Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:36]=[CH:35][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14](=[O:34])[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=3)[C:16]([CH3:23])=[C:17]([C:19](=[NH:22])[NH:20][OH:21])[CH:18]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[C:37](OC(=O)C)(=O)[CH3:38]>C1(C)C=CC=CC=1>[CH3:1][S:2]([C:5]1[CH:36]=[CH:35][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:14](=[O:34])[N:15]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:31])([F:33])[F:32])[CH:25]=3)[C:16]([CH3:23])=[C:17]([C:19]3[N:22]=[C:37]([CH3:38])[O:21][N:20]=3)[CH:18]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c(C(=N)NO)cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)n1-c1cccc(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: Cc1nc(-c2cc(C(=O)NCc3ccc(S(C)(=O)=O)cc3)c(=O)n(-c3cccc(C(F)(F)F)c3)c2C)no1
Temperature: 110 °C
Reaction time: 5 h
Yield: 34.9 %

Procedure:
5-(N-Hydroxycarbamimidoyl)-6-methyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide (0.011 g, 0.021 mmol), acetic anhydride (0.02 g, 0.195 mmol), toluene (2 ml) and a magnetic stirrer bar were placed in a vial. The vial was sealed and was heated (110° C.) with stirring for 5 h. LC-MS confirmed the consumption of the starting material and the formation of a product with the expected MW. Evaporation and purification on preparative HPLC gave the title compound (0.004 g, 35%) as a white solid after freeze-drying the pure fractions.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[O:17]=[C:18]([CH2:24][C@@H:25]([O:31][C:32]([O:34][CH2:35][C:36]([Cl:39])([Cl:38])[Cl:37])=[O:33])[C@@H:26]([CH3:30])[CH2:27][CH:28]=[CH2:29])[C:19]([CH3:23])([CH3:22])[CH:20]=[O:21].O>CCOCC.C1COCC1>[O:17]=[C:18]([CH2:24][C@@H:25]([O:31][C:32]([O:34][CH2:35][C:36]([Cl:37])([Cl:38])[Cl:39])=[O:33])[C@@H:26]([CH3:30])[CH2:27][CH:28]=[CH2:29])[C:19]([CH3:23])([CH3:22])[C@@H:20]([OH:21])[CH2:2][C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])=[O:3]
Reactant: CC(=O)OC(C)(C)C
Reactant: C=CC[C@H](C)[C@@H](CC(=O)C(C)(C)C=O)OC(=O)OCC(Cl)(Cl)Cl
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: C=CC[C@H](C)[C@@H](CC(=O)C(C)(C)[C@@H](O)CC(=O)OC(C)(C)C)OC(=O)OCC(Cl)(Cl)Cl
Temperature: -30 °C
Reaction time: 1 h

Procedure:
Tert-butyl acetate (0.865 mL) is added to a solution of lithium diisopropylamide (7.52 mmol) in 30 mL of ether at −78° C., and the mixture is stirred for 1 hour. A solution of bis(1,2:5,6-di-O-isopropylidene-α-L-glucofuranos-3-O-yl)cyclopentadienyltitanium chloride (8.34 mmol) in 90 mL of ether is added dropwise over 40 minutes, and the reaction is stirred for an additional 30 minutes at −78° C., warmed to −30° C. and kept for 45 minutes, then recooled to −78° C. A solution of (5R,6S)-3-oxo-5-(2,2,2-trichloroethoxycarbonyl-oxy)-2,2,6-trimethyl-8-nonenal (2.4 g) in 15 mL of ether is added over 10 minutes and the reaction is continued for 2 hours before addition of 14 mL of 5 M water in THF. The mix is stirred for 1 hour, then filtered through Celite. The filtrate is washed with sat. aq. NaCl, and the brine layer is back extracted with ether. The organic phases are combined, dried with Na2SO4, filtered, and evaporated. The product is purified by chromatography on SiO2.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[C:10](O)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.OS(O)(=O)=O.C(OC(=O)C)(=O)C.[OH-].[Na+]>C(O)(=O)C.O>[CH:26]1[CH:27]=[CH:28][C:23]([C:10]([NH:5][C:4]([CH2:3][C@H:2]([NH2:1])[C:7]([OH:9])=[O:8])=[O:6])([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:24][CH:25]=1
Reactant: NC(=O)C[C@H](N)C(=O)O
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: N[C@@H](CC(=O)NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 60 °C
Reaction time: 1 h

