Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(#N)C1C=CC=CC=1.OO.[C:11](=[O:14])(O)[O-].[K+].[CH2:16]([O:19][C:20]1[C:29]2[O:28][NH:27][C:26](=[O:30])[CH2:25][C:24]=2[CH:23]=[CH:22][CH:21]=1)[CH:17]=C>CO>[O:14]1[CH2:11][CH:17]1[CH2:16][O:19][C:20]1[C:29]2[O:28][NH:27][C:26](=[O:30])[CH2:25][C:24]=2[CH:23]=[CH:22][CH:21]=1
Reactant: C=CCOc1cccc2c1ONC(=O)C2
Reactant: O=C([O-])O
Agent: OO
Agent: [K+]
Solvent: N#Cc1ccccc1
Solvent: CO
Product: O=C1Cc2cccc(OCC3CO3)c2ON1
Reaction time: 72 h

Procedure:
5.2 g of benzonitrile, 18 ml of a 30 percent strength aqueous solution of hydrogen peroxide and 1.0 g of potassium bicarbonate are added to a suspension of 10.1 g of 8-allyloxy-2,3-dihydro-(4H)-benz[5.6]oxazin-3-one in 400 ml of methanol and the mixture is then stirred for 3 days at 20°. The reaction mixture is then concentrated to a volume of 40 ml under reduced pressure. After leaving to stand at 0°, 8-(2,3-epoxy-propoxy)-2,3-dihydro-(4H)-benz[5.6]oxazin-3-one is obtained in the form of colourless crystals, which are filtered off and washed with a little cold methanol; melting point 158°-160°.
Reaction SMILES: [CH2:1]([OH:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]1(=[O:21])[O:16][C:14](=[O:15])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12>CS(O)(=O)=O.C1(C)C=CC=CC=1>[C:14]([O:16][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])(=[O:15])[C:13]1[C:12](=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:11]([O:10][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:21]
Reactant: CCCCCCCCCO
Reactant: O=C1OC(=O)c2ccccc21
Agent: CS(=O)(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCOC(=O)c1ccccc1C(=O)OCCCCCCCCC
Yield: 103.4 %

Procedure:
567 g of nonyl alcohol produced in Example 1 was combined with 280 g of phthalic anhydride, 200 g of toluene and 5.5 g of methanesulfonic acid. The reaction was set up for reflux through a Dean-Stark trap using a nitrogen purge and slow stiffing. The reactor contents were refluxed for 5 hours. Residual catalyst was neutralized with a 10% NaCO3 solution and the product was water washed. The product was purified by vacuum stripping and distillation to yield 818 g of dinonyl phthalate.
Reaction SMILES: [I:1][C:2]1[CH:17]=[CH:16][C:5]2[NH:6][C:7]([CH2:12][C:13]([OH:15])=O)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.[CH2:18]([O:20][C:21]([C@H:23]1[C@@H:28]([NH:29][CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C@H:27]2[CH2:35][C@@H:24]1[CH2:25][CH2:26]2)=[O:22])[CH3:19].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1.Cl>CN(C)C=O>[CH2:18]([O:20][C:21]([C@H:23]1[C@@H:28]([N:29]([C:13](=[O:15])[CH2:12][C:7]2[NH:6][C:5]3[CH:16]=[CH:17][C:2]([I:1])=[CH:3][C:4]=3[S:9](=[O:10])(=[O:11])[N:8]=2)[CH2:30][CH2:31][CH:32]([CH3:34])[CH3:33])[C@H:27]2[CH2:35][C@@H:24]1[CH2:25][CH2:26]2)=[O:22])[CH3:19]
Reactant: O=C(O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Reactant: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1NCCC(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H]1[C@H]2CC[C@H](C2)[C@@H]1N(CCC(C)C)C(=O)CC1=NS(=O)(=O)c2cc(I)ccc2N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
