Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCCCCC.C([Li])CCC.[C:12]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[N:21]=[C:20]([C:36]3[CH:41]=[CH:40][C:39](Br)=[CH:38][CH:37]=3)[N:19]=2)=[CH:14][CH:13]=1.Br[C:50]1[N:55]=[C:54]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][N:57]=2)[CH:53]=[CH:52][CH:51]=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCCC1>[C:12]1([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH:17]=[CH:16][C:15]([C:18]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[N:21]=[C:20]([C:36]3[CH:41]=[CH:40][C:39]([C:58]4[N:57]=[C:56]([C:54]5[CH:53]=[CH:52][CH:51]=[CH:50][N:55]=5)[CH:61]=[CH:60][CH:59]=4)=[CH:38][CH:37]=3)[N:19]=2)=[CH:14][CH:13]=1
Reactant: Brc1cccc(-c2ccccn2)n1
Reactant: Brc1ccc(-c2nc(-c3ccc(-c4ccccc4)cc3)nc(-c3ccc(-c4ccccc4)cc3)n2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: c1ccc(-c2ccc(-c3nc(-c4ccc(-c5ccccc5)cc4)nc(-c4ccc(-c5cccc(-c6ccccn6)n5)cc4)n3)cc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 67.2 %

Procedure:
Under a stream of argon, 2.1 ml of a hexane solution containing 3.3 mmol of butyl lithium was slowly added to 70 ml of tetrahydrofuran cooled to −78° C. in which 1.62 g of 2,4-bis(4-biphenylyl)-6-(4-bromophenyl)-1,3,5-triazine obtained in Reference Example 3 had been dissolved. After stirring at −78° C. for 15 minutes, 0.91 g of dichloro(tetramethylethylenediamine)zinc(II) was added thereto and stirred at −78° C. for 10 minutes and then at room temperature for 2 hours. A 20 ml portion of tetrahydrofuran prepared by dissolving 0.85 g of 6-bromo-2,2′-bipyridyl and 0.14 g of tetrakis(triphenylphosphine)palladium(0) therein was added to this solution and stirred under heating reflux for 4 hours. The reaction solution was concentrated under a reduced pressure and the thus obtained solid was recrystallized from dichloromethane-methanol. The thus obtained crude product was washed with chloroform to obtain a white solid of the intended 6-{4-[4,6-bis(4-biphenylyl)-1,3,5-triazin-2-yl]phenyl}-2,2′-bipyridyl (1.24 g, yield 67%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH:7]([CH:11]([C:22]([N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:23])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8](O)=O)([CH3:4])([CH3:3])[CH3:2].N1CCCCC1.C=O>C(O)C>[C:1]([O:5][C:6](=[O:30])[C:7]([CH:11]([C:22]([N:24]1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1)=[O:23])[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)=[CH2:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(C(=O)O)C(CCCc1ccc(Cl)cc1)C(=O)N1CCCCC1
Agent: C=O
Solvent: CCO
Solvent: C1CCNCC1
Product: C=C(C(=O)OC(C)(C)C)C(CCCc1ccc(Cl)cc1)C(=O)N1CCCCC1
Temperature: 50 °C
Yield: 40.2 %

Procedure:
2-[4-(4-Chloro-phenyl)-1-(piperidine-1-carbonyl)-butyl]-malonic acid tert-butyl ester (2.0 g, 4.6 mmol) was dissolved in ethanol (100 ml) and treated with piperidine (0.43 ml, 5.5 mmol) and 37% w/w formaldehyde (1.9 ml, 23 mmol). The reaction mixture was heated at 50° C. overnight. The solvent was removed under reduced pressure, the residue was dissolved in ethyl acetate (60 ml), and the solution was washed with water (3×30 ml), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 20% ethyl acetate in hexane) to give the 2-[4-(4-Chloro-phenyl)-1-(piperidine-1-carbonyl)-butyl]-acrylic acid tert-butyl ester as a colourless oil (750 mg, 41%). 1H-NMR: δ (CDCl3), 7.21 (2H, d, J=8.4 Hz), 7.09 (2H, d, J=8.4 Hz), 6.19 (1H, s), 5.71 (1H, s), 3.82 (1H, dd, J=4.9, 8.2 Hz), 3.64 (1H, m), 3.51-3.32 (3H, m), 2.67-2.50 (2H, m), 1.90 (1H, m), 1.61-1.38 (9H, m) and 1.48 (9H, s).
Reaction SMILES: C(OC(=O)[N:7]([CH2:11][C:12](=[O:14])[NH2:13])[CH:8]([CH3:10])[CH3:9])(C)(C)C.[ClH:16].C(OCC)C>O1CCOCC1>[ClH:16].[CH:8]([NH:7][CH2:11][C:12]([NH2:13])=[O:14])([CH3:10])[CH3:9]
Reactant: CC(C)N(CC(N)=O)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: CC(C)NCC(N)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 97 %