Procedure:
Bpoc-Asn(Trt)--OH: H-Asn(Trt)--OH was prepared according to the procedure of Sieber and Riniker (40) with the following modifications. H-Asn-OH (13.2 g, 0.1 mol), trityl alcohol (52 g, 0.2 mol), conc. H2SO4 (6.1 mL, 0.115 mol) were suspended in glacial acetic acid (300 mL) for 10 min. Acetic anhydride (9 mL, 0.2 mol) was added and the reaction was heated to 60° C. After 4 h the solution was slowly added to cold water (600 mL) and adjusted to pH 6 by addition of 10 N NaOH. After 1 h at 0° C., white crystals were collected and washed thoroughly with water and toluene. Drying under vacuum for 24 h yielded white crystals (36 g, 94%). mp>240 dec., lit. >240 dec.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=2)([OH:17])[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.[CH3:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41]Cl)=[CH:37][CH:36]=1)=[O:33].C(N(CC)C(C)C)(C)C>CS(C)=O>[CH3:31][C:32]([NH:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][N:14]2[CH2:15][CH2:16][CH:11]([C:10]([C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:29])([F:1])[F:30])=[CH:9][CH:8]=3)([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:26])[F:27])=[CH:20][CH:19]=3)[OH:17])[CH2:12][CH2:13]2)=[CH:37][CH:36]=1)=[O:33]
Reactant: OC(c1ccc(OC(F)(F)F)cc1)(c1ccc(OC(F)(F)F)cc1)C1CCNCC1
Reactant: CC(=O)Nc1ccc(CCl)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1ccc(CN2CCC(C(O)(c3ccc(OC(F)(F)F)cc3)c3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.4 %

Procedure:
To a stirred solution of 0.4 gram (0.0008 mole) of 4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine in 10 mL of dimethyl sulfoxide was added a mixture of 0.2 gram (0.0008 mole) of 4-(methylcarbonylamino)phenylmethyl chloride and 0.6 mL (0.003 mole) of N,N-diisopropylethylamine. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 18 hours. After this time the reaction mixture was partitioned between an aqueous solution saturated with sodium bicarbonate and ethyl acetate. The organic layer was separated and washed with an aqueous solution saturated with sodium chloride. The organic layer was then concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with methylene chloride and mixtures of 10-50% acetone in methylene chloride as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding about 0.3 gram of N-[4-(methylcarbonylamino)phenylmethyl]-4-[bis(4-trifluoromethoxyphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([OH:12])=[CH:5][C:4]=1[CH3:13])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].C(O)(=O)C>O>[C:14]([O:12][C:6]1[CH:5]=[C:4]([CH3:13])[C:3]([CH2:1][CH3:2])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])(=[O:16])[CH3:15]
Reactant: CCc1cc(C(=O)O)c(O)cc1C
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CCc1cc(C(=O)O)c(OC(C)=O)cc1C
Reaction time: 8 h

Procedure:
A mixture of 5-ethyl-4-methylsalicylic acid (15.00 g), acetic anhydride (80 ml) and acetic acid (80 ml) was heated under reflux for 1.5 hours, poured into water (1 l) and allowed to stand overnight. The solid formed was filtered off and recrystallised from benzene to give 2-acetoxy-5-ethyl-4-methylbenzoic acid, m.p. 132°-134° C. (Found; C, 64.71; H, 6.46; C12H14O4 requires; C, 64.85; H, 6.35).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH2:8][S:9][C:10]2[N:15]=[C:14]([NH2:16])[C:13]([NH2:17])=[C:12]([S:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=3[F:27])[N:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH:29]([N:32](C(C)C)CC)(C)[CH3:30].BrCC#N>O1CCOCC1>[NH2:16][C:14]1[C:13]([NH:17][CH2:30][C:29]#[N:32])=[C:12]([S:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=2[F:27])[N:11]=[C:10]([S:9][CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])[N:15]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1nc(SCc2cccc(Cl)c2F)nc(SCc2cccc(Cl)c2F)c1N
Agent: N#CCBr
Solvent: C1COCCO1
Product: N#CCNc1c(N)nc(SCc2cccc(Cl)c2F)nc1SCc1cccc(Cl)c1F
Temperature: 100 °C

