Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH2:16])[CH:10]=1>C1(C)C(C)=CC=CC=1>[Cl:8][C:4]1[N:3]=[C:2]([NH:16][CH2:15][C:11]2[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=2)[CH:7]=[N:6][CH:5]=1
Reactant: Clc1cncc(Cl)n1
Reactant: NCc1cccnc1
Solvent: Cc1ccccc1C
Product: Clc1cncc(NCc2cccnc2)n1
Yield: 93 %

Procedure:
A mixture 2,6-dichloropyrazine (0.671 mmol) and 3-picolylamine (2.014 mmol) in xylene (25 ml) was refluxed overnight. The residue obtained after evaporation of the solvent was suspended between CH2Cl2 (100 ml) and water (100 ml). The organic layer was separated and the aqueous layer was extracted with CH2Cl2 (3×50 ml). The combined organic extracts were washed with brine (1×100 ml), dried (Na2SO4) and the solvent removed in vacuo. The residue was then purified by column chromatography eluting with a hexane:ethyl acetate gradient mixture to afford the desired product (93%).
Reaction SMILES: [Na].[OH:2][C:3]([C:10]([F:13])([F:12])[F:11])([C:6]([F:9])([F:8])[F:7])[C:4]#[N:5].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=2)=[CH:17][CH:16]=1>CN(C)C=O.O>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:28]=[CH:27][C:24]([CH2:25][O:2][C:3]([C:6]([F:7])([F:9])[F:8])([C:10]([F:11])([F:12])[F:13])[C:4]#[N:5])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1
Reactant: N#CC(O)(C(F)(F)F)C(F)(F)F
Reactant: ClCc1ccc(-c2ccc(Cl)cc2)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(OCc1ccc(-c2ccc(Cl)cc2)cc1)(C(F)(F)F)C(F)(F)F

Procedure:
A solution of 2-hydroxy-3,3,3-trifluoro-2-trifluoromethylpropionitrile sodium salt (4.3 g.) and 4-(4-chlorophenyl)-benzyl chloride (4.7 g.) in dimethylformamide (25 ml.) is stirred at ambient temperature for 10 days, then diluted with water. During this reaction, 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionitrile is formed and is subsequently hydrolysed to the corresponding amide. The mixture is extracted with 1,2,2-trichloro-1,1,2-trifluoroethane, and the extract is dried with sodium sulphate, then evaporated. The residue is crystallised from cyclohexane to give 2-[4-(4-chlorophenyl)benzyloxy]-3,3,3-trifluoro-2-trifluoromethylpropionamide, m.p. 123°-124° C. (1.6 g.).
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.[N+](C1C=CC([C:17]2[C:25]([CH2:26][C@H:27]3[C@@H:32]([OH:33])[C:31]4[CH:34]=[C:35]([O:38][CH2:39][C:40]5[S:41][C:42]6[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:43]=6[N:44]=5)[CH:36]=[CH:37][C:30]=4[O:29][CH2:28]3)=[CH:24][CH:23]=[CH:22][C:18]=2[C:19]([O-])=[O:20])=CC=1)([O-])=O.C(OC(Cl)=O)C(C)C>O1CCCC1>[F:49][C:46]1[CH:47]=[CH:48][C:42]2[S:41][C:40]([CH2:39][O:38][C:35]3[CH:36]=[CH:37][C:30]4[O:29][CH2:28][C@@H:27]([CH2:26][C:25]5[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=5)[C:19]([N:3]([CH3:4])[CH3:1])=[O:20])[C@@H:32]([OH:33])[C:31]=4[CH:34]=3)=[N:44][C:43]=2[CH:45]=1
Reactant: CCN(CC)CC
Reactant: O=C([O-])c1cccc(C[C@@H]2COc3ccc(OCc4nc5cc(F)ccc5s4)cc3[C@@H]2O)c1-c1ccc([N+](=O)[O-])cc1
Agent: CC(C)COC(=O)Cl
Solvent: C1CCOC1
Product: CN(C)C(=O)c1cccc(C[C@@H]2COc3ccc(OCc4nc5cc(F)ccc5s4)cc3[C@@H]2O)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 42.4 %

