Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:5]([C:18]2[CH:23]=[C:22]([OH:24])[C:21]([Cl:25])=[CH:20][C:19]=2[F:26])[C:6](=[O:17])[CH:7]=[C:8]([C:10]([F:16])([F:15])[C:11]([F:14])([F:13])[F:12])[N:9]=1)[CH3:2].[CH2:27](Br)[C:28]#[CH:29].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[CH2:1]([O:3][C:4]1[N:5]([C:18]2[CH:23]=[C:22]([O:24][CH2:29][C:28]#[CH:27])[C:21]([Cl:25])=[CH:20][C:19]=2[F:26])[C:6](=[O:17])[CH:7]=[C:8]([C:10]([F:16])([F:15])[C:11]([F:12])([F:13])[F:14])[N:9]=1)[CH3:2]
Reactant: C#CCBr
Reactant: CCOc1nc(C(F)(F)C(F)(F)F)cc(=O)n1-c1cc(O)c(Cl)cc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: C#CCOc1cc(-n2c(OCC)nc(C(F)(F)C(F)(F)F)cc2=O)c(F)cc1Cl

Procedure:
using 2-ethoxy-1-(4-chloro-2-fluoro-5 -hydroxyphenyl) -4-pentafluoroethyl-6(1H)-pyrimidinone and propargyl bromide with sodium carbonate in acetone there is obtained 2-ethoxy-1-[4-chloro-2-fluoro-5 -(2-propynyloxy)-phenyl]-4-pentafluoroethyl-6(1H)-pyrimidinone, 1H-NMR (CDCl3, 400 MHz): 7.35 ppm (d,1H), 6.98 ppm (d,1H), 6.65 ppm (s,1H), 4.77 ppm (m,2H), 4.48 ppm (m,2H), 2.57 ppm (t,1H), 1.29 ppm (t,3H);
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=O)[C:8]2[NH:13][N:12]=[C:11]([I:14])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[CH3:16][O:17][C:18]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[CH:20][C:19]=1[CH2:26][NH2:27].N1CCCN2CCCCCC=12.C1CN([P+](ON2N=NC3C2=CC=CC=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(#N)C>[CH2:1]([C:5]1[N:6]=[C:7]([NH:27][CH2:26][C:19]2[CH:20]=[CH:21][C:22]([O:24][CH3:25])=[CH:23][C:18]=2[O:17][CH3:16])[C:8]2[NH:13][N:12]=[C:11]([I:14])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(I)n[nH]c2c(=O)[nH]1
Reactant: COc1ccc(CN)c(OC)c1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(I)c2n1
Temperature: 25 °C
Reaction time: 6 h
Yield: 51 %

Procedure:
A solution of 5-butyl-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (50 g, 157 mmol), (2,4-dimethoxyphenyl)methanamine (60 g, 359 mmol) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (47.9 g, 314 mmol) in acetonitrile (500 mL) was treated with ((1H-benzo[d][1,2,3]triazol-1-yl)oxy)tri(pyrrolidin-1-yl)phosphonium hexafluorophosphate(V) (100 g, 192 mmol) and stirred for 6 hours at room temperature under nitrogen. The resulting suspension was filtered to remove precipitate and the filtrate was evaporated. The residue was purified on a silica cartridge (1500 g) (applied in minimum DCM) eluted with 0-80% cyclohexane-EtOAc (12 column volumes). Product-containing fractions were part evaporated to give a heavy suspension that was filtered and the solid air-dried to give the title compound (37.5 g, 80 mmol) as a white powder.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=O)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.Cl.[CH2:34]([O:36][C:37](=[O:40])[CH2:38][NH2:39])[CH3:35].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1>O1CCCC1>[CH2:34]([O:36][C:37](=[O:40])[CH2:38][NH:39][C:30](=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][NH:24][C:16](=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:35]
Reactant: O=C(O)CCCCCNC(=O)c1ccccc1
Reactant: CCOC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)CCCCCNC(=O)c1ccccc1
Temperature: 0 °C