(7-Iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (prepared as described in US patent application US 2008/0031852, 0.2 g, 0.546 mmol) was dissolved in anhydrous N,N-dimethylformamide (5 mL). (1S,2R,3S,4R)-3-(3-Methyl-butylamino)-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester (prepared as described in Example 22a, 0.138 g, 0.546 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.11 g, 0.573 mmol). Then N-methylmorpholine (0.116 g, 1.15 mmol) was added into the above reaction mixture. The mixture was stirred at 25° C. for 16 h. The solution was poured into 1.0 M aqueous hydrochloric acid solution (100 mL). The aqueous layer was extracted with ethyl acetate (2×100 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to afford the crude product, (1S,2R,3S,4R)-3-[[2-(7-iodo-1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(3-methyl-butyl)-amino]-bicyclo[2.2.1]heptane-2-carboxylic acid ethyl ester, as a light yellow oil, which was used in the next step without any further purification. LC-MS (ESI) calcd for C24H32IN3O5S 601.11. found 602.6 [M+H+].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[CH:9]=[N:10][N:11]3[CH:16]=[CH:15][N:14]=[CH:13][C:12]=23)[N:3]=1.[F:17][C:18]1[CH:19]=[CH:20][C:21]([C@@H:24]([NH2:26])[CH3:25])=[N:22][CH:23]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[F:17][C:18]1[CH:19]=[CH:20][C:21]([C@@H:24]([NH:26][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]3[CH:9]=[N:10][N:11]4[CH:16]=[CH:15][N:14]=[CH:13][C:12]=34)[N:3]=2)[CH3:25])=[N:22][CH:23]=1
Reactant: C[C@H](N)c1ccc(F)cn1
Reactant: Clc1ccnc(-c2cnn3ccncc23)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Nc1ccnc(-c2cnn3ccncc23)n1)c1ccc(F)cn1
Yield: 4.4 %

Procedure:
A solution of 3-(4-chloropyrimidin-2-yl)pyrazolo[1,5-a]pyrazine (Preparation 31, 170 mg, 0.61 mmol), (S)-1-(5-fluoropyridin-2-yl)ethanamine (85 mg, 0.61 mmol, prepared as described in WO2006/82392A1) and diisopropylethylamine (122 μL, 0.70 mmol) in N,N′-dimethylformamide (5 mL) was heated to 150° C. in a microwave oven for 75 min. The solvent was then removed under reduced pressure and the residue was partitioned between 4% aqueous sodium hydrogen carbonate solution and ethyl acetate. The organic phase was separated, washed with brine, dried (MgSO4) and concentrated to give a crude which was purified by reverse phase chromatography (C-18 silica from Waters, water/acetonitrile/methanol as eluents [0.1% v/v formic acid buffered] 5% to 50%) to give the title compound (9 mg, 4%) as an oil. The corresponding fumarate salt was prepared by adding a solution of fumaric acid (3.1 mg, 0.027 mmol) in ethanol (0.5 mL) to a solution of the title compound (as free base, 9 mg, 0.027 mmol) in ethanol (2 mL) followed by evaporation of the solvent. The resulting solid was dried in an oven under vacuum to give 11 mg of the desired fumarate salt.
Reaction SMILES: C([O:5][C:6]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([NH2:17])[C:11]=2[N:10]=[C:9]1[NH:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.[CH2:35]([N:37]=C=O)[CH3:36].O1CCOCC1.Cl>C(#N)C>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[CH2:26][N:23]1[CH2:24][CH2:25][CH:20]([CH2:19][NH:18][C:9]2[NH:17][C:16]3[CH:15]=[CH:14][CH:13]=[C:12]([NH:8][C:6]([NH:37][CH2:35][CH3:36])=[O:5])[C:11]=3[N:10]=2)[CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)n1c(NCC2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)nc2c(N)cccc21
Reactant: CCN=C=O
Agent: Cl
Solvent: CC#N
Solvent: C1COCCO1
