Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=[N:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:27]1([C:33]2[O:37][N:36]=[C:35]([C:38]3[O:42][N:41]=[C:40]4[C:43]5[C:48]([CH2:49][CH2:50][C:39]=34)=[CH:47][C:46]([CH:51]=[CH2:52])=[CH:45][CH:44]=5)[C:34]=2[C:53]([F:56])([F:55])[F:54])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CS(C)=O>[C:1]1([C:7](=[N:14][CH:15]([CH2:52][CH2:51][C:46]2[CH:47]=[C:48]3[C:43](=[CH:44][CH:45]=2)[C:40]2=[N:41][O:42][C:38]([C:35]4[C:34]([C:53]([F:55])([F:56])[F:54])=[C:33]([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=5)[O:37][N:36]=4)=[C:39]2[CH2:50][CH2:49]3)[C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: C=Cc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CCOC(=O)C(CCc1ccc2c(c1)CCc1c-2noc1-c1noc(-c2ccccc2)c1C(F)(F)F)N=C(c1ccccc1)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 84.5 %

Procedure:
A mixture of ethyl 2-(diphenylmethyleneamino)acetate (236 mg, 0.882 mmol), Cs2CO3 (144 mg, 0.441 mmol), 3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-7-vinyl-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 6A, 100 mg, 0.245 mmol), and anhydrous DMSO (0.6 mL) was purged with nitrogen for 5 min. and then sealed in a 1 dram vial. The mixture was stirred at 50° C. for 2 h. The mixture was cooled, diluted with water (15 mL) and extracted with ethyl acetate (3×5 mL). The combined ethyl acetate extracts were dried (sodium sulfate) and concentrated under reduced pressure. Flash chromatography purification (12 g silica gel column, 10→100% ethyl acetate in hexanes) afforded ethyl 2-(diphenylmethyleneamino)-4-(3-(5-phenyl-4-(trifluoromethyl)isoxazol-3-yl)-4,5-dihydronaphtho[1,2-c]isoxazol-7-yl)butanoate (140 mg, 0.207 mmol, 85% yield) as a sticky liquid. The compound had an LC/MS M+1=676.2.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C1(C)C=CC(S(O[CH2:16][C:17]([I:21])=[C:18]([I:20])[I:19])(=O)=O)=CC=1>CN(C=O)C>[I:21][C:17](=[C:18]([I:20])[I:19])[CH2:16][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: Cc1ccc(S(=O)(=O)OCC(I)=C(I)I)cc1
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Product: IC(I)=C(I)Cn1ccnc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 340 mg (5 mmoles) of imidazole in 5.0 ml of dry DMF were added 606 mg (1 mmole) of 3-p-toluenesulfonyloxy-1,1,2-triiodo-1-propene and the reaction was effected at 25° C. for 2 hours. The reaction mixture was poured into 20 ml of ice-water while stirring vigorously and the mixture was allowed to stand for a further one hour. The crystalline substance thus separated was recovered by filtration, washed with water and then dried. Yield 440 mg (96%), mp 127°-128° C. (with decomposition).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=O)[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][O:18][C:19](=[O:23])[CH2:20][C:21]#[N:22].N1CCCCC1.NCCC(O)=O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][C:11](=[C:20]([C:21]#[N:22])[C:19]([O:18][CH3:17])=[O:23])[CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CC#N
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(=O)C2
Agent: NCCC(=O)O
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: COC(=O)C(C#N)=C1CC2CCC(C1)N2C(=O)OC(C)(C)C

Procedure:
A solution of 2 g of 3-oxo-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester, 1.2 ml of cyano-acetic acid methyl ester, 130 μl of piperidine and 38 mg of β-alanine in 4 ml of DMF is stirred at 70° C. for 48 hours, the mixture obtained is diluted with EtAc, washed with H2O and brine, the organic layer obtained is dried, solvent is removed in vacuo and the residue obtained is subjected to chromatography on silica gel. 3-(cyano-methoxycarbonyl-methylene)-8-aza-bicyclo[3.2.1]octane-8-carboxylic acid tert-butyl ester is obtained in the form of an oil. 13C-NMR: 174.13, 162.27, 153.68, 115.37, 107.45, 80.70, 53.92, 53.08, 28.81.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12](=[O:17])[NH:13][CH2:14][CH2:15][N:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C(O)C.[Ni]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[NH:16][CH2:15][CH2:14][NH:13][C:12]2=[O:17])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2=NCCNC2=O)cc1OC
Agent: [Ni]
Solvent: CCO
Product: COc1ccc(C2NCCNC2=O)cc1OC

