Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[CH2:12]1[O:15][CH:13]1[CH3:14]>C(O)(C)C>[OH:15][CH:13]([CH3:14])[CH2:12][N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1]
Reactant: CC1CO1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Solvent: CC(C)O
Product: CC(O)CN1C(C)(C)CC(O)CC1(C)C
Temperature: 160 °C

Procedure:
A mixture of 3.14 parts of 2,2,6,6-tetramethylpiperidin-4-ol, 10 parts of propylene oxide and 10 parts of isopropanol was charged to an autoclave. A pressure of 100 atmospheres of nitrogen was applied and the mixture heated at 160°C for 6 hours. The isopropanol solvent and unreacted propylene oxide were removed by distillation under reduced pressure. Crystallisation of the residue from cyclohexane gave 3.0 parts of 1[2-hydroxypropyl]-2,2,6,6-tetramethylpiperidin-4-ol having a melting point of 97°-8°C and on further purification of 107°-8°C and the following elemental analysis by weight:
Reaction SMILES: O.[NH2:2][NH2:3].[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:12]([C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[O:15])=O)[CH:9]=[CH:10][CH:11]=1>C(O)C.C(O)(=O)C>[CH3:4][O:5][C:6]1[CH:7]=[C:8]([C:12](=[N:2][NH2:3])[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[CH:17]=2)=[O:15])[CH:9]=[CH:10][CH:11]=1
Reactant: NN
Reactant: COc1cccc(C(=O)C(=O)c2cccc(OC)c2)c1
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: COc1cccc(C(=O)C(=NN)c2cccc(OC)c2)c1
Temperature: 65 °C
Reaction time: 48 h

Procedure:
To a solution of 1.0 g hydrazine hydrate in 25 ml ethanol is added a warm solution of 3,3'-dimethoxybenzil, 7.0 g in 125 ml ethanol. The solution is heated to 65° C for 48 hours. Three drops of acetic acid are added and heating is continued for 48 hours. The solution is concentrated, diluted with 100 ml water and extracted with methylene chloride. The organic layer is removed, dried over magnesium sulfate and the solvent removed. The oily residue is chromatographed on 200 g of BioSil-A using chloroform-benzene mixtures. Elution of product is completed with methylene chloride. The product from chromatography is recrystallized from chloroform-hexane yielding 2.8 g of pale yellow needles. M.P. 109°-110.5°.
Reaction SMILES: Cl.[O:2]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:21][O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26]Br>>[CH3:21][O:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][N:18]1[CH2:19][CH2:20][N:15]([C:12]2[CH:13]=[CH:14][C:9]([O:2][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=3)=[CH:10][CH:11]=2)[CH2:16][CH2:17]1
Reactant: COC(=O)CCCBr
Reactant: c1ccc(Oc2ccc(N3CCNCC3)cc2)cc1
Agent: Cl
Product: COC(=O)CCCN1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Yield: 33.2 %

Procedure:
The title compound (106 mg, 32.6%) was prepared from the compound from step 2, Example 8 (165 mg, 0.9 mmol) and 4-bromo-butyric acid methyl ester (165 mg, 90 mmol) by the procedure described in step 3 of Example 4: MS (ESI) m/z 355 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.84 (m, 2H), 2.36-2.44 (m, 4H), 2.60 (t, J=4.8 Hz, 4H), 3.14 (t, J=4.8 Hz, 4H), 3.68 (s, 3H), 6.89-7.04 (m, 7H), 7.26-7.29 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([O:19][CH2:20][CH2:21][CH3:22])=[C:7]([C:9]2[N:17]=[C:16]3[C:12](=[N:13][N:14]=[N:15]3)[C:11](=[O:18])[N:10]=2)[CH:8]=1)#[N:2].[N-:23]=[N+:24]=[N-:25].[Na+].[Cl-].[NH4+].Cl>O.CN1CCCC1=O>[CH2:20]([O:19][C:6]1[CH:5]=[CH:4][C:3]([C:1]2[NH:25][N:24]=[N:23][N:2]=2)=[CH:8][C:7]=1[C:9]1[N:17]=[C:16]2[C:12](=[N:13][N:14]=[N:15]2)[C:11](=[O:18])[N:10]=1)[CH2:21][CH3:22]
Reactant: CCCOc1ccc(C#N)cc1C1=NC(=O)C2=NN=NC2=N1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCOc1ccc(-c2nnn[nH]2)cc1C1=NC(=O)C2=NN=NC2=N1
Reaction time: 7 h
Yield: 28.4 %