Product: CCNC(=O)Nc1cccc2[nH]c(NCC3CCN(Cc4ccc(Cl)c(Cl)c4)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 4-amino-2-{[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amino}-benzimidazole-1-carboxylic acid tert-butyl ester (10 mg, 0.02 mmol) in acetonitrile (1 ml), ethyl isocyanate (0.08 mmol) was added and the mixture was stirred at room temperature overnight. After adding a 4N hydrogen chloride-1,4-dioxane solution (1 ml) to the reaction mixture, it was stirred at 50° C. for 1 hour and then the reaction mixture was passed through SCX (Bond Elute SCX500MG). The SCX was washed with methanol and elution was performed with a 2N ammonia-methanol solution. The solvent was distilled off under reduced pressure to obtain 1-(2-{[1-(3,4-dichloro-benzyl)-piperidin-4-ylmethyl]-amino}-1H-benzimidazol-4-yl)-3-ethyl-urea. The compound was identified by LC-MS.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C:7]1[CH:12]=[C:11]([SH:13])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:6])[CH3:5].Br[CH:20]1[CH2:25][CH2:24][O:23][C:21]1=[O:22].Cl>CO.O>[CH3:6][C:4]([C:7]1[CH:12]=[C:11]([S:13][CH:20]2[CH2:25][CH2:24][O:23][C:21]2=[O:22])[CH:10]=[C:9]([C:14]([CH3:17])([CH3:16])[CH3:15])[C:8]=1[OH:18])([CH3:3])[CH3:5]
Reactant: O=C1OCCC1Br
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)c1cc(SC2CCOC2=O)cc(C(C)(C)C)c1O
Temperature: 25 °C

Procedure:
Sodium hydroxide (0.20 g, 5 mmole) was added to a solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (1.11 g, 4.6 mmole) in methanol (20 ml) and stirred at room temperature until dissolved. 2-Bromobutyrolactone (0.82 g, 5 mmole) was added and the mixture was stirred at room temperature for 48 hours. The mixture was diluted with water, acidified with 1 N hydrochloric acid, and extracted with diethyl ether. The ether extract was washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue was dissolved in a minimum of hexane and cooled to induce crystallization. Chromatography of the solid on silica gel and recrystallization from hexane gave the title compound, m.p. 98°'100°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:24]4[CH2:28][CH2:27][NH:26][C:25]4=[O:29])=[N:21][CH:22]=3)[C:9]=2[F:30])[CH:5]=[CH:6][CH:7]=1.[CH2:31]1COCC1.[H-].[Na+].CI>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([CH2:23][N:24]4[CH2:28][CH2:27][N:26]([CH3:31])[C:25]4=[O:29])=[N:21][CH:22]=3)[C:9]=2[F:30])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cc2ccc(CN3CCNC3=O)nc2)c(F)c1-c1cccc(Cl)c1
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CI
Product: COc1ccc(Cc2ccc(CN3CCN(C)C3=O)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Into an 8 mL vial was added P-374 (21 mg, 0.05 mmol), THF (1 mL) and the solution was cooled to 0° C. Sodium hydride (3 mg, 0.076 mmol) was added and after 15 minutes at room temperature, methyl iodide (6 uL, 0.101 mmoL) was added. The reaction was stirred for 30 minutes at room temperature and then 1 mL of water was added. The THF was evaporated and the product was extracted with ethyl acetate and concentrated. The residue was passed through a silica gel plug eluting with methanol, which afforded P-375 (18.1 mg, 82%) as a colorless oil. 1H NMR (400 MHz, DMSO-d6) 8.42 (d, J=1.6 Hz, 1H), 7.60 (dd, J=2.0, 7.9 Hz, 1H), 7.50-7.39 (m, 2H), 7.37 (s, 1H), 7.34 (t, J=8.7 Hz, 1H), 7.28 (d, J=6.4 Hz, 1H), 7.19 (d, J=8.1 Hz, 1H), 6.94 (d, J=8.5 Hz, 1H), 4.31 (s, 2H), 3.95 (s, 2H), 3.72 (s, 3H), 3.24 (s, 4H), 2.67 (s, 3H) ppm. LC/MS=97.8%, 440.1 (APCI+).