Procedure:
364 milligrams triethylamine was added to a solution containing 1.5 grams cis-4-nitrophenyl-3-[[6-[(5-fluoro-2-benzothiazolyl)methoxy]-3,4-dihydro-4-hydroxy-2H-1-benzopyran-3-yl]methyl]benzoate in tetrahydrofuran at 0° C. After stirring for 5 minutes at 0° C., a solution of isobutylchloroformate in 5 milliliters of tetrahydrofuran was added dropwise. After stirring at 1° C. for 15 minutes, 364 milligrams anhydrous dimethylamine was bubbled into the reaction mixture for 1-2 minutes. The reaction mixture was allowed to warm to room temperature and the volatiles were evaporated. The residue was purified by chromatography on silica gel eluting with methylene dichloride/ethyl acetate to give 535 mg of product.
Reaction SMILES: C(O[C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:16]=2[F:22])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5])C.[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:27][NH2:28]>>[F:23][C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:27][NH:28][C:4]([C:6]1[N:7]=[C:8]([C:15]2[C:16]([F:22])=[CH:17][CH:18]=[CH:19][C:20]=2[F:21])[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:5]
Reactant: NCc1ccc(F)c(F)c1
Reactant: CCOC(=O)c1nc(-c2c(F)cccc2F)n(C)c(=O)c1O
Product: Cn1c(-c2c(F)cccc2F)nc(C(=O)NCc2ccc(F)c(F)c2)c(O)c1=O

Procedure:
Prepared according to the procedure described for example 2 from 2-(2,6-difluoro-phenyl)-5-hydroxy-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylic acid ethyl ester (31 mg, 0.1 mmol) and 3,4-difluorobenzylamine (72 mg, 0.5 mmol). The title product was obtained as an off-white solid (32.7 mg, 80% yield). 1HNMR (500 MHz, CDCl3) δ: 12.18 (1H, s), 7.83 (1H, br s), 7.53–7.47 (1H, m), 7.15–7.02 (5H, m), 4.53 (2H, d, J=6.41 Hz), 3.41 (3H, s). HRMS (ESI) calcd for C19H14F4N3O3 (M+H): 408.0971; found: 408.0969.
Reaction SMILES: [OH-].[Na+].ClC1C=CC(C([O:10][CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[C:16]([F:18])[F:17])=O)=CC=1>O.C(O)C>[F:17][C:16]([F:18])=[CH:15][CH2:14][CH2:13][CH2:12][CH2:11][OH:10]
Reactant: O=C(OCCCCC=C(F)F)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: OCCCCC=C(F)F
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.1 %

Procedure:
To a stirred solution of 0.84 gram (0.0121 mole) of sodium hydroxide in 1.5 ml of water was added a solution of 3.3 grams (0.0121 mole) of 6,6-difluoro-5-hexenyl 4-chlorobenzoate (prepared in Example 19) in 20 ml of ethanol. Upon completion of addition, the reaction mixture was warmed to reflux where it was stirred for 18 hours. After this time the reaction mixture was cooled to ambient temperature, and it was concentrated under reduced pressure to a residual semi-solid. The semi-solid was taken up in water and diethyl ether. The aqueous layer was separated, and it was washed with two 100 ml portions of diethyl ether. The ether washes were combined with the organic layer, and the combination was washed in turn with one 50 ml portion of water and one 100 ml portion of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure yielding 1.6 grams of 6,6-difluoro-5-hexen-1-ol. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C@@H:2]1[C@@H:6]([CH2:7][OH:8])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1.[C:20]([NH:37][C@H:38]([C:42]([O:44][CH:45]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[C:46](O)=[O:47])=[O:43])[CH:39]([CH3:41])[CH3:40])([O:22][CH2:23][CH:24]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CN(C=O)C>[F:1][C@@H:2]1[C@@H:6]([CH2:7][O:8][C:46](=[O:47])[CH:45]([O:44][C:42](=[O:43])[C@H:38]([CH:39]([CH3:40])[CH3:41])[NH:37][C:20]([O:22][CH2:23][CH:24]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]3[C:25]2=[CH:26][CH:27]=[CH:28][CH:29]=3)=[O:21])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[O:5][C@@H:4]([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=[O:14])[C:12]=3[N:11]=[CH:10]2)[CH2:3]1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](F)[C@@H](CO)O2)c(=O)[nH]1
Reactant: CCCCCCCCCCCCCCCCC(OC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCCCCCC(OC(=O)[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(C)C)C(=O)OC[C@H]1O[C@@H](n2cnc3c(=O)[nH]c(N)nc32)C[C@@H]1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2′,3′-dideoxy-3′-fluoroguanosine (404 mg, 1.5 mmole), 2-(N-FMOC-L-valyloxy)stearic acid (1.24 g, 2 mmole), DMAP (24 mg, 0.2 mmole) and HOBT (264 mg, 1,95 mmole) was coevaporated two times with DMF and reduced to about 30 ml. DCC (372 mg, 1.8 mmole) was added and the mixture was stirred overnight at room temperature. The mixture was filtered and the solution was evaporated under reduced pressure. Ethyl acetate (50 ml) was added and the organic phase washed twice with 5% acetic acid, with 5% sodium hydrogen carbonate and with water. The organic phase was dried with sodium sulfate and evaporated under reduced pressure.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[C:11]([CH2:12][P:13]([OH:16])([OH:15])=[O:14])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1.[O-:17][Mn](=O)(=O)=O.[K+].[OH-].[Na+]>O>[C:2]([C:3]1[NH:4][C:5]2[C:11]([CH2:12][P:13]([OH:16])([OH:15])=[O:14])=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1)([OH:17])=[O:1]
Reactant: O=P(O)(O)Cc1cccc2nc(CO)[nH]c12
Reactant: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1nc2cccc(CP(=O)(O)O)c2[nH]1
Temperature: 80 °C