Procedure:
A mixture of 2-(5-cyano-2-propoxyphenyl)-8-azapurin-6-one (2.0 g), sodium azide (1.05 g), ammonium chloride (0.9 g) and N-methylpyrrolid-2-one (16 ml) was cautiously heated, with stirring, in a sealed flask for 7 hours at 100°-110° C. The mixture was then cooled and added to water (80 ml) and the mixture was acidified by treatment with concentrated hydrochloric acid. The solid which separated was filtered off and recrystallised from acetic acid to give 2-[2-propoxy-5-(tetrazol-5-yl)phenyl]-8-azapurin-6-one (0.65 g), m.p. 253°-259° C. (with decomposition).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](O)=[O:23].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl>C(Cl)Cl>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH:14][C:22](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: O=C(O)c1ccccn1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Cc1noc(C)c1Cn1cc(NC(=O)c2ccccn2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (example 4-1a) (400 mg, 2.1 mmol), picolinic acid (256 mg, 2.1 mmol), and HOBt (388 mg, 2.50 mmol) were mixed in DCM (7 mL). The reaction was treated with triethylamine (670 mL, 4.8 mmol) and stirred for 15 minutes at room temperature under a nitrogen atmosphere. EDC (598 mg, 3.1 mmol) was added and the reaction was stirred for an additional 4 hours. The reaction was then diluted with dichloromethane (5 mL) and washed with aqueous saturated NaHCO3 solution (5 mL, 2×) and then with aqueous saturated NaCl solution (5 mL). The organic layer was collected, dried, and filtered. Solvents were removed under vacuum. The crude product was re-suspended in EtOH (5 mL) and purified by reversed phase HPLC (5%-95% ACN in H2O:25 minute gradient). The pure fractions were combined and concentrated to afford N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)picolinamide (372 mg, 60%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 2.21 (s, 3H), 2.44 (s, 3H), 5.05 (s, 2H), 7.49-7.47 (m, 1H), 7.59 (s, 1H), 7.93-7.88 (dt, J=14, 2 Hz, 1H), 8.07 (s, 1H), 8.24-8.21 (d, J=8 Hz, 1H), 8.61-8.56 (m, 1H), 9.83 (bs, 1H). LC/MS; [M+H] calculated for C15H15N5O2; expected 297.1; found 298.3. Melting point: 135-137° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:37]=[CH:36][C:10]([CH2:11][N:12]2[C:16](=[O:17])[C:15]3([CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[N:14]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:13]2)=[CH:9][CH:8]=1.N1C=CC=CC=1>ClCCl>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:11][N:12]2[C:16](=[O:17])[C:15]3([CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]3)[N:14]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH2:13]2)=[CH:36][CH:37]=1)(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1ccc(N)cc1)CN2c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)C(=O)N(Cc1ccc(NS(C)(=O)=O)cc1)CN2c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.1 %

Procedure:
Methanesulfonyl chloride (0.39 mL, 5.02 mmol) was added dropwise at 0° C. to tert-butyl 3-(4-aminobenzyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (2.19 g, 5.02 mmol) and pyridine (0.61 mL, 7.53 mmol) in dichloromethane (10 mL). The reaction was allowed to warm to room temperature and stirred for 30 minutes. The mixture was diluted with dichloromethane, washed with 2M aqueous hydrochloric acid and brine, dried (MgSO4) and evaporated. The residue was purified by PTLC (50% ethyl acetate/hexanes) to give product as an oil (2.38 g, 92%); 1H NMR (DMSO-d6); δ1.45 (s, 9H); 1.63 (d, J=14 Hz, 2H); 2.18-2.23 (m, 2H); 2.98 (s, 3H); 3.30-3.55 (m, 2H); 3.80-3.95 (m, 2H); 4.52 (s, 2H); 4.59 (s, 2H); 6.67 (d, J=8 Hz, 2H); 6.76 (t, J=7.2 Hz, 2H); 7.15-7.21 (m, 4H); 7.26-7.28 (m, 2H); MS for C26H34N4O5S m/z 515 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[Br:12]Br.O>ClC1C=CC=CC=1>[Br:12][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: BrBr
Solvent: Clc1ccccc1
Solvent: O
Product: O=C(O)C(Br)c1ccc(Cl)cc1
Temperature: 105 °C
Yield: 95 %