Procedure:
23.4 g (0.1 mol) of 3-(3,4-dimethoxyphenyl)-5,6-dihydro-2(1H)-pyrazinone are dissolved in 230 ml of ethanol and hydrogenated, in the presence of Raney nickel as the catalyst, at 40° to 60° C. and under a hydrogen pressure of 50 bar until saturation is reached. The catalyst is then filtered off, the filtrate is evaporated in vacuo and the residue is triturated with ether.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:13][NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-])=O)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]>CCO.[Pd]>[NH2:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[NH:14][CH2:13][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:10]([OH:12])=[O:11]
Reactant: CC(C)(C)OC(=O)NC(CNc1ccccc1[N+](=O)[O-])C(=O)O
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)NC(CNc1ccccc1N)C(=O)O

Procedure:
A suspension of 1.0 eq of 89 and 0.1 wt/wt eq of 10% Pd on carbon in 35 mL of EtOH was hydrogenated under 50 psi of H2 for 30 min, until consumption of H2 ceased. The reaction mixture was filtered through Celite. The filtrate was concentrated by rotary evaporation. The crude material was dried under vacuum to give acid 90.
Reaction SMILES: Br[CH:2]([C:9](=O)[CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[Cl:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[S:25])[NH2:24])=[CH:19][CH:18]=1.C(OCC)(=O)C>CN(C)C=O>[Cl:12][CH2:13][CH2:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[S:25][C:2]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:9]([CH3:10])[N:24]=2)=[CH:19][CH:18]=1
Reactant: CCOC(=O)CC(Br)C(C)=O
Reactant: NC(=S)c1ccc(OCCCCl)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1sc(-c2ccc(OCCCCl)cc2)nc1C
Temperature: 100 °C
Reaction time: 2 h
Yield: 40 %

Procedure:
A mixture of ethyl 3-bromo-4-oxopentanoate (2 g, 8.98 mmol, 1 eq), and 4-(3-chloropropoxy)benzenecarbothioamide ax71 (2.06 g, 8.97 mmol, 1 eq) in dimethylformamide (4 ml) is stirred at 100° C. for 2 h. The reaction mixture is then added to ethyl acetate (200 ml) and the precipitate filtered off. The organic layer is washed with water (4×100 ml), brine, dried over magnesium sulfate and filtered. The solvent is removed under reduced pressure. Purification by chromatography over silicagel (eluent: benzine/ethyl acetate 95:5 to 85:15) affords 1.3 g of ethyl {2-[4-(3-chloropropoxy)phenyl]-4-methyl-1,3-thiazol-5-yl}acetate i102.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([S:7](Cl)(=[O:9])=[O:8])[CH:2]=1.[C:11]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:16]=[CH:15][C:14]([CH2:17][NH2:18])=[CH:13][CH:12]=1>O>[C:11]1([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]=[CH:13][C:14]([CH2:17][NH:18][S:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)(=[O:9])=[O:8])=[CH:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: NCc1ccc(-c2ccccc2)cc1
Solvent: O
Product: O=S(=O)(NCc1ccc(-c2ccccc2)cc1)c1cccnc1
Reaction time: 1 h
Yield: 91.7 %

Procedure:
Reaction was carried out in the same manner as in Reference Example 2-(d) except for using 3-pyridylsulfonyl chloride (890 mg, 5.01 mmol), and using (biphenyl-4-ylmethyl)amine (1.01 g, 5.51 mmol) in place of (6-phenylpyridazin-3-ylmethyl)amine hydrochloride. After completion of the reaction, water was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane:ethyl acetate=1:1 (V/V)→chloroform:ethyl acetate=1:1 (V/V)→ethyl acetate), and fractions containing the desired compound were concentrated under reduced pressure. To the resulting crude product were added methylene chloride (5 ml) and diisopropyl ether (10 ml), followed by being left for 1 hour. A precipitated solid was collected by filtration, and dried under reduced pressure at 35° C. to afford the title compound (1.49 g) as a white solid. (Yield: 92%)
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:21](=[O:26])[NH:22][CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[C:37]([F:40])([F:39])[F:38]>>[Si:1]([O:18][CH2:19][C:20]1[C:21](=[O:26])[N:22]([C:28]2[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=2[C:37]([F:38])([F:39])[F:40])[CH:23]=[CH:24][CH:25]=1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Reactant: CC(C)(C)[Si](OCc1ccc[nH]c1=O)(c1ccccc1)c1ccccc1
Product: CC(C)(C)[Si](OCc1cccn(-c2ccc([N+](=O)[O-])cc2C(F)(F)F)c1=O)(c1ccccc1)c1ccccc1

