Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH:4](C)[C:5]([O:7][CH3:8])=[O:6].N[C@@H:11](C)CC(O)=O>>[ClH:1].[NH2:2][C@@H:3]([CH3:11])[CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)C(C)CN
Reactant: C[C@H](N)CC(=O)O
Agent: Cl
Product: COC(=O)C[C@H](C)N

Procedure:
Compound 58-B was prepared in analogy to compound W in Example 20 by using (S)-3-aminobutanoic acid instead of DL-3-aminoisobutyric acid.
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH2:19][CH2:20][C:21](O)=[O:22])=[C:8]2[CH3:24])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.O>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH2:19][CH2:20][C:21]([NH:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[O:22])=[C:8]2[CH3:24])=[CH:4][CH:3]=1
Reactant: COc1ccc2c(c1)c(CCCC(=O)O)c(C)n2Cc1ccc(Br)cc1
Reactant: Nc1ccccn1
Agent: O=C(Cl)C(=O)Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc2c(c1)c(CCCC(=O)Nc1ccccn1)c(C)n2Cc1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 21.4 %

Procedure:
To the acid of Example 4, (400 mg, 0.96 mmol) in 30 mL CH2Cl2 at 0° C. was added a few drops of DMF followed by oxalyl chloride (100 μL, 1.15 mmol, dropwise). The reaction was stirred 15 min at 0° C., and then 2-amino pyridine (306 mg, 3.26 mmol) was added. The reaction mixture was stirred overnight at r.t., poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4 and evaporated in vacuo. Purification by flash chromatography (20%, ethyl acetate in hexane) provided 101 mg of the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][C:14]=1Br)=[O:5])[CH3:2].[CH2:26]([O:33][C:34]1[C:39](B(O)O)=[CH:38][CH:37]=[CH:36][N:35]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[Na+].[Na+]>CO.C(Cl)Cl.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>[CH2:1]([O:3][C:4]([C@H:6]1[CH2:10][CH2:9][C:8](=[O:11])[N:7]1[CH2:12][C:13]1[CH:18]=[C:17]([O:19][CH3:20])[C:16]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][C:14]=1[C:39]1[C:34]([O:33][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)=[N:35][CH:36]=[CH:37][CH:38]=1)=[O:5])[CH3:2]
Reactant: OB(O)c1cccnc1OCc1ccccc1
Reactant: CCOC(=O)[C@H]1CCC(=O)N1Cc1cc(OC)c(C(C)(C)C)cc1Br
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: ClCCl
Solvent: CO
Product: CCOC(=O)[C@H]1CCC(=O)N1Cc1cc(OC)c(C(C)(C)C)cc1-c1cccnc1OCc1ccccc1
Yield: 75.3 %

Procedure:
step 2—A sealed tube containing 100 (150 mg, 0.36 mmol), 2-benzyloxy-pyridin-3-yl boronic acid (125 mg, 0.56 mmol), Na2CO3 (116 mg, 1.1 mmol) and Pd(PPh3)4 (42 mg, 0.036 mmol) in a mixture of MeOH (1.5 mL) and DCM (0.5 mL) was irradiated on a microwave synthesizer at 100° C. for 30 min. The reaction mixture was diluted with DCM, filtered through a pad of CELITE, and the filtrate was concentrated. The crude residue was purified on a preparative SiO2 TLC plate developed with 50% EtOAc/hexanes to afford 140 mg (84%) of (R)-1-[2-(2-benzyloxy-pyridin-3-yl)-4-tert-butyl-5-methoxy-benzyl]-5-oxo-pyrrolidine-2-carboxylic acid ethyl ester (102).
Reaction SMILES: C(O[C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]([N:19]2[C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=3[CH:23]=[CH:22][C:21]3[CH:30]=[CH:31][CH:32]=[CH:33][C:20]2=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])C1C=CC=CC=1.Br.N1(C(N2C3C=CC=CC=3C=CC3C=CC=CC2=3)=O)CCNCC1.C1(=O)[O:64][C:62](=[O:63])[CH2:61][CH2:60][CH2:59]1>>[C:62]([CH2:61][CH2:60][CH2:59][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]([N:19]2[C:20]3[CH:33]=[CH:32][CH:31]=[CH:30][C:21]=3[CH:22]=[CH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]2=3)=[O:18])[CH2:15][CH2:16]1)=[O:10])([OH:64])=[O:63]
Reactant: O=C1CCCC(=O)O1
Reactant: O=C(OCc1ccccc1)N1CCN(C(=O)N2c3ccccc3C=Cc3ccccc32)CC1
Agent: Br
Agent: O=C(N1CCNCC1)N1c2ccccc2C=Cc2ccccc21
Product: O=C(O)CCCC(=O)N1CCN(C(=O)N2c3ccccc3C=Cc3ccccc32)CC1