Procedure:
In a stirred reactor with reflux condenser (connected to a caustic scrubber) 171 g 4-chlorophenyl acetic acid are pre-charged in 750 g chlorobenzene and 41 g phosphortrichloride (0.3 Mol) are added. The mixture is heated to 100-110° C. and 280 g bromine (1.75 mole) are added within 1 hour through a dropping funnel. The reaction mixture is stirred for another 3-4 hour at 110-115° C. until the conversion of the 4-chlorophenyl acetic acid is complete (control by LC). The reaction mixture is cooled to 50° C. and 100 ml water is added. Excess bromine is destroyed by addition of NaHSO3 solution. The reaction mixture is adjusted to pH 1 with aqueous NaOH solution and then the organic product phase is separated from the aqueous phase. The chlorobenzene phase contains 237 g bromo-(4-chloro-phenyl)acetic acid by LC analysis (yield=95% of theory based on 4-chlorophenylacetic acid). The “bromoacid” bromo-(4-chloro-phenyl)acetic acid can be isolated partly by concentration to a 50% solution and crystallisation/filtration at 0° C. About 200 g of bromo-(4-chloro-phenyl)acetic acid can be isolated in a crystallised form. Melting point=92-93° C. 1H-NMR (CDCl3) δ (ppm): 5.3 (s, 1H); 7.4 (4H, Ar); 9.7 (1H, OH)
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([CH3:8])[S:6][CH:7]=1)#[N:2].C[Si]([N:13]=[N+:14]=[N-:15])(C)C.C([Sn](=O)CCCC)CCC>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:8][C:5]1[S:6][CH:7]=[C:3]([C:1]2[NH:15][N:14]=[N:13][N:2]=2)[N:4]=1
Reactant: Cc1nc(C#N)cs1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Cc1nc(-c2nnn[nH]2)cs1

Procedure:
A mixture of 4-cyano-2-methylthiazole (5.74 g) (U.S. Pat. No. 4,010,173 1977), trimethylsilyl azide (10.64 g) and dibutyltin oxide (115 g) in toluene (300 ml) was heated at 120° C. for 24 hours. The reaction mixture was diluted with ethyl acetate and extracted with dilute aqueous sodium hydroxide solution. The combined extracts were acidified to pH 5 with 1M HCl and extracted with ethyl acetate. The extracts were dried (MgSO4) and evaporated. Yield 4.53 g.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[O:32]1[CH2:37][CH2:36][N:35]([CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH2:34][CH2:33]1>C(Cl)Cl>[OH:19][C:20]1[C:21](=[O:22])[C:13]2[CH:8]3[C:7]([CH3:31])([CH:11]([OH:12])[CH2:10][CH2:9]3)[CH2:6][CH:5]([O:4][C:2](=[O:3])[CH3:1])[C:14]=2[C:15]2([CH3:30])[C:16]=1[C:17](=[CH:18][N:43]1[CH2:42][CH2:41][N:40]([CH2:39][CH2:38][N:35]3[CH2:34][CH2:33][O:32][CH2:37][CH2:36]3)[CH2:45][CH2:44]1)[C:23](=[O:24])[O:25][CH:26]2[CH2:27][O:28][CH3:29]
Reactant: C1CN(CCN2CCOCC2)CCN1
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN2CCN(CCN3CCOCC3)CC2)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added 1-(2-morpholinoethyl)piperazine (93 mg, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 631 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:39](OC(=O)C)(=[O:41])[CH3:40].O>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:32]=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[CH:26]=3)[C:39](=[O:41])[CH3:40])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC/C=C/c3cccc(C#N)c3)cc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N(C/C=C/c1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
To a solution of 3-[3-[N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzonitrile (503 mg) and pyridine (0.14 ml) in dichloromethane (10 ml) was added acetic anhydride (0.13 ml) in an ice bath. The mixture was stirred at room temperature for 1 hour. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=1/1→ethyl acetate as an eluant to afford yellow crystals. The crystals were washed with diisopropyl ether to give the desired compound (403 mg, yield 50%) as pale yellow crystals.
Reaction SMILES: FC(F)(F)C(O)=O.O.[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:20]([CH3:21])[C:19]([C:22]([CH3:35])([CH3:34])[CH:23]([O:30]COC)[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[N:18][N:17]=1>C(Cl)Cl>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[N:20]([CH3:21])[C:19]([C:22]([CH3:34])([CH3:35])[CH:23]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[OH:30])=[N:18][N:17]=1
Reactant: COCOC(c1ccccc1)C(C)(C)c1nnc(-c2ccccc2Cl)n1C
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 71.8 %

