Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:18][CH3:19])[CH:17]=1)[C:12](O)=[O:13]>C1COCC1>[CH3:19][O:18][C:16]1[CH:15]=[C:11]([CH:10]=[C:9]([O:8][CH3:7])[CH:17]=1)[CH2:12][OH:13]
Reactant: COc1cc(OC)cc(C(=O)O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(CO)cc(OC)c1
Temperature: 0 °C
Reaction time: 5 h
Yield: 97.9 %

Procedure:
A stirred suspension of lithium aluminum hydride (13.1 g, 329 mmol, 2 equiv) in dry THF (400 mL) was cooled at 0° C. A solution of 3,5-dimethoxybenzoic acid (30.0 g, 164 mmol, 1 equiv) in dry THF (400 mL) was added over 45 min via addition funnel. Upon completion of the addition the reaction became a gray heterogeneous mixture, therefore and additional 300 mL of THF was added. The reaction mixture was allowed to warm to room temperature and stir for 5 h. The reaction mixture was quenched with a saturated aqueous solution of Na/K tartrate added. The resulting mixture was allowed to stir at room temperature for 1 h and the organic layer was separated. The remaining aqueous layer was extracted with EtOAc (×2). The combined organic layers were dried (MgSO4), filtered, and concentrated under reduced pressure to give 27.0 g (97% yield) of 5 product as a colorless oil: Rf 0.33 (EtOAc/hexanes, 1:2); IR (CDCl3) 3390, 2937, 1594, 1456, 1428, 1318, 1294, 1202, 1146, 1057, 829 cm−1; 1H NMR (600 MHz, CDCl3) δ 6.45 (d, 2 H, J=2.4 Hz), 6.32 (d, 1 H, J=2.4 Hz), 4.50 (d, 2 H, J=5.4 Hz), 3.71 (s, 6 H), 3.49 (t, 1 H, J=5.4 Hz); 13C NMR (150 MHz, CDCl3) δ 160.5, 143.3, 104.2, 99.2, 64.5, 55.0.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:12][NH:13][CH3:14]>>[CH3:12][N:13]([CH3:14])[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[N:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Brc1ccnc2ccncc12
Reactant: CNC
Product: CN(C)c1ccnc2ccncc12

Procedure:
Paudler et al., J. Heterocyclic Chem. 2 (4), 393-8 (1965), show the synthesis and NMR spectra of various 4-substituted-1,6-naphthyridines, for example, the reaction of 4-hydroxy-1,6-naphthyridine with POBr3 or POCl3 to obtain 4-bromo-1,6-naphthyridine or 4-chloro-1,6-naphthyridine, respectively. Also shown is the reaction of 4-bromo-1,6-naphthyridine with dimethylamine to produce 4-dimethylamino-1,6-naphthyridine and the reaction 4-chloro-1,6-naphthyridine with piperidine or hydrazine to produce 4-(1-piperidinyl)-1,6-naphthyridine or 4-hydrazino-1,6-naphthyridine, respectively.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][N:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[N:20]1([C:25]2[N:30]=[C:29]([CH:31]=O)[CH:28]=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[N:21]1>>[N:20]1([C:25]2[N:30]=[C:29]([CH2:31][N:1]3[CH:2]([C:10]4[C:15]([O:16][CH3:17])=[CH:14][N:13]=[CH:12][C:11]=4[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]3=[O:8])[CH:28]=[CH:27][CH:26]=2)[CH:24]=[CH:23][CH:22]=[N:21]1
Reactant: O=Cc1cccc(-n2cccn2)n1
Reactant: COC(=O)CCCC(N)c1c(OC)cncc1OC
Product: COc1cncc(OC)c1C1CCCC(=O)N1Cc1cccc(-n2cccn2)n1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(3,5-dimethoxypyridin-4-yl)pentanoate with 6-(1H-pyrazol-1-yl)picolinaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.49 min.; [M+H]+: 393.79 g/mol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[C:7]([NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[O:8])([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:21]=[CH:22][CH:23]=1)[C:7]([NH:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1)(=[O:12])=[O:11])=[O:8]
Reactant: COc1ccc(S(=O)(=O)NC(=O)c2cccc([N+](=O)[O-])c2)cc1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(S(=O)(=O)NC(=O)c2cccc(N)c2)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 48.9 %

