Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][C:7]([S:11][CH3:12])=[N:8][CH:9]=2)[NH:4][N:3]=1.[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.P(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[CH3:12][S:11][C:7]1[N:6]=[C:5]2[NH:4][N:3]=[C:2]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:10]2=[CH:9][N:8]=1
Reactant: OB(O)c1ccccc1
Reactant: CSc1ncc2c(Br)n[nH]c2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=[PH]([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CSc1ncc2c(-c3ccccc3)n[nH]c2n1
Temperature: 150 °C
Yield: 87.7 %

Procedure:
A microwave tube was charged with 3-bromo-6-(methylthio)-1H-pyrazolo[3,4-d]pyrimidine (1.0 g, 4.0 mmol), phenylboronic acid (1.5 g, 12 mmol), potassium phosphonate (2.5 g, 12 mmol), tetrakis(triphenylphosphine)palladium (0.35 g, 0.30 mmol), dioxane (16 mL) and water (4 mL). The mixture was heated in microwave at 150° C. for 20 min. The reaction mixture was poured into water. The aqueous layer was extracted with EtOAc (10×). The combined organic layer was dried (Na2SO4), concentrated, and purified to provide 6-(methylthio)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidine (0.85 g, 87%) as a white solid. MS m/z 243.1 [M+H]+.
Reaction SMILES: [CH:1]1([N:4]([CH3:21])[CH:5]2[CH2:14][CH2:13][C:12]([CH3:16])([CH3:15])[C:11]3[CH:10]=[C:9]([C:17]#[CH:18])[CH:8]=[C:7]([O:19][CH3:20])[C:6]2=3)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:31]=[CH:30][C:29](I)=[CH:28][CH:27]=1.C(N(CC)CC)C.C(OCC)(=O)C>CCCCCC.[Cu]I>[CH3:22][O:23][C:24](=[O:33])[CH2:25][C:26]1[CH:27]=[CH:28][C:29]([C:18]#[C:17][C:9]2[CH:8]=[C:7]([O:19][CH3:20])[C:6]3[CH:5]([N:4]([CH:1]4[CH2:3][CH2:2]4)[CH3:21])[CH2:14][CH2:13][C:12]([CH3:15])([CH3:16])[C:11]=3[CH:10]=2)=[CH:30][CH:31]=1
Reactant: C#Cc1cc(OC)c2c(c1)C(C)(C)CCC2N(C)C1CC1
Reactant: COC(=O)Cc1ccc(I)cc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc(C#Cc2cc(OC)c3c(c2)C(C)(C)CCC3N(C)C2CC2)cc1

Procedure:
Following General Procedure B and using 5-(cyclopropyl-methyl-amino)-2-ethynyl-8,8-dimethyl-4-methoxy-5,6,7,8-tetrahydro-naphthalene (Intermediate 81, 0.065 g, 0.23 mmol), methyl-4-iodophenylacetate (0.063 g, 0.23 mmol), triethyl amine (8 mL), copper(I)iodide (0.018 g, 0.093 mmol) and dichlorobis(triphenylphosphine)palladium(I) (0.065 g, 0.093 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 5-20% ethyl acetate in hexane as the eluent, the title compound was obtained as a yellow solid (0.09 g, 90%).
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[S:15][C:14]([C:16]([OH:18])=O)=[CH:13][CH:12]=2)=[N:4][O:5][C:6]=1[C:7]([F:10])([F:9])[F:8].[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH2:22]>>[Cl:19][C:20]1[CH:26]=[CH:25][CH:24]=[CH:23][C:21]=1[NH:22][C:16]([C:14]1[S:15][C:11]([C:3]2[C:2]([CH3:1])=[C:6]([C:7]([F:8])([F:9])[F:10])[O:5][N:4]=2)=[CH:12][CH:13]=1)=[O:18]
Reactant: Nc1ccccc1Cl
Reactant: Cc1c(-c2ccc(C(=O)O)s2)noc1C(F)(F)F
Product: Cc1c(-c2ccc(C(=O)Nc3ccccc3Cl)s2)noc1C(F)(F)F
Yield: 43 %