Procedure:
2-Hydroxymethyl-4-phosphonomethylbenzimidazole (411 mg) and KMnO4 (70 mg) in water (7 mL) containing 3 equivalents of NaOH were warmed to 80° C. KMnO4 (636 mg) was divided into 9 equal portions and added over 3.5 hours. The reaction was stirred at 80° C. for one additional hour then cooled and filtered through diatomaceous earth. The pale yellow solution was concentrated to a yellow solid. The solid was taken up in water and applied to a column of Amberlite CG 400 (0.5×16 cm). The column was eluted with water (50 mL), then 1N HOAc, 2N HOAc, 4N HOAc, and finally 1N HCl (50 mL each). The HCl fractions were pooled and concentrated to a yellow solid. The solid was triturated with water, then collected by suction filtration and washed with a small amount of ethanol and ether to obtain a white solid. H NMR data: D2O (HDO at 4.64 ppm) 3.06 (d, 2H), 7.15 (m, 2H), 7.41 (d, 1H). E.A. Cal'd for C9H9N2O5P.0.6 H2O; C, 40.49, H, 3.85, N, 10.49. Found; C, 40.10, N, 3.57, N, 10.30.
Reaction SMILES: [NH2:1][C:2]1[C:19]([O:20][CH3:21])=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:17])[C:13]([F:16])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:23]1[N:28]=[C:27]([NH:29][C@@H:30]2[C@@H:35]3[CH2:36][C@@H:32]([CH:33]=[CH:34]3)[C@@H:31]2[C:37]([NH2:39])=[O:38])[C:26]([Cl:40])=[CH:25][N:24]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>COCCO>[Cl:40][C:26]1[C:27]([NH:29][C@@H:30]2[C@@H:35]3[CH2:36][C@@H:32]([CH:33]=[CH:34]3)[C@@H:31]2[C:37]([NH2:39])=[O:38])=[N:28][C:23]([NH:1][C:2]2[C:19]([O:20][CH3:21])=[CH:18][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@H:12]([OH:17])[C:13]([F:14])([F:15])[F:16])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:24][CH:25]=1
Reactant: COc1cc2c(cc1N)CCN(C[C@H](O)C(F)(F)F)CC2
Reactant: NC(=O)[C@@H]1[C@H](Nc2nc(Cl)ncc2Cl)[C@H]2C=C[C@@H]1C2
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: COCCO
Product: COc1cc2c(cc1Nc1ncc(Cl)c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)n1)CCN(C[C@H](O)C(F)(F)F)CC2
Reaction time: 0.5 h
Yield: 44.4 %