Procedure:
To a solution of N-carbamoylmethyl-N-isopropyl-carbamic acid t-butyl ester (2.67 g, 12.3 mmol) (obtained as described in Reference Example 49(1)) in 1,4-dioxane (30 ml) was added a solution of 4N hydrogen chloride in 1,4-dioxane (30 ml) in an ice bath, and then the mixture was stirred at room temperature overnight. After checking the completion of the reaction, diethyl ether was added thereto and the reaction mixture was stirred for 30 minutes. The resulting mixture was filtered, and the residue was washed with diethyl ether and then dried under reduced pressure to give 2-isopropylaminoacetamide hydrochloride (1.82 g, yield 97%) as white crystals.
Reaction SMILES: [C:1]([C:3]1[S:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]=1Cl)#[N:2].[CH3:13][NH:14][NH2:15].O>CS(C)=O>[CH3:13][N:14]1[C:4]2[C:5]3[C:6]([S:11][C:3]=2[C:1]([NH2:2])=[N:15]1)=[N:7][CH:8]=[CH:9][CH:10]=3
Reactant: N#Cc1sc2ncccc2c1Cl
Reactant: CNN
Solvent: O
Solvent: CS(C)=O
Product: Cn1nc(N)c2sc3ncccc3c21
Yield: 81.6 %

Procedure:
15 Grams (0.066 mole) of 2-cyano-3-chlorothieno (2,3-b)pyridine and 17.5 ml (0.33 mole) of methylhydrazine were dissolved in 110 ml of dimethylsulfoxide and heated to 75° for 15 hr under nitrogen. The reaction was cooled and poured into water. The solid was filtered and dried to give 11 g of 1-methyl-1H-pyrazolo(3',4':4,5)thieno(2,3-b)pyridine-3-amine. m.p. 194°-196° C. NMR(CDCl3) δ4.0(s,3); 5.2(s,2); 7.4(dd,1); 8.4(m,2).
Reaction SMILES: C([NH:4][C:5]([CH2:16][C:17]#[C:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH2:11][O:12]C(=O)C)[CH2:6][O:7]C(=O)C)(=O)C.[OH-].[Na+]>CO>[NH2:4][C:5]([CH2:16][C:17]#[C:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)([CH2:11][OH:12])[CH2:6][OH:7]
Reactant: CC(=O)NC(CC#Cc1ccccc1)(COC(C)=O)COC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(CO)(CO)CC#Cc1ccccc1
Yield: 86.4 %

Procedure:
2-Acetamido-1,3-diacetoxy-2-(3-phenyl-2-propynyl)propane (430 mg) was dissolved in 8 ml of methanol and 8 ml of a 1 N aqueous sodium hydroxide solution was added thereto. The mixture was refluxed under heating for 2 hours. The solvent was distilled away and the residue was purified by silica gel column chromatography (methanol:chloroform=1:50-1:7) to give 230 mg of 2-amino-2-(3-phenyl-2-propynyl)-1,3-propanediol as a pale yellow, amorphous-like solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([C@H:14]1[CH2:18][O:17][C:16](=[O:19])[N:15]1[C:20](=[O:35])[CH2:21][C@@H:22]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)[C:23]1[CH:27]=[CH:26][O:25][N:24]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[C:36]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46]Cl)=[CH:42][C:41]=1[CH:48]([CH3:50])[CH3:49])([CH3:39])([CH3:38])[CH3:37].O>CN(C=O)C>[C:36]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][O:34][C:31]2[CH:32]=[CH:33][C:28]([C@@H:22]([C:23]3[CH:27]=[CH:26][O:25][N:24]=3)[CH2:21][C:20]([N:15]3[C@@H:14]([CH2:7][C:8]4[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=4)[CH2:18][O:17][C:16]3=[O:19])=[O:35])=[CH:29][CH:30]=2)=[CH:42][C:41]=1[CH:48]([CH3:50])[CH3:49])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)c1cc(CCl)ccc1C(C)(C)C
Reactant: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1cc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)ccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 31 %