Procedure:
Prepared from 5-(4-Methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophene-2-carboxylic acid and 2-chloroaniline by the method described in Example 2 Method B. The reaction mixture was evaporated in vacuo, triturated and filtered with the aid of water, then washed with an aqueous 1 N hydrochloric acid solution followed by water. The crude solid was then chromatographed on silica gel with EtOAc/hexanes (10 then 15%) as eluant to afford product as a colorless solid (42 mg, 43%). 1H NMR (CDCl3) 2.39 (d, J=1.3, 3 H), 7.10 (td, J=7.9, 1.3, 1 H), 7.33 (td, J=7.9, 1.3, 1 H), 7.42 (dd, J=8.3, 1.8, 1 H), 7.56 (d, J=4.0, 1 H), 7.69 (d, J=4.0, 1 H), 8.34 (s, 1 H), 8.46 (dd, J=1.3, 1 H). 13C NMR 8.0, 114.8, 118.7 (q, J=271), 123.2, 125.4, 128.2, 129.0, 129.3, 134.0, 134.3, 141.7, 155.5 (q, J=40), 157.8, 159.0. 19F NMR −63.1. LC/MS 7.19 min, [M+1]+ 387.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21](I)[C:16]2=[CH:15][N:14]=1.[CH3:23][N:24]([CH3:46])[CH2:25][CH2:26][N:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=2)[C:28]1=[O:45]>>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[C:17]2[NH:19][N:20]=[C:21]([C:32]3[CH:33]=[C:34]4[C:29](=[CH:30][CH:31]=3)[C:28](=[O:45])[N:27]([CH2:26][CH2:25][N:24]([CH3:46])[CH3:23])[CH2:35]4)[C:16]2=[CH:15][N:14]=1
Reactant: CN(C)CCN1Cc2cc(B3OC(C)(C)C(C)(C)O3)ccc2C1=O
Reactant: COc1cc(OC)c(F)c(-c2ncc3c(I)n[nH]c3n2)c1F
Product: COc1cc(OC)c(F)c(-c2ncc3c(-c4ccc5c(c4)CN(CCN(C)C)C5=O)n[nH]c3n2)c1F

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 4, Step 2 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 2-[2-(dimethylamino)ethyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolin-1-one. LCMS (M+H)+=495.1.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.[Cl:5][C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[C:10](Cl)[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:7]=1[C:19]([F:22])([F:21])[F:20]>C1CCCCC1>[CH:1]1([NH:4][C:10]2[C:9]([N+:16]([O-:18])=[O:17])=[CH:8][C:7]([C:19]([F:20])([F:21])[F:22])=[C:6]([Cl:5])[C:11]=2[N+:12]([O-:14])=[O:13])[CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: NC1CC1
Solvent: C1CCCCC1
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1NC1CC1

Procedure:
The compound was prepared by reacting cyclopropylamine with 2,4-dichloro-3,5-dinitrobenzotrifluoride in cyclohexane to give the product having a melting point of 86°-87° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([F:40])[C:28]=1[O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])[CH2:5][CH:6](/[CH:17]=[CH:18]/[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])[CH2:7][CH2:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].[C:47]([C:51]1[CH:58]=[CH:57][C:54]([CH2:55]Br)=[CH:53][CH:52]=1)([CH3:50])([CH3:49])[CH3:48]>C(#N)C.C(OCC)(=O)C>[C:47]([C:51]1[CH:52]=[CH:53][C:54]([CH2:55][O:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2/[CH:18]=[CH:17]/[CH:6]([CH2:5][C:4]2[CH:26]=[C:27]([F:40])[C:28]([O:29][Si:30]([CH:37]([CH3:39])[CH3:38])([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:32])[CH3:33])=[C:2]([F:1])[CH:3]=2)[CH2:7][CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]#[N:14])=[CH:15][CH:16]=2)=[CH:57][CH:58]=1)([CH3:50])([CH3:48])[CH3:49]
Reactant: CC(C)[Si](Oc1c(F)cc(CC(/C=C/c2ccccc2O)CCc2ccc(C#N)cc2)cc1F)(C(C)C)C(C)C
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)[Si](Oc1c(F)cc(CC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCc2ccc(C#N)cc2)cc1F)(C(C)C)C(C)C