Procedure:
These materials were prepared using the procedures outlined in Steps 2 and 3 of Preparatory Example 2, except starting with 5-[4-(benzyloxycarbonyl)piperazinocarbonyl]-5H-dibenzo[b,f]azepine in place of the N-[3-(benzyloxycarbonylamino)propyl]carbamazepine in step 2, and thus the product 5-(Piperazinocarbonyl)-5H-dibenzo-[b,f]azepine Hydrobromide in place of the product of step 2, and glutaric anhydride in place of succinic anhydride in the procedures of step 3. The residue (2B) was crystallized from ethyl acetate (10 mL) and petroleum ether (2 mL), placed in a freezer, and filtered to give the acid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[CH:20]=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1.[CH3:22][N:23]([CH3:33])[CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1.[CH2:34]=O>C(O)C>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[C:11]2\[O:12][C:13]3[C:20]([CH2:34][N:30]4[CH2:29][CH2:28][N:27]([CH2:26][CH2:25][CH2:24][N:23]([CH3:22])[CH3:33])[CH2:32][CH2:31]4)=[C:19]([OH:21])[CH:18]=[CH:17][C:14]=3[C:15]\2=[O:16])=[CH:2]1
Reactant: CN(C)CCCN1CCNCC1
Reactant: C=O
Reactant: O=C1/C(=C/c2c[nH]c3ccccc23)Oc2cc(O)ccc21
Solvent: CCO
Product: CN(C)CCCN1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 43.4 %

Procedure:
The synthesis was performed with reference to the known literature (Heterocycles, Vol. 53, p. 197, 2000). A solution of (Z)-2-[(1H-indol-3-yl)methylene]-6-hydroxybenzofuran-3(2H)-one (0.028 g, 0.10 mmol) in ethanol (2.0 mL) was added with 1-[3-(dimethylamino)propyl]piperazine (0.022 g, 0.13 mmol), and 37% aqueous formaldehyde (0.011 g, 0.13 mmol), and the mixture was stirred overnight at 80° C. in a sealed tube. The solvent was evaporated under reduced pressure, and then the residue was subjected to silica gel column chromatography (aminopropyl silica was used, eluted with chloroform/methanol (90:10)) to obtain (Z)-2-[(1H-indol-3-yl)methylene]-7-({4-[3-(dimethylamino)propyl]piperazin-1-yl}methyl)-6-hydroxybenzofuran-3(2H)-one (0.020 g, 43%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.Cl[CH2:12]Cl.[CH:14]([NH2:16])=O>>[Br:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:14]=[N:16][CH:12]=[N:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NC=O
Reactant: NNc1cccc(Br)c1
Reactant: ClCCl
Agent: Cl
Product: Brc1cccc(-n2cncn2)c1
Temperature: 140 °C

