Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH2:15].[C:16](Cl)(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20].N1C=CC=CC=1>C(#N)C>[CH:1]1[C:9]2[C:8]3[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[NH:15][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: Nc1ccc2oc3c(c2c1)CCCCC3
Reactant: CCCCC(=O)Cl
Solvent: CC#N
Solvent: c1ccncc1
Product: CCCCC(=O)Nc1ccc2oc3c(c2c1)CCCCC3
Yield: 49.6 %

Procedure:
Following the procedure of Example 1, 7,8,9,10-tetrahydro-6H-benzo[b]-cyclohepta[d]furan-2-ylamine (0.25 g, 1.2 mmol), valeryl chloride (0.16 mL, 1.4 mmol), and pyridine (0.30 mL, 3.7 mmol) in acetonitrile (15 mL) provided N-(7,8,9,10-tetrahydro-6H-benzo[b]cyclohepta[d]furan-2-yl)pentanamide (0.17 g). MS (ESI) m/z 286([M+H]+).
Reaction SMILES: [Na].[OH:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[Cl:11][P:12]1([Cl:22])[N:17]=[P:16](Cl)([Cl:18])[N:15]=[P:14]([Cl:21])([Cl:20])[N:13]=1>C1COCC1>[Cl:20][P:14]1([Cl:21])[N:15]=[P:16]([Cl:18])([O:2][C:3]2[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=2)[N:17]=[P:12]([Cl:22])([Cl:11])[N:13]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: ClP1(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N1
Agent: [Na]
Solvent: C1CCOC1
Product: O=Cc1ccc(OP2(Cl)=NP(Cl)(Cl)=NP(Cl)(Cl)=N2)cc1
Reaction time: 12 h
Yield: 75 %

Procedure:
500 mg of 4-hydroxybenzaldehyde sodium salt (3.47 mmol) is added at 0° C. and under an inert atmosphere to a solution containing 4.8 g of hexachlorocyclotriphosphazene (13.8 mmol) in THF (200 mL). The reaction medium is stirred for 12 hours while the temperature is left to gradually return to room temperature. The crude reaction product is evaporated to dryness then purified by “flash” chromatography on a silica column. The product is isolated in the form of a translucent oil with a yield of 75%.
Reaction SMILES: CSCS(C)=O.[OH-:7].C([N+](C)(C)C)C1C=CC=CC=1.[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([O:28]COC)=[C:24]([CH:27]=1)[CH:25]=O.[O:32]1[CH2:36]CC[CH2:33]1>CO.O>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([OH:28])=[C:24]([CH2:25][C:33]([O:32][CH3:36])=[O:7])[CH:27]=1
Reactant: C1CCOC1
Reactant: [OH-]
Reactant: COCOc1ccc(Cl)cc1C=O
Agent: CSCS(C)=O
Agent: C[N+](C)(C)Cc1ccccc1
Solvent: CO
Solvent: O
Product: COC(=O)Cc1cc(Cl)ccc1O
Yield: 91 %