Procedure:
Analogously to Example 4A, 1.50 g (4.13 mmol) of the compound from Example 3A are reacted with 949 mg (4.54 mmol) of 1-fluoro-4-nitro-2-(trifluoromethyl)benzene. The product is purified by chromatography on silica gel (mobile phase pentane/ethyl acetate=5:1), giving 1.00 g (44% of theory) of the title compound.
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:5]=[C:6]([C:10](=[O:12])[CH3:11])[CH:7]=[N:8][CH:9]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:10]([C:6]1[CH:7]=[N:8][CH:9]=[C:4]([CH:5]=1)[CH:3]=[O:2])(=[O:12])[CH3:11]
Reactant: COC(OC)c1cncc(C(C)=O)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)c1cncc(C=O)c1
Reaction time: 24 h
Yield: 68.3 %

Procedure:
To a stirred solution of 1-(5-(dimethoxymethyl)pyridin-3-yl)ethanone (214 mg, 1.1 mmol) in CH2Cl2 (5 mL) was added TFA (2 mL). The resulting mixture was stirred for 24 h and the solvent was removed. The residue was dissolved in CHCl3 and saturated aqueous NaHCO3. The layers were separated and the organic layer was washed with brine and dried over Na2SO4. The solvent was removed to provide 5-acetylnicotinaldehyde (112 mg) as a yellow solid.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][O:10][C:9](=[O:12])[NH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:24][C:25]1[CH:40]=[CH:39][C:28]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])=[CH:27][CH:26]=1>C1COCC1>[CH2:32]([O:31][C:29]([C:28]1[CH:27]=[CH:26][C:25]([CH2:24][N:8]2[C@H:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH2:11][O:10][C:9]2=[O:12])=[CH:40][CH:39]=1)=[O:30])[C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: O=C(OCc1ccccc1)c1ccc(CBr)cc1
Reactant: O=C1N[C@H](c2ccccc2)CO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)c1ccc(CN2C(=O)OC[C@H]2c2ccccc2)cc1

Procedure:
490 mg (3 mmol) of (4R)-(-)-4-phenyl-2-oxazolidinone are dissolved in 9 ml of absolute THF, first 3.3 ml of sodium bistrimethylsilylamide (1M in THF) and then 1050 mg (3.45 mmol) of benzyl 4-bromomethylbenzoate, dissolved in 2 ml of absolute THF, are added. The crude product is purified by chromatography (eluent: CH2Cl2)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]Br)=[CH:4][CH:3]=1.[CH3:17][O-:18].[Na+].Cl>CO.CCC(C(OCCN1C(C)C(C2C=CC=CC=2)OCC1)=O)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:18][CH3:17])=[CH:4][CH:3]=1
Reactant: BrCCCCCCCSc1ccc(Br)cc1
Reactant: C[O-]
Agent: CCC(C(=O)OCCN1CCOC(c2ccccc2)C1C)c1ccccc1
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COCCCCCCCSc1ccc(Br)cc1

Procedure:
To a solution of 1-bromo-4-(7-bromoheptylthio)benzene (5 g) in methanol (25 ml) was added 28% sodium mehtylate in nethanol (7.9 g) and the mixture was stirred under refluxing for 2 hours. The residue was adjusted to pH 2 with dilute HCl aq. and extracted with ethyl acetate. The organic layer was seperated, wahsed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (50:1) to give 1-bromo-4-(7-methoxyheptylthio)benzene (3.59 g).
Reaction SMILES: Cl[C:2]1[C:21]([C:22]2[NH:26][N:25]=[CH:24][CH:23]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[NH2:27][CH2:28][CH:29]([OH:33])[CH2:30][CH2:31][OH:32].CCN(C(C)C)C(C)C.O(C(C)C)C(C)C>CC(O)C>[Cl:19][C:16]([F:18])([F:17])[O:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6](=[O:7])[C:5]2[CH:20]=[C:21]([C:22]3[NH:26][N:25]=[CH:24][CH:23]=3)[C:2]([NH:27][CH2:28][CH:29]([OH:33])[CH2:30][CH2:31][OH:32])=[N:3][CH:4]=2)=[CH:10][CH:11]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2ccn[nH]2)c1
Reactant: NCC(O)CCO
Solvent: CC(C)OC(C)C
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(NCC(O)CCO)c(-c2ccn[nH]2)c1
Temperature: 130 °C
Reaction time: 20 h