Procedure:
Cesium carbonate (360 mg, 1.1 mmol) was added to a mixture of 7.5 (40.0 mg, 0.10 mmol) and 26.5 (27.0 mg, 0.12 mmol) in DMF (2.0 mL). The resulting mixture was stirred at room temperature for 19 hours. The mixture was then treated with water (5 mL) and extracted with EtOAc (15 mL). The organic layer was separated, washed twice with brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (0-30% EtOAc/hexane) to give (S)-3-((S)-3-(4-(4-tert-butyl-3-isopropylbenzyloxy)phenyl)-3-(isoxazol-3-yl)propanoyl)-4-benzyloxazolidin-2-one (18.0 mg, 30%) as a clear oil. The ester (18.0 mg, 0.031 mmol) was treated with THF/H2O (3/1, v/v, 2.0 mL) and hydrogen peroxide (30%, 0.021 mL, 0.19 mmol) and cooled to 0° C. LiOH (2.60 mg, 0.062 mmol) was added. The resulting mixture was stirred at 0° C. for 1 hour. A saturated solution of Na2SO3 was added to the mixture, and the reaction was stirred for 1 hour. The mixture was extracted with EtOAc (10 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (0-30% EtOAc/hexane) to give 26 (5.80 mg, 44%) as a colorless film. MS ESI (neg.) m/e: 420 (M−H). 1H NMR (500 MHz) (CDCl3) δ 8.28 (1H, s); 7.37-7.34 (2H, m); 7.20-7.17 (3H, m); 6.96-6.94 (2H, d, J=8.2Hz); 6.07 (1H, s); 4.98 (2H, s); 4.56 (1H, dd, J=7.8, 7.4 Hz); 3.64 (1H, m), 2.36 (1H, dd, J=16.8, 7.8 Hz), 2.99 (1H, dd, J=16.8, 7.4Hz), 1.43 (9H, s), 1.26 (6H, d, J=7.1Hz).
Reaction SMILES: O.Cl.[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([C:21](=O)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=[C:12]2[CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])=[CH:7][CH:6]=1>C1(C)C=CC=CC=1>[CH3:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]=[C:10]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:11]=[C:12]2[CH2:15][CH2:16][NH:17][C:18](=[O:20])[CH3:19])=[CH:7][CH:6]=1
Reactant: COc1ccc2cc(C(=O)c3ccccc3)cc(CCNC(C)=O)c2c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc2cc(Cc3ccccc3)cc(CCNC(C)=O)c2c1

Procedure:
Next, add 3.6 cm3 of water to this amalgam, then 3.6 cm3 of concentrated hydrochloric acid and then 5.26 mmol of N-[2-(7-methoxy-3-benzoylnaphth-1-yl)ethyl]acetamide, prepared according to Example 1, and 25 cm3 of toluene.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH2:8]O)=[C:6]([CH3:10])[N:5]=[CH:4]1)[CH3:2].S(Cl)([Cl:13])=O>ClCCl>[ClH:13].[Cl:13][CH2:8][C:7]1[N:3]([CH2:1][CH3:2])[CH:4]=[N:5][C:6]=1[CH3:10]
Reactant: CCn1cnc(C)c1CO
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCn1cnc(C)c1CCl
Product: Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To (1-ethyl-4-methyl-1H-imidazol-5-yl)methanol (754 mg, 5.4 mmol) in anhydrous dichloromethane (35 mL) was added thionyl chloride (2 mL). The mixture was stirred at room temperature overnight. Dichloromethane was evaporated and then co-evaporated with toluene (2×15 mL). The residue was dried in vacuo, affording 5-(chloromethyl)-1-ethyl-4-methyl-1H-imidazole hydrochloride (1.0 g, 95% yield). The product was used without further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=[C:6]([C:8]2[C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10][O:11][C:12]=2[CH3:13])[N:7]=1.[NH2:29][CH2:30][CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>CN(C=O)C>[CH3:13][C:12]1[O:11][N:10]=[C:9]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]=1[C:6]1[N:7]=[C:3]([CH2:2][NH:29][CH2:30][CH2:31][CH2:32][N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:4]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[CH:22][CH:21]=2)[CH:5]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CCl)n1
Reactant: NCCCN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1onc(-c2ccccc2)c1-c1cn(-c2ccc([N+](=O)[O-])cc2)c(CNCCCN2CCOCC2)n1
Temperature: 80 °C
Yield: 71.9 %