Procedure:
A mixture of methyl methylthiomethyl sulfoxide (11.7 g), 40% solution of benzyltrimethylammonium hydroxide in methanol (7.5 mL), 5-chloro-2-methoxymethoxybenzaldehyde (9.43 g) and tetrahydrofuran (150 mL) was heated under reflux for 20 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. A mixture of the obtained residue and 10% hydrogen chloride-methanol (100 mL) was heated under reflux for 15 hrs. The reaction mixture was concentrated, and ethyl acetate was added to the residue. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (7.24 g, 91%) of methyl 2-(5-chloro-2-hydroxyphenyl)acetate from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 84-85° C.
Reaction SMILES: [CH:1](=[N:8][N:9]([C:21]1[CH:26]=[C:25]([Cl:27])[C:24]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)=[C:23]([Cl:36])[CH:22]=1)[C:10]([NH:12][CH2:13]C(OCC)OCC)=[O:11])C1C=CC=CC=1>C(#N)C.Cl>[Cl:27][C:25]1[CH:26]=[C:21]([N:9]2[C:10](=[O:11])[NH:12][CH2:13][CH:1]=[N:8]2)[CH:22]=[C:23]([Cl:36])[C:24]=1[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1
Reactant: CCOC(CNC(=O)N(N=Cc1ccccc1)c1cc(Cl)c(Cc2ccc(Cl)cc2)c(Cl)c1)OCC
Agent: Cl
Solvent: CC#N
Product: O=C1NCC=NN1c1cc(Cl)c(Cc2ccc(Cl)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
In 5 ml of acetonitrile was dissolved 0.4 g of 1-benzylidene-2-[4-(4-chlorobenzyl)-3,5-dichlorophenyl]-4-(2,2-diethoxyethyl)-semicarbazide. To the solution was added one drop of 35% hydrochloric acid. The mixture was stirred for one hour at room temperature. The reaction mixture was cooled, then resulting crystalline precipitate-of the titled compound was collected by filtration. The yield was 95%. m.p. 199-200° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=O.[Na+].[BrH:19]>O.[Cu](Br)Br>[Br:19][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: Nc1cc(C(=O)O)cc(C(F)(F)F)c1
Reactant: Br
Agent: Br[Cu]Br
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87 %

Procedure:
To a stirred suspension of 3-amino-5-(trifluoromethyl)benzoic acid (7.90 gm, 38.5 mmol) in a mixture of hydrobromic acid (43% w/v, 100 mL) and water (100 mL) at 0° C. was slowly added a solution of sodium nitrite (7.97 gm, 0.116 mol) in water (50 mL). After 1 hour the inhomogeneous yellow liquid was added to a solution of copper (II) bromide (16.44 gm, 0.115 mol) in water (100 mL) and the mixture was stirred at room temperature for 16 hours. The mixture was extracted with diethyl ether (250 mL), the aqueous layer was separated and extracted with diethyl ether (3×75 mL). The combined organic layers were dried with anhydrous sodium sulfate and the solvent removed under vacuum to give the title compound as a yellow solid (9.0 gm, 87%) which was used in the following reaction without further purification.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH:14]1(Br)[CH2:16][CH2:15]1.C(Cl)Cl>CN(C)C=O.O>[CH:14]1([N:1]2[CH:5]=[C:4]([CH:6]=[O:7])[CH:3]=[N:2]2)[CH2:16][CH2:15]1
Reactant: O=Cc1cn[nH]c1
Reactant: BrC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1cnn(C2CC2)c1
Temperature: 130 °C

Procedure:
Dissolve 1H-pyrazole-4-carboxaldehyde in N,N-dimethylformamide (1.9 mL). Add potassium carbonate (0.539 g, 3.90 mmol) and cyclopropylbromide (0.346 g, 2.86 mmol). Heat in a pressure tube to 130° C. for 18 hr. Cool to ambient temperature and add DCM and water. Separate layers and extract water layer 3 times with DCM. Wash combined DCM layers with brine, dry (magnesium sulfate), filter, and concentrated to give the free base of the title preparation. GC-MS: m/z=136 [M+].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28][C:29](=[O:35])OC(Cl)(Cl)Cl)Cl.[CH3:37][N:38]1[CH2:43]C[CH2:41][CH:40](O)[CH2:39]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:29](=[O:35])[O:28][CH:26]2[CH2:41][CH2:40][CH2:39][N:38]([CH3:43])[CH2:37]2)=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN1CCCC(O)C1
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2nccc(Oc3ccc(NC(=O)OC4CCCN(C)C4)c(C)c3C)c2cc1OC
Yield: 30.7 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml) and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-methyl-3-piperidinol (27 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (22 mg, yield 27%).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:10]2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:29]1([C:34](Cl)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1>ClCCl>[CH:29]1([C:34]([N:13]2[CH2:14][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([C:2]([F:20])([F:1])[F:21])=[CH:4][CH:5]=3)[CH2:10][CH:11]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:12]2)=[O:35])[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=C(Cl)C1CCCC1
Reactant: CCOC(=O)C1CNCC(c2ccc(C(F)(F)F)cc2)C1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)C2CCCC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.2 g (13.5 mmol) of ethyl 5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylate were dissolved in 33 ml of dichloromethane, and 2.04 g (20.2 mmol) of triethylamine were added at 0° C. 2.37 g (17.5 mmol) of cyclopentanecarbonyl chloride were then added dropwise. The reaction mixture was stirred at RT for 2 h. For work-up, the mixture was twice washed with water. The organic phase was dried over sodium sulphate and concentrated under reduced pressure. Yield: 5.9 g (100% of theory)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)[N:5]=[C:4]([NH:15][CH:16]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17]2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:14][C:10]1[CH:11]=[C:12]([CH3:13])[N:8]([C:6]2[N:5]=[C:4]([NH:15][CH:16]3[CH2:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:17]3)[CH:3]=[C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[N:7]=2)[N:9]=1
Reactant: Cc1cc(C)n(-c2nc(Cl)cc(NC3Cc4ccccc4C3)n2)n1
Reactant: C1COCCN1
Product: Cc1cc(C)n(-c2nc(NC3Cc4ccccc4C3)cc(N3CCOCC3)n2)n1