Procedure:
1.7 g (3 mmol) of 4-[(4E)-3-{3,5-difluoro-4-[(triisopropylsilyl)oxy]benzyl}-5-(2-hydroxyphenyl)pent-4-en-1-yl]benzonitrile in 35 ml of acetonitrile are mixed with 627 mg (4.5 mmol) of potassium carbonate and 1 g (4.5 mmol) of 4-tert-butylbenzyl bromide and stirred under reflux for 12 hours. The solvent is stripped off in vacuo, and the residue is taken up in ethyl acetate. The organic phase is washed once with sodium bicarbonate solution and once with sodium chloride solution, dried over sodium sulfate and concentrated. The crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 10:1). 628 mg (85% purity, 0.76 mmol, 25% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]=[CH:2][C:3](=[CH2:5])[CH3:4].[CH:6]([Li])([CH2:8][CH3:9])[CH3:7]>C1CCCCC1>[CH2:1]=[CH:2][C:3](=[CH2:4])[CH3:5].[CH2:9]=[CH:8][C:6]1[CH:7]=[CH:4][CH:3]=[CH:2][CH:1]=1.[CH2:1]=[CH:2][C:3](=[CH2:4])[CH3:5]
Reactant: [Li]C(C)CC
Solvent: C1CCCCC1
Solvent: C=CC(=C)C
Product: C=Cc1ccccc1
Reaction time: 2.5 h

Procedure:
A living poly(isoprene/styrene/isoprene) three block copolymer was prepared by polymerizing isoprene (151.3 g) in cyclohexane (1362 g) solution. Polymerization was initiated by the addition of 79.5 ml of a 95 mmole/liter solution of secondary butyllithium. The reaction was continued for 2.5 hours at 50° C. The living polyisoprene (number average molecular weight 25,600) solution formed was then reacted with styrene (37.9 g) and the reaction was continued for a further 2.5 hours at 50° C. The living poly(isoprene/styrene) block copolymer (number average molecular weight 31,200) solution formed was then reacted with a further amount of isoprene (151.3 g) and the reaction was continued for a further 2.5 hours at 50° C. The number average molecular weight of the living poly(isoprene/styrene/isoprene) block copolymer was 54,400.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:3]=1[C:4]([NH:9][CH2:10][CH2:11][CH3:12])=NCCC.C(O[C:22]([O:31][CH2:32][CH2:33][CH3:34])(OCCC)OCCC)CC>>[Cl:17][C:14]1[CH:13]=[C:3]2[C:2](=[CH:16][CH:15]=1)[N:1]=[C:22]([O:31][CH2:32][CH2:33][CH3:34])[N:9]([CH2:10][CH2:11][CH3:12])[C:4]2=[CH:4][CH2:3][CH2:2][NH2:1]
Reactant: CCCN=C(NCCC)c1cc(Cl)ccc1N
Reactant: CCCOC(OCCC)(OCCC)OCCC
Product: CCCOC1=Nc2ccc(Cl)cc2C(=CCCN)N1CCC

