Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:9][C@H:8]1[CH2:17][CH2:18]OS(C)(=O)=O)=[O:6])[CH:2]=[CH2:3].[CH:24]([C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)=[O:25].CC(C)([O-])C.[K+].O>CN(C)C=O>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][S:13]([CH3:16])(=[O:14])=[O:15])[CH2:9][C@H:8]1[CH2:17][CH2:18][N:27]1[C:26]([CH:24]=[O:25])=[CH:30][N:29]=[CH:28]1)=[O:6])[CH:2]=[CH2:3]
Reactant: O=Cc1c[nH]cn1
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCOS(C)(=O)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCn1cncc1C=O
Reaction time: 2 h
Yield: 36.6 %

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-{2-(methanesulfonyloxy)ethyl}pyrrolidine (38.8 g) in N,N-dimethylformamide (380 ml) were added 4-formylimidazole (13.0 g) and potassium t-butoxide (15.2 g) and the mixture was stirred at 50°-60° C. for 2 hours. The reaction mixture was poured into water (600 ml) and extracted three times with ethyl acetate (400 ml). The extract was washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (750 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2R,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-{2-(5-formylimidazol-1-yl)ethyl}pyrrolidine (14.2 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[O:9]([C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CCN(C(C)C)C(C)C>C(O)CCC>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:17]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: Nc1cccc(Oc2ccccc2)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Clc1cc(Nc2cccc(Oc3ccccc3)c2)ncn1
Yield: 57 %

Procedure:
A solution of 4,6-dichloropyrimidine (0.5 g, 3.3 mmol), 3-phenoxyaniline (0.75 g, 4 mmol) and DIPEA (0.65 g, 5 mmol) in n-butanol (5 mL) was subjected to microwave irradiation (110° C., 30 min). The reaction mixture was cooled, concentrated under reduced pressure and the residue was dissolved in EtOAc (10 mL). This solution was washed with water (5 mL) and brine (5 mL), and was dried over Na2SO4. Concentrated under reduced pressure gave a residue that was purified by column chromatography (SiO2, 60-120, hexane/ethylacetate, 8/2) to give 6-chloro-N-(3-phenoxyphenyl)pyrimidine-4-amine (0.56 g, 56%) as an off-white solid.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24][CH3:25])[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20]N(CC)CC2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].C(OC1NC(N)=C2C(N=1)=NC(OC)=N2)CCC.[CH2:44]([N:46]1[CH2:51]CC(CCO)[CH2:48][CH2:47]1)[CH3:45]>>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24][CH3:25])[N:12]2[CH2:15][CH2:16][CH:21]2[CH2:20][CH2:51][N:46]([CH2:47][CH3:48])[CH2:44][CH2:45]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(CC)CC3)c2n1
Reactant: CCN1CCC(CCO)CC1
Agent: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCN(CC)CC3)c2n1

Procedure:
Prepared similarly to Intermediate 19 from 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine and 2-(1-ethyl-4-piperidinyl)ethanol.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[C:4]([O:9][CH3:10])[N:3]=1.C(Cl)Cl.S(=O)(=O)(O)O.[I:19]N1C(=O)CCC1=O>C(OCC)(=O)C.CC(O)=O>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([I:19])=[C:4]([O:9][CH3:10])[N:3]=1
Reactant: COc1ccc(Cl)c(Cl)n1
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1nc(Cl)c(Cl)cc1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.1 %

Procedure:
A RBF was charged with 2,3-dichloro-6-methoxypyridine (4.84 g, 27.2 mmol, Accel Pharmtech), DCM (40.0 ml), AcOH (40.0 ml), and sulfuric acid (0.797 ml, 14.95 mmol) to give a clear solution. N-iodosuccinimide (6.12 g, 27.2 mmol) was added in one portion to give a maroon-colored solution. The reaction was stirred for three hours at RT. The mixture was diluted with ethyl acetate, washed with water, washed with 10% aq. sodium thiosulfate, washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by chromatography on silica gel (80-g Redi-Sep Gold column, 0-15% Et20/Heptane) to afford 2,3-dichloro-5-iodo-6-methoxypyridine (6.29 g, 20.70 mmol, 76% yield) as a white solid. m/z (ESI) 304.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[CH2:13][N:12]([C:14]([C@@H:16]([NH2:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[C@H:11]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:10]=1.Br[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(N(CC)C(C)C)(C)C>CCCCO>[C:17]([C@H:16]([NH:21][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:14]([N:12]1[CH2:13][C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])=[CH:10][C@H:11]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)=[O:15])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)[C@H](N)C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1
Reactant: CCOC(=O)CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CCOC(=O)CN[C@H](C(=O)N1CC(c2cc(F)ccc2F)=C[C@H]1c1ccccc1)C(C)(C)C