Procedure:
A mixture of N-(m-Nitrobenzoyl)-4-methoxybenzenesulfonamide (920 mg, 2.87 mmol) and 100 mg of 10% Pd/C in ethanol (20 mL) was shaken under H2 (60 Psi) for 2 days at room temperature. After removing the catalyst by filtration, the filtrate was concentrated to afford 430 mg of the title compound which was used in the next reaction without further purification.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.Br[C:36]1[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:37]=1[C:43]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=1[CH3:51])=[O:44].[O:52]1[CH2:57][CH2:56][N:55]([C:58]2[C:59]([NH2:77])=[N:60][C:61]3[C:66]([CH:67]=2)=[CH:65][C:64](B2OC(C)(C)C(C)(C)O2)=[CH:63][CH:62]=3)[CH2:54][CH2:53]1.O1CCOCC1>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[NH2:77][C:59]1[C:58]([N:55]2[CH2:56][CH2:57][O:52][CH2:53][CH2:54]2)=[CH:67][C:66]2[C:61](=[CH:62][CH:63]=[C:64]([C:36]3[C:41]([CH3:42])=[CH:40][CH:39]=[CH:38][C:37]=3[C:43]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=3[CH3:51])=[O:44])[CH:65]=2)[N:60]=1
Reactant: CC1(C)OB(c2ccc3nc(N)c(N4CCOCC4)cc3c2)OC1(C)C
Reactant: Cc1ccccc1C(=O)c1cccc(C)c1Br
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccccc1C(=O)c1cccc(C)c1-c1ccc2nc(N)c(N3CCOCC3)cc2c1
Temperature: 140 °C

Procedure:
A mixture of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (0.013 g, 0.028 mmol), (2-bromo-3-methylphenyl)(o-tolyl)methanone (0.16 g, 0.563 mmol), 3-morpholino-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinolin-2-amine (0.050 g, 0.141 mmol), Pd2(dba)3 (6.44 mg, 7.04 μmol) were treated with dioxane (0.94 mL) and water (0.47 mL) in a medium-sized Smith synthesizer vial. The mixture was heated to 140° C. for 12 min in a microwave reactor. The reaction mixture was filtered then partitioned between EtOAc and water. The organic layer was washed with water and brine and then concentrated in vacuo. The crude product was purified first by column chromatography (1-10% MeOH:DCM) and then by HPLC (10-90% CH3CN/H2O; TFA modifier). A single fraction was treated with NH4OH, concentrated, filtered and air-dried to afford (2-(2-amino-3-morpholinoquinolin-6-yl)-3-methylphenyl)(o-tolyl)methanone. MS (ESI, pos. ion) m/z: 438 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][N:6]=1)=[O:4].C>C(O)(C)C.[OH-].[Na+]>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([OH:4])=[O:2])=[N:6][CH:7]=1)[CH:13]=[CH:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: COC(=O)c1ccc(NCC=Cc2ccccc2)cn1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: O=C(O)c1ccc(NCC=Cc2ccccc2)cn1

Procedure:
To the solution of 11.9 g of 5-cinnamylamino-pyridine-2-carboxylic acid methyl ester in 25 ml of isopropanol, 28 ml of 2 N aqueous sodium hydroxide are added and the mixture intermittently heated on the steam bath for 40 minutes. It is cooled, decolorized with charcoal, filtered and the filtrate slightly acidified with hydrochloric acid and acetic acid. The mixture is extracted with benzene, the extract dried, evaporated and the residue recrystallized from benzene/methanol, to yield the 5-cinnamylaminopyridine-2-carboxylic acid melting at 178°-183°.
Reaction SMILES: S(Cl)([Cl:3])=O.[Br:5][C:6]1[S:10][C:9]2=[C:11]([C:14]([OH:16])=O)[N:12]=[CH:13][N:8]2[CH:7]=1>C1(C)C=CC=CC=1>[Br:5][C:6]1[S:10][C:9]2=[C:11]([C:14]([Cl:3])=[O:16])[N:12]=[CH:13][N:8]2[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ncn2cc(Br)sc12
Solvent: Cc1ccccc1
Product: O=C(Cl)c1ncn2cc(Br)sc12
Yield: 100.4 %