Procedure:
Trifluoroacetic acid (3 ml) and water (1 ml) were added to a methylene chloride (3 ml) solution of 3-(2-chlorophenyl)-5-[2-(methoxymethoxy)-1,1-dimethyl-2-phenylethyl]-4-methyl-4H-1,2,4-triazole (173 mg) under ice cooling, followed by stirring at room temperature for 19 hours. Then, the whole was stirred at 40° C. for 3.5 hours, at 50° C. for 2.5 hours and at 60° C. for 65 hours. The reaction mixture was concentrated under reduced pressure and ethyl acetate and a saturated sodium hydrogen carbonate solution were added thereto. The organic layer was dried over anhydrous sodium sulfate and then the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=40:1) to obtain 2-[5-(2-chlorophenyl)-4-methyl-4H-1,2,4-triazol-3-yl]-2-methyl-1-phenylpropan-1-ol (110 mg).
Reaction SMILES: NC(CCCCCCCCC(N)CCC)CCC.C(C1CC=CCCC=CCC(CCC)N=N1)CC.[CH2:37]([CH:48]1[CH2:59][CH:58]=[CH:57][CH2:56][CH2:55][CH:54]=[CH:53][CH2:52][CH:51]([CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])[N:50]=[N:49]1)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]>>[NH2:49][CH:48]([CH2:59][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][CH2:52][CH:51]([NH2:50])[CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47]
Reactant: CCCCCCCCCCCC1CC=CCCC=CCC(CCCCCCCCCCC)N=N1
Agent: CCCC(N)CCCCCCCCC(N)CCC
Agent: CCCC1CC=CCCC=CCC(CCC)N=N1
Product: CCCCCCCCCCCC(N)CCCCCCCCC(N)CCCCCCCCCCC
Yield: 63.7 %