Procedure:
A solution of (1S)-1-{[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]carbonyl}-2,2-dimethylpropylamine (6-1, 325 mg, 0.877 mmol, 1 equiv), ethyl bromoacetate (0.195 mL, 1.76 mmol, 2.00 equiv), and N,N-diisopropylethylamine (0.613 mL, 3.51 mmol, 4.00 equiv) in n-BuOH (4.0 mL) was heated under microwave irradiation at 150° C. for 15 min. The reaction mixture was concentrated and the residue was partitioned between a ethyl acetate (100 mL) and a 1:1 mixture of saturated aqueous potassium bisulfate solution and brine (100 mL). The organic layer was then washed with saturated aqueous sodium bicarbonate solution (100 mL) followed by brine (100 mL), then dried over magnesium sulfate and concentrated to give ethyl ({(1S)-1-tert-butyl-2-[(2S)-4-(2,5-difluorophenyl)-2-phenyl-2,5-dihydro-1H-pyrrol-1-yl]-2-oxoethyl}amino)acetate (7-1) as an off-white solid. LRMS m/z (M+H) 457.5 found, 457.2 required.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15]([CH:20]=[CH:21][C:22]2[C:30]3[C:25](=[CH:26][C:27]([NH:31][C:32]4[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=4[C:34]([OH:36])=O)=[CH:28][CH:29]=3)[NH:24][N:23]=2)[CH:14]=1.[NH2:41][CH2:42][C:43]#[C:44][CH2:45][O:46][C:47](=[O:49])[CH3:48]>>[CH3:12][C:13]1[CH:18]=[C:17]([CH3:19])[N:16]=[C:15](/[CH:20]=[CH:21]/[C:22]2[C:30]3[C:25](=[CH:26][C:27]([NH:31][C:32]4[CH:40]=[CH:39][CH:38]=[CH:37][C:33]=4[C:34]([NH:41][CH2:42][C:43]#[C:44][CH2:45][O:46][C:47](=[O:49])[CH3:48])=[O:36])=[CH:28][CH:29]=3)[NH:24][N:23]=2)[CH:14]=1
Reactant: CC(=O)OCC#CCN
Reactant: Cc1cc(C)nc(C=Cc2n[nH]c3cc(Nc4ccccc4C(=O)O)ccc23)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)OCC#CCNC(=O)c1ccccc1Nc1ccc2c(/C=C/c3cc(C)cc(C)n3)n[nH]c2c1