Procedure:
A solution of dicyclohexylcarbodiimide (112 mmoles) in anhydrous tetrahydrofuran (44 ml) was gradually added to a suspension of N-benzoyl-6-aminohexanoic acid (93.5 mmoles), prepared as described in example 1, glycine ethyl ester hydrochloride (112 mmoles), triethylamine (112 mmoles) and anhydrous 1-hydroxybenzotriazole (112 mmoles) in tetrahydrofuran (330 ml), kept under stirring at 0° C. The reaction mixture was brought at room temperature and kept under stirring for 16 hours.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5])[CH3:2].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:32]3[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:7]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5])[CH3:2]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccccc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(Cl)cc3)ccc2n1-c1ccccc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-phenylindole-3-carboxylic acid ethyl ester (140 mg, 0.38 mmol, see step (b) Example 3) and 4-chlorophenylboronic acid (119 mg, 0.76 mmol). Yield 100 mg, 55%.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([N+:9]([O-:11])=[O:10])[C:4]=1[F:12].[CH3:13][C:14]1[C:15]2[CH:22]=[CH:21][C:20]([O:23][C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:19][C:16]=2[S:17][CH:18]=1>ClCCl.[Cl-].[Zn+2].[Cl-]>[F:12][C:4]1[C:5]([N+:9]([O-:11])=[O:10])=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][C:18]1[S:17][C:16]2[CH:19]=[C:20]([O:23][C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[CH:21]=[CH:22][C:15]=2[C:14]=1[CH3:13]
Reactant: O=[N+]([O-])c1cccc(CBr)c1F
Reactant: Cc1csc2cc(Oc3ncccn3)ccc12
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Product: Cc1c(Cc2cccc([N+](=O)[O-])c2F)sc2cc(Oc3ncccn3)ccc12
Yield: 36.3 %

Procedure:
1-Bromomethyl-2-fluoro-3-nitrobenzene (120 mg, 0.513 mmol) and zinc chloride (71 mg, 0.520 mmol) were added to a solution of 2-(3-methyl-benzo[b]thiophen-6-yloxy)pyrimidine (114 mg, 0.470 mmol) in dichloromethane (1.0 mL), and the mixture was heated under reflux for 17.5 hours. After returning to room temperature, 1-bromomethyl-2-fluoro-3-nitrobenzene (120 mg, 0.513 mmol) and zinc chloride (71 mg, 0.520 mmol) were added thereto, and the mixture was heated under reflux for 23 hours. The reaction mixture was then concentrated under reduced pressure, and purified by column chromatography to yield the title compound (67.5 mg, 36%) as a white solid.
Reaction SMILES: [N:1]1([C:7]2[C:12]3[CH:13]=[CH:14][O:15][C:11]=3[CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O)(=O)C.[H][H]>CO.[Pd]>[N:1]1([C:7]2[C:12]3[CH2:13][CH2:14][O:15][C:11]=3[CH:10]=[CH:9][N:8]=2)[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]1
Reactant: c1cc2occc2c(N2CCNCC2)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: c1cc2c(c(N3CCNCC3)n1)CCO2
Yield: 38.6 %

Procedure:
A mixture of commercially available 4-(piperazin-1-yl)-furo[3,2-c]pyridine [CAS-No. 81078-84-4] (1 g, 4.92 mmol), Pd/C 5% (0.46 g, 4.32 mmol), acetic acid (2.3 ml) in MeOH (6.9 ml) was stirred in a hydrogen atmosphere at room temperature for 48 h. After removal of the catalyst by filtration the mixture was evaporated, the residue was dissolved in dichloromethane/MeOH/NH4OH 80:10:1, washed with 2N sodium carbonate solution, dried (MgSO4) and evaporated. The crude material (0.68 g) was purified by chromatography on silica gel (dichloromethane/MeOH/NH4OH 80:10:1) to yield 4-(piperazin-1-yl)-2,3-dihydrofuro[3,2-c]pyridine as a white solid (0.39 g, 39%), MS (ISP) m/z=206.2 [(M+H)+], mp 89.5° C.
Reaction SMILES: BrC1C=CC=C2C=1C(C1C(O)=CC3OCOC=3C=1)[C:5](=[O:16])N2CCCCC.[OH:27][C:28]1[C:29]([CH:37]2[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][CH2:47][CH2:48][N:49]3[C:57](=[O:58])[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:50]3=[O:59])[C:38]2=[O:60])=[CH:30][C:31]2[O:35][CH2:34][O:33][C:32]=2[CH:36]=1>>[OH:27][C:28]1[C:29]([C:37]2([CH2:5][OH:16])[C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[N:39]([CH2:46][CH2:47][CH2:48][N:49]3[C:57](=[O:58])[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C:50]3=[O:59])[C:38]2=[O:60])=[CH:30][C:31]2[O:35][CH2:34][O:33][C:32]=2[CH:36]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2ccccc21
Reactant: CCCCCN1C(=O)C(c2cc3c(cc2O)OCO3)c2c(Br)cccc21
Product: O=C1c2ccccc2C(=O)N1CCCN1C(=O)C(CO)(c2cc3c(cc2O)OCO3)c2ccccc21