Procedure:
A suspension of 3-bromophenylhydrazine hydrochloride (3.78 g, 17 mmol) in formamide (15 ml) was heated at 140° C. for 16 h. The reaction mixture was cooled to ambient temperature, diluted into dichloromethane (100 ml) and washed with water (2×100 ml). The organic phase was dried over anhydrous magnesium sulphate, filtered and evaporated to dryness to give 1-(3-bromophenyl)-1H-[1,2,4]triazole (3.44 g) as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.57 (1H, s), 8.11 (1H, s), 7.90 (1H, t, J 2 Hz), 7.62-7.64 (1H, m), 7.53-7.55 (1H, m), 7.38 (1H, t, J 8 Hz).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][CH:4]=1.[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[C:28]([F:33])[CH:27]=1>>[ClH:2].[Cl:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:3]2[C:12]3[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[C:10]([O:13][CH3:14])[CH:11]=3)[N:6]=[CH:5][CH:4]=2)=[C:28]([F:33])[CH:27]=1
Reactant: COc1cc2c(Cl)ccnc2cc1OCCCN1CCOCC1
Reactant: Nc1ccc(Cl)cc1F
Agent: Cl
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ccnc2cc1OCCCN1CCOCC1
Yield: 25 %

Procedure:
Using an analogous procedure to that described for Example 31, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinoline hydrochloride (300 mg, 0.73 mmol), (prepared as described for the starting material in Example 7), was reacted with 4-chloro-2-fluoroaniline (160 μl, 1.4 mmol) to give 4-(4-chloro-2-fluoroanilino)-6-methoxy-7-(3-morpholinopropoxy)quinoline hydrochloride (88 mg, 23%).
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]1[C@H:21]([OH:22])[C@H:20]([CH3:23])[CH:19]=[C:18]([CH3:24])[CH:17]=[C:16]([O:25][CH3:26])[C:14](=[O:15])[O:13][C@H:12]([C@H:27]([C@@H:29]([OH:56])[C@@H:30]([C@:32]2([OH:55])[O:37][C@H:36](/[CH:38]=[CH:39]/[CH3:40])[C@@H:35]([CH3:41])[C@H:34]([O:42][C@@H:43]3[O:48][C@H:47]([CH3:49])[C@@H:46]([O:50][C:51]([NH2:53])=[O:52])[C@H:45]([OH:54])[CH2:44]3)[CH2:33]2)[CH3:31])[CH3:28])[C@@H:11]([O:57][CH3:58])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:59])[CH2:6][C@@H:5]([CH3:60])[C@@H:4]1[OH:61].P([O-])([O-])([O-])=O.[CH3:67]O>>[CH3:1][CH2:2][C@@H:3]1[C@H:21]([OH:22])[C@H:20]([CH3:23])[CH:19]=[C:18]([CH3:24])[CH:17]=[C:16]([O:25][CH3:26])[C:14](=[O:15])[O:13][C@H:12]([C@H:27]([C@@H:29]([OH:56])[C@@H:30]([C@:32]2([O:55][CH3:67])[O:37][C@H:36](/[CH:38]=[CH:39]/[CH3:40])[C@@H:35]([CH3:41])[C@H:34]([O:42][C@@H:43]3[O:48][C@H:47]([CH3:49])[C@@H:46]([O:50][C:51]([NH2:53])=[O:52])[C@H:45]([OH:54])[CH2:44]3)[CH2:33]2)[CH3:31])[CH3:28])[C@@H:11]([O:57][CH3:58])[CH:10]=[CH:9][CH:8]=[C:7]([CH3:59])[CH2:6][C@@H:5]([CH3:60])[C@@H:4]1[OH:61]
Reactant: CO
Reactant: C/C=C/[C@H]1O[C@@](O)([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)C(OC)=CC(C)=C[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)CC(C)=CC=C[C@@H]2OC)C[C@@H](O[C@H]2C[C@@H](O)[C@H](OC(N)=O)[C@@H](C)O2)[C@@H]1C
Agent: C/C=C/[C@H]1O[C@@](O)([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)/C(OC)=C/C(C)=C/[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)C/C(C)=C/C=C/[C@@H]2OC)C[C@@H](O[C@H]2C[C@@H](O)[C@H](OC(N)=O)[C@@H](C)O2)[C@@H]1C
Agent: C/C=C/[C@H]1O[C@@](OC)([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)/C(OC)=C/C(C)=C/[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)C/C(C)=C/C=C/[C@@H]2OC)C[C@@H](O[C@H]2C[C@@H](O)[C@H](OC(N)=O)[C@@H](C)O2)[C@@H]1C
Agent: O=P([O-])([O-])[O-]
Product: C/C=C/[C@H]1O[C@@](OC)([C@@H](C)[C@H](O)[C@H](C)[C@H]2OC(=O)C(OC)=CC(C)=C[C@@H](C)[C@@H](O)[C@@H](CC)[C@@H](O)[C@H](C)CC(C)=CC=C[C@@H]2OC)C[C@@H](O[C@H]2C[C@@H](O)[C@H](OC(N)=O)[C@@H](C)O2)[C@@H]1C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
In a thoroughly heated 50 ml flask, 800 mg (0.92 mmol) of concanamycin A are dissolved in 19 ml of dry MeOH. 15 mg of FeCl3 (0.09 mmol, 0.1 equiv.) in 1 ml of MeOH are then added and the mixture is stirred for 15 min at room temperature. After the addition of 20 ml of phosphate buffer (pH=7, Merck), the solution is transferred to a 250 ml flask and the organic solvent is carefully removed in vacuo. The remaining aqueous residue is extracted with CHCl3 and, after customary working-up, is filtered on silica gel (system D, 4×10) to yield the title compound. M.p. 141° C.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:24][S-:25].[Na+]>CN(C=O)C.CCOC(C)=O>[CH3:24][S:25][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: C[S-]
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCOCC3)cc2n1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSc1nc(N2CCOCC2)c2sc(CN3CCOCC3)cc2n1
Temperature: 100 °C
Yield: 99.9 %