Procedure:
Was prepared according to example 4 from [6-chloro-2-(3,5-dimethyl-pyrazol-1-yl)-pyrimidin-4-yl]-indan-2-yl-amine and morpholine. Mp. 66-70° C.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:40][CH2:39][C:15]3([O:19][N:18]=[C:17]([C:20]4[C:21]([NH:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[C:22]5[C:28]([CH3:29])=[N:27][N:26]([CH2:30][CH3:31])[C:23]5=[N:24][CH:25]=4)[CH2:16]3)[CH2:14][CH2:13]2)(=O)=O)=CC=1.[C-:41]#[N:42].[Na+].O>CN(C)C=O>[CH:33]1([NH:32][C:21]2[C:20]([C:17]3[CH2:16][C:15]4([CH2:14][CH2:13][CH:12]([C:41]#[N:42])[CH2:40][CH2:39]4)[O:19][N:18]=3)=[CH:25][N:24]=[C:23]3[N:26]([CH2:30][CH3:31])[N:27]=[C:28]([CH3:29])[C:22]=23)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: [C-]#N
Reactant: CCn1nc(C)c2c(NC3CCCCC3)c(C3=NOC4(CCC(OS(=O)(=O)c5ccc(C)cc5)CC4)C3)cnc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(C)c2c(NC3CCCCC3)c(C3=NOC4(CCC(C#N)CC4)C3)cnc21
Temperature: 62.5 °C
Reaction time: 8 h

Procedure:
3-[4-(Cyclohexylamino)-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl 4-methylbenzenesulfonate (0.0018 mole) (example 39) is taken in dimethylformamide. Sodium cyanide (0.0036 mole) is added and the reaction mixture is stirred at 60-65° C. overnight. Water is added and extraction is done with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure to give crude compound, which is purified by column chromatography.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([NH2:22])=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:5][CH:4]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25].C(N(CC)CC)C.O>C(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][N:9]2[C:12]2[C:21]3[C:16](=[CH:17][C:18]([NH:22][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:19][CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1ccc2c(N3CCc4ccc(Cl)cc43)ncnc2c1

