>>[C:1]([NH:5][C:6]([C:8]1[S:25][C:11]2[N:12]=[C:13]([S:23][CH3:24])[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C:28]([O:30][C:31]4[CH:32]=[CH:33][C:34]([N+:37]([O-:39])=[O:38])=[CH:35][CH:36]=4)=[O:29])[CH:17]=3)[C:10]=2[C:9]=1[NH2:26])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CSc1nc(-c2cccc(O)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1
Product: CSc1nc(-c2cccc(OC(=O)Oc3ccc([N+](=O)[O-])cc3)c2)c2c(N)c(C(=O)NC(C)(C)C)sc2n1

Procedure:
The reaction of tert-butyl 5-amino-2-methylthio-4-(3-hydroxyphenyl)-thieno[2,3-d]pyrimidine-6-carboxamide (example 1f, 400 mg) with p-nitro-phenyl chloroformate (207 mg) was performed according to the methods described in example 1g. Evaporation of the solvent under reduced pressure yielded the crude title compound.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:39])/[C:13](=[N:27]\[O:28][C:29]([CH3:38])([CH3:37])[C:30]([O:32]C(C)(C)C)=[O:31])/[C:14]3[N:15]=[C:16]([NH:19]C(OC(C)(C)C)=O)[S:17][CH:18]=3)[C:9](=[O:40])[N:8]2[S:41]([OH:44])(=[O:43])=[O:42])[CH:5]=[N:4][CH:3]=[N:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:1]1([CH2:6][C@@H:7]2[C@H:10]([NH:11][C:12](=[O:39])/[C:13](=[N:27]\[O:28][C:29]([CH3:38])([CH3:37])[C:30]([OH:32])=[O:31])/[C:14]3[N:15]=[C:16]([NH2:19])[S:17][CH:18]=3)[C:9](=[O:40])[N:8]2[S:41]([OH:44])(=[O:42])=[O:43])[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC(C)(C)C(=O)OC(C)(C)C)C(=O)N[C@@H]2C(=O)N(S(=O)(=O)O)[C@@H]2Cn2cncn2)cs1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(O/N=C(\C(=O)N[C@@H]1C(=O)N(S(=O)(=O)O)[C@@H]1Cn1cncn1)c1csc(N)n1)C(=O)O
Yield: 38.8 %

Procedure:
Followed the general procedure for the acid mediated deprotection using (2R,3S)-2-((1H-1,2,4-triazol-1-yl)methyl)-3-((Z)-2-(((1-(tert-butoxy)-2-methyl-1-oxopropan-2-yl)oxy)imino)-2-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)acetamido)-4-oxoazetidine-1-sulfonic acid (50.1 mg, 0.076 mmol), DCM (760 μL) and TFA (351 μl, 4.56 mmol). The crude residue purified by reverse phase prep HPLC (XSelect CSH, 19×100 mm, 5 μm, C18 column; ACN-water with 0.1% formic acid modifier, 24 mL/min), affording the title compound (14.8 mg, 34%) as a white powder. LCMS: Rt=0.31 min, m/z=503.1 (M+1) Method 2m_acidic; 1H NMR (500 MHz, DMSO-d6) δ 9.39 (d, J=8.83 Hz, 1H), 8.52 (s, 1H), 8.02 (s, 1H), 6.74 (s, 1H), 5.28 (dd, J=8.8, 5.4 Hz, 1H), 4.74-4.64 (m, 1H), 4.58 (d, J=6.9 Hz, 1H), 4.32 (d, J=5.7 Hz, 1H), 1.37 (s, 3H) 1.41 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:14](=[O:16])[CH3:15])[C:3]=1[OH:17].[C:18](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O.O>[Br:1][C:2]1[C:11]2[C:10]([CH3:12])([CH3:13])[CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([C:14](=[O:16])[CH3:15])[C:3]=1[O:17][CH3:18]
Reactant: CC(=O)c1cc2c(c(Br)c1O)C(C)(C)CCC2
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(C(C)=O)cc2c(c1Br)C(C)(C)CCC2
Temperature: 25 °C