Procedure:
To a solution of 4-[2-chloromethyl-1-(4-nitro-phenyl)-1H-imidazol-4-yl]-5-methyl-3-phenyl-isoxazole (50 mg, 0.13 mmol) in DMF (2 mL) was added 4-(3-aminopropyl)morpholine (36.5 mg, 0.25 mmol) and KI (4.2 mg, 0.03 mmol) and the resulting mixture heated at 80° C. for 2 h. After cooling to room temperature, the mixture was then poured onto water and extracted with ethyl acetate. The combined organic layers were then washed with brine and water and then dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, dichloromethane:methanol=100:0 to 80:20) afforded the title compound (47 mg, 74%) which was obtained as a yellow gum. MS: m/e=503.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:9]([CH3:16])=[N:10][C:11]([CH3:15])=[N:12][C:13]=2[CH3:14])[CH2:5][C:4](=[O:17])[C:3]=1[C:18](=O)[CH2:19][CH2:20][CH3:21].Cl.[CH2:24]([O:26][NH2:27])[CH3:25].O.O.O.C([O-])(=O)C.[Na+]>C(O)C>[CH2:24]([O:26][N:27]=[C:18]([C:3]1[C:4](=[O:17])[CH2:5][CH:6]([C:8]2[C:9]([CH3:16])=[N:10][C:11]([CH3:15])=[N:12][C:13]=2[CH3:14])[CH2:7][C:2]=1[OH:1])[CH2:19][CH2:20][CH3:21])[CH3:25]
Reactant: CCCC(=O)C1=C(O)CC(c2c(C)nc(C)nc2C)CC1=O
Reactant: CCON
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCC(=NOCC)C1=C(O)CC(c2c(C)nc(C)nc2C)CC1=O

Procedure:
3-Hydroxy-5-(2,4,6-trimethylpyrimidin-5-yl)-2-butyrylcyclohex-2-en-1-one (0.29 g) was stirred with O-ethylhydroxylamine hydrochloride (0.1 g) and sodium acetate trihydrate (0.14 g) in ethanol (30 ml) at room temperature for 15 hr. The mixture was poured into a saturated aqueous salt solution (50 ml), which was subsequently extracted with ethyl acetate. The dried (Na2SO4) organic extract was evaporated to give 2-[1-(ethoxyimino)butyl]-3-hydroxy-5-(2,4,6-trimethylpyrimidin-5-yl)cyclohex-2-en-1-one as a colourless oil. Pmr spectrum (CDCl3 ; δ in ppm): 1.01 (3H, t); 1.34 (3H, t); ca 1.64 (2H, m); ca 2.3-3.8 (7H, m); 2.59 (6H, s); 2.63 (3H, s); 4.13 (2H, q); 10.66 (1H,s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C@H:5]([CH2:7][S:8][CH2:9][CH2:10][S:11][CH:12]([CH3:14])C)[NH2:6])[CH3:2].[C:16]([O:20][C:21](=[O:25])[CH:22](Br)[CH3:23])([CH3:19])([CH3:18])[CH3:17].[CH2:26](N(CC)CC)C>CN(P(N(C)C)(N(C)C)=O)C>[C:16]([O:20][C:21](=[O:25])[C@H:22]([CH3:23])[NH:6][C@H:5]([C:4]([O:3][CH2:1][CH3:2])=[O:15])[CH2:7][S:8][CH2:9][CH2:10][S:11][CH2:12][CH2:14][CH3:26])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCOC(=O)[C@@H](N)CSCCSC(C)C
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCSCCSC[C@H](N[C@@H](C)C(=O)OC(C)(C)C)C(=O)OCC
Temperature: 25 °C
Reaction time: 40 h

Procedure:
In 50 ml of HMPA were dissolved 12.2 g of S-2-propylthioethyl-L-cysteine ethyl ester and 11.2 g of 2-bromopropionic acid t-butyl ester. A 7.5 ml quantity of triethylamine was added to the solution and the mixture was stirred at room temperature for 40 hours. The reaction mixture was poured into ice water and the mixture was extracted with ethyl acetate. The extract was washed with water and with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure and the residue was purified by silica gel column chromatography (a 1:3 mixture of ether and n-hexane as an eluent), giving the α-isomer of the title compound as a colorless oil from the first eluate. Yield 2.58 g.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[CH2:9]1>C(Cl)Cl>[O:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCN(C2COC2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C1CN(C2COC2)CCN1
Temperature: 25 °C
Yield: 98 %