Procedure:
To a solution of the product of example 13, step (a) (4.2 g) and diisopropylethylamine (1.2 ml) in dioxan (40 ml) was added bromoacetonitrile (1.2 g) and the mixture heated at 100° C. for 23 hours. After cooling, the red reaction solution was adsorbed onto silica and purified by silica gel flash column chromatography, eluting with dichloromethane then 95:5 dichloromethane:ethyl acetate, to give the subtitled compound as a pale orange solid (3.1 g).
Reaction SMILES: C1C=CC(C[C@@H](NC([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=O)C(O)=O)=CC=1.C1C=C[C:26]2[N:31](O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CC[O:48]CC1>CN(C=O)C>[C:16]1(=[O:15])[NH:31][C:26](=[O:48])[C:18]2=[CH:19][CH:20]=[CH:21][CH:22]=[C:17]12
Reactant: On1nnc2ccccc21
Reactant: CN1CCOCC1
Reactant: O=C(N[C@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc21
Reaction time: 16 h
Yield: 329 %

Procedure:
Part A BOC derivative (2.27 g, 4.567 mmol) was dissolved in dichloromethane (10 mL) and TFA (30 mL) and stirred at RT 2.5 hours. The TFA was removed by distillation under reduced pressure and by coevaporation with toluene to give the TFA salt of the amine. This and Z-D-phenylalanine (1.50 g, 5.02 mmol) were dissolved in DMF (20 mL) at RT. HOBT (680 mg, 5.02 mmol), WSC (965 mg, 5.02 mmol) and NMM (1.1 mL, 10 mmol) were added. The reaction was stirred for 16 h, partitioned between ethyl acetate (70 mL) and 10% KHSO4 (70 mL). The aqueous layer was extracted with ethyl acetate (2×70 mL), and the organic layers were combined. The combined organic layers were washed with saturated NaHCO3 (50 mL) and saturated NaCl (50 mL), dried over magnesium sulfate and concentrated in vacuo to provide a viscous oil. The crude material was purified by chromatography on silica gel. Elution with ethyl acetate:hexanes (1:1) followed by ethyl acetate gave title phthalimide, (2.43 g, 78%) as a viscous oil which was characterized by NMR.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]1[CH2:14][NH:13][CH2:12][C@@H:11]1[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.Cl[C:31]([O:33][C:34]1[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=1)=[O:32]>C1COCC1>[Si:1]([O:8][CH2:9][C@@H:10]1[C@@H:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:12][N:13]([C:31]([O:33][C:34]2[CH:35]=[CH:36][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:42][CH:43]=2)=[O:32])[CH2:14]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1cccnc1
Reactant: COC(=O)c1ccc(OC(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COC(=O)c1ccc(OC(=O)N2C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c3cccnc3)C2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-[(3S,4R)-4-({[Tert-butyl(dimethyl)silyl]oxy}methyl)pyrrolidin-3-yl]pyridine and N,N-diisopropylethylamine were dissolved in THF, methyl 4-[(chlorocarbonyl)oxy]benzoate (mfd. by Fluka) was added in one portion thereto at room temperature and stirred for 3 hours, and then the reaction solution was concentrated under a reduced pressure. Work-up and purification of the residue was carried out in the standard method to produce 4-(methoxycarbonyl)phenyl (3R,4S)-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-4-pyridin-3-ylpyrrolidine-1-carboxylate.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=[C:6]([Cl:8])[CH:7]=1.[CH2:22]([NH2:24])[CH3:23].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:8][C:6]1[CH:7]=[C:2]([NH:24][CH2:22][CH3:23])[C:3]2[N:4]([C:9]([C:12]([NH:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[F:21])=[O:13])=[CH:10][N:11]=2)[N:5]=1
Reactant: CCN
Reactant: O=C(Nc1ccncc1F)c1cnc2c(Br)cc(Cl)nn12
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNc1cc(Cl)nn2c(C(=O)Nc3ccncc3F)cnc12
Temperature: 80 °C
Yield: 76.6 %

Procedure:
A suspension of 5A (80 mg, 0.245 mmol), ethanamine (0.6 mL, 1.200 mmol, 2 M/THF) and DIEA (0.086 mL, 0.491 mmol) in NMP (0.7 mL) was heated at 80° C. for 5 h. The reaction mixture was cooled to room temperature and the solid was collected by filtration and washed with a small amount of DCM to give 6-chloro-8-(ethylamino)-N-(3-fluoropyridin-4-yl)imidazo[1,2-b]pyridazine-3-carboxamide as a yellow solid 62.8 mg. HPLC Rt=2.517 minutes (Chromolith SpeedROD 4.6×50 mm, 10-90% aqueous methanol containing 0.1% TFA, 4 min gradient, monitored at 220 nm). [M+H]=335.
Reaction SMILES: [K].[NH2:2][C:3]1[N:8]=[C:7]([F:9])[CH:6]=[C:5](F)[N:4]=1.[CH:11]([OH:14])([CH3:13])[CH3:12]>>[NH2:2][C:3]1[N:8]=[C:7]([F:9])[CH:6]=[C:5]([O:14][CH:11]([CH3:13])[CH3:12])[N:4]=1
Reactant: CC(C)O
Reactant: Nc1nc(F)cc(F)n1
Agent: [K]
Product: CC(C)Oc1cc(F)nc(N)n1