Procedure:
Thionyl chloride (0.1 ml, 1.37 mmol) was added dropwise to a solution of 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid (97 mg, 0.39 mmol) in toluene (10 ml), and the mixture was heated under reflux for 1.5 hr. The excessive amount of thionyl chloride was removed at the atmospheric pressure, and the solvent was then removed by distillation under the reduced pressure to give 2-bromoimidazo[5,1-b]thiazole-7-carboxylic acid chloride (104 mg, quantitative) as a light brown solid.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[C:9](Br)=[N:10][CH:11]=[CH:12][CH:13]=1)(=O)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].COCCOC>CO>[O:7]([C:8]1[C:9]([C:32]2[CH:33]=[CH:34][C:29]([O:28][CH3:27])=[CH:30][CH:31]=2)=[N:10][CH:11]=[CH:12][CH:13]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: COc1ccc(B(O)O)cc1
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccnc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: CO
Product: COc1ccc(-c2ncccc2O[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)cc1
Temperature: 120 °C

Procedure:
A mixture of 0.8 g (1.8 mM) of the 2-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside obtained according to Preparation 28, 0.325 g (2.14 mM) of 4-methoxyphenylboronic acid, 0.8 g (0.08 mM) of Suzuki's catalyst supported on resin (Argonaut, PSPPh3Pd resin), 1.16 g (3.56 mM) of cesium carbonate, 5 ml of DME and 4 ml of methanol is placed in a reactor adapted for microwaves. The mixture is heated at 120° C. for 30 minutes by microwaves. After filtration, rinsing with methanol and evaporation of the solvents, the residue obtained is chromatographed directly on silica gel using firstly pure dichloro-methane and then a dichloromethane/methanol mixture (9/1; v/v) as the eluent. The foam obtained is crystallized from ether to give the expected product in the form of a white powder (yield=65%).
Reaction SMILES: C[O:2][C:3](=[O:53])[C@@H:4]([NH:20][C:21]([C@@H:23]1[CH2:32][C:31]2[CH:30]=[C:29]3[O:33][CH2:34][C@H:35]([C:37]4[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([Cl:51])=[C:47]([Cl:52])[CH:46]=5)=[CH:39][CH:38]=4)[O:36][C:28]3=[CH:27][C:26]=2[CH2:25][NH:24]1)=[O:22])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=2[CH3:19])=[CH:8][CH:7]=1.[F:54][C:55]1([F:64])[CH2:60][CH2:59][N:58]([C:61](Cl)=[O:62])[CH2:57][CH2:56]1>C(Cl)Cl>[Cl:52][C:47]1[CH:46]=[C:45]([CH:50]=[CH:49][C:48]=1[Cl:51])[CH2:44][O:43][C:40]1[CH:39]=[CH:38][C:37]([C@H:35]2[CH2:34][O:33][C:29]3=[CH:30][C:31]4[CH2:32][C@@H:23]([C:21]([NH:20][C@@H:4]([CH2:5][C:6]5[CH:11]=[CH:10][C:9]([C:12]6[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[C:13]=6[CH3:19])=[CH:8][CH:7]=5)[C:3]([OH:53])=[O:2])=[O:22])[N:24]([C:61]([N:58]5[CH2:59][CH2:60][C:55]([F:64])([F:54])[CH2:56][CH2:57]5)=[O:62])[CH2:25][C:26]=4[CH:27]=[C:28]3[O:36]2)=[CH:42][CH:41]=1
Reactant: O=C(Cl)N1CCC(F)(F)CC1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)CO3
Solvent: ClCCl
Product: Cc1nccc(-c2ccc(C[C@H](NC(=O)[C@@H]3Cc4cc5c(cc4CN3C(=O)N3CCC(F)(F)CC3)O[C@@H](c3ccc(OCc4ccc(Cl)c(Cl)c4)cc3)CO5)C(=O)O)cc2)c1C