Procedure:
(S)-3-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-benzo[d]azepin-3-yl)-1,1,1-trifluoro-propan-2-ol (88 mg, 0.29 mmol), (1S,2S,3R,4R)-3-(2,5-Dichloro-pyrimidin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (89 mg, 0.30 mmol), and 10-Camphorsulfonic acid (105 mg, 0.452 mmol) in 2-Methoxyethanol (4 mL) was heated in a microwave vial at 120° C. for 4 h. The brown solution was added dropwise to a satd. sodium bicarbonate solution (10 mL) and the vial was rinsed with 2 mL water and also added. The precipitated product was allowed to stand for 30 min, filtered and washed with water (5 mL). The crude solid was chromatographed (2×12 g silica gel, 0-80% EtOAc:Hex) to afford (1S,2S,3R,4R)-3-{5-Chloro-2-[8-methoxy-3-((S)-3,3,3-trifluoro-2-hydroxy-propyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamino]-pyrimidin-4-ylamino}-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide as a beige solid (73 mg, 44%). LCMS: 567 (M+H); MP=120-126° C.; 1H-NMR, CDCl3: 8.24 (s, 1H), 7.92 (s, 1H), 7.43 (s, 1H), 6.66 (s, 1H), 6.61 (d, 1H, J=7.9 Hz), 6.33 (m, 2H), 5.57 (br s, 1H), 5.29 (br s, 1H), 4.46 (m, 1H), 4.07 (m, 1H), 3.89 (s, 3H), 3.10 (br s, 1H), 2.8-3.0 (m, 9H), 2.70 (m, 3H), 2.53 (d, 1H, J=8.1 Hz), 2.28 (d, 1H, J=9.4 Hz), 1.68 (d, 1H, J=8.7 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[CH3:10]>C(Cl)Cl.O=[Mn]=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(CO)ccc1Br
Agent: O=[Mn]=O
Solvent: ClCCl
Product: Cc1cc(C=O)ccc1Br
Reaction time: 12 h
Yield: 89.4 %

Procedure:
To a solution of (4-bromo-3-methylphenyl)methanol (420 mg, 2.09 mmol) in DCM (6 mL) at rt was added MnO2 (1.82 g, 20.9 mmol). The reaction mixture was stirred for 12 h, filtered and concentrated under reduced pressure to give 4-bromo-3-methyl-benzaldehyde (372 mg; yield 89%) as an oil.
Reaction SMILES: [Na].[SH:2][C:3]1[NH:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2[N:11]=1.[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>CO>[C:13]1([CH2:12][S:2][C:3]2[NH:4][C:5]3[CH:10]=[CH:9][N:8]=[CH:7][C:6]=3[N:11]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: ClCc1ccccc1
Reactant: Sc1nc2cnccc2[nH]1
Agent: [Na]
Solvent: O
Solvent: CO
Product: c1ccc(CSc2nc3cnccc3[nH]2)cc1
Reaction time: 0.33 h

Procedure:
To a solution of 1.26 g (0.055 g atom) of sodium in 300 mL of methanol was added 7.56 g (0.05 mol) of 2-mercapto-1H-imidazo[4,5-c]pyridine with stirring. After 20 minutes, the reaction mixture was evaporated to dryness in a rotary evaporator. Dimethyl formamide (200 mL) was added to the residue. To the resulting solution was added dropwise 6.33 g (0.05 mol) of benzylchloride. The reaction mixture was stirred for 5 hours at room temperature and was then poured into 1500 mL of water. The product was removed by filtration and amounted to 9.5 g, m.p. 175°-177° C. The product was triturated with hot ethyl acetate and refiltered. The product amounted to 8.11 g, m.p. 175°-177° C. A portion recrystallized from ethyl acetate gave the analytical sample (m.p. 175°-177° C.).
Reaction SMILES: [NH:1]([C:8]1[N:13]=[C:12]2[N:14]([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([CH2:33][CH2:34][N:35]4C(=O)C5=CC=CC=C5C4=O)[CH:28]=3)[C:15](=[O:26])[N:16]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[Cl:25])[CH2:17][C:11]2=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.NN>CO>[NH2:35][CH2:34][CH2:33][C:29]1[CH:28]=[C:27]([N:14]2[C:12]3=[N:13][C:8]([NH:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[N:9][CH:10]=[C:11]3[CH2:17][N:16]([C:18]3[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=3[Cl:25])[C:15]2=[O:26])[CH:32]=[CH:31][CH:30]=1
Reactant: O=C1c2ccccc2C(=O)N1CCc1cccc(N2C(=O)N(c3cc(Cl)ccc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Agent: NN
Solvent: CO
Solvent: O
Product: NCCc1cccc(N2C(=O)N(c3cc(Cl)ccc3Cl)Cc3cnc(Nc4ccccc4)nc32)c1
Yield: 52.3 %