Reaction SMILES: [C@H:1]12[NH:8][C@H:5]([CH2:6][CH2:7]1)[CH2:4][CH2:3][CH:2]2[NH:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]2[NH:18][N:19]=[C:20]([C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH3:30])[N:25]=[CH:24]4)[C:14]=2[CH2:13]1)=[O:11].[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34]Br.C(N(C(C)C)CC)(C)C>ClCCl>[F:31][C:32]1[CH:39]=[CH:38][CH:37]=[CH:36][C:33]=1[CH2:34][N:8]1[CH:5]2[CH2:6][CH2:7][CH:1]1[CH:2]([NH:9][C:10]([N:12]1[CH2:17][CH2:16][C:15]3[NH:18][N:19]=[C:20]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[N:26]([CH3:30])[N:25]=[CH:24]5)[C:14]=3[CH2:13]1)=[O:11])[CH2:3][CH2:4]2
Reactant: Cn1ncc2cc(-c3n[nH]c4c3CN(C(=O)NC3CC[C@H]5CC[C@@H]3N5)CC4)ccc21
Reactant: Fc1ccccc1CBr
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc2cc(-c3n[nH]c4c3CN(C(=O)NC3CCC5CCC3N5Cc3ccccc3F)CC4)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dichloromethane (1.78 mL) was added to N-((1S,5R)-8-azabicyclo[3.2.1]octan-2-yl)-3-(1-methyl-1H-indazol-5-yl)-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxamide (72.3 mg, 0.178 mmol) in a flask. 2-Fluorobenzylbromide (0.0214 mL, 0.178 mmol) was added to the reaction. At room temperature, diisopropylethylamine (0.0920 mL, 0.534 mmol) was added dropwise to the reaction. The reaction was allowed to stir at room temperature for 1 hr. The reaction was quenched using water, was extracted three times using dichloromethane. The dichloromethane extractions were combined, dried over sodium sulfate, filtered, and concentrated. The crude was further purified using HPLC. The endo and exo products were separated. LC-MS: 514.3 [M+H]. LC/MS RT=2.17 and 2.238 min.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N:19]1([C:24]2[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:29][C:28]([C:27]3[CH:26]=[CH:25][C:24]([N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:31][CH:30]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: NCc1ccc(N2CCCC2)cc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(OC)cc1
Product: CCOC(=O)c1nc(-c2ccc(N3CCCC3)cc2)[nH]c1-c1ccc(OC)cc1

Procedure:
Ethyl 2-hydroxyimino-3-(4-methoxyphenyl)-3-oxopropionate, 4-(1-pyrrolidinyl)benzylamine is reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-methoxyphenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylate. Ethyl 5-(4-methoxyphenyl)-2-(4-(1-pyrrolidinyl)-phenyl)imidazole-4-carboxylate is reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-methoxyphenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylic acid. 5-(4-Methoxyphenyl)-2-(4-(1-pyrrolidinyl)phenyl)imidazole-4-carboxylicacid isreactedandtreatedinthesamemanneras in Example 1 to give 5-(4-methoxyphenyl)-2-(4-(1-pyrrolidinyl)phenyl)-N-(2-thiazolyl)imidazole-4-carboxamide.
Reaction SMILES: CN(C)[N:3]=[CH:4]/[CH:5]=[CH:6]/[CH3:7].Br[C:10]1[C:11](=[O:21])[C:12]2[C:17]([C:18](=[O:20])[CH:19]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2>C1(C)C(C)=CC=CC=1>[CH3:7][C:6]1[CH:5]=[CH:4][N:3]=[C:19]2[C:18](=[O:20])[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:11](=[O:21])[C:10]=12
Reactant: O=C1C=C(Br)C(=O)c2ccccc21
Reactant: C/C=C/C=NN(C)C
Solvent: Cc1ccccc1C
Product: Cc1ccnc2c1C(=O)c1ccccc1C2=O
Yield: 57.3 %

Procedure:
(E)-2-Butenal N,N-dimethylhydrazone, (3.70 g, 0.033 mol) in dry xylene (10 mL, Fisher) was added to a xylene solution (50 mL) of 2-bromo-1,4-naphthoquinone, (6.00 g, 0.025 mol) in a 200-mL, round-bottomed flask fitted with a condensor. The dark mixture was then heated at reflux for 6 h under a nitrogen atmosphere before decanting the solution into a 500-mL separatory funnel. The solids coating the wall of the flask were washed thoroughly with ethyl acetate (6×25 mL) and these washings added to the separatory funnel. The combined organic solutions were extracted with 2N sulfuric acid solution (1×100 mL followed by 2×75 mL). The acid layers were then combined, chilled in ice, and made basic (~pH 10 test paper) with sodium hydroxide before extracting with ethyl acetate (4×100 mL). The latter organic layers were dried over potassium carbonate and concentrated to dryness on a rotary evaporator. This material was applied to a 4×70 cm column of Silica gel (Merck 230-400 mesh) and the product eluted with ethyl acetate. Concentration of the appropriate column fractions yielded pure cleistopholine (3.20 g, 57%); mp 202°-204° C. (lit. mp 198°-201° C.). IR (KBr) 1680, 1660, 1590, 1300, 980, 720 cm-1 ; 1H NMR (CDCl3) δ 8.86 (d,J=4.9 Hz, 1H), 8.34-8.30 (m, 1H), 8.24-8.19 (m, 1H), 7.82-7.76 (m, 2H), 7.47 (dd,J=4.9,0.7 Hz, 1H), 2.88 (br s, 3H); 13C NMR (CDCl3) 184.7 (0), 181.9 (0), 153.4 (1), 151.5 (0), 150.0 (0), 134.5 (1), 134.1 (1), 133.8 (0), 132.5 (0), 131.2 (1), 129.1 (0), 127.3 (1), 127.1 (1), 2.28 (3) ppm.