Procedure:
In a small distillation apparatus 2.5 g (9.8 mmol) of 2-amino-5-chloro-N,N′-dipropylbenzamidine and 3.4 g (13.8 mmol) tetra-n-propylorthocarbonate are heated at 135° C. for 14 hours. Then propanol and excess tetra-n-propylorthocarbonate are distilled off in a water jet vacuum and the residue is purified by column chromatography on silica gel (eluant: hexane/tert.butylmethylether 10:1). Yield: 1.1 g of (6-chloro-2-propoxy-3-propyl-3H-quinazolidine-4-ylidene)propylamine in the form of brownish crystals, m.p. 50-51° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][C:16]2[N:24]=[C:23]3[C:19]([N:20]=[CH:21][N:22]3[C@@H:25]3[CH2:29][C@H:28]([N:30]4[CH:34]=[C:33]([CH3:35])[CH:32]=[N:31]4)[C@@H:27]([OH:36])[C@H:26]3[OH:37])=[C:18]([NH:38][CH2:39][CH:40]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=3)[C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[N:17]=2)[CH2:11][CH2:10]1.C1(C)C=CC=CC=1.CC(O)C.[N:64]1[CH:69]=[CH:68][CH:67]=[CH:66][C:65]=1[N:70]1[CH2:75][CH2:74][CH:73]([NH:76][C:77](N2C=CN=C2)=[O:78])[CH2:72][CH2:71]1>C(Cl)Cl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[OH:37][C@@H:26]1[C@H:27]([OH:36])[C@@H:28]([N:30]2[CH:34]=[C:33]([CH3:35])[CH:32]=[N:31]2)[CH2:29][C@H:25]1[N:22]1[CH:21]=[N:20][C:19]2[C:23]1=[N:24][C:16]([NH:15][CH:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:77]([NH:76][CH:73]3[CH2:72][CH2:71][N:70]([C:65]4[CH:66]=[CH:67][CH:68]=[CH:69][N:64]=4)[CH2:75][CH2:74]3)=[O:78])[CH2:14][CH2:13]1)=[N:17][C:18]=2[NH:38][CH2:39][CH:40]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[C:47]1[CH:48]=[CH:49][CH:50]=[CH:51][CH:52]=1
Reactant: O=C(NC1CCN(c2ccccn2)CC1)n1ccnc1
Reactant: Cc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCC(N)CC5)nc43)[C@H](O)[C@@H]2O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CC(C)O
Product: Cc1cnn([C@H]2C[C@@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(NC5CCC(NC(=O)NC6CCN(c7ccccn7)CC6)CC5)nc43)[C@H](O)[C@@H]2O)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
(1R,2S,3R,5S)-3-[2-(4-Amino-cyclohexylamino)-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-5-(4-methyl-pyrazol-1-yl)-cyclopentane-1,2-diol trifluoroacetate (Example 1) (0.020 g, 0.028 mmol) is dissolved in DCM (2 ml). Toluene (2 ml) and iPrOH (1 ml) are added followed by N-[1-(2-pyridinyl)-4-piperidinyl]-1H-imidazole-1-carboxamide (which is prepared using the method described in international patent application WO 01/94368) (0.03 mmol of a 0.1 M solution in DCM). The dichloromethane is removed by vacuo and the reaction mixture is stirred at room temperature. The reaction is shown to be complete by LCMS after 48 hours. The solvent is removed in vacuo. The title compound is obtained by flash column chromatography (Isolute™ C18, 0-100% acetonitrile in water—0.1% TFA). MS (ES+) m/e 811.5 (MH+).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([NH:21][C:22]3[CH:23]=[N:24][C:25](Cl)=[CH:26][C:27]=3[CH3:28])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([NH:21][C:22]3[CH:23]=[N:24][C:25]([N:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)=[CH:26][C:27]=3[CH3:28])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1cc(Cl)ncc1Nc1ncnc(OC2CCN(C(=O)OC(C)C)CC2)c1C
Reactant: C1COCCN1
Product: Cc1cc(N2CCOCC2)ncc1Nc1ncnc(OC2CCN(C(=O)OC(C)C)CC2)c1C
Yield: 74 %

Procedure:
A solution of 4-[6-(6-chloro-4-methyl-pyridin-3-ylamino)-5-methyl-pyrimidin-4-yloxy]-piperidine-1-carboxylic acid isopropyl ester (223 mg, 0.53 mmol) in 4.5 mL morpholine was reacted under microwave irradiation at 180° C. for 16 hours. Mixture was concentrated and purified by HPLC to give Compound A102 as a white solid (200 mg, 74%). 1H NMR (MeOH-d4, 400 MHz) δ 1.16-1.18 (d, 6H), 1.64-1.71 (m, 2H), 1.89-1.98 (m, 2H), 2.10 (s, 3H), 2.28 (s, 3H), 3.31-3.38 (m, 2H), 3.61-3.69 (m, 6H), 3.78-3.80 (m, 4H), 4.77-4.82 (m, 1H), 5.28-5.35 (m, 1H), 7.34 (s, 1H), 7.98 (s, 1H), 8.16 (s, 1H). Exact mass calculated for C24H34N6O4 470.26, found 471.4 (MH+).
Reaction SMILES: [CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[NH:15][C:16]([NH2:18])=[NH:17])[CH:2]=[CH2:3].CN(C)[CH:21]=[CH:22][C:23]([C:25]1[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=1)=O.C(N(C(C)C)C(C)C)C>C(O)CCC.C(OCC)(=O)C>[CH2:1]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][C:7]=1[NH:15][C:16]1[N:18]=[C:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:21][N:17]=1)[CH:2]=[CH2:3]
Reactant: CN(C)C=CC(=O)c1cccnc1
Reactant: C=CCOCc1ccc([N+](=O)[O-])cc1NC(=N)N
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C=CCOCc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Temperature: 120 °C