Procedure:
Prepared in a similar manner to that described for Example 6 above, except using 2-[3-[2-(4,6-dimethyl-pyridin-2-yl)-vinyl] 1H-indazol-6-ylamino]-benzoic acid p-toluene sulfonate and Acetic acid 4-amino-but-2-ynyl ester. 1H NMR (CD3CN): δ 11.00 (1H, bs), 9.59 (1H, s), 7.99 (1H, d, J=8.6 Hz), 7.86 (1H, d, J=16.4 Hz), 7.58 (1H, d, J=7.8 Hz), 7.49–7.37 (4H, m), 7.32 (1H,s ), 7.21 (1H, s), 7.06 (1H, dd, J=8.8, 1.8 Hz), 6.96 (1H, s), 6.90 (1H, t, J=7.8 Hz), 4.63 (2H, s), 4.16 (2H, d, J=5.6 Hz), 2.49 (3H, s), 2.32 (3H, s), 2.01 (3H, s).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:8]([NH:10][CH2:11][C:12]([NH:14][C@H:15]([C:23]([CH:25]1[C:32]2([NH2:34])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:35][C:26]1([C:36]([O:38][CH3:39])=[O:37])[CH2:27]3)[CH2:31]2)=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])=[O:9])[CH2:4][CH2:5][S:6][CH3:7].ClC1C([O:47][C:48](=O)[C@H:49]([CH2:58][C:59]2[CH:64]=[CH:63][C:62]([OH:65])=[CH:61][CH:60]=2)[NH:50][C:51]([O:53][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:52])=C(Cl)C(Cl)=C(Cl)C=1Cl.CN1CCOCC1>O1CCCC1.C(OCC)(=O)C>[C:51]([NH:50][C@H:49]([C:48]([NH:2][C@@H:3]([C:8]([NH:10][CH2:11][C:12]([NH:14][C@H:15]([C:23]([CH:25]1[C:32]2([NH2:34])[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:35][C:26]1([C:36]([O:38][CH3:39])=[O:37])[CH2:27]3)[CH2:31]2)=[O:24])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)=[O:13])=[O:9])[CH2:4][CH2:5][S:6][CH3:7])=[O:47])[CH2:58][C:59]1[CH:64]=[CH:63][C:62]([OH:65])=[CH:61][CH:60]=1)([O:53][C:54]([CH3:56])([CH3:55])[CH3:57])=[O:52]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@H](N)CCSC)C2
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: COC(=O)C12CC3CC(CC(N)(C3)C1C(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)[C@@H](CCSC)NC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C)C2
Reaction time: 4 h

Procedure:
To a solution of 3.513 g of methyl D-methionylglycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate hydrochloride in 30 ml of tetrahydrofuran is added 3.17 g of Boc-L-tyrosine pentachlorophenyl ester followed by 1.12 ml of N-methylmorpholine. The reaction mixture is allowed to stand for 4 hours at room temperature then diluted with 200 ml ethyl acetate. The ethyl acetate layer is separated and washed three times with a 0.5 M solution of potassium bisulfate then dried over magnesium sulfate. The solvent is removed under reduced pressure and the residue is purified by low pressure chromatography on silica gel to give methyl Boc-L-tyrosyl-D-methionyl-glycyl-L-phenylalanyl-3-amino-1-adamantanecarboxylate which is represented by the following formula ##STR19##
Reaction SMILES: FC(F)(F)[N:3](C1C=CC=CC=1)[C:4]([C:6]1[C:7]([CH3:12])=[N:8][O:9][C:10]=1[CH3:11])=[O:5].FC(F)(F)C1C=CC(CN)=CC=1>>[CH3:12][C:7]1[C:6]([C:4]([NH2:3])=[O:5])=[C:10]([CH3:11])[O:9][N:8]=1
Reactant: Cc1noc(C)c1C(=O)N(c1ccccc1)C(F)(F)F
Agent: NCc1ccc(C(F)(F)F)cc1
Product: Cc1noc(C)c1C(N)=O

Procedure:
P22 was made using the same conditions as described for N-trifluoromethylphenyl 3,5-dimethylisoxazole-4-carboxamide (A13), but starting with 4-trifluoromethylbenzylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14]([O:16]C)=[O:15])=[C:12]([C:18]([O:20]C)=[O:19])[S:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:13]([C:14]([OH:16])=[O:15])=[C:12]([C:18]([OH:20])=[O:19])[S:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COC(=O)c1snc(-c2ccc(Cl)c(Cl)c2)c1C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1snc(-c2ccc(Cl)c(Cl)c2)c1C(=O)O
Yield: 96.6 %

Procedure:
A mixture of 51.9 g (0.15 mol) of dimethyl 3-(3,4-dichlorophenyl)-4,5-isothiazoledicarboxylate and 30 g (0.75 mol) of NaOH in 150 ml of water was held at reflux for 2 hours, was cooled, acidified with HCl, and was extracted with ether several times (total ether volume equals 1300 ml). The ether solution was dried (CaSO4) and concentrated to give 46.12 g of solid. A small sample was recrystallized twice from water and once from ether-dichloroethane to give pure product, m.p. 187.5°-188.5° with decomposition (fast).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Cl:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[C:11]([Cl:16])[C:10]=1[N:17]=[C:18]=[O:19]>C1(C)C=CC=CC=1>[N:5]1[CH:6]=[CH:7][C:2]([NH:1][C:18]([NH:17][C:10]2[C:11]([Cl:16])=[CH:12][C:13]([Cl:15])=[CH:14][C:9]=2[Cl:8])=[O:19])=[CH:3][CH:4]=1
Reactant: O=C=Nc1c(Cl)cc(Cl)cc1Cl
Reactant: Nc1ccncc1
Solvent: Cc1ccccc1
Product: O=C(Nc1ccncc1)Nc1c(Cl)cc(Cl)cc1Cl
Temperature: 110 °C
Reaction time: 3 h