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH2:16])=[O:10])[CH:5]=[CH:4][N:3]=1.[CH:18]1([CH:21]=O)[CH2:20][CH2:19]1.C(O)C.C([BH3-])#N.[Na+]>O>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[N:12]=[C:13]([CH3:17])[S:14][C:15]=2[NH:16][CH2:21][CH:18]2[CH2:20][CH2:19]2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(NC(=O)c2nc(C)sc2N)ccn1
Reactant: O=CC1CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(NC(=O)c2nc(C)sc2NCC2CC2)ccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
5-Amino-2-methyl-thiazole-4-carboxylic acid (2-methyl-pyridin-4-yl)-amide (0.200 g, 0.806 mmol) was treated with cyclopropanecarboxaldehyde (0.230 g, 3.22 mmol) and tetraisopropyl-orthotitanate (0.916 g, 3.22 mmol) and stirred at room temperature overnight. Ethanol (5 mL) and sodium cyanoborohydride (0.213 g, 3.22 mmol) were added and the reaction mixture was stirred for 5 h. Water (0.5 mL) was added to the reaction mixture and the solvent was evaporated. The residue was purified by flash chromatography on silica gel with ethyl acetate/methanol 100:0→90:10 gradient to yield the title compound (0.110 g, 45%) as a light yellow solid, MS (ISP): m/e=303.1 (M+H+).
Reaction SMILES: Cl.C(O)C.[N+:5]([C:8]1[CH:19]=[CH:18][C:11]([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:10][CH:9]=1)([O-])=O>O.[Pd]>[NH2:5][C:8]1[CH:19]=[CH:18][C:11]([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(Cn2cncn2)cc1
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CCO
Product: Nc1ccc(Cn2cncn2)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 96 %

Procedure:
A stainless steel vessel was inerted with nitrogen and connected via its vent to a mobile scrubber unit. The scrubber was charged with very dilute hydrochloric acid. The vessel was charged with 96% ethanol (40 kg) followed by 1-(4-nitrobenzyl)-1,2,4-triazole (9.62 kg). The vessel was re-inerted with nitrogen and a slurry of 10% Pd/c catalyst (Engelhardt type 4505, 192 g) in water added to the stirred batch via the addition funnel. The vessel, funnel and line were rinsed with water. Total water used was 16 l. The batch was well stirred and heated to 60° C. A solution of ammonium formate (13.95 kg) in water (3 l) was metered into the reactor over 1 hour. Batch temperature settled at 65° C. At the end of this addition, the batch was heated at 70°-75° C. for a further 1 hour. Tlc showed complete reaction and single spot formation. The batch was cooled to 60° C. and passed through a pressure filter coated with hyflo (1.5 kg) to another vessel. The reaction vessel, filter and lines were washed with water (10 l). A further batch of 1-(4-nitrobenzyl)-1,2,4-triazole (9.585 kg) was then reduced in the same way. This batch was filtered and added to the previously filtered batch together with a 10 1 water wash of the vessel, filter and lines. The combined, filtered batch (215 l) was distilled at atmospheric pressure until 70 1 of distillate had been removed (vapour temperature was 83° C. at this point). Water (30 l) was added and the distillation continued until the vapour temperature reached 95° C. (106 1 total distillate). The pressure in the distillation vessel was then reduced to allow distillation at a boiling point of ≤70° C. A further 70 1 of distillate was removed to leave a residual volume of 69 l. The batch had crystallised at this point and the slurry was cooled to ≤20° C. over 1 hour. The batch was gently stirred and aged overnight. The batch was cooled to 0° C., aged for 1 hour and then filtered. The solid was washed with water at 0°-5° C. (10 l). The batch was dried overnight at 50° C., in vacuo with a nitrogen bleed to give 1-(4-aminobenzyl)-1,2,4-triazole in 96% yield.