Procedure:
(S)-2-({(3S,8S)-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl}-amino)-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (30 mg) in DCM (3 mL), 4,4-difluoro-piperidine-1-carbonyl chloride (5.0 eq, prepared according to General Procedure AD) according to General Procedure H and purified over silica (hexanes to 1:1 hexanes EtOAc to 1:1 hexanes EtOAc+1% MeOH). The resulting compound was hydrolyzed according to General Procedure B to give the title compound (8 mg). LCMS (m/z) 886.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].[Br:17]C(Br)(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:17][CH2:2][C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: BrC(Br)(Br)Br
Reactant: COC(=O)c1ccc(CO)cc1C(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc(CBr)cc1C(=O)OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
36 g (176 mmol) of dimethyl 4-hydroxymethylphthalate are dissolved in 300 mL of dichloromethane and 70 g (211 mmol) of tetrabromomethane are added. A solution of 55.3 g (211 mmol) of triphenylphosphine in 200 mL of dichloromethane is then added slowly and the reaction mixture is stirred for 3 h at room temperature. After treatment with water and extraction with dichloromethane, the residue is purified by chromatography on a column of silica (eluent: dichloromethane). The desired product is obtained in the form of a colourless oil (m=25 g; Y=50%).
Reaction SMILES: [C:1]([N:5]1[CH2:22][CH:21]([CH:23]([OH:26])CO)[O:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+].O.[BH4-].[Na+]>O1CCCC1.[Cl-].[Na+].O.C(OCC)(=O)C.CO.ClCCl>[C:1]([N:5]1[CH2:22][CH:21]([CH2:23][OH:26])[O:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][CH2:8]2)[CH2:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C(C)(C)C)CC(C(O)CO)O2
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C(C)(C)C)CC(CO)O2
Temperature: 40 °C
Reaction time: 16 h
Yield: 71.2 %

Procedure:
To a solution of tert-butyl 8-tert-butyl-10-(1,2-dihydroxyethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (1.10 g, 2.95 mmol) in tetrahydrofuran (22 mL) was added sodium periodate (1.58 g, 7.38 mmol) and water (8.0 mL), resulting in a thick white precipitate. The reaction mixture was heated at 40° C. for 3 h, then additional sodium periodate added (2.95 mmol) and the mixture stirred for 16 h. The reaction mixture was filtered through Celite and rinsed with tetrahydrofuran (30 mL). The filtrate solution was cooled to 0° C. and treated portion-wise with sodium borohydride (223 mg, 5.91 mmol) over 5 min. The reaction mixture was stirred for 30 min then diluted with brine (400 mL) and ethyl acetate (400 mL). The organic phase was separated and the aqueous phase extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. Silica gel chromatography (80 g silica, 1-10% methanol/dichloromethane) provided tert-butyl 8-tert-butyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (720 mg, 2.10 mmol, 71%) as colorless oil. ESI-MS m/z calc. 342.3. found 343.5 (M+1)+; Retention time: 0.89 minutes (3 min run).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19](I)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:21].[CH3:22][Si:23]([C:26]#[CH:27])([CH3:25])[CH3:24].C(N(CC)CC)C>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([CH:14]([F:16])[F:15])[N:11]3[N:17]=[CH:18][C:19]([C:27]#[C:26][Si:23]([CH3:25])([CH3:24])[CH3:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:21]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cc(-c2cc(C(F)F)n3ncc(I)c3n2)ccc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cc(C(F)F)n3ncc(C#C[Si](C)(C)C)c3n2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72.6 %