Procedure:
Trifluoroacetic acid (100 mL, 33.0 eq, 1327.9 mmol) was added to a solution of tert-butyl 4-(oxetan-3-yl)piperazine-1-carboxylate (9.8 g, 1.0 eq, 40.2 mmol) in CH2Cl2 (500 mL). Reaction mixture was allowed to stir at room temperature. Progress of the reaction was monitored by TLC analysis. After 30 minutes the reaction mixture was concentrated on a rotovap (bath temperature was maintained at 20° C.) to remove the volatiles. The crude solution was loaded on to SCX-2 (100 g, obtained from Sillicycle) and eluted with CH2Cl2/MeOH [1:1 CH2Cl2/MeOH (100 mL) & then with neat MeOH (100 mL)]. Then the product was eluted with 2M NH3 in MeOH (200 mL). Fractions eluted with 2M NH3 in MeOH were combined and concentrated under reduced pressure to leave 1-(oxetan-3-yl)piperazine as a colourless oil in 98% yield.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]([N:19]3[CH2:24][CH2:23][NH:22][C@@H:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:20]3)[C:8]3[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1.C=O.[C:34](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.C(=O)(O)[O-].[Na+]>[F:1][C:2]1[CH:31]=[CH:30][C:5]2[N:6]=[C:7]([N:19]3[CH2:24][CH2:23][N:22]([CH3:34])[C@@H:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH2:20]3)[C:8]3[CH:14]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:12]=[CH:11][C:9]=3[NH:10][C:4]=2[CH:3]=1
Reactant: COCCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3ccc(C(F)(F)F)cc32)CCN1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: COCCC[C@H]1CN(C2=Nc3ccc(F)cc3Nc3ccc(C(F)(F)F)cc32)CCN1C
Yield: 82.3 %

Procedure:
Combine (S)-7-fluoro-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-piperazin 1-yl]-5H-dibenzo[b,e][1,4]diazepine (0.259 g, 0.593 mmol), formaldehyde (67 μL, 0.831 mmol, 37%), and sodium triacetoxyborohydride (0.189 g, 0.890 mmol) in dichloroethane (10 mL) and stir at room temperature overnight. Dilute the mixture with saturated sodium bicarbonate and extract three times with methylene chloride. Combine the organic layers, dry over sodium sulfate and concentrate under reduced pressure to give the crude product. Purification by flash chromatography, eluting with a step gradient starting with dichloromethane going to 5% 2N ammonia-methanol in dichloromethane gives (S)-7-fluoro-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-4-methyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine (0.220 g, 0.488 mmol, 82%) as a yellow oil. Mass spectrum (APCI): m/z=451.3 (M+1). Isolate clean product as the corresponding dihydrochloride in the following manner: dissolve the yellow foam in ethanol (5 mL) and add a solution of about 5 equivalents of HCl in ethanol (5 mL). Evaporate the mixture to obtain (S)-7-fluoro-2-trifluoromethyl-11-[3-(3-methoxy-propyl)-4-methyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine dihydrochloride.
Reaction SMILES: C(C1N=C(N2CCC(F)(F)C2)C2C(=NN(CC)N=2)N=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:42])([F:41])[C:38]([F:44])([F:43])[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl[CH2:46][C:47]1[O:48][C:49]([CH3:52])=[N:50][N:51]=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:40][C:39]([F:41])([F:42])[C:38]([F:43])([F:44])[CH2:37]2)[C:30]2[C:31](=[N:33][N:34]([CH2:46][C:47]3[O:48][C:49]([CH3:52])=[N:50][N:51]=3)[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)c1nc(N2CC(F)(F)C(F)(F)C2)c2nn[nH]c2n1
Reactant: Cc1nnc(CCl)o1
Agent: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Product: Cc1nnc(Cn2nc3nc(C(C)(C)C)nc(N4CC(F)(F)C(F)(F)C4)c3n2)o1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl-7-(3,3,4,4-tetrafluoro-pyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole and isolated as white solid. MS (m/e): 415.3 (MH+).
Reaction SMILES: [BH4-].[Na+].CO.[CH3:5][O:6][C:7](=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C@@H:19](/[CH:20]=[CH:21]/[C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][CH2:17][CH2:16][C:15]1=[O:29]>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:30])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:15](=[O:29])[CH2:16][CH2:17][CH2:18][C@@H:19]1/[CH:20]=[CH:21]/[CH:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCC(=O)/C=C/[C@H]1CCCC(=O)N1CCCCCCC(=O)OC
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCCCC(O)/C=C/[C@H]1CCCC(=O)N1CCCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
Sodium borohydride (28 mg, 0.74 mmol), followed by MeOH (0.25 mL), was added to a solution of 7-[(R)-2-oxo-6-((E)-3-oxo-oct-1-enyl)-piperidin-1-yl]-heptanoic acid methyl ester (55 mg, 0.15 mmol) in CH2Cl2 (0.75 mL) at 0° C. The mixture was allowed to warm to rt. After 1 h at rt, the reaction was quenched with aqueous HCl (1.0 M, 2 mL) and extracted with EtOAc (3×10 mL). The combined organic phase was washed with brine (10 mL) then dried (Na2SO4), filtered and concentrated in vacuo to afford 55 mg (99%) of the title compound.
Reaction SMILES: [C:1]([CH2:4][N:5]([CH2:10][CH2:11][N:12]([CH2:26][C:27]([OH:29])=[O:28])[CH2:13][CH2:14][N:15]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:16][C:17]([OH:19])=[O:18])[CH2:6][C:7](O)=[O:8])([OH:3])=[O:2].[NH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CO>[C:17]([CH2:16][N:15]([CH2:14][CH2:13][N:12]([CH2:26][C:27]([OH:29])=[O:28])[CH2:11][CH2:10][N:5]([CH2:6][C:7](=[O:8])[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:4][C:1]([OH:3])=[O:2])[CH2:20][C:21]([OH:23])=[O:22])([OH:19])=[O:18]
Reactant: Nc1ccccc1
Reactant: CCOC(=O)CN(CCN(CCN(CC(=O)O)CC(=O)O)CC(=O)O)CC(=O)O
Solvent: CO
Product: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC(=O)Nc1ccccc1