Procedure:
A solution of 90 mg (0.14 mmol) of 7-anilino-3-(2,5-dichlorophenyl)-3,4-dihydro-1-[3-(2-phthalimidoethyl)phenyl]pyrimido[4,5-d]pyrimidin-2(1H)-one and 0.07 ml of hydrazine hydrate in 15 ml of methanol was stirred at room temperature under an atmosphere of nitrogen for 18 hours. The reaction was evaporated and the residue purified by flash column chromatography on silica gel, eluting with dichloromethane/methanol/acetic acid/water (240:24:3:2). Product containing fractions were combined and evaporated and the residue re-evaporated with toluene. The residue was then dissolved in 20 ml of dichloromethane, washed with 20 ml of saturated aqueous sodium bicarbonate, dried over magnesium sulfate, filtered and evaporated to give 37 mg (52%) of 1-[3-(2-aminoethyl)phenyl]-7-anilino-3-(2,5-dichlorophenyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid of melting point 120-123° C. [Mass spectrum (ESI) MH+ =505].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([CH2:20]Cl)[O:17][N:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+]>CN(C=O)C>[N:22]([CH2:20][C:18]1[O:17][N:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:10][CH:11]=2)[CH:19]=1)=[N+:23]=[N-:24]
Reactant: [N-]=[N+]=[N-]
Reactant: ClCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1cc(-c2ccc(OCc3ccccc3)cc2)no1
Reaction time: 12 h

Procedure:
0.13 g of 3-(4-benzyloxy-phenyl)-5-chloromethyl-isoxazole was dissolved in 10 ml of DMF, to which solution was added 85 mg (3 equivalents) of NaN3, and the mixture was stirred for 12 hours. The solvent was dried off under reduced pressure and removed, followed by column chromatography to obtain 5-azidomethyl-3-(4-benzyloxy-phenyl)-isoxazole. A reduction of the compound was performed under NaBH4 conditions to obtain C-[3-(4-benzyloxy-phenyl)-isoxazol-5-yl]-methylamine as a desired compound.
Reaction SMILES: [O-]CC.[Na+].Cl.[C:6]([NH2:14])(=[NH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:15](OCC)(=[O:22])[CH2:16][C:17](OCC)=[O:18]>C(O)C>[OH:18][C:17]1[CH:16]=[C:15]([OH:22])[N:14]=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:13]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: N=C(N)c1ccccc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Oc1cc(O)nc(-c2ccccc2)n1
Yield: 83.8 %

Procedure:
Using a 20% solution of sodium ethoxide in ethanol (150 g), benzamidine hydrochloride (34.5 g), diethyl malonate (32 g) and ethanol (500 ml), the same procedures as Reference Example 11-(1) are repeated to give crude 4,6-dihydroxy-2-phenylpyrimidine (31.5 g).
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([CH:11]=[O:12])[S:10][C:6]=2[C:5](=[O:13])[NH:4][C:3]1([CH3:15])[CH3:14].C(N)C.C1COCC1.[N+:24]([CH2:26]S(C1C=CC(C)=CC=1)(=O)=O)#[C-:25].C(=O)([O-])[O-].[K+].[K+].C([O-])(O)=O.[Na+]>[O-]S([O-])(=O)=O.[Mg+2].CO>[CH3:1][N:2]1[C:7]2[CH:8]=[C:9]([C:11]3[O:12][CH:26]=[N:24][CH:25]=3)[S:10][C:6]=2[C:5](=[O:13])[NH:4][C:3]1([CH3:15])[CH3:14]
Reactant: CN1c2cc(C=O)sc2C(=O)NC1(C)C
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CCN
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CO
Solvent: C1CCOC1
Product: CN1c2cc(-c3cnco3)sc2C(=O)NC1(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 9.8 %