Procedure:
A mixture of 5-(4-chloro-3-methyl-phenyl)-3-iodo-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine (7.01 g, 16.7 mmol), trimethylsilylacetylene (4.16 mL, 30.0 mmol) and triethylamine (4.66 mL, 33.4 mmol) in N,N-dimethylformamide (18 mL) was stirred for 10 min at room temperature while being purged with Argon, then PdCl2(PPh3)2 (117 mg, 1 mol %), PPh3 (44 mg, 1 mol %) and CuI (10 mg, 0.3 mol %) were added. Stirring was continued at 90° C. for 4.5 h. The reaction mixture was cooled to room temperature, diluted with water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (2×50 mL) and brine (70 mL), dried (MgSO4), evaporated and further purified by column chromatography on silica gel (dischloromethane/heptane 7:3) to give 5-(4-chloro-3-methyl-phenyl)-7-difluoromethyl-3-trimethylsilanylethynyl-pyrazolo[1,5-a]pyrimidine (4.73 g, 73%) as an orange solid, which was dissolved in THF (74 mL) and MeOH (56 mL), while stirring at 0° C. potassium carbonate (168 mg, 1.22 mmol) was added and the mixture was stirred at 0° C. for 5 h. The mixture was diluted with ice water (250 mL) and extracted with TBME (3×250 mL). The combined organic layers were washed with brine (200 mL), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (heptane/EtOAc) followed by crystallization fromethyl acetate/hexane to give 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-difluoromethyl-pyrazolo[1,5-a]pyrimidine (3.8 g, 72%) as a light brown solid. MS (EI) 317.2 [(M)+]; mp 143° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:7][C:8]([F:24])([C:15]([F:23])([F:22])[C:16]([F:21])([F:20])[CH:17]([F:19])[F:18])[CH2:9][O:10][CH2:11][CH:12]1[O:14][CH2:13]1>>[O:4]1[CH2:5][CH2:6][N:1]([CH2:13][CH:12]([OH:14])[CH2:11][O:10][CH2:9][C:8]([F:7])([F:24])[C:15]([F:22])([F:23])[C:16]([F:21])([F:20])[CH:17]([F:19])[F:18])[CH2:2][CH2:3]1
Reactant: FC(F)C(F)(F)C(F)(F)C(F)(F)COCC1CO1
Reactant: C1COCCN1
Product: OC(COCC(F)(F)C(F)(F)C(F)(F)C(F)F)CN1CCOCC1
Temperature: 80 °C
Reaction time: 10 h
Yield: 89.1 %

Procedure:
To 8.7 g of morpholine was added dropwise 28.8 g of glycidyl 2,2,3,3,4,4,5,5-octafluoropentyl ether. The mixture was then stirred at 80° C. for 10 hours. The reaction mixture was directly purified by silica gel column chromatography. There was obtained 33.4 g of 1-morpholino-3-(2,2,3,3,4,4,5,5-octafluoropentyloxy)-2-propanol (yield 89%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])/[C:4](/[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=1)=[C:5](/[CH:10]([CH3:12])[CH3:11])\[C:6]([O:8][CH3:9])=[O:7].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[C:47]([O:50][CH:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1)(=[O:49])[CH3:48].C(N(CC)CC)C>ClCCl.O>[CH3:1][O:2][C:3](=[O:23])/[C:4](/[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:54]2[CH2:55][CH2:56][CH:51]([O:50][C:47](=[O:49])[CH3:48])[CH2:52][CH2:53]2)=[O:21])=[CH:16][CH:15]=1)=[C:5](/[CH:10]([CH3:11])[CH3:12])\[C:6]([O:8][CH3:9])=[O:7]
Reactant: CC(=O)OC1CCNCC1
Reactant: COC(=O)/C(Cc1ccc(C(=O)O)cc1)=C(\C(=O)OC)C(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)/C(Cc1ccc(C(=O)N2CCC(OC(C)=O)CC2)cc1)=C(\C(=O)OC)C(C)C
Yield: 77.4 %