Procedure:
In a 1-liter autoclave, 42.1 g (0.1 mol) of N3,N6 -bis(carboxymethyl)-N9 -ethoxycarbonylmethyl-3,6,9-triazaundecanedioic acid is heated with 93.1 g (1 mol) of aniline for 30 hours to 110° C. After cooling, the content is dissolved in 800 ml of methanol and the solution concentrated to dryness under vacuum. The residue is combined with 800 ml of water and the excess aniline exhaustively extracted with methylene chloride. The aqueous phase is passed, after an initial distillation, over 100 ml of "Amberlite" IR 120. The acidic eluate is concentrated and the residue dried under vacuum at 50° C., thus obtaining 35.1 g (75% of theory) in the form of a white powder with a melting point of 125° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([Cl:12])=[C:9]([Cl:11])[Cl:10])[C:5]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[S:17]([NH2:20])(=[O:19])=[O:18].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)(=O)C>[CH2:21]([NH:28][C:2]1[CH:7]=[C:6]([C:8]([Cl:12])=[C:9]([Cl:11])[Cl:10])[C:5]([S:13]([NH2:16])(=[O:15])=[O:14])=[CH:4][C:3]=1[S:17]([NH2:20])(=[O:19])=[O:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NS(=O)(=O)c1cc(S(N)(=O)=O)c(C(Cl)=C(Cl)Cl)cc1Br
Reactant: NCc1ccccc1
Solvent: CC(=O)O
Product: NS(=O)(=O)c1cc(S(N)(=O)=O)c(C(Cl)=C(Cl)Cl)cc1NCc1ccccc1

Procedure:
A mixture of 0.31 g. of 4-bromo-6-trichlorovinyl-1,3-benzenedisulfonamide and 0.76 ml. of benzylamine is stirred at 100° C for 2 hours and then added to 25 ml. of aqueous acetic acid and cooled in ice. A precipitate is collected by filtration which weighs 0.26 g. after drying, which gives after recrystallization from a ethylacetate/benzene/petroleum benzene mixture 0.17 g. of 4-benzylamino-6-(1,2,2-trichlorovinyl)-1,3-benzenedisulfonamide with m.p. 188°-190° C.