Procedure:
If there are used in the manner described under (a), instead of 942 g (3.79 mols) of 3,12-dipropyl-1,2-diaza-1,5,9-cyclododecatriene, 100 g (0.21mol) of crude 3,12-diundecyl-1,2-diaza-1,5,9-cyclododecatriene (diastereoisomeric mixture) and correspondingly reduced amounts of catalyst and solvent, with the procedure otherwise being the same, there is obtained 64.3 g (64% of theory) of 12,21-diaminodotriacontane [m.p. 45°-46° C.; IR (CH2Cl2) inter alia bands at 3174 and 1582 cm-1 ].
Reaction SMILES: [N+]([CH:4]([CH3:14])[CH2:5][CH2:6][C:7]([C-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)=[O:8])([O-])=O.[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20].C(Cl)(Cl)Cl.C(=O)(O)[O-:26].[Na+]>C(COC)OC.O.[Cl-].[Cl-].[Cl-].[Ti+3].[O-2].[O-2].[Ti+4]>[O:26]=[C:4]([CH3:14])[CH2:5][CH2:6][C:7]([C-:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1)=[O:8].[CH-:15]1[CH:19]=[CH:18][CH:17]=[CH:16]1.[Fe+2:20]
Reactant: CC(CCC(=O)[c-]1cccc1)[N+](=O)[O-]
Reactant: O=C([O-])O
Agent: [Fe+2]
Agent: [Ti+3]
Agent: [Ti+4]
Solvent: COCCOC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)CCC(=O)[c-]1cccc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The nitro compound (315 mg; 1 m mole) in glyme (5 ml) was treated with titanium trichloride (4 m mole) in water (5 ml) under N2 with stirring at room temperature. After 2 days a further 4 m mole of TiCl3 was added and stirring was continued for 24 hrs. The product was poured into chloroform (50 ml) and saturated sodium bicarbonate was added until precipitation of titanium dioxide was complete. The two layers were filtered through `Hiflo` and the chloroform layer was washed with sodium bicarbonate solution, water and dried (sodium sulphate) to yield an oil which was chromatographed on silica to yield starting material (eluted with 5% ethyl acetate/toluene) and 4-oxopentanoyl ferrocene (30 mg; 10.6%) NMR 8, 4.75 (t, 2H); 4.44 (t, 2H); 4.21 (S, 5H); 3.1 2.6 (A2B2, 4H); 2.21 (S, 3H).
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].[Br:19][C:20]1[C:21]([F:31])=[C:22]([F:30])[C:23](F)=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26]>C1COCC1>[Br:19][C:20]1[C:21]([F:31])=[C:22]([F:30])[C:23]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[Cl:11])=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26]
Reactant: O=C(O)c1cc(Br)c(F)c(F)c1F
Reactant: Nc1ccccc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Br)c(F)c(F)c1Nc1ccccc1Cl
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
To a solution of LiHMDS (49.0 mL, 2 M in THF/heptane) in THF (40 mL) was added 2-chlorophenylamine (6.50 mL, 60.6 mmol) at −78° C. After vigorous stirring for 10 minutes, a solution of 5-bromo-2,3,4-trifluoro-benzoic acid (2) (7.70 g, 30.2 mmol) in THF (60 mL) was added. The dry-ice bath was removed and the reaction mixture stirred for 4 hours at room temperature. The mixture was concentrated, treated with 10% aqueous HCl (75 mL), and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered, and concentrated. Purification by trituration with boiling CH2Cl2 gave 7.24 g (66%) of the desired acid (3) as a yellow solid
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]3[C:15](=[N:16][CH:17]=2)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]3)[CH:5]=[N:6][CH:7]=1.O1CCOCC1.O.CC1(C)C(C)(C)OB([C:36]2[CH2:37][CH2:38][O:39][CH2:40][CH:41]=2)O1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CCOC(C)=O>[O:39]1[CH2:38][CH:37]=[C:36]([C:2]2[CH:3]=[C:4]([C:8]3[CH:9]=[C:10]4[C:15](=[N:16][CH:17]=3)[N:14]([C:18]([NH2:20])=[O:19])[CH2:13][CH2:12][CH2:11]4)[CH:5]=[N:6][CH:7]=2)[CH2:41][CH2:40]1
Reactant: NC(=O)N1CCCc2cc(-c3cncc(Br)c3)cnc21
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)N1CCCc2cc(-c3cncc(C4=CCOCC4)c3)cnc21
Temperature: 100 °C