Procedure:
4-Aminopyridine (500 mg, 3.56 mmol) and 2,4,6-trichlorophenyl isocyanate (503.6 mg, 3.56 mmol 1.0 moleg), were dissolved in toluene, and the mixture was then stirred at 110° C. for 3 hr.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.Br[CH2:10][CH2:11][OH:12]>>[OH:12][CH2:11][CH2:10][N:5]1[CH2:6][CH2:7][CH2:8][C@H:4]1[CH2:3][O:2][CH3:1]
Reactant: OCCBr
Reactant: COC[C@@H]1CCCN1
Product: COC[C@@H]1CCCN1CCO

Procedure:
Using an analogous procedure to those described in Note [39] immediately above, (2S)-2-methoxymethylpyrrolidine was reacted with 2-bromoethanol to give (2S)-1-(2-hydroxyethyl)-2-methoxymethylpyrrolidine; NMR Spectrum: (CDCl3) 1.5–1.65 (m, 1H), 1.65–1.8 (m, 2H), 1.8–2.0 (m, 2H), 2.3 (m, 1H), 2.6 (m, 1H), 2.8 (m, 1H), 2.95–3.05 (m, 1H), 3.17 (m, 1H), 3.3 (t, 1H, 3.35 (t, 1H), 3.37 (s, 3H), 3.5–3.7 (m, 2H).
Reaction SMILES: [OH:1][CH:2]([CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH:7]([CH3:9])[CH3:8])=[O:4].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.C1N2CCN(CC2)C1.C(N(CC)CC)C>C(OCC)(=O)C.C(#N)C>[S:18]([O:1][CH:2]([CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH:7]([CH3:8])[CH3:9])=[O:4])([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCC(O)C(=O)OCC(C)C
Agent: C1CN2CCN1CC2
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCC(OS(=O)(=O)c1ccc(C)cc1)C(=O)OCC(C)C
Reaction time: 4 h

Procedure:
To a solution of (S) isobutyl 2-hydroxybutyrate (2.72 Kg) and p-toluenesulfonylchloride (3.6 Kg) in ethyl acetate (14 L) at 20° C. was added a solution of DABCO (286 g) and triethylamine (4.7 L) in ethyl acetate (10 L) over 2 h. The reaction was aged at 20-25° C. for 4 h. The mixture was washed with three times with water (10 L, 2 L and 2 L) and the organics concentrated and solvent switched into toluene. The concentrated toluene solution of (S) 2-isobutyl tosylbutyrate was used as is in coupling reaction. Alternatively, acetonitrile can be used in place of ethyl acetate, in which case the reaction proceeds faster.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:14]=3[OH:26])[N:10]=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][OH:45])=[CH:29][C:28]=3[OH:46])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:47](Cl)(=[O:51])[C:48]([CH3:50])=[CH2:49].N1C=CC=CC=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]1([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:14]=3[OH:26])[N:10]=[C:9]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][O:45][C:47](=[O:51])[C:48]([CH3:50])=[CH2:49])=[CH:29][C:28]=3[OH:46])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(C)C(=O)Cl
Reactant: CCCCCCOc1ccc(-c2nc(-c3ccccc3)nc(-c3ccc(OCCCCCCCCCCCO)cc3O)n2)c(O)c1
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)OCCCCCCCCCCCOc1ccc(-c2nc(-c3ccccc3)nc(-c3ccc(OCCCCCC)cc3O)n2)c(O)c1
Temperature: 55 °C
Yield: 91.6 %