Procedure:
2-Chloro-4-morpholin-4-yl-6-morpholin-4-ylmethyl-thieno[3,2-d]pyrimidine (0.2 g, 0.56 mmol) in DMF (3 mL) was treated with sodium thiomethoxide (0.12 g, 1.71 mmol) in a sealed tube and the reaction mixture heated at 100° C. with stirring. After 2 h the contents of the tube were diluted with EtOAc, washed with saturated aqueous NaHCO3 (×2) then brine, and the organic phase was isolated, dried (Na2SO4), filtered and concentrated to afford the title compound as a light brown solid (0.205 g, 100%). LCMS (Method D): RT=1.80 min, [M+H]+ 366.
Reaction SMILES: Cl[CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([F:14])[CH:9]=2)[N:4]=1.[CH3:15][C:16]1[S:17][C:18]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH:27]([OH:35])[CH2:28][N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:21][C:19]=2[N:20]=1.C(N(C(C)C)CC)(C)C>CCO>[F:14][C:10]1[CH:9]=[C:8]([C:5]2[N:4]=[C:3]([CH2:2][N:32]3[CH2:33][CH2:34][N:29]([CH2:28][CH:27]([OH:35])[CH2:26][O:25][C:22]4[CH:23]=[CH:24][C:18]5[S:17][C:16]([CH3:15])=[N:20][C:19]=5[CH:21]=4)[CH2:30][CH2:31]3)[O:7][N:6]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Fc1cccc(-c2noc(CCl)n2)c1
Reactant: Cc1nc2cc(OCC(O)CN3CCNCC3)ccc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc2cc(OCC(O)CN3CCN(Cc4nc(-c5cccc(F)c5)no4)CC3)ccc2s1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To 5-(chloromethyl)-3-(3-fluorophenyl)-1,2,4-oxadiazole (300 mg, 1.41 mmol) and 1-(2-methylbenzothiazol-5-yloxy)-3-piperazine-1-yl-propan-2-ol, a compound of formula (6) (291 mg, 0.94 mmol) in EtOH (20 mL, anhydrous) was added diisopropylethylamine (0.329 m, 1.89 mmol), and the reaction was shaken on a J-Kem™ block overnight at 90° C. Upon cooling to room temperature, the solution was concentrated to an oil and purified on an Isco™ Combi Flash Si 10X, using Redi Sep columns (10 g), eluting with ethyl acetate, then gradient to 4:1 ethyl acetate/methanol, to yield 3-(4-{[3-(3-fluorophenyl)(1,2,4-oxadiazol-5-yl)]methyl}piperazinyl)-1-(2-methylbenzothiazol-5-yloxy)propan-2-ol, a compound of Formula I, (136 mg, 30%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1I.[C:10]([OH:14])(=[O:13])[C:11]#[CH:12].C(NC(C)C)(C)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:12]#[C:11][C:10]([OH:14])=[O:13]
Reactant: C#CC(=O)O
Reactant: Fc1ccc(I)c(F)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: O=C(O)C#Cc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.3 %