Procedure:
29.4 g (0.3 mol) of potassium isopropylate were reacted as in 1.2 with 39.3 g (0.3 mol) of 2-amino-4,6-difluoropyrimidine (A.1a) in a total of 400 ml of isopropanol. After the working up, washing with petroleum ether and water in the usual manner, 38.5 g (75% of theory) of the title compound of melting point 66°-68° C. were obtained.
Reaction SMILES: O1C=CC=N1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][CH:8]=1.[C:16](OCC)(=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18]>>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH2:14][C:16](=[O:22])[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:9][CH:8]=1
Reactant: CC(=O)c1ccc(F)cc1
Reactant: CCOC(=O)C(=O)OCC
Agent: c1cnoc1
Product: CCOC(=O)C(=O)CC(=O)c1ccc(F)cc1

Procedure:
In a further embodiment, an isoxazole cyclization reaction is provided in Scheme 15A. In this embodiment, 1-(4-fluorophenyl)ethanone is reacted with diethyl oxalate to provide ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate. In one embodiment, this reaction is performed in the presence of a base such as potassium tert-butoxide. In another embodiment, this reaction is performed at about room temperature for about 24 hours. The isoxazole ring is then generated by reaction of ethyl 4-(4-fluorophenyl)-2,4-dioxobutanoate with hydroxylamine hydrochloride to provide ethyl 5-(4-fluorophenyl)isoxazole-3-carboxylate. In one embodiment, this reaction is performed in at elevated temperatures. In another embodiment, this reaction is performed in ethanol for about 2 hours. Ethyl 5-(4-fluorophenyl)-isoxazole-3-carboxylate is then reduced with lithium aluminum hydride to provide 5-(4-fluorophenyl)isoxazol-3-yl)methanol. In one embodiment, the reduction is performed in THF, at a temperature of about 0° C. to about room temperature overnight. 5-(4-Fluorophenyl)isoxazole-3-carbaldehyde is then formed by oxidizing (5-(4-fluorophenyl)isoxazol-3-yl)methanol. In one embodiment, the oxidation is performed using PCC. In another embodiment, the oxidation is performed in dichloromethane at about room temperature overnight. 5-(4-Fluorophenyl)isoxazole-3-carbaldehyde may then converted to a compound of Formula (I-A) using the methods described herein.
Reaction SMILES: ClC1C=CC(OC2C=CC(NC(=O)[NH:15][C@@H:16]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:17]([NH:19][CH2:20][CH2:21][N:22]([CH:26]([CH3:28])[CH3:27])[CH:23]([CH3:25])[CH3:24])=[O:18])=CC=2)=CC=1.Cl.O1CCOCC1.[F:46][C:47]1[CH:62]=[CH:61][C:50]([O:51][C:52]2[CH:57]=[CH:56][C:55]([N:58]=[C:59]=[S:60])=[CH:54][CH:53]=2)=[CH:49][CH:48]=1>C(Cl)Cl>[CH:26]([N:22]([CH:23]([CH3:25])[CH3:24])[CH2:21][CH2:20][NH:19][C:17](=[O:18])[C@@H:16]([NH:15][C:59]([NH:58][C:55]1[CH:54]=[CH:53][C:52]([O:51][C:50]2[CH:61]=[CH:62][C:47]([F:46])=[CH:48][CH:49]=2)=[CH:57][CH:56]=1)=[S:60])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)([CH3:27])[CH3:28]
Reactant: Fc1ccc(Oc2ccc(N=C=S)cc2)cc1
Reactant: CC(C)N(CCNC(=O)[C@H](Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccc(Cl)cc2)cc1)C(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)N(CCNC(=O)[C@H](Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccc(F)cc2)cc1)C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
To a solution of [(S)-1-(2-diisopropylamino-ethylcarbamoyl)-2-phenyl-ethyl]-carbamic acid tert-butyl ester (Example 3, step B) (0.093 g, 0.24 mmol) in CH2Cl2 (2 mL) a 4 M solution of HCl in dioxane (0.6 mL, 2.4 mmol) was added, and the mixture was stirred for 3 h at rt. The solvents were removed, and the residue was treated with CH2Cl2. The solvents were removed again under reduced pressure. The residue was dissolved in MeOH and treated with strongly basic ion exchange resin. After 10 min of stirring, the resin was filtered off and the solvents were removed. The residue was dissolved in CH2Cl2 (2 mL), and 4-(4-fluoro-phenoxy)-phenylisothiocyanate (0.064 g, 0.26 mmol) was added. After the mixture was stirred for 4 h, a small amount of 4-(4-fluoro-phenoxy)-phenylisothiocyanate (0.02 g) was added, and the mixture was stirred for 12 h. The crude mixture was purified by flash column chromatography using 0–20% MeOH(1% NH4OH)/CH2Cl2 afforded 0.07 g (55%) of the desired product. MS (electrospray): mass calculated for C30H37FN4O2S, 536.26; m/z found, 537.3 [M+H]+. 1H NMR (400 MHz, CD3OD): 7.26–6.89 (m, 13H), 5.17 (t, J=7 Hz, 1H), 3.17–2.96 (m, 6H), 2.44 (m, 2H), 1.02 (d, J=6.5 Hz, 12H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH:4]=[CH:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:14](#[N:16])[CH3:15]>CC([O-])=O.CC([O-])=O.[Cu+2].CC(OC)(C)C.CCOC(C)=O>[CH3:1][O:2][C:3]([C:4]1[C:14]([CH3:15])=[N:16][N:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:5]=1)=[O:13]
Reactant: COC(=O)C=CNc1ccccc1
Reactant: CC#N
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: COC(C)(C)C
Solvent: CCOC(C)=O
Product: COC(=O)c1cn(-c2ccccc2)nc1C