Procedure:
A mixture of 22.0 g (35.0 mmoles) of 2-phenyl-4-(2-hydroxy-4-n-hexyloxy-phenyl)-6-[2-hydroxy-4-(11-hydroxy-undecyloxy)phenyl]-1,3,5-triazine, 4.4 g (42.0 mmoles) of methacryloyl chloride (Fluka, 97% ), 0.5 g (6.3 mmoles) of pyridine in 100 mL of toluene (Merck, 99.5%) are heated at 80°-85° C. for 21 hours. After cooling to 55° C., there are added 8.9 g (87.5 mmoles) of triethylamine (Fluka, 99.5%). The mixture is heated at 80° C. for further 7 hours then filtered hot. The filtrate is evaporated. The crude product (25.7 g ) is dissolved in 120 mL of CH2Cl2, filtered through a Kieselgel 60 pad (230-400 mesh; 6.5 cm diameter; h=5 cm) and eluted with 380 mL of CH2Cl2. Solvent removal and drying at 80° C./0.1 mmHg for 2 hours 30 min. give 22.3 g (91.4% yield ) of 2-phenyl-4-(2-hydroxy-4-hexyloxyphenyl)-6-[2-hydroxy-4-(11-methacryloyloxy-undecyloxy)-phenyl]-1,3,5-triazine, as an orange resin, Tg=-13° C. (DSC).
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[F:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1.[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34](N(OC)C)=[O:35])=[N:32][CH:33]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.CCCCCC>[CH2:20]([O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([C:15]2[C:14]([F:13])=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:35])=[N:32][CH:33]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CON(C)C(=O)c1ccc(OCc2ccccc2)cn1
Reactant: Fc1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(c1ccc(OCc2ccccc2)cn1)c1ncccc1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 52 %

Procedure:
To a solution of diisopropylamine (2.08 g) in THF (50 mL) was added 1.6 M n-BuLi in hexane (12.3 mL) at −5° C. The mixture was stirred for 15 min. The mixture was cooled to −78° C., and a solution of 3-fluoropyridine (1.74 g) in THF (10 mL) was added. The mixture was stirred for 1 h. To the mixture was added a solution of 5-(benzyloxy)-N-methoxy-N-methylpicolinamide (4.87 g) in THF (5 mL). The mixture was stirred at −78° C. for 2 h. The mixture was quenched with saturated NH4Cl aqueous solution at −78° C. and extracted with AcOEt. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to give the title compound (2.87 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[O:7][CH2:6][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)([N+:8]([O-])=O)[CH2:4][O:3]1.O>C(O)C.[Ni]>[CH3:1][C:2]1([CH3:18])[O:3][CH2:4][C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=2)([NH2:8])[CH2:6][O:7]1
Reactant: Cc1cccc(C2([N+](=O)[O-])COC(C)(C)OC2)c1
Agent: [Ni]
Solvent: O
Solvent: CCO
Product: Cc1cccc(C2(N)COC(C)(C)OC2)c1
Reaction time: 22 h
Yield: 110 %