Procedure:
To a solution of 1-(4-bromo-3-hydroxy-5,5-dimethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-ethanone (Compound A-91, 11.8 g, 39.7 mmol), potassium carbonate (14.4 g, 119.1 mmol) in acetone (350 mL) was added methyl iodide (19.8 mL, 317.6 mmol). After heating to reflux for 16 h, the mixture was cooled to room temperature, diluted with water and extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo to give the title compound as a yellow oil. The material was used in the next step without further purification.
Reaction SMILES: [C:1]([N:11]([CH3:17])[C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1.[C:49]([O:53][C:54]([N:56]1[CH2:60][CH:59]([O:61][C:62]2[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=2)[CH:58]2[N:70]([C:73](=[O:80])[CH:74]([NH2:79])[C:75]([CH3:78])([CH3:77])[CH3:76])[CH2:71][CH2:72][CH:57]12)=[O:55])([CH3:52])([CH3:51])[CH3:50]>CN1C(=O)CCC1.CCOC(C)=O.CCOCC>[C:49]([O:53][C:54]([N:56]1[CH2:60][CH:59]([O:61][C:62]2[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=2)[CH:58]2[N:70]([C:73](=[O:80])[CH:74]([NH:79][C:14](=[O:16])[CH:12]([N:11]([C:1]([O:3][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:2])[CH3:17])[CH3:13])[C:75]([CH3:78])([CH3:77])[CH3:76])[CH2:71][CH2:72][CH:57]12)=[O:55])([CH3:52])([CH3:50])[CH3:51]
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(F)c(F)c2)C2C1CCN2C(=O)C(N)C(C)(C)C
Reactant: C[C@@H](C(=O)O)N(C)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Solvent: CN1CCOCC1
Product: CC(C(=O)NC(C(=O)N1CCC2C1C(Oc1ccc(F)c(F)c1)CN2C(=O)OC(C)(C)C)C(C)(C)C)N(C)C(=O)OCc1ccccc1
Reaction time: 16 h
Yield: 89.2 %