Procedure:
According to AVV A, 3-phenylamino acrylic acid methylester (197) (177.2 mg, 1.0 mmol, 1.0 equiv.) was stirred with Cu(OAc)2 (544.9 mg, 3.0 mmol, 3.0 equiv.) into acetonitrile (3.0 ml, 57.1 mmol, 57.1 equiv.) for 22 hours at 110° C. The greenish solid obtained as raw product (242.4 mg) was purified by means of column chromatography (silica gel (50 g), pentane/MTBE 95:5→0:100, then MTBE/EtOAc 100:0→0:100), whereby the desired product was obtained in the form of a yellowish solid (35.1 mg, 0.16 mmol, 16%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:19][CH2:18][C:13]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:12][CH:11]=2)=[C:6]([F:20])[C:5]=1[F:21])[CH3:2].C([OH:24])C.[OH-].[Na+].OO>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:19][CH2:18][C:13]3([O:14][CH2:15][CH2:16][O:17]3)[CH2:12][CH:11]2[OH:24])=[C:6]([F:20])[C:5]=1[F:21])[CH3:2]
Reactant: CCO
Reactant: CCOc1ccc(C2=CCC3(CC2)OCCO3)c(F)c1F
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(C2CCC3(CC2O)OCCO3)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1400 ml (1.40 mol) of borane/THF complex (1 M solution) are added at −7° C. to a solution of 320.0 g (1.08 mol) of 8-(4-ethoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene in 3000 ml of THF, and the reaction mixture is stirred at room temperature for 3 h. 262 ml (4.50 mol) of ethanol, 650 ml (2.6 mol) of aqueous sodium hydroxide solution (4 M) and 360 ml (4.11 mol) of aqueous hydrogen peroxide soln. (35%) are added successively to the batch, during which the internal temperature does not exceed 47° C. (ice bath). When the addition is complete, the mixture is refluxed for 2 h, and the solution is cooled, added to water and stirred vigorously. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the crude product (336 g of yellow oil) is purified by column chromatography (SiO2, dichloromethane: MTBE=8:2), giving 8-(4-ethoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]decan-7-ol as pale-yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:16])([F:15])[F:14])=[N:5][N:4]=[C:3]1[C:17]12[CH2:24][CH2:23][C:20]([C:25]([NH2:27])=O)([CH2:21][CH2:22]1)[CH2:19][CH2:18]2.N1C(Cl)=NC(Cl)=NC=1Cl>CN(C=O)C>[CH3:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:13]([F:15])([F:14])[F:16])=[N:5][N:4]=[C:3]1[C:17]12[CH2:22][CH2:21][C:20]([C:25]#[N:27])([CH2:23][CH2:24]1)[CH2:19][CH2:18]2
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(C(N)=O)(CC1)CC2
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C12CCC(C#N)(CC1)CC2
Reaction time: 2 h