Procedure:
To a mixture of 1.6 g of 2,2-dimethyl-5-(3-methylphenyl)-5-nitro-1,3-dioxane in 24 ml of ethanol was added a suspension of a Raney nickel (manufactured by Aldrich, product obtained by washing 1 ml of an aqueous suspension with water and ethanol) in 9 ml of ethanol, followed by stirring for 22 hours under a hydrogen atmosphere at 4 atm. The reaction mixture was filtered over Celite and the solvent was then evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.55 g of 2,2-dimethyl-5-(3-methylphenyl)-1,3-dioxan-5-amine.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:11][CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:3][CH:4]=1)=[O:7]
Reactant: CC(C)(C)OC(=O)NCCBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NCCOc1ccc(C=O)cc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
2.54 g (20.81 mmol) of 4-hydroxybenzaldehyde were initially charged in 50 ml of DMF. 5.13 g (22.89 mmol) of tert-butyl (2-bromoethyl)carbamate, 10.17 g (31.25 mmol) of cesium carbonate and 0.78 g (5.20 mmol) of sodium iodide were added, and the mixture was then stirred at 65° C. overnight. Water was added, and the reaction mixture was extracted three times with ethyl acetate. The combined organic phases were washed in each case twice with 1N aqueous sodium hydroxide solution, saturated aqueous ammonium chloride solution and water, dried over sodium sulfate, filtered and concentrated.
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5].[C:28]([O:32][C:33]([NH:35][C@H:36]([C:44](O)=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:34])([CH3:31])([CH3:30])[CH3:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>ClCCl.CN(C)C1C=CN=CC=1>[C:28]([O:32][C:33]([NH:35][C@H:36]([C:44]([O:1][CH:2]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]([CH3:27])[CH3:26])[CH2:3][C:4]([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])=[O:45])[CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:34])([CH3:30])([CH3:31])[CH3:29]
Reactant: CC(C)CCCCCCCCCCCC(O)CC(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CC(C)CCCCCCCCCCCC(CC(=O)OCc1ccccc1)OC(=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of benzyl 3-hydroxy-15-methylhexadecanoate (1.77 g) and N-tertiarybutoxycarbonyl-L-phenylalanine (1.25 g) in dichloromethane (50 ml) was added benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (2.08 g) and 4-dimethylaminopyridine (1.22 g). The mixture was stirred at room temperature for 14 hours and evaporated. The residue was poured into a mixture of ethyl acetate and diluted hydrochloric acid. The organic layer was washed with water, dried over magnesium sulfate and evaporated to give almost pure benzyl 3-(N-tertiary butoxycarbonyl-L-phenylalanyl)oxy-15-methylhexadecanoate, which can be used for next step without further purification (2.87 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[NH:20][C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1.Cl.Cl[CH2:33][CH2:34][N:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1>>[CH3:1][O:2][C:3]1[CH:26]=[CH:25][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](/[CH:17]=[C:18]4/[C:19](=[O:24])[N:20]([CH2:33][CH2:34][N:35]5[CH2:39][CH2:38][CH2:37][CH2:36]5)[C:21](=[O:23])[S:22]/4)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[C:5]([C:27]([F:30])([F:29])[F:28])[CH:4]=1
Reactant: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)NC4=O)ccc32)c(C(F)(F)F)c1
Reactant: ClCCN1CCCC1
Agent: Cl
Product: COc1ccc(Cn2ncc3cc(/C=C4\SC(=O)N(CCN5CCCC5)C4=O)ccc32)c(C(F)(F)F)c1

Procedure:
(5Z)-5-({1-[4-Methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(2-pyrrolidin-1-ylethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-methoxy-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 8) and 1-(2-chloroethyl)pyrrolidine hydrochloride following General Procedure H.
Reaction SMILES: [NH2:1][C@H:2]([CH3:14])[C@@H:3]([C:5]1[CH:13]=[CH:12][C:8]2[CH2:9][CH2:10][O:11][C:7]=2[CH:6]=1)[OH:4].[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[C:25](=[CH:26][C:27](I)=[CH:28][CH:29]=3)[CH:24]=[N:23]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)CCC.[Cu]I>[O:11]1[C:7]2[CH:6]=[C:5]([C@@H:3]([O:4][C:27]3[CH:26]=[C:25]4[C:30](=[CH:29][CH:28]=3)[N:22]([C:19]3[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=3)[N:23]=[CH:24]4)[C@@H:2]([NH2:1])[CH3:14])[CH:13]=[CH:12][C:8]=2[CH2:9][CH2:10]1
Reactant: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Reactant: C[C@@H](N)[C@H](O)c1ccc2c(c1)OCC2
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCC#N
Product: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc2c(c1)OCC2
Temperature: 105 °C
Yield: 21.3 %

Procedure:
A stirred mixture of (1R,2R)-2-amino-1-(2,3-dihydrobenzofuran-6-yl)propan-1-ol (306b, 180 mg, 0.93 mmol), 1-(4-fluorophenyl)-5-iodo-1H-indazole (346 mg, 1.02 mmol), and cesium carbonate (0.910 g, 2.79 mmol) in butyronitrile (2 mL) was degassed for 5 min. Then copper(I) iodide (35 mg, 190 μmol) was added. The tube was sealed and heated at 105° C. for 12 h. The solvent was removed, the residue was taken in dichloromethane (20 mL), and filtered on a prepact silica column (10 g), washed with dichloromethane (50 ml) followed by ethyl acetate (50 ml). Than the product was eluted with a mixture of 0.35M ammmonia solution in ethylacetate/methanol (5:95) (100 ml) to give 80 mg (22%) of subtitle compound.