Procedure:
6-Chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-(1H-pyrazol-5-yl)nicotinamide (Stage 48.1, 500 mg, 1.253 mmol), 4-aminobutane-1,3-diol (Stage 97.1, 152 mg, 1.447 mmol), DIPEA (0.667 mL, 3.82 mmol) and iPrOH (2 mL) were added to a MW vial, which was sealed, flushed with argon and stirred at 130° C. for 20 h. The RM was diluted with EtOAc and washed with water and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give a residue which was treated with iPr2O and the resulting solid was filtered off and purified by flash chromatography (Silica gel column, 40 g, DCM/DCM-MeOH (9:1)) to afford the title compound as a white solid. UPLC-MS (Condition 8) tR=0.94 min, m/z=468 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1H NMR (400 MHz, DMSO-d6) δ ppm 1.46-1.74 (m, 2H) 3.44-3.58 (m, 3H) 3.64-3.72 (m, 1H) 3.77-3.90 (m, 1H) 4.40 (t, J=5.07 Hz, 1H) 4.82 (d, J=5.38 Hz, 1H) 6.96 (t, J=1.96 Hz, 1H) 7.36 (d, J=8.93 Hz, 2H) 7.83-7.99 (m, 3H) 8.41 (d, J=2.32 Hz, 1H) 8.65 (d, J=2.20 Hz, 1H) 9.04 (s, 1H) 10.21 (s, 1H) 13.21 (s, 1H).
Reaction SMILES: [CH:1]1[C:6]([CH:7]2[O:16][C:15]3[CH:14]=[C:13]([OH:17])[CH:12]=[C:11]([OH:18])[C:10]=3[CH2:9][CH:8]2[OH:19])=[CH:5][C:4]([OH:20])=[C:3]([OH:21])[CH:2]=1.OO>CC(C)=O>[CH2:9]1[C:10]2[C:15](=[CH:14][C:13]([OH:17])=[CH:12][C:11]=2[OH:18])[O:16][C@H:7]([C:6]2[CH:1]=[C:1]3[C:6]([C@H:7]4[O:16][C:15]5[C:10](=[C:11]([OH:18])[CH:12]=[C:13]([OH:17])[CH:14]=5)[CH2:9][C@@H:8]4[OH:19])=[CH:5][C:4]([OH:20])=[C:3]([OH:21])[C:2]3=[C:3]([OH:21])[C:4](=[O:20])[CH:5]=2)[C@@H:8]1[OH:19]
Reactant: Oc1cc(O)c2c(c1)OC(c1ccc(O)c(O)c1)C(O)C2
Agent: OO
Solvent: CC(C)=O
Product: O=c1cc([C@H]2Oc3cc(O)cc(O)c3C[C@H]2O)cc2c([C@H]3Oc4cc(O)cc(O)c4C[C@@H]3O)cc(O)c(O)c2c1O

Procedure:
C (catechin) (0.8 g) and EGC (0.8 g) were dissolved in a mixture of acetone-pH 5.0 phosphate citrate buffer (1:10, v/v, 50 mL), which contained 4 mg horseradish peroxidase. While being stirred, 2.0 mL of 3.13% H2O2 was added four times during 45 minutes. The reaction mixture was extracted by ethyl acetate (50 mL×3). After concentration, the residue was subjected to Sephadex LH 20 column eluted with acetone-water solvent system (45%). 120 mg neotheaflavin was obtained.
Reaction SMILES: [CH3:1][O:2][CH:3]([CH2:17][CH3:18])[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]1[CH2:15][CH2:14][CH:13]2[CH:9]1[CH2:10][CH:11]([OH:16])[CH2:12]2.[I-].[Na+].[CH3:21]I>O1CCCC1>[CH3:21][O:16][CH:11]1[CH2:10][CH:9]2[CH:13]([CH2:14][CH2:15][CH:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([O:2][CH3:1])[CH2:17][CH3:18])[CH2:12]1
Reactant: CI
Reactant: CCC(CCCCC1CCC2CC(O)CC12)OC
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CCCCC1CCC2CC(OC)CC12)OC
Temperature: 50 °C