Procedure:
To a solution Cbz-N(Me)-Ala-OH (1.2 g, 4.8 mmol) and HATU (2.0 g, 5.3 mmol) in NMP (30 mL) was added NMM (0.7 mL) followed by a solution of compound 33 (1.8 g, 4.0 mmol crude) in NMP (30 mL) at ambient temperature. After 16 h, the reaction mixture was diluted with 10% EtOAc in Et2O, washed successively with water, 1N HCl, 1N NaOH, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue was purified by RP-HPLC (2″ Dynamax® C18; 10-100% ACN/water containing 0.1% HOAc over 30 min; Flow: 40 mL/min) to afford 2.4 g of compound 34 as white solid. Mass spectrum, m/z [673.0] (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([N:12]2[CH2:26][CH2:25][C:15]3([O:20][CH2:19][C:18](=[O:21])[N:17]([CH:22]4[CH2:24][CH2:23]4)[CH2:16]3)[CH2:14][CH2:13]2)[C:9]([NH2:11])=[O:10])=[C:4]([F:27])[CH:3]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)O1.C([O-])(=O)C.[K+].Br[C:52]1[CH:61]=[C:60]2[C:55]([CH:56]=[C:57]([F:62])[CH:58]=[N:59]2)=[CH:54][CH:53]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:22]1([N:17]2[CH2:16][C:15]3([CH2:25][CH2:26][N:12]([CH:8]([C:5]4[CH:6]=[CH:7][C:2]([C:52]5[CH:61]=[C:60]6[C:55]([CH:56]=[C:57]([F:62])[CH:58]=[N:59]6)=[CH:54][CH:53]=5)=[CH:3][C:4]=4[F:27])[C:9]([NH2:11])=[O:10])[CH2:13][CH2:14]3)[O:20][CH2:19][C:18]2=[O:21])[CH2:24][CH2:23]1
Reactant: Fc1cnc2cc(Br)ccc2c1
Reactant: NC(=O)C(c1ccc(Br)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: NC(=O)C(c1ccc(-c2ccc3cc(F)cnc3c2)cc1F)N1CCC2(CC1)CN(C1CC1)C(=O)CO2
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(4-bromo-2-fluorophenyl)-2-(4-cyclopropyl-3-oxo-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)acetamide (110 mg, 0.25 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (63 mg, 0.25 mmol), and potassium acetate (49 mg, 0.5 mmol) in 1,4-dioxane (2.5 mL) was added PdCl2(dppf)-CH2Cl2 adduct (20.4 mg, 0.025 mmol). The reaction mixture was purged with nitrogen and then was heated at 120° C. for 4 h. The reaction mixture was cooled and 7-bromo-3-fluoroquinoline (56.5 mg, 0.25 mmol) and 2M aq K2CO3 (0.27 mL, 0.55 mmol) were added. The reaction mixture was purged with nitrogen and was heated with stirring at 100° C. for one hour. The reaction mixture was diluted with dichloromethane (60 mL), and salts were filtered away. The organic mixture was filtered through a plug of celite and sodium sulfate. The filtrate was treated with a small amount of Silicycle Si-thiol resin for 30 min and was then filtered and concentrated in vacuo. Purification of the residue by reverse phase HPLC (10-70% acetonitrile:water with 0.1% NH4OH) followed by chiral HPLC (Chromegachiral CC4, methanol) afforded the title product in >98% ee (34 mg, 27%). αD=+37 deg (c=0.04, methanol); MS(ES)+ m/e 507 [M+H]+; 1H NMR (400 MHz, CD2Cl2) δ ppm 0.60-0.69 (m, 2 H) 0.77-0.86 (m, 2 H) 1.64-1.77 (m, 2 H) 1.85-1.97 (m, 2 H) 2.26-2.38 (m, 1 H) 2.57 (d, J=14.40 Hz, 1 H) 2.66-2.76 (m, 2 H) 2.79 (d, J=10.86 Hz, 1 H) 3.15 (s, 2 H) 4.00 (d, J=1.77 Hz, 2 H) 4.53 (s, 1 H) 5.63 (br. s., 1 H) 7.26 (d, J=3.79 Hz, 1 H) 7.46 (t, J=7.71 Hz, 1 H) 7.56 (d, J=1.77 Hz, 1 H) 7.62 (dd, J=7.96, 1.89 Hz, 1 H) 7.84-7.93 (m, 2 H) 7.93-8.00 (m, 1 H) 8.38 (s, 1 H) 8.88 (d, J=2.78 Hz, 1 H).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=C1CCN(c2ccc(CN3CCOCC3)cc2)CC1
Reactant: C1CCNCC1
Product: c1cc(N2CCC(N3CCCCC3)CC2)ccc1CN1CCOCC1

Procedure:
Prepared from the product of Example 19 and piperidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH3:11])=[O:5])[CH3:2].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.[W]>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][S:9][C:10]=1[CH2:11][Br:12])=[O:5])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)c1ncsc1C
Agent: [W]
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)c1ncsc1CBr
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.6 %