Procedure:
A stirred mixture of {2-[(2-propenyloxy)-methyl]-5-nitro-phenyl}-guanidine (3.75 g, 15 mmol), 3-(dimethylamino)-1-(3-pyridinyl)-2-propen-1-one (2.60 g, 15 mmol) and ethyl diisopropylamine (2.6 mL, 15 mmol) in 1-butanol (50 mL) is heated at 120° C. for 20 h. The solvent is then evaporated off under reduced pressure to give a residue which is dissolved in ethyl acetate (100 mL). The resulting mixture is filtered (celite), washed with saturated aqueous sodium chloride (50 mL), dried (MgSO4), filtered and the solvent is evaporated off under reduced pressure to yield the crude product which is purified by column chromatography on silica gel, eluent ethyl acetate, and recrystallised from ethyl acetate-hexane to give the title compound as a yellow crystalline solid, m.p. 213-2150C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]2[C:8]([F:26])([F:25])[CH2:9][O:10][C:11]3[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])=[CH:15][C:12]=3[C:13]=2[N:14]=1)=O.[NH3:27].CO>C1COCC1>[F:25][C:8]1([F:26])[C:7]2[S:6][C:5]([C:3]([NH2:27])=[O:2])=[N:14][C:13]=2[C:12]2[CH:15]=[C:16]([C:19]#[C:20][C:21]([OH:24])([CH3:23])[CH3:22])[CH:17]=[CH:18][C:11]=2[O:10][CH2:9]1
Reactant: N
Reactant: COC(=O)c1nc2c(s1)C(F)(F)COc1ccc(C#CC(C)(C)O)cc1-2
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)sc1C(F)(F)CO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 30 %

Procedure:
To a solution of 4,4-Difluoro-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid methyl ester (86 mg, 0.227 mmol) in THF (5 mL) at room temperature, NH3/CH3OH (self-made, 5 mL) was added. The mixture was stirred at room temperature for 3 h, then concentrated to give a residue which was purified by flash column chromatography (silica gel, EtOAc in hexane from 0 to 50%) to give 4,4-Difluoro-9-(3-hydroxy-3-methyl-but-1-ynyl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide as an off-white solid (25 mg, 30%). 1H NMR (400 MHz, DMSO-d6): δ 8.76 (s, 1H), 8.60 (d, J=2.1 Hz, 1H), 8.18 (s, 1H), 7.46 (dd, J1=8.4 Hz, J2=2.2 Hz, 1H), 7.22 (d, J=8.4 Hz, 1H), 5.49 (s, 1H), 4.75 (t, J=10.7 Hz, 2H), 1.49 (s, 6H); LC-MS (ESI & APCI): 365.4 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([OH:11])=[O:10])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:13]=1.Cl.[CH3:24][CH2:25]OC(C)=O.CCCCCC>CCO>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([O:11][CH2:24][CH3:25])=[O:10])[C:4]=1[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:13]=1
Reactant: CCOC(C)=O
Reactant: CCOC(=O)c1cccc(-c2c(OC)cccc2C(=O)O)c1
Agent: Cl
Solvent: CCCCCC
Solvent: CCO
Product: CCOC(=O)c1cccc(-c2c(OC)cccc2C(=O)OCC)c1
Yield: 73 %