Procedure:
4.95 ml (41.4 mmol) of 2,4-difluoroiodobenzene and 2.56 ml (41.4 mmol) of propiolic acid were dissolved in DMF (16 ml). Following cooling of the reaction medium to 0° C. (ice-water bath), 578 mg (0.83 mmol) of Pd(PPh3)2Cl2 and 308 mg (1.66 mmol) of Cul were added. The reaction solution was then cooled to −10° C. (ice methanol bath) and 14.5 ml (103.4 mmol) of diisopropylamine were added dropwise at this temperature. The cooling bath was then removed and the reaction mixture was stirred a further 16 h after RT had been re-established. The reaction solution was then diluted with EA and washed successively with a 2N HCl solution and a satd aq. NaCl solution. Following drying over MgSO4, filtration, and removal of solvent in vacuo, the residue was boiled with hexane and filtered after cooling to RT. The residue was dissolved in diethyl ether at 30° C. and filtered at this temperature. By removal of solvent in vacuo there were obtained from the filtrate 6.43 g (35.3 mmol, 85%) of (2,4-difluorophenyl)propiolic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23](B4OC(C)(C)C(C)(C)O4)[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:35][C:36]1[CH:37]=[CH:38][CH:39]=[C:40]2[C:45]=1[CH:44]=[N:43][C:42](OS(C(F)(F)F)(=O)=O)=[CH:41]2.C([O-])([O-])=O.[Cs+].[Cs+].O>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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:34])=[C:23]([C:42]4[N:43]=[CH:44][C:45]5[C:40]([CH:41]=4)=[CH:39][CH:38]=[CH:37][C:36]=5[Cl:35])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(B4OC(C)(C)C(C)(C)O4)c3)cn2)CC1
Reactant: O=S(=O)(Oc1cc2cccc(Cl)c2cn1)C(F)(F)F
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(n2cc(-c3cnc(N)c(-c4cc5cccc(Cl)c5cn4)c3)cn2)CC1
Temperature: 105 °C