Procedure:
Following the procedure as described in PREPARATION 1E, and making non-critical variations to replace 4-bromo-3-(6-hydroxy-1,3-benzodioxol-5-yl)-1-pentyl-1,3-dihydro-2H-indol-2-one with 2-{3-[3-(6-hydroxy-1,3-benzodioxol-5-yl)-2-oxo-2,3-dihydro-1H-indol-1-yl]propyl}-1H-isoindole-1,3(2H)-dione, the title compound was obtained (94%) as a foam solid: 1H NMR (300 MHz, CDCl3) δ 9.20 (s, 1H), 7.81-7.79 (m, 2H), 7.68-7.61 (m, 2H), 7.35-7.25 (m, 2H), 7.16-7.14 (m, 1H), 6.90 (d, 1H), 6.80 (s, 1H), 6.48 (s, 1H), 5.86 (dd, 2H), 4.64 (d, 1H), 3.67-4.13 (m, 5H), 2.18-2.05- (m, 2H); 13C NMR (75 MHz, CDCl3) δ 180.6, 168.6, 151.2, 147.8, 143.2, 141.2, 134.2, 134.2, 131.9, 130.0, 128.7, 125.1, 123.2, 113.9, 108.7, 108.3, 101.3, 100.6, 64.9, 58.0, 37.6, 36.1, 26.5; MS (ES+) m/z 487.3 (M+1).
Reaction SMILES: [ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([OH:15])=[O:14])[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4].O[C:17]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:19][C:18]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(N=C=NC2CCCCC2)CCCCC1>N1C=CC=CC=1>[ClH:1].[NH:2]([CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]([O:15][C:30]2[CH:29]=[C:28]([CH:33]=[CH:32][CH:31]=2)[C:18]2[O:19][C:20]3[C:25]([C:26](=[O:27])[CH:17]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:14])[CH2:9][CH2:8]1)[C:3]([NH2:5])=[NH:4]
Reactant: O=c1c(O)c(-c2ccccc2)oc2ccccc12
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: c1ccncc1
Product: N=C(N)NC[C@H]1CC[C@H](C(=O)Oc2cccc(-c3cc(=O)c4ccccc4o3)c2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 9.89 g of trans-4-guanidinomethylcyclohexanecarboxylic acid hydrochloride, 10.1 g of 3-hydroxyflavon and 8.66 g of dicyclohexylcarbodiimide was added to 100 ml of dry pyridine, and the resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was filtered to remove any insoluble materials which were washed with pyridine. The filtrate and the washing were combined and evaporated. 0.1N hydrochloric acid was added to the residue, and the mixture was washed with ethyl acetate. The aqueous layer was concentrated to 30 ml and allowed to stand overnight in a refrigerator to obtain 1 g of 3'-flavonyl trans-4-guanidinomethylcyclohexanecarboxylate hydrochloride as colorless needles having a melting point of 201°-203° C.
Reaction SMILES: [NH:1]([C:3]([S:5][CH3:6])=[NH:4])[NH2:2].[CH3:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([CH:18]=O)=O)=[CH:12][CH:11]=1>>[CH3:7][O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:4]=[C:3]([S:5][CH3:6])[N:1]=[N:2][CH:18]=2)=[CH:12][CH:11]=1
Reactant: COCc1ccc(C(=O)C=O)cc1
Reactant: CSC(=N)NN
Product: COCc1ccc(-c2cnnc(SC)n2)cc1
Yield: 72 %