Procedure:
The starting material, 2-(5-methoxyhept-1-yl)bicyclo[3.3.0]7 octanol {octahydro-4-(5-methoxyheptyl)-2-pentalenol} (1.0 g, 3.9 mmoles) is added to a reaction vessel containing sodium iodide (0.12 g, 4.9 mmoles) and tetrahydrofuran (12 ml). The solution is stirred while methyl iodide (0.84 g, 5.9 mmoles) is rapidly added. The reaction is heated in a 50° C. water bath for 4 hours. The water bath is removed and the reaction neutralized with the addition of water (5 ml). The organic phase is separated and the aqueous phase extracted with ether (2×50 ml). The ether extracts are combined and washed with brine (50 ml). The solution is dried over anhydrous magnesium sulfate and the solvent removed under vacuum leaving a clear yellow oil. The product is then kugelrohred under reduced pressure leaving a pale yellow oil (0.8 g, 3.1 mmoles).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[C:13](=O)[N:12]2[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>C1COCC1>[OH:1][CH2:2][CH2:3][CH:4]1[CH2:13][N:12]2[CH:7]([CH2:8][CH2:9][CH2:10][CH2:11]2)[CH2:6][CH2:5]1
Reactant: O=C1C(CCO)CCC2CCCCN12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCCC1CCC2CCCCN2C1
Yield: 74.5 %

Procedure:
A solution of 3-(2-hydroxyethyl)quinolizidin-4-one (1.4 g, 0.0071 mole) in THF (40 ml) was added to a stirred suspension of lithium aluminium hydride (0.5 g, 0.013 mole) in THF (50 ml) under nitrogen and the mixture heated under reflux for 2.5 hours, then cooled to ice bath temperature and treated dropwise with water (0.5 ml), 10% sodium hydroxide solution (0.5 ml) and water (1.5 ml). The mixture was filtered through kieselguhr and the filtrate concentrated in vacuo. The residue was distilled in a Kugelr ohr apparatus (bp approx. 140° C. at 2 mmHg) to give the title compound as a colourless oil (0.97 g, 75%).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[N:3]=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:6]=1
Reactant: Cc1nnn[nH]1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nnn(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 110 °C

Procedure:
5-methyl-1H-tetrazole (715 mg, 8.5 mmol) was dissolved in DMF (7 mL) in a 40 mL biotage microwave tube. 4-fluoro-nitrobenzene (1 g, 7.09 mmol) was added, followed by addition of potassium carbonate (1.175 g, 8.5 mmol). The tube was crimp sealed and heated at 110° C. for 4 hours (caution: build-up of pressure possible; use a safety shield). TLC indicated complete consumption of starting materials. Most DMF was removed under vacuum. Water (50 mL) was added. Large amount of brown solid formed (1 gram) and was collected by filtration. The solid was further purified by column through a 80 gram biotage silica gel cartridge using 30-75% ethyl acetate/hexanes to give clean fraction of 5-methyl-2-(4-nitrophenyl)-2H-tetrazole, LRMS calc: 205.1; obs: 206.3 (W+1).
Reaction SMILES: [CH3:1][NH2:2].[C:3]([NH:5][C:6](=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[S:18][CH:17]=[N:16][C:15]=1[CH3:19])SC)#[N:4]>C(O)C>[C:3]([NH:5][C:6]([NH:2][CH3:1])=[N:9][CH2:10][CH2:11][S:12][CH2:13][C:14]1[S:18][CH:17]=[N:16][C:15]=1[CH3:19])#[N:4]
Reactant: CSC(=NCCSCc1scnc1C)NC#N
Reactant: CN
Solvent: CCO
Product: CNC(=NCCSCc1scnc1C)NC#N
Reaction time: 2.5 h