Procedure:
To a solution of 4-{4-[6-Amino-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-yl]-pyrazol-1-yl}-piperidine-1-carboxylic acid tert-butyl ester (BB3) (70.1 mg, 0.149 mmol), trifluoromethanesulfonic acid 8-chloroisoquinolin-3-yl ester (47.9 mg, 0.154 mmol), and Pd(PPh3)4 (11.5 mg, 0.00995 mmol) in 1,4-dioxane (2.3 mL, 29 mmol in a sealable microwave tube was added a solution of Cs2CO3 (95.5 mg, 0.293 mmol) in H2O (0.65 mL, 36 mmol). The tube was sealed, evacuated and refilled with nitrogen (3×), and heated in the microwave reactor to 105° C. for 30 minutes. The reaction mixture was diluted with DCM, washed with water, sat. NaHCO3 solution, and brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude material was chromatographed on silica gel [20 g/70 mL prepacked cartridge, eluting with DCM→1% MeOH in DCM→2% MeOH in DCM→3% MeOH in DCM]. Fractions containing the title compound were combined and dried in vacuo, yielding the title compound as a glassy, yellow solid. 1H NMR (400 MHz, CDCl3): δ=9.70 (t, J=0.8 Hz, 1H), 8.29 (d, J=2.0 Hz, 1H), 8.04 (d, J=0.4 Hz, 1H), 7.96 (d, J=2.4 Hz, 1H), 7.82 (dt, J=5.8, 3.0 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H), 7.67 (d, J=0.8 Hz, 1H), 7.66-7.62 (m, 2H), 6.47 (brs, 2H), 4.40-4.19 (m, 3H), 2.92 (brt, J=11.6 Hz, 2H), 2.19 (brdd, J=12.2 Hz, 2H), 1.95 (dq, J=4.0, 12.0 Hz, 2H), 1.49 (s, 9H). MS(ES+): m/z=505.16/507.13 (100/42) [MH+], 449.05/451.07 (3/1) [MH+-isobutene]. HPLC: tR=3.15 min (polar—5 min, ZQ3).
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:51][O:52][CH3:53])[N:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[N:31](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:9]=1[C:10]([O:12][CH3:13])=[O:11])([CH3:4])[CH3:3].O.C(O)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(O)(=O)C>[OH:1][C:2]([C:5]1[N:6]=[C:7]([CH2:51][O:52][CH3:53])[N:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:19][CH:20]=2)[C:9]=1[C:10]([O:12][CH3:13])=[O:11])([CH3:3])[CH3:4]
Reactant: COCc1nc(C(C)(C)O)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(=O)O
Solvent: O
Product: COCc1nc(C(C)(C)O)c(C(=O)OC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 99.4 %

Procedure:
705 mg of methyl 4-(1-hydroxy-1-methylethyl)-2-methoxymethyl-1-{4-[2-(trityltetrazol-5-yl)phenyl]-phenyl}methylimidazole-5-carboxylate [prepared as described in step (a) above] were dissolved in 10 ml of a 25% aqueous solution of acetic acid, and the mixture was stirred at 60° C. for 4 hours. At the end of this time, 10 ml of water were added, whilst ice-cooling, and the trityl alcohol which appeared as crystals was filtered off. The filtrate was concentrated by distillation under reduced pressure, and then acetic acid and water were distilled off as azeotropic mixtures with benzene, to give 460 mg of the title compound as an amorphous powder.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].N1C=CC=CC=1.[C:26](Cl)(=[O:30])[C:27]([CH3:29])=[CH2:28]>O1CCCC1>[C:26]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])(=[O:30])[C:27]([CH3:29])=[CH2:28]
Reactant: C=C(C)C(=O)Cl
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: C=C(C)C(=O)OCCCCCCCCCCCCCCCC(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 58.7 %

Procedure:
16-Hydroxyhexadecanoic acid (6.81 g, 25.0 mmol) was dissolved in tetrahydrofuran (150 ml) and the solution was cooled to 0° C. before adding pyridine (2.73 g, 34.5 mmol). Methacryloyl chloride (2.61 g, 25.0 mmol) was dissolved in tetrahydrofuran (75 ml) and added dropwise. The mixture was stirred for 1 hour at 0° C., and then at room temperature for 24 hours. The solvent was removed under reduced pressure (room temperature), the residue suspended in ether (100 ml) and the mixture washed with distilled water. The ether layer was dried (MgSO4) and the ether evaporated. Chromatographic purification on a silica gel column (1:2 ethyl acetate/hexane) afforded 5.0 g (64%) of the title compound. 1H NMR (60 MHz, CDCl3): δ1.3 (br s, 26H, (CH2)13), 1.95 (m, 3H, C=CCH3), 2.1-2.6 (m, 2H, CH2COO), 4.0-4.4 (m, 2H, COOCH2), 5.52 (m, 1H, vinyl), 6.10 (m, 1H, vinyl).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[S:11]([NH:14]C(OCC1C=CC=CC=1)=O)(=[O:13])=[O:12])=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][N:6]1[S:11]([NH2:14])(=[O:13])=[O:12])=[O:4]
Reactant: COC(=O)C1CCCCN1S(=O)(=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CCCCN1S(N)(=O)=O
Reaction time: 2 h
Yield: 94.7 %