Procedure:
Heat to reflux a mixture of 5-methyl-thiazole-4-carboxylic acid ethyl ester (4.87 g, 28.5 mmol) and N-bromosuccinimide (5.06 g, 28.5 mmol) in CCl4 (100 mL) by irradiation with a 275 watt tungsten sun lamp. After 3 h, cool to room temperature and filter off a tan solid. Concentrate the filtrate by rotavap to give 6.42 g crude product as an orange oil. Purify on silica gel [115 g, 0-15% (2M NH3/MeOH)/(1:1 CH2Cl2/hexanes)] to give 3.61 g (51%) of the title compound as a yellow solid. LC-ES/MS m/z 250, 252 (M+1), TR=2.0 min (86%). Starting material: m/z 172 (M+1), TR=1.7 min (14%).
Reaction SMILES: [CH:1]([CH:9]1[CH:13]([CH:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:12](=[O:25])[CH2:11][CH:10]1[O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].CN(C1C=CC=CN=1)C.CS(Cl)(=O)=O.Cl>ClCCl>[CH:1]([CH:9]1[C:13](=[CH:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])[C:12](=[O:25])[CH2:11][CH:10]1[O:26][Si:27]([C:30]([CH3:31])([CH3:33])[CH3:32])([CH3:29])[CH3:28])=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCC=CC1C(O[Si](C)(C)C(C)(C)C)CC(=O)C1C(O)CCCCCC(=O)OC
Agent: CN(C)c1ccccn1
Agent: CS(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCCCCCC=CC1C(=CCCCCCC(=O)OC)C(=O)CC1O[Si](C)(C)C(C)(C)C
Yield: 61.3 %

Procedure:
3.1 g (6.4 millinmols) of 4-(1-octenyl)-5-(1-hydroxy-6-methoxycarbonylhexyl)-3-(t-butyldimethylsilyloxy)cyclopentanone was dissolved in 40 ml of dichloromethane, and 3.92 g (32.1 mmoles) of dimethylaminopyridine was added. With ice cooling and stirring, 1.0 ml (12.9 mmoles) of methanesulfonyl chloride was added. The mixture was stirred at 0° C. for 5 minutes, and then at room temperature for hours. Furthermore, 0.78 g (6.4 millimoles) of dimethylaminopyridine was added, and the mixture was stirred for 100 minutes. The mixture was poured into 200 ml of 0.5N hydrochloric acid and washed. The aqueous layer was extracted with dichloromethane. The organic layers were combined, washed first with a saturated aqueous solution of sodium bicarbonate and then with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The dried product was filtered, concentratd and subjected to silica gel column chromatography (silica gel 150 g; eluent, hexane:ethyl acetate=20:1 →7:1) to give 1.83 g (yield 61%) of 4-(1-octenyl)-5-(6-methoxycarbonylhexylidene)-3-(t-butyldimethylsilyloxy) cyclopentanone. The spectral data of this compound were as follows.
Reaction SMILES: C([O:5][CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1)(C)(C)C.FC(F)(F)C(O)=O>>[OH:5][CH:6]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[CH2:7][CH2:8][C@@H:9]1[C@@H:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:12](=[O:25])[CH2:11][CH2:10]1
Reactant: CCCCCC(CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCCCCC(O)CC[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)OCC
Reaction time: 0.25 h

Procedure:
A solution of 25 g. of 15-(tert-butoxy)-9-oxoprostanoic acid, ethyl ester in 100 ml. of trifluoroacetic acid is stirred in an ice bath for 1 hour and is then poured into 500 ml. of ice water and extracted several times with chloroform. The combined chloroform extracts are washed with saturated sodium bicarbonate solution, saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and taken to dryness. The resulting oil is dissolved in 200 ml. of 1 N ammonium hydroxide in ethanol, kept at ambient temperature for 15 minutes, then taken to dryness. The residual oil is dissolved in chloroform and washed with 1 N hydrochloric acid, saturated sodium chloride solution, dried and taken to dryness to give 21.7 g. (100%) of product as a yellow syrup. There is essentially no uv absorption; λmaxKBr 2.90, 5.75, 8.45μ; nmr 2H quartet δ4.13 (OCH2 of ester), 1H broad singlet 3.63 (carbinolic proton), 3H triplet (CH3 of ester), and 3H distorted triplet 0.92 (terminal methyl); mass spectrum: m/e 368.
Reaction SMILES: [H-].[CH2:2]([Al+:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH:3]([CH3:5])[CH3:4]>C1(C)C=CC=CC=1>[CH3:4][CH:3]([CH2:2][AlH:6][CH2:7][CH:8]([CH3:10])[CH3:9])[CH3:5]
Reactant: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CC(C)C[AlH]CC(C)C