Procedure:
A solution of 75 ml. of 33% methylamine in ethanol is added to a solution of the N-cyano-N'-[2-(4-methyl-5-thiazolylmethylthio)ethyl]-S-methylisothiourea prepared above in 30 ml. of ethanol. The reaction mixture is set aside at ambient temperature for 2.5 hours, and the precipitate is collected to give N-cyano-N'-methyl-N"-[2-(4-methyl-5-thiazolylmethylthio)ethyl]guanidine.
Reaction SMILES: N1(C2N=C(CC([O-])=O)NC(=O)C=2)CCOCC1.[Na+].[ClH:19].CN(C)CCCN=C=NCC.CO[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:40]=1[CH2:41][CH2:42][N:43]2[C:48](=[O:63])[CH2:49][C:50]1[NH:55][C:54](=[O:56])[CH:53]=[C:52]([N:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)[N:51]=1>N1C=CC=CC=1.C(OCC)(=O)C>[Cl:19][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1[CH:47]=[CH:46][CH:45]=[C:44]2[C:40]=1[CH2:41][CH2:42][N:43]2[C:48](=[O:63])[CH2:49][C:50]1[NH:55][C:54](=[O:56])[CH:53]=[C:52]([N:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)[N:51]=1
Reactant: COc1ccccc1-c1cccc2c1CCN2C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Cl
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)N1CCc2c(-c3ccccc3Cl)cccc21
Temperature: 25 °C
Reaction time: 96 h
Yield: 110.3 %

Procedure:
300 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate (example 1d, step 2d), 330 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride and 6 ml of pyridine are successively added to a solution of 264 mg of 4-(2-chlorophenyl)-2,3-dihydro-1H-indole (reference example 6d) in 5 ml of pyridine. The reaction mixture is stirred at ambient temperature for 4 days. The reaction medium is diluted with ethyl acetate (60 ml) and then successively washed with an aqueous 1M hydrochloric acid solution, an aqueous 1M sodium hydroxide solution, and a saturated aqueous sodium chloride solution. The organic phase is then dried over magnesium sulfate and filtered through sintered glass. A precipitate appears after a few hours, which is then filtered off through sintered glass and washed with diethyl ether. 294 mg of 2-{2-[4-(2-chlorophenyl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a beige solid, the characteristics of which are the following:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[O:10])[C:5]([OH:8])=[N:6][CH:7]=1.[CH3:11][O:12][C:13](=[O:18])[C:14](Br)([CH3:16])[CH3:15].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:11][O:12][C:13](=[O:18])[C:14]([O:8][C:5]1[C:4]([CH:9]=[O:10])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)([CH3:16])[CH3:15]
Reactant: COC(=O)C(C)(C)Br
Reactant: O=Cc1cc(Cl)cnc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C(C)(C)Oc1ncc(Cl)cc1C=O
Temperature: 126 °C
Yield: 47.2 %

Procedure:
A mixture of 5-chloro-2-hydroxy-pyridine-3-carbaldehyde (8 g, 51 mmol), 2-bromo-2-methyl-propionic acid methyl ester (27.6 g, 153 mol), Cs2CO3 (28 g, 86.7 mol) in DMF (80 mL) was heated at 126° C. for 3 h. After cooled to room temperature, the mixture was poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried and concentrated. The residue was purified by flash column to give the title compound (6.2 g).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([CH2:12][CH2:13][CH2:14][C@H:15]2[C@H:19]([Cl:20])[CH2:18][C@@H:17]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[C@@H:16]2/[CH:28]=[CH:29]/[C:30](=[O:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:10][CH:11]=1)=[O:6]>CO>[CH3:3][O:4][C:5]([C:7]1[S:8][C:9]([CH2:12][CH2:13][CH2:14][C@H:15]2[C@H:19]([Cl:20])[CH2:18][C@@H:17]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)[C@@H:16]2/[CH:28]=[CH:29]/[CH:30]([OH:36])[CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])=[CH:10][CH:11]=1)=[O:6]
Reactant: CCCCCC(=O)/C=C/[C@@H]1[C@@H](CCCc2ccc(C(=O)OC)s2)[C@H](Cl)C[C@H]1OC1CCCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCCCC(O)/C=C/[C@@H]1[C@@H](CCCc2ccc(C(=O)OC)s2)[C@H](Cl)C[C@H]1OC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78 %

Procedure:
NaBH4 (9.2 mg, 0.24 mmol) was added to a solution of ketone 4-3 (59 mg, 0.12 mmol) in methanol (1 mL). The reaction was stirred at room temperature for 2 h and then was quenched by addition of 5 mL 1 M HCl. The resulting mixture was extracted with CH2Cl2 and the combined CH2Cl2 solution was dried (Na2SO4), filtered and evaporated. Purification by flash chromatography on silica gel (ethyl acetate/hexanes) gave the title compound (48 mg, 80%).