Procedure:
A solution of N-(carbobenzyloxyaminosulfonyl)-2-piperidinecarboxylic acid methyl ester (28.8 g) in methanol (300 ml) under nitrogen was cooled to 0° C. and 1.8 g of 10% Pd/C was added. The mixture was placed into a Parr Apparatus and hydrogenated for 2 hours at 55 psi. The catalyst was removed on a pad of CELITE®and the filtrate was concentrated in vacuo and purified by flash silica gel chromatography (35%-40% ethyl acetate/hexane) to afford 17 g (90%) of N-(aminosulfonyl)-2-piperidinecarboxylic acid methyl ester (Formula VII: R=CH3 ; R1 =H; R2 and R3 together =-(CH2)4-) as a solid, m.p. 72°-74° C.
Reaction SMILES: [N:1]([C@@H:4]([C:24]1[C:25]([CH3:34])=[C:26]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[O:28][CH2:27]2)[CH2:5][N:6]1[CH2:23][CH2:22][C:9]2([C:13](=[O:14])[N:12]([C:15]3[CH2:16][O:17][C:18](=[O:21])[C:19]=3[CH3:20])[CH2:11][CH2:10]2)[CH2:8][CH2:7]1)=[N+]=[N-].O1CCCC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O>[NH2:1][C@@H:4]([C:24]1[C:25]([CH3:34])=[C:26]2[C:30](=[CH:31][CH:32]=1)[C:29](=[O:33])[O:28][CH2:27]2)[CH2:5][N:6]1[CH2:7][CH2:8][C:9]2([C:13](=[O:14])[N:12]([C:15]3[CH2:16][O:17][C:18](=[O:21])[C:19]=3[CH3:20])[CH2:11][CH2:10]2)[CH2:22][CH2:23]1
Reactant: CC1=C(N2CCC3(CCN(C[C@@H](N=[N+]=[N-])c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC1=C(N2CCC3(CCN(C[C@@H](N)c4ccc5c(c4C)COC5=O)CC3)C2=O)COC1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-8-(2-azido-2-(4-methyl-1-oxo-1,3-dihydroisobenzofuran-5-yl)ethyl)-2-(4-methyl-5-oxo-2,5-dihydrofuran-3-yl)-2,8-diazaspiro[4.5]decan-1-one (200 mg, 0.43 mmol) in a mixed solvent of tetrahydrofuran and water (v:v, 12:1, 20 mL) was added triphenylphosphine (225 mg, 0.86 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 18 h. The solvent was removed by evaporation and the residue was purified by preparative TLC (dichloromethane: methanol=10:1) to afford the title compound as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([C:11](O)=[O:12])[CH2:8][CH2:7][C:6]=2[CH:14]=1.B.S(C)C.CO>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]([CH2:11][OH:12])[CH2:8][CH2:7][C:6]=2[CH:14]=1
Reactant: O=C(O)C1CCc2cc(Br)ccc2O1
Agent: B
Solvent: CO
Solvent: CSC
Solvent: C1CCOC1
Product: OCC1CCc2cc(Br)ccc2O1
Reaction time: 4 h
Yield: 86 %

Procedure:
To a stirred mixture of 80 parts of 6-bromo-3,4-dihydro-2H-benzopyran-2-carboxylic acid and 225 parts of tetrahydrofuran were added dropwise 400 parts of a solution of borane, compound with thiobismethane 0.2N in tetrahydrofuran. Upon completion, stirring was continued for 4hours at room temperature. 80 parts of methanol were added dropwise and stirring was continued for 30 minutes at reflux temperature. The solvent was distilled off till half its volume. The remaining solvent was evaporated and the residue was distilled, yielding 63 parts (86%) of 6-bromo-3,4-dihydro-2H-1-benzopyran-2-methanol; bp. 150° C. at 39.9 Pa (intermediate 1).