Procedure:
6-(5-Bromo-pyridin-3-yl)-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid amide (100 mg, 0.30 mmol, which is prepared according to the procedure for Step 1 to Step 4 of Example 15) is dissolved into 2 mL of dioxane/water (9:1). 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (94.6 mg, 0.45 mmol), K3PO4 (318 mg, 1.50 mmol) and PdCl2(DPPF)CH2Cl2 (24.5 mg, 0.03 mmol) are added. The mixture is heated at 100° C. for 48 hrs. The mixture is diluted with 100 mL EtOAc and quenched with 100 mL of saturated aqueous NH4Cl. The organic phase is washed with 2×20 mL of H2O and 1×20 mL of brine. The organic phase is dried with MgSO4, filtered and concentrated. The crude material is applied to a silica preparative TLC plate and purified twice to give 52.1 mg of the titled product.
Reaction SMILES: C(=O)([O-])[O-:2].[K+].[K+].CI.[CH2:9]([O:12][C@@H:13]([CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:14][CH:15]1SCCCS1)[CH:10]=[CH2:11].COC(C)(C)C>C(#N)C.O>[CH2:9]([O:12][C@@H:13]([CH2:21][O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:14][CH:15]=[O:2])[CH:10]=[CH2:11]
Reactant: C=CCO[C@@H](COCc1ccccc1)CC1SCCCS1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: COC(C)(C)C
Solvent: CC#N
Product: C=CCO[C@H](CC=O)COCc1ccccc1
Temperature: 40 °C
Reaction time: 4 h
Yield: 115.4 %

Procedure:
Potassium carbonate (5.14 g) and methyl iodide (4.90 mL) were added to a mixed solution of 2-((R)-2-allyloxy-3-benzyloxy-propyl)-[1,3]dithiane (12 g) in acetonitrile (27 mL) and water (4.5 mL), and then the mixture was stirred at 40° C. After four hours, water (3 mL) and methyl iodide (2 mL) were added to the reaction solution. After further three hours, methyl iodide (1 mL) was added to the reaction solution. After stirring for eight hours in total, water and t-butyl methyl ether were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine. The organic layer was dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to obtain crude (R)-3-allyloxy-4-benzyloxy-butyraldehyde (about 10 g). The crude product was used for the next reaction without further purification. Hydroxylamine hydrochloride (4.29 g) and sodium acetate (4.92 g) were sequentially added to a solution of ethanol (60 mL) and water (15 mL). The above aldehyde (10 g) was added to the mixture, followed by stirring for 20 hours. A saturated sodium bicarbonate solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The organic layer was sequentially washed with a saturated sodium bicarbonate solution and brine and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and then the filtrate was concentrated under reduced pressure to obtain a residue. The residue was subjected to silica gel column chromatography to obtain the title compound (5.74 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[NH:12]C(=O)[O:10][C:8](=O)[C:7]2=[CH:14][CH:15]=1)([O-:3])=[O:2].[CH3:16][O:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[NH2:12][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:15]=[CH:14][C:7]=1[C:8]([NH:22][C:21]1[CH:23]=[CH:24][C:18]([O:17][CH3:16])=[CH:19][CH:20]=1)=[O:10]
Reactant: COc1ccc(N)cc1
Reactant: O=c1[nH]c2cc([N+](=O)[O-])ccc2c(=O)o1
Product: COc1ccc(NC(=O)c2ccc([N+](=O)[O-])cc2N)cc1
Yield: 95 %

Procedure:
Using a procedure analogous to Example 16-F, 4-nitroisatoic anhydride and 4-methoxyaniline gave the desired product as a greenish-yellow solid (2.73 g, 95%).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:27])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.C[Si]([Cl:41])(C)C>CC(CC)=O>[ClH:41].[CH2:1]([N:8]1[C:12]2([CH2:17][CH2:16][N:15]([C:18](=[O:27])[C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)[CH2:14][CH2:13]2)[NH:11][C@@H:10]([CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:9]1=[O:35])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Agent: COc1cccc(C(=O)N2CCC3(CC2)N[C@@H](Cc2ccccc2)C(=O)N3Cc2ccccc2)c1
Solvent: CCC(C)=O
Solvent: O
Product: Cl
Reaction time: 8 h

Procedure:
1,3-(S)-dibenzyl-8-(3-methoxybenzoyl)-1,4,8-triazaspiro[4,5]decan-2-one (404 mg, 0.9 mmol) was dissolved in ethyl methyl ketone (3.2 mL), and water (9 μL) and TMSCl (120 μL) were added and the mixture was stirred overnight. The solid matter was isolated by filtration, washed with ether, and dried in vacuo. The product 1,3-(S)-dibenzyl-8-(3-methoxybenzoyl)-1,4,8-triazaspiro[4,5]decan-2-one hydrochloride was obtained in a yield of 358 mg (82%).