Procedure:
A mixture of 1,2,2-trimethyl-4-oxo-1,2,3,4-tetrahydrothieno[3,2-d]pyrimidine-6-carbaldehyde (100 mg, 0.446 mmol), MS4A powder (100 mg) and 2 M ethylamine in THF (2.00 mL, 4.00 mmol) was stirred for 1 h at room temperature. Then, the mixture was concentrated under reduced pressure to give a yellow solid. Then, the residue was suspended with 2 M ethylamine in THF (2.00 mL, 4.00 mmol) and MgSO4 (100 mg). The mixture was stirred overnight and concentrated under reduced pressure to give yellow solid. Then, the residue was suspended with 2 M ethylamine in THF (2.00 mL, 4.00 mmol). The mixture was stirred for 4 h and concentrated under reduced pressure to give yellow solid. Then, 1-[(isocyanomethyl)sulfonyl]-4-methylbenzene (131 mg, 0.669 mmol), potassium carbonate (123 mg, 0.892 mmol) and MeOH (3 mL) were added to the residue, and the mixture was stirred at 60° C. for 1 h. 1-[(Isocyanomethyl) sulfonyl]-4-methylbenzene (131 mg, 0.669 mmol) and potassium carbonate (123 mg, 0.892 mmol) were added again, and the mixture was stirred at 60° C. overnight. 1-[(Isocyanomethyl) sulfonyl]-4-methylbenzene (131 mg, 0.669 mmol) and potassium carbonate (123 mg, 0.892 mmol) were added again, and the mixture was stirred at 60° C. for 2 h. The mixture was poured into saturated aqueous NaHCO3 (80 mL) and extracted with EtOAc (80 mL), and the extract was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure to afford orange gum. This residue was purified by column chromatography (Purif, NH, 95:5 hexane/EtOAc to EtOAc) and preparative HPLC (YMC CombiPrep. Hydrosphere C18). The fractions containing the title compound were collected and basified by addition of saturated aqueous NaHCO3. Extraction with EtOAc, drying over MgSO4, filtration and concentration under reduced pressure gave the title compound (11.5 mg, 9.8%) as pale yellow solid:
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[C:10](=O)[CH3:11].[CH:13]1([NH2:16])[CH2:15][CH2:14]1.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH:2]1[CH:10]([NH:16][CH:13]1[CH2:15][CH2:14]1)[CH3:11]
Reactant: CC(=O)C1Cc2ccccc2C1
Reactant: NC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC(NC1CC1)C1Cc2ccccc2C1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 27.3 %

Procedure:
To a cooled solution of 3.5 g (21.8 mmol) of 1-(indan-2-yl)ethanone in 100 ml of methanol, are added 10 g of 3 Å molecular sieves and 2.3 g (40.2 mmol) of cyclopropylamine followed by a slow addition of 2.87 ml (50.2 mmol) of acetic acid. The reaction mixture is stirred for 2.5 hrs at reflux. The reaction mixture is then cooled to 0° C. and 1.9 g (30 mmol) of sodium cyanoborohydride are slowly added and the reaction mixture is further stirred for 2 hrs at reflux. The cooled reaction mixture is then filtered over a cake of diatomaceous earth. The cake is washed twice by 80 ml of methanol and the combined methanolic extracts are concentrated under vacuum. 100 ml of water are then added to the residue and the pH is ajusted to 12 with a 0.5 N solution of sodium hydroxyde. The watery layer is extracted with 300 ml of ethyl acetate. The organic layer is washed twice by brine and filtered over a phase separator paper to yield after concentration 5 g of a yellow oil. Column chromatography on silica gel (gradient heptane/ethyl acetate) yields 1.2 g (28% yield) of N-[1-(indan-2-yl)ethyl]cyclopropanamine as a colourless oil (M+H =202).
Reaction SMILES: CS(Cl)(=O)=[O:3].[C:6]([NH:13][CH:14]([CH2:17][OH:18])[CH2:15][OH:16])([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].C(N(CC)CC)C>ClCCl>[C:17]([O-:18])(=[O:3])[CH3:14].[C:6]([NH:13][CH:14]([CH2:15][OH:16])[CH2:17][OH:18])([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])=[O:7]
Reactant: CS(=O)(=O)Cl
Agent: CC(C)(C)OC(=O)NC(CO)CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)[O-]
Temperature: 20 °C
Reaction time: 20 h

Procedure:
Methanesulfonyl chloride (130 mmol) was added at 5° C. to a stirred solution of boc-serinol (40 mol) and triethylamine (25 ml) in dichloromethane (100 ml). The mixture was stirred at 5° C. for 5 h and at 20° C. for 20 h. Dichloromethane (200 ml) was added and the mixture was washed with an aqueous solution of sodium hydrogen carbonate (50 mM), dried (Na2SO4) and concentrated to dryness under vacuum. Chromatography of the residue on silicagel (1.2 L) eluting with hexane/ethyl:acetate (50:50) gave bis-(methanesulfonic acid ester) of boc-serinol.