Procedure:
Acid 5a (0.583 g., 1.90 mmol, 1 equiv.) is dissolved in 12 mL of absolute EtOH. Concentrated HCl (0.6 mL) is added, and the mixture heated to reflux for 24 hours. The mixture is then partitioned between EtOAc and water. The organic phase is washed with brine, dried (MgSO4), and concentrated in vacuo. Chromatography on silica gel using 5%, then 10% EtOAc/hexane yields 2-methoxy-3'-carboethoxy-[1,1'-biphenyl]-6-carboxylic acid, ethyl ester (6a) (0.432 g., 1.32 mmol, 73%) as a clear oil: UVmax (CHCl3) 242 nm (ε=12036), 296 nm (ε=4724); 1H NMR (300 MHz, CDCl3) δ 8.01 (m, 1H, ArH), 7.92 (m, 1H, ArH), 7.47-7.40 (m, 3H, ArH), 7.39 (dd, J=8, 8 Hz, 1H, ArH), 7.09 (dd, J= 2, 8 Hz, 1H, ArH), 4.34 (q, J=7 Hz, 2H, CO2CH2), 3.98 (q, J=7 Hz, 2H, CO2CH2), 3.73 (s, 3H, OCH3), 1.35 (t, J=7 Hz, 3H, CH2CH3), 0.91 (t, J=7 Hz, 3H, CH2CH3); 13C NMR (75 MHz, CDCl3) δ 168.04 (C=O), 166.65 (C=O), 156.92, 137.28, 134.11, 133.22, 130.73, 130.07, 129.98, 128.78, 128.22, 127.63, 121.63, 113.87, 60.88, 56.02, 14.34, 13.65; IR (film) 2982, 1718, 1466, 1366, 1298, 1260, 1234, 1110, 1060 cm-1 ; MS (DCI) m/e 329 (MH+), 283 (M--C2H5O). Anal. Calcd for C19H20O5 : C, 69.50; H, 6.14. Found: C, 69.44; H, 6.19.
Reaction SMILES: [CH2:1]1[O:3][CH2:2]1.[CH3:4][CH:5]([CH3:31])[CH:6]([NH:18][C:19]([CH:21]1[CH2:25][CH:24]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:23][NH:22]1)=[O:20])[CH:7]1[CH:12]([OH:13])[CH:11]([OH:14])[CH:10]([OH:15])[CH:9]([S:16][CH3:17])[O:8]1>CO>[CH3:4][CH:5]([CH3:31])[CH:6]([NH:18][C:19]([CH:21]1[CH2:25][CH:24]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:23][N:22]1[CH2:1][CH2:2][OH:3])=[O:20])[CH:7]1[CH:12]([OH:13])[CH:11]([OH:14])[CH:10]([OH:15])[CH:9]([S:16][CH3:17])[O:8]1
Reactant: C1CO1
Reactant: CSC1OC(C(NC(=O)C2CC(CCC(C)C)CN2)C(C)C)C(O)C(O)C1O
Solvent: CO
Product: CSC1OC(C(NC(=O)C2CC(CCC(C)C)CN2CCO)C(C)C)C(O)C(O)C1O
Temperature: 4 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
Ethylene oxide (0.6 mL) was added to a solution of 4-(3-methyl-butyl)-pyrrolidine-2-carboxylic acid [2-methyl-1-(3,4,5-trihydroxy-6-methylsulfanyl-tetrahydro-pyran-2-yl)-propyl]-amide (35.1 mg, 0.084 mmol), prepared as in Example 9, in methanol (3 mL), at 0° C. The reaction mixture was stirred at 4° C. overnight. Additional ethylene oxide (0.6 mL) was added and stirred at 4° C. overnight. The reaction mixture was concentrated and purified by chromatography to give the title compound as a white solid (24.1 mg, 62%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:2]([O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:20])=[CH:17][CH:16]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCOc1ccc(C=O)cc1
Yield: 67.5 %