Procedure:
5-[4-(methoxymethyl)phenyl]-3-(methylsulfanyl)-1,2,4-triazine (4.0 g, 72%) was prepared from methyl hydrazinecarbimidothioate (7.33 g, 31.46 mmol) and 4-(methoxymethyl)phenylglyoxal (4 g, 22.47 mmol) according to the general procedure of Preparation 2.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]=[CH:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[CH:14]=[CH:15][CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:4][CH:3]=2)[CH2:30][CH2:31]1)=[O:28])[CH3:25]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C=CCCc1ccccc1
Reactant: CCOC(=O)C1(c2ccccc2B2OC(C)(C)C(C)(C)O2)CC1
Product: CCOC(=O)C1(c2ccccc2-c2ccc(-c3onc(C)c3C=CCCc3ccccc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 5, using 5-(4-Bromo-phenyl)-3-methyl-4-(4-phenyl-but-1-enyl)-isoxazole and 1-[2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2O[CH:12]=[C:13]([C:25](=[O:30])[C:26]([CH3:29])([CH3:28])[CH3:27])[C:14](=[O:24])[C:15]=2[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:9])=[CH:4][CH:3]=1.C(O)C.[CH3:36][O:37][CH:38]([O:41][CH3:42])[CH2:39][NH2:40]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:40]([CH2:39][CH:38]([O:41][CH3:42])[O:37][CH3:36])[CH:12]=[C:13]([C:25](=[O:30])[C:26]([CH3:27])([CH3:28])[CH3:29])[C:14](=[O:24])[C:15]=2[O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[O:9])=[CH:31][CH:32]=1
Reactant: COC(CN)OC
Reactant: CC(C)(C)C(=O)c1coc(C(=O)NCc2ccc(F)cc2)c(OCc2ccccc2)c1=O
Solvent: C1CCOC1
Solvent: CCO
Product: COC(Cn1cc(C(=O)C(C)(C)C)c(=O)c(OCc2ccccc2)c1C(=O)NCc1ccc(F)cc1)OC
Temperature: 70 °C
Reaction time: 72 h

Procedure:
To a solution of 3-benzyloxy-5-(2,2-dimethylpropionyl)-4-oxo-4H-pyran-2-carboxylic acid 4-fluorobenzylamide (0.13 g) in tetrahydrofuran (0.5 ml)-ethanol (0.5 ml) was added aminoacetaldehyde dimethyl acetal (0.033 ml) and the mixture was stirred at 70° C. for 3 days. After cooling to room temperature, the solvent was evaporated to give 3-benzyloxy-1-(2,2-dimethoxyethyl)-5-(2,2-dimethylpropionyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid 4-fluorobenzylamide (157 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C@H:4]([CH2:14][OH:15])[NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(Cl)(Cl)=O>C(Cl)Cl>[C:7]1([C:6]2[O:15][CH2:14][C@@H:4]([C:3]([O:2][CH3:1])=[O:16])[N:5]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)[C@H](CO)NC(=O)c1ccccc1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)[C@@H]1COC(c2ccccc2)=N1
Yield: 78.7 %

Procedure:
A stirred mixture of N-benzoyl-L-serine methyl ester (21.0 g), thionyl chloride (21.0 g), and methylene chloride (150 ml) is stirred at reflux for 1 hour. The solvent is evaporated and the residue is diluted with cold water. Neutralize with sodium bicarbonate, and extract with ethyl acetate. Purification on silica gel (250 g), eluting with methanol:methylene chloride (01:99), yields methyl (S)-2-phenyl-2-oxazoline-4-carboxylate (15.2 g).
Reaction SMILES: [O:1]1[C@H:9]2[C@@H:10]3[C@@H:14]([C@@H:2]1[C@H:3]1[C@@H:8]2[CH2:7][CH2:6][CH2:5][CH2:4]1)[C@@H:13]([CH3:15])[O:12][C:11]3=[O:16].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1>>[OH:1][C@@H:2]1[C@H:14]2[C:10]([C:11](=[O:16])[O:12][C@@H:13]2[CH3:15])=[CH:9][C@H:8]2[C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7]2
Reactant: C[C@H]1OC(=O)[C@@H]2[C@@H]3O[C@@H]([C@@H]4CCCC[C@@H]43)[C@H]21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@H]1OC(=O)C2=C[C@@H]3CCCC[C@H]3[C@H](O)[C@@H]21
Yield: 101.5 %

Procedure:
Similarly to Example 3, 1.35 g(6.07 mmol) of (3R,3aR,4S,4aR,8aS,9R,9aS)-4,9-epoxy-3-methyl-decahydronaphtho[2,3-c]furan-1(3H)-one were reacted with 27.6 mg(5 equivalents) of lithium bis(trimethylsilyl)amide-tetrahydrofuran solution(1.1M) to obtain 1.37 g of (3R,3aR,4S,4aR,8aS)-4-hydroxy-3-methyl-3a,4,4a,5,6,7,8,8a-octahydronaphtho[2,3-c]furan-1(3H)-one and then reacted with 4.54 ml(5 equivalents) of 1,8-diazabicyclo[5.4.0]undec-7-ene to obtain 1.05 g of (3R,3aR,4S,4aR,9aR)-4-hydroxy-3-methyl-3a,4,4a,5,6,7,8,9a-octahydronaphtho[2,3-c]furan-1(3H)-one(yield after 2 processes 78%).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][C:29]([O:37][CH2:38][CH2:39]O)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH3:30]>C(Cl)Cl.[Al]>[Br:1][CH2:39][CH2:38][O:37][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([CH3:30])[CH3:28]
Reactant: CC(C)(OCCO)c1ccccc1
Reactant: O=C1CCC(=O)N1Br
Agent: [Al]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(OCCBr)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 42 %