Procedure:
1M toluene solution of diisobutylaluminum hydride (Tosoh Finechem Corporation)
Reaction SMILES: C([N:3](C(=O)C1C=CC(O)=CC=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[CH:12]1[CH2:21][CH2:20][C:19]2[CH:18]=[C:17]([O:22]C(=O)C(C)(C)C)[CH:16]=[CH:15][C:14]=2[CH2:13]1)C.[CH2:38]([N:42]([CH3:47])[C:43](=O)[CH2:44]Cl)[CH2:39][CH2:40][CH3:41]>>[CH2:38]([N:42]([CH3:47])[CH2:43][CH2:44][O:10][C:8]1[CH:9]=[CH:4][C:5]([CH2:12][CH2:13][CH2:14][NH:3][C:4]2[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=2[CH:12]2[CH2:21][CH2:20][C:19]3[CH:18]=[C:17]([OH:22])[CH:16]=[CH:15][C:14]=3[CH2:13]2)=[CH:6][CH:7]=1)[CH2:39][CH2:40][CH3:41]
Reactant: CCN(C(=O)c1ccc(O)cc1)c1cc(OC)ccc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CCCCN(C)C(=O)CCl
Product: CCCCN(C)CCOc1ccc(CCCNc2cc(OC)ccc2C2CCc3cc(O)ccc3C2)cc1
Yield: 46.6 %

Procedure:
Synthesized from pivalic acid 6-{2-[ethyl(4-hydroxybenzoyl)amino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (20 mg) and N-butyl-2-chloro-N-methylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (4.8 mg) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=3)[CH:14]=2)[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.[C:47]([O:51][C:52](=[O:55])[CH:53]=[CH2:54])([CH3:50])([CH3:49])[CH3:48]>C(Cl)Cl>[C:47]([O:51][C:52](=[O:55])[CH2:53][CH2:54][N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([C:27]([F:29])([F:28])[F:30])[CH:21]=3)[CH:14]=2)[CH2:9]1)([CH3:50])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(COc3ccc(Cl)c(C(F)(F)F)c3)ccc2C1
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCN1CCc2cc(COc3ccc(Cl)c(C(F)(F)F)c3)ccc2C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 6-(4-chloro-3-trifluoromethyl-phenoxymethyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (70 mg, 0.158 mmol) in CH2Cl2 (1 mL) is added TFA(1 mL). The mixture is stirred at room temperature for 30 minutes. All the solvents are removed under reduced pressure. The mixture is dissolved in CH3OH (1.5 mL). Then DIEA (269 μL, 10 eq.) and acrylic acid tert-butyl ester (46 μL, 2 eq.) are added. The mixture is heated to 90° C. for 20 minutes using microwave irradiation. All the solvent is evaporated and the mixture is purified by column chromatography (silica gel, EtOAc/Hexane, gradient) to give 56 mg of 3-[6-(4-chloro-3-trifluoromethyl-phenoxymethyl)-3,4-dihydro-1H-isoquinolin-2-yl]-propionic acid tert-butyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:47]=[CH:46][CH:45]=[CH:44][C:4]=1[CH2:5][O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]2[O:30][CH2:31][CH2:32][O:33]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:13][CH:12]=1.[OH:48][CH2:49][CH2:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1O>>[OH:48][CH2:49][CH2:50][CH2:51][C:52]1[CH:57]=[CH:56][CH:55]=[CH:54][C:53]=1[O:33][CH2:32][CH2:31][O:30][CH:18]1[CH:17]([C:14]2[CH:13]=[CH:12][C:11]([O:10][CH2:9][CH2:8][CH2:7][O:6][CH2:5][C:4]3[CH:44]=[CH:45][CH:46]=[CH:47][C:3]=3[O:2][CH3:1])=[CH:16][CH:15]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:27])[CH3:28])=[O:24])[CH2:19]1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: OCCCc1ccccc1O
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCCOc2ccccc2CCCO)cc1