Reaction SMILES: [N:1]1([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4][C@@H:3]2[CH2:7][NH:8][CH2:9][C@H:2]12.Br[C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[N:22][CH:23]=1>>[Cl:24][C:21]1[N:22]=[CH:23][C:18]([N:8]2[CH2:7][C@@H:3]3[C@@H:2]([N:1]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5][CH2:4]3)[CH2:9]2)=[CH:19][CH:20]=1
Reactant: Clc1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2CNC[C@@H]21
Product: CC(C)(C)OC(=O)N1CCC[C@@H]2CN(c3ccc(Cl)nc3)C[C@@H]21
Yield: 49 %

Procedure:
tert-Butyl cis-octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (374 mg, 1.65 mmol), prepared as described in (EP0603887A2) and 5-bromo-2-chloropyridine (314 mg, 1.65 mmol), prepared as described in (Tetrahedron Lett. (1998), 39, 2059-2062) were processed as described in Example 1E to provide the title compound (273 mg, 49% yield). MS (DCI/NH3) m/z 338/340 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:16][CH3:17])[CH2:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[H-].[Na+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.C(OCC)(=O)C>CN(C=O)C>[CH3:17][O:16][CH:3]([O:2][CH3:1])[CH2:4][N:5]([CH2:25][C:24]1[CH:27]=[CH:28][CH:29]=[C:22]([O:21][CH3:20])[CH:23]=1)[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7]
Reactant: COC(CNS(=O)(=O)c1ccc(C)cc1)OC
Reactant: COc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1cccc(CN(CC(OC)OC)S(=O)(=O)c2ccc(C)cc2)c1
Reaction time: 0.17 h

Procedure:
13.0 g (50 mmol) of N-(2,2-dimethoxyethyl)-4-methylbenzenesulfonamide was dissolved in 40 ml of DMF. 2.01 g (50 mmol) of sodium hydride was added to the obtained solution at room temperature. After stirring for 10 minutes, 9.18 g (46 mmol) of 3-methoxybenzyl bromide was added to the obtained mixture, and they were stirred for 2 hours. After the treatment with ethyl acetate as the extraction solvent in an ordinary manner, the obtained crude product was purified by the silica gel column chromatography to obtain the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([NH:15][C@@H:16]1[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[C:27](Cl)(=[O:30])[CH:28]=[CH2:29].O>CO>[C@@H:16]1([N:15]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14])[C:27](=[O:30])[CH:28]=[CH2:29])[O:24][C@H:23]([CH2:25][OH:26])[C@@H:21]([OH:22])[C@H:19]([OH:20])[C@H:17]1[OH:18]
Reactant: CCCCCCCCN[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: C=CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C=CC(=O)N(CCCCCCCC)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reaction time: 0.42 h

Procedure:
62.5 mmol (6.63 g) of sodium carbonate are added to 24 mmol (7 g) of N-octyl-β-D-glucopyranosylamine in 100 ml of methanol at 30° C.; 48 mmol (3.9 ml) of acryloyl chloride are run in at 0° C. over 5 minutes into the heterogeneous mixture. The reaction mixture is left at ambient temperature with stirring for 25 minutes. After addition of 100 ml of water and evaporation of the methanol the acrylamidosugar is extracted with 300 ml of ethyl acetate. The organic phase is washed with a saturated solution of NaHCO3. dried over MgSO4 and evaporated at reduced pressure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH:25]=[C:26]1[C:32]2[CH:33]=[CH:34][CH:35]=[N:36][C:31]=2[CH2:30][O:29][C:28]2[CH:37]=[CH:38][C:39]([C:41]([OH:44])([CH3:43])[CH3:42])=[CH:40][C:27]1=2>C(#N)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][N:11]([CH2:23][CH2:24][CH:25]=[C:26]3[C:32]4[CH:33]=[CH:34][CH:35]=[N:36][C:31]=4[CH2:30][O:29][C:28]4[CH:37]=[CH:38][C:39]([C:41]([OH:44])([CH3:43])[CH3:42])=[CH:40][C:27]3=4)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Reactant: N#CC1(c2ccc(Cl)cc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCC(C#N)(c3ccc(Cl)cc3)CC1)c1cccnc1CO2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4-(4-chloro-phenyl)-piperidine-4-carbonitrile (180 mg, 0.8 mmol) in acetonitrile/water (4/1) was added potassium carbonate (221 mg, 1.6 mmol), followed by 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (150 mg, 0.4 mmol). The reaction mixture was stirred at room temperature for 48 hours and then concentrated in vacuo. The resulting residue was treated with water and extracted with ethyl acetate. Solvent was evaporated from the combined dried (MgSO4) organic extracts, and the residue was purified by column chromatography on silica gel using hexane-ethyl acetate (6:4) to afford the title compound.