Procedure:
N-bromosuccinimide (119 mg, 0.666 mmol) was added to resin-bound triphenylphosphine (222 mg, 0.666 mEquiv, Fluka) and 2-[(1-methyl-1-phenylethyl)oxy]ethanol (60 mg, 0.333 mmol) in DCM (4 mL). The reaction vial was sealed with a Teflon-lined cap, wrapped in aluminum foil, and shaken at rt for 17 h. The reaction was filtered through a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: DCM (fraction 1), 30% EtOAc/hexanes (fraction 2), and 50% EtOAc/hexanes (fraction 3) to give the title compound (34 mg, 42%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.Br[C:14]1[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([C:14]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:15]=3[C:16]([OH:18])=[O:17])=[O:12])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: O=C(O)c1ccc2c(c1)OCO2
Reactant: COc1ccc(Br)c(C(=O)O)c1
Product: COc1ccc(C(=O)c2ccc3c(c2)OCO3)c(C(=O)O)c1

Procedure:
This compound is obtained according to the procedure described in 1.1. by reacting 1,3-benzodioxole-5-carboxylic acid and 2-bromo-5-methoxybenzoic acid after halogen-lithium exchange. It is used in crude form in the following reaction.
Reaction SMILES: Cl[C:2]1[C:7]2[O:8][CH2:9][CH2:10][N:11]([CH2:12][CH3:13])[C:6]=2[N:5]=[C:4]([CH3:14])[N:3]=1.O.[NH2:16][NH2:17]>>[CH2:12]([N:11]1[CH2:10][CH2:9][O:8][C:7]2[C:2]([NH:16][NH2:17])=[N:3][C:4]([CH3:14])=[N:5][C:6]1=2)[CH3:13]
Reactant: CCN1CCOc2c(Cl)nc(C)nc21
Reactant: NN
Solvent: O
Product: CCN1CCOc2c(NN)nc(C)nc21

Procedure:
Using the method of Example 87, 4-chloro-6,7-dihydro-8-ethyl-2-methylpyrimido [5,4-b][1,4]oxazine, from Example 102, was reacted with hydrazine hydrate to provide 6,7-dihydro-8-ethyl-4-hydrazino-2-methylpyrimido[5,4-b][1,4]oxazine.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[N:6][N:7]2[C:12]([N:13]([CH3:20])C3C=CC=CC=3)=[N:11][C:10]([S:21][CH3:22])=[N:9][C:8]=12)([CH3:3])[CH3:2].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]1[CH:36]=[CH:35][C:32](CN)=[CH:31][CH:30]=1>CCO>[CH:1]([C:4]1[CH:5]=[N:6][N:7]2[C:12]([NH:13][CH2:20][C:32]3[CH:31]=[CH:30][C:29]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][N:23]=4)=[CH:36][CH:35]=3)=[N:11][C:10]([S:21][CH3:22])=[N:9][C:8]=12)([CH3:2])[CH3:3]
Reactant: NCc1ccc(-c2ccccn2)cc1
Reactant: CSc1nc(N(C)c2ccccc2)n2ncc(C(C)C)c2n1
Solvent: CCO
Product: CSc1nc(NCc2ccc(-c3ccccn3)cc2)n2ncc(C(C)C)c2n1
Yield: 60 %