Procedure:
To a solution of 2-(4-carboxybenzyl)-3-isopropylmaleic acid dimethyl ester (10.3 mg, 0.0322 mmol) in dichloromethane (500 μL) were added 1-hydroxybenzotriazole (13.3 mg, 0.0965 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (20.8 mg, 0.109 mol), piperidin-4-yl acetate hydrochloride (28.8 mg, 0.161 mmol) and triethylamine (14.6 mg, 0.145 mmol) with stirring under ice cooling. After stirring at room temperature for 1 h, the reaction mixture was diluted with water to separate the phases. The aqueous layer was extracted again with ethyl acetate, and the combined organic layer was concentrated under reduced pressure and the residue thus obtained was subjected to silica gel column chromatography (hexane-ethyl acetate1:2) to give 11.1 mg of the title compound as a solid (yield: 78%).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH3:10])[C:7]([N+:11]([O-])=O)=[CH:6][N:5]=2)[CH2:3][CH2:2]1.Cl.C([O-])(O)=O.[Na+]>CO.[Zn]>[CH:1]1([C:4]2[N:5]=[CH:6][C:7]([NH2:11])=[C:8]([CH3:10])[CH:9]=2)[CH2:3][CH2:2]1
Reactant: Cc1cc(C2CC2)ncc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: Cc1cc(C2CC2)ncc1N
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-cyclopropyl-4-methyl-5-nitropyridine (201 mg, 0.96 mmol) in MeOH (5 mL) were added 3N aqueous HCl (9.6 mL, 28.8 mmol) and Zn powder (376 mg, 5.75 mmol). The mixture was stirred 18 h at RT. The solution was neutralized with a sat. aq. NaHCO3 solution and extracted with CH2Cl2 (3×). The combined organics were dried (Phase Separator) and concentrated under reduced pressure. MS (LC-MS): 149 [M+H]+, tR (HPLC conditions c): 2.22 min.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([OH:22])=[C:17]([C:19](=[O:21])[CH3:20])[CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>C(O)(=O)C>[CH2:5]([O:12][C:13]1[CH:14]=[C:15]([N+:1]([O-:4])=[O:2])[C:16]([OH:22])=[C:17]([C:19](=[O:21])[CH3:20])[CH:18]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])O
Reactant: CC(=O)c1cc(OCc2ccccc2)ccc1O
Solvent: CC(=O)O
Product: CC(=O)c1cc(OCc2ccccc2)cc([N+](=O)[O-])c1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
18 mL of fuming nitric acid are added dropwise to a solution of 81.5 g (0.34 mol) 1-(5-benzyloxy-2-hydroxy-phenyl)-ethanone (known from U.S. Pat. No. 4,460,581) in 700 mL acetic acid, while cooling with the ice bath, such that the temperature does not exceed 20° C. Then the reaction mixture is stirred for two hours at ambient temperature, poured onto ice water and filtered. The product is recrystallised from isopropanol, suction filtered and washed with isopropanol and diisopropylether. Yield: 69.6 g (72%); mass spectroscopy [M+H]+=288.
Reaction SMILES: [S:1]1[N:5]=[CH:4][C:3]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:2]1.[N:12](OCCC(C)C)=[O:13]>>[OH:13][N:12]=[C:6]([C:3]1[CH:4]=[N:5][S:1][N:2]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)Cc1cnsn1
Reactant: CC(C)CCON=O
Product: CCOC(=O)C(=NO)c1cnsn1

Procedure:
Ethyl 2-(1,2,5-thiadiazol-3-yl)acetate (9.5 g.) and isopentyl nitrite (10 ml.) were reacted according to a similar manner to that of Example 3(a)(1) to give ethyl 2-hydroxyimino-2-(1,2,5-thiadiazol-3-yl)acetate (a mixture of syn and anti isomers) (10.5 g.), mp 60° to 66° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2C=CC(OC)=C(Cl)C=2)[C:5](C(OCC)=O)=CN=1.[CH2:24]([N:26](CC)CC)C>C(Cl)(Cl)Cl>[N:8]1[CH:9]=[CH:10][N:7]2[CH2:2][CH2:24][NH:26][CH2:5][C:6]=12
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cnc(Cl)nc1NCc1ccc(OC)c(Cl)c1
Solvent: ClC(Cl)Cl
Product: c1cn2c(n1)CNCC2

Procedure:
A mixture of 2-chloro-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (285 mg) obtained in the above (3), 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (197 mg), triethylamine (0.22 ml) and chloroform (3 ml) is stirred at room temperature for 2.5 hours, and stirred at 60° C. for 2.5 hours. The reaction mixture is diluted with ethyl acetate, and washed with water. The aqueous layer is extracted with ethyl acetate, and the organic layer is washed with water and a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (silica gel: 10 g, solvent; chloroform:methanol=50:1), and concentrated under reduced pressure. The resultant is triturated with isopropyl ether to give 2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-ethoxycarbonylpyrimidine (290 mg) as colorless crystalline powder, m.p. 179-182° C., MS (m/z): 443 (MH+).