Procedure:
Analogously to Method F, 2.24 g of tert-butyl 4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}-3-[2-(toluene-4-sulphonyloxy)ethoxy]piperidine-1-carboxylate (Example 14b) and 1.28 g of 2-(3-hydroxypropyl)phenol are reacted. The title compound is obtained as a colourless oil. Rf=0.41 (2:1 EtOAc-heptane); Rt=5.90.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([CH3:43])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([F:14])[C:11]([C:15]([F:17])([F:18])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[C:38]([CH3:43])[N:39]=[C:40]([CH3:42])[CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Reactant: CC(C)(C)OC(=O)Nc1cc(F)c(C(F)(F)F)cc1N
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(F)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-amino-5-fluoro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J37) (221 mg, 0.75 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (301 mg, 74%).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:14][N:13]=2)=[O:10])=[CH:4][CH:3]=1.[NH:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].N1CCC[C@H]1C(O)=O>CS(C)=O.[Cu]I>[N:24]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:14][N:13]=3)=[O:10])=[CH:4][CH:3]=2)[CH:28]=[CH:27][N:26]=[CH:25]1
Reactant: O=C(Cc1ccc(I)cc1)Nc1ccc(-c2ccccc2)cn1
Reactant: c1c[nH]cn1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Solvent: CS(C)=O
Product: O=C(Cc1ccc(-n2ccnc2)cc1)Nc1ccc(-c2ccccc2)cn1
Temperature: 100 °C
Reaction time: 10 h

Procedure:
A mixture of 2-(4-iodophenyl)-N-(5-phenylpyridin-2-yl)acetamide 53-3 (41 mg, 0.1 mmol), imidazole (10 mg, 0.15 mmol), potassium phosphate (41 mg, 0.3 mmol), CuI (2 mg, 0.01 mmol) and L-proline (2.3 mg, 0.02 mmol) in DMSO (0.5 mL) was stirred under an atmosphere of dry Argon at 100° C. for 10 hours. The crude product was purified by reverse phase HPLC to give 2-(4-(1H-imidazol-1-yl)phenyl)-N-(5-phenylpyridin-2-yl)acetamide 53 as white solid. MS m/z 355.1 (M+1); 1H NMR 400 MHz (CDCl3) δ 8.47-8.46 (m, 1H), 8.29 (d, 1H, J=8.8 Hz), 7.99 (s, 1H), 7.92 (dd, 1H, J1=16.8 Hz, J2=2.4 Hz), 7.88 (s, 1H), 7.55-7.53 (m, 2H), 7.49-7.38 (m, 6H), 7.29 (s, 1H), 7.23 (s, 1H), 3.83 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:28]=[CH:27][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[N:39][NH:40][CH:41]=2)O1>>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:15]1[C:14]([C:8]2[S:9][C:10]3[CH2:11][CH2:12][O:13][C:4]4[CH:3]=[C:2]([C:37]5[CH:38]=[N:39][NH:40][CH:41]=5)[CH:28]=[CH:27][C:5]=4[C:6]=3[N:7]=2)=[N:18][CH:17]=[N:16]1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Reactant: Fc1ccc(-n2ncnc2-c2nc3c(s2)CCOc2cc(Br)ccc2-3)c(F)c1
Product: Fc1ccc(-n2ncnc2-c2nc3c(s2)CCOc2cc(-c4cn[nH]c4)ccc2-3)c(F)c1

Procedure:
Following the procedure for 114, 8-Bromo-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole to give 144. MS(ESI+) 449.0. 1H NMR (400 MHz, DMSO) δ 12.96 (s, 1H), 8.42 (s, 1H), 8.25 (s, 1H), 7.94 (s, 1H), 7.90-7.83 (m, 1H), 7.74-7.66 (m, 1H), 7.45-7.35 (m, 2H), 7.26 (d, J=1.5, 1H), 7.16 (dd, J=8.3, 1.6, 1H), 4.33 (t, J=4.9, 2H), 3.41 (t, J=4.9, 2H)