Procedure:
A mixture of 1-bromododecane (43.5 g, 0.22 mol), 4-hydroxybenzaldehyde (25 g, 0.20 mol), potassium carbonate (69 g, 0.5 mol) and butanone (500 cm3) was heated under reflux for 24 hours. The cooled solution was filtered and the filtrate evaporated down under reduced pressure. The crude product was then distilled at 142° C.@0.6 mmHg, to give a liquid, which crystallised on cooling to yield 39.2 g (67.6%) of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([O:27][CH2:28][CH2:29][NH:30][C:31](=[O:34])[CH2:32][CH3:33])=[N:10][CH:11]=[C:12]([C:14]([N:16]3[C@H:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:19][O:18]C3(C)C)=[O:15])[CH:13]=2)=[CH:4][CH:3]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.O.C(=O)(O)[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([O:27][CH2:28][CH2:29][NH:30][C:31](=[O:34])[CH2:32][CH3:33])=[N:10][CH:11]=[C:12]([CH:13]=2)[C:14]([NH:16][C@@H:20]([CH2:19][OH:18])[CH2:21][CH:22]([CH3:24])[CH3:23])=[O:15])=[CH:6][CH:7]=1
Reactant: CCC(=O)NCCOc1ncc(C(=O)N2[C@H](CC(C)C)COC2(C)C)cc1-c1ccc(Cl)cc1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(=O)NCCOc1ncc(C(=O)N[C@@H](CO)CC(C)C)cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.7 %

Procedure:
N-{2-[3-(4-Chloro-phenyl)-5-((R)-4-isobutyl-2,2-dimethyl-oxazolidine-3-carbonyl)-pyridin-2-yloxy]-ethyl}-propionamide (82 mg, 0.16 mmol) was dissolved in methanol (0.35 mL). To the solution was added camphorsulfonic acid (1.6 mg, 0.007 mmol) and the reaction mixture was stirred for 1 h at RT. The mixture was poured into water, sodiumbicarbonate was added and the mixture extracted with ethyl acetate. Organic phases were pooled, the solvent was evaporated in vacuo and the residue was purified by column chromatography on silica (dichloromethane/methanol gradient) to yield 55 mg of the title compound as a white solid, MS (ISP) 448.3 (M+H)+.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1[CH:19]=[C:20]([O:24][CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:21]=[N:22][CH:23]=1)(C1C=CC(C)=CC=1)(=O)=O.CCCC[N+](CCCC)(CCCC)CCCC.[F-:55]>C1COCC1>[F:55][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]1[CH:19]=[C:20]([O:24][CH2:25][C@@H:26]2[CH2:30][CH2:29][CH2:28][N:27]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH:21]=[N:22][CH:23]=1
Reactant: Cc1ccc(S(=O)(=O)OCCCCC#Cc2cncc(OC[C@@H]3CCCN3C(=O)OC(C)(C)C)c2)cc1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1COc1cncc(C#CCCCCF)c1
Yield: 97 %

Procedure:
A mixture of 5-(6-tosyloxy-1-hexynyl)-3-(1-tert-butoxycarbonyl -2(S)-pyrrolidinylmethoxy)pyridine (195 mg, 0.37 mmol) and in 2 mL of 1.0 M solution of TBAF in THF was stirred at room temperature for 15 h. The reaction mixture concentrated. The residue was purified by chromatography with hexane-EtOAc (3:1) to give a viscous oil (135 mg, 97%), [α]D=−58 (c 0.44, CHCl3). 1H NMR (CDCl3) δ 8.21 (m, 2H), 7.23 (br s, 1H), 4.52 (dt, 2H, J=47.3, 6.0 Hz), 4.14 (br s, 2H), 4.05-3.75 (m, 1H), 3.50-3.25 (m, 2H), 2.49 (t, 2H, J=6.9 Hz), 2.08-1.70 (m, 8H), 1.48 (s, 9H); 13C NMR (CDCl3) δ 154.37, 144.82 and 144.57, 137.38 and 137.08, 123.03, 121.03, 83.56 (d, J=165.2 Hz), 79.53, 68.65 and 68.41, 55.99 and 55.62, 46.97 and 46.60, 29.67 and 29.41, 28.51, 28.03, 24.32 (d, J=4.5 Hz), 23.87, 22.82, 19.04; 19F NMR (CDCl3, CFCl3) δ 131.0 (tt, J=47.3, 24.4 Hz).