Procedure:
According to the same conditions resulting in the preparation of the compound IIa.1, the compound IIa.2 is prepared from 8-isopropyl-4-(N-methyl-N-phenylamino)-2-(methylsulfanyl)pyrazolo[1,5-a]-1,3,5-triazine and from 4-(pyridin-2-yl)benzylamine. Yield=60%. Mp=136-138° C. (EtOH). 1H NMR (300 MHz, CDCl3): δ 8.71 (d, 1H, J=4.7 Hz, Harom), 8.00 (d, 2H, J=8.1 Hz, Harom), 7.82-7.72 (m, 3H, Harom), 7.49 (d, 2H, J=8.1 Hz, Harom), 7.26 (dd, 1H, J=4.7 Hz, 7.2 Hz, Harom), 6.76 (bs, 1H, NH), 4.86 (d 2H, J=6.0 Hz, CH2), 3.16 (hept, 1H, J=7.0 Hz, CH), 2.57 (s, 3H, CH3), 1.33 (d, 6H, J=7.0 Hz, 2 CH3). MS (ESI): m/z 391 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16](=O)[C:15]3[C:10](=[N:11][CH:12]=[CH:13][N:14]=3)[CH:9]2[OH:18])=[N:6][CH:7]=1.[CH2:19]([O:21][C:22]([CH:24]=[PH3])=[O:23])[CH3:20]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9](=[O:18])[C:10]3[C:15](=[N:14][CH:13]=[CH:12][N:11]=3)[CH:16]2[CH2:24][C:22]([O:21][CH2:19][CH3:20])=[O:23])=[N:6][CH:7]=1
Reactant: O=C1c2nccnc2C(O)N1c1ccc(Cl)cn1
Reactant: CCOC(=O)C=[PH3]
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1c2nccnc2C(=O)N1c1ccc(Cl)cn1
Yield: 90.2 %

Procedure:
6-(5-Chloro-2-pyridyl)-6,7-dihydro-7-hydroxy-5H-pyrrolo[3,4-b]pyrazin-5-one (1.05 g) and ethoxycarbonylmethylenephosphorane (1.39 g) were dissolved in dry toluene (30 ml) and the solution was refluxed for 6 hours. After cooling, the solvent was distilled off and the residue was purified by silica gel column chromatography. Fractions eluted with dichloromethaneethyl acetate (2:1) were collected and the solvent was distilled off to give crude crystals. Recrystallization from ether-dichloromethane (5:1) gave 1.2 g of 6(5-chloro pyridyl)-6,7-dihydro-7-ethoxycarbonylmethyl-5H-pyrrolo[3,4-b]pyrazin-5-one
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[CH3:14][C:15](=[N:17][OH:18])[CH3:16].O>N1C=CC=CC=1>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:18][N:17]=[C:15]([CH3:16])[CH3:14])(=[O:11])=[O:10]
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CC(C)=NO
Solvent: O
Solvent: c1ccncc1
Product: CC(C)=NOS(=O)(=O)c1c(C)cc(C)cc1C
Reaction time: 16 h

Procedure:
To a solution of mesitylenesulfonyl chloride (2.0 g, 9.05 mmol) in pyridine (30 mL) was added acetone oxime (0.67 g, 9.05 mmol), and the solution was stirred under N2 for 16 hours. It was poured into 500 ml of water and stirred for 1 hour. The precipitate was filtered and dried. Acetone O-(2,4,6-trimethylphenylsulfonyl)oxime was obtained as white powder (57.6%) yield.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[CH3:29][NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[CH3:29][N:30]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CNc1ccccc1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1)c1ccccc1
Yield: 75 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and N-methylaniline, the title compound was isolated as a yellow solid in 75% yield (99% purity by HPLC).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:24]=[CH:23][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=3)[C:18]#[N:19])[O:12][C:13]=2[CH3:14])=[C:5]([O:25][CH3:26])[CH:4]=1.[CH:27]([Si:30](Cl)([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28].N1C=CN=C1.CN(C)C=O>O>[CH3:26][O:25][C:5]1[CH:4]=[C:3]([CH2:2][O:1][Si:30]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:27]([CH3:29])[CH3:28])[CH:24]=[CH:23][C:6]=1[O:7][CH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[O:12][C:13]=1[CH3:14]
Reactant: COc1cc(CO)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1OCc1nc(-c2cccc(C#N)c2)oc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.6 %

Procedure:
A mixture of 3-{4-[(4-hydroxymethyl-2-methoxyphenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile (0.40 g), triisopropylsilyl chloride (0.75 g), imidazole (0.27 g) and N,N-dimethylformamide (5 mL) was stirred at room temperature for 3 days. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give 3-{4-[(2-methoxy-4-{[(triisopropylsilyl)oxy]methyl}phenoxy)methyl]-5-methyl-1,3-oxazol-2-yl}benzonitrile as a colorless oil (0.53 g, yield 95%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).