Procedure:
A solution of carboxamide 1-E (0.64 g, 1.7 mmol) and cyanuric chloride (0.47 g, 2.53 mmol) in DMF (15 ml) was stirred at room temperature under a nitrogen atmosphere. After 2 h, DMF was removed in vacuo and the solid was redissolved in methylene chloride (100 ml). This solution was washed with saturated aqueous sodium bicarbonate and brine, dried (Na2SO4), and stripped to give 1-F as a pale yellow solid. MS (ESI+)=361.3 (M+1); 1H NMR (500 MHz, CDCl3): δ2.15 (6H, m), 2.22 (6H, m), 3.47 (3H, s), 7.51 (1H, m), 7.72 (2H, m), 7.87 (1H, m) ppm.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[OH:14])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2].[CH:15]([O:18][C:19]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][C:20]=1[C:21](Cl)=[O:22])([CH3:17])[CH3:16].N1C=CC=CC=1>O1CCOCC1>[C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14][C:21](=[O:22])[C:20]1[CH:24]=[C:25]([CH3:28])[CH:26]=[CH:27][C:19]=1[O:18][CH:15]([CH3:16])[CH3:17])[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[CH3:2]
Reactant: COC(=O)c1ccc(O)c(C(C)=O)c1
Reactant: Cc1ccc(OC(C)C)c(C(=O)Cl)c1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: COC(=O)c1ccc(OC(=O)c2cc(C)ccc2OC(C)C)c(C(C)=O)c1
Yield: 113.6 %

Procedure:
Methyl 3-acetyl-4-hydroxy-benzoate (6 g) in dioxane (100 ml) was reacted with 2-isopropoxy-5-methyl-benzoyl chloride (10 g) in the presence of pyridine (10 ml) at room temperature for 16 hours. After dilution with water, the precipitate was extracted with ethyl acetate and the organic solution was washed with 5% NaHCO3 and water and then evaporated to dryness to give methyl 3-acetyl-4-(2'-isopropoxy-5'-methyl-benzoyloxy)-benzoate (13 g, oil), which was dissolved in methyl-ethyl-ketone (200 ml) and treated with anhydrous potassium carbonate (22 g) under stirring at the reflux temperature for 4 hours.
Reaction SMILES: O1CCOCC1.C(=O)([O-])[O-].[Na+].[Na+].CC1(C)C(C)(C)OB([C:21]2[CH:22]=[N:23][C:24]([NH2:27])=[N:25][CH:26]=2)O1.Cl[C:30]1[N:38]=[C:37]2[C:33]([N:34]=[CH:35][N:36]2[CH2:39][CH:40]2[CH2:44][CH2:43][O:42][CH2:41]2)=[C:32]([N:45]2[CH2:50][CH2:49][O:48][CH2:47][CH2:46]2)[N:31]=1>O.C(OCC)(=O)C>[N:45]1([C:32]2[N:31]=[C:30]([C:21]3[CH:26]=[N:25][C:24]([NH2:27])=[N:23][CH:22]=3)[N:38]=[C:37]3[C:33]=2[N:34]=[CH:35][N:36]3[CH2:39][CH:40]2[CH2:44][CH2:43][O:42][CH2:41]2)[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: Clc1nc(N2CCOCC2)c2ncn(CC3CCOC3)c2n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CC4CCOC4)c3n2)cn1
Yield: 60.2 %

Procedure:
1,4-Dioxane (40 ml), water (20 ml), and sodium carbonate (3.6 g, 33.9 mmol) were added to 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine (2.5 g, 11.3 mmol) and 2-chloro-6-morpholin-4-yl-9-(tetrahydrofuran-3-ylmethyl)-9H-purine (3.7 g, 11.3 mmol) and the atmosphere in the reaction vessel was substituted with nitrogen. Tetrakis triphenylphosphine palladium (0.65 g, 0.57 mmol) was added, then the atmosphere in the reaction vessel was substituted with nitrogen again, and the resulting mixture was heated to reflux for 2 hours. The reaction mixture was cooled followed by the addition of ethyl acetate and water and the insoluble matter was collected by filtration, then washed with ethyl acetate and water, and dried to give the title compound (2.6 g, 59%) as a pale orange solid.