Procedure:
4-(6-Chloro-2,3-dihydro-indol-1-yl)-quinazolin-7-yl amine hydrochloride (0.155 g, 0.465 mmol) was reacted with methanesulfonyl chloride (0.0531, 0.465 mmol) and triethylamine (0.290 g, 2.87 mmol) in 5 mL of chloroform at 0° C. for one hour and 16 hours at room temperature. The reaction mixture was poured into 50 mL of water and extracted with 3×50 mL of ethyl acetate. The pooled organic layers were washed with 50 mL of brine, dried with magnesium sulfate, filtered and vacuum evaporated to a yellow residue, 0.121 g. This was purified by chromatography using a Chromatotron mounted with a 2 mm silica gel plate and eluted with 5% methanol in chloroform. Pure product was isolated by vacuum evaporation of the appropriate fractions; 0.015 g (8.7%) M.P. 240°-245° C. (dec).
Reaction SMILES: [Cl:1]Cl.[NH2:3][C:4]1[N:9]=[C:8](SC)[N:7]=[C:6]([CH:12]([F:14])[CH3:13])[N:5]=1.[OH-].[Na+]>C(O)(=O)C>[NH2:3][C:4]1[N:9]=[C:8]([Cl:1])[N:7]=[C:6]([CH:12]([F:14])[CH3:13])[N:5]=1
Reactant: CSc1nc(N)nc(C(C)F)n1
Reactant: ClCl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(F)c1nc(N)nc(Cl)n1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
Chlorine gas was passed into a suspension of 38 g of 2-amino-4-methylthio-6-(1-fluoroethyl)-1,3,5-triazine in 0.25 l of glacial acetic acid (15 min) at 20 to 25° C. The reaction mixture was stirred for 30 min at approx. 20° C., sprayed for 1 hour with nitrogen gas at room temperature, poured into 1.25 l of ice-cold aqueous solution of 87 g of sodium hydroxide and stirred for 5 min. After extraction with ethyl acetate, the organic phase was washed with water and dried over magnesium sulfate, and the solvent was removed in vacuo. The crude product was purified by stirring in heptane. After filtration with suction and drying, 25 g (70%) of 2-amino-4-chloro-6-(1-fluoroethyl)-1,3,5-triazine were obtained as a white powder (m.p. 131° C.); 1H NMR (CDCl3): δ=1.7 (dd, 3 H), 5.4 (dq, 1 H), 6.1 (s br., 1 H), 6.7 (s br., 1H).
Reaction SMILES: Cl.C([NH:9][C@@H:10]([C@@H:44]1[C@H:48]([CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[O:47]C(C)(C)[O:45]1)[CH2:11][O:12][C@H:13]1[C@H:19]([O:20]CC2C=CC=CC=2)[C@@H:18]([O:28]CC2C=CC=CC=2)[C@@H:17]([O:36]CC2C=CC=CC=2)[CH:16]=[CH:15][CH2:14]1)C1C=CC=CC=1.C1CCCCC=1>CO.C(Cl)(Cl)Cl.[Pd]>[NH2:9][C@@H:10]([C@@H:44]([OH:45])[C@@H:48]([OH:47])[CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH3:62])[CH2:11][O:12][C@@H:13]1[CH2:14][CH2:15][CH2:16][C@H:17]([OH:36])[C@H:18]([OH:28])[C@H:19]1[OH:20]
Reactant: CCCCCCCCCCCCCC[C@@H]1OC(C)(C)O[C@@H]1[C@@H](CO[C@@H]1CC=C[C@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1)NCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Solvent: C1=CCCCC1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCC[C@H](O)[C@H](O)[C@H](N)CO[C@@H]1CCC[C@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 1M solution of HCl (150 μL, 0.15 mmol) and Pd—C (10% wt, 32 mg, 0.03 mmol) were added to a solution of ether 71 (130 mg, 0.15 mmol) and cyclohexene (2 mL) in MeOH (10 mL) and heated under reflux. After stirring overnight the reaction mixture was cooled to rt and diluted with a 5:1 solution of CHCl3:MeOH, before being filtered thought a bed of celite. The filtrate was concentrated under reduced pressure to provide the crude amine 72, which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:6]([CH2:7][N:8]2[CH:13]([C:14]([O:16]CC)=[O:15])[CH:12]3[CH2:19][CH:9]2[CH2:10][CH2:11]3)=[CH:5][CH:4]=1.CO.[OH-].[Na+].Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH:13]([C:14]([OH:16])=[O:15])[CH:12]3[CH2:19][CH:9]2[CH2:10][CH2:11]3)=[CH:20][CH:21]=1
Reactant: CCOC(=O)C1C2CCC(C2)N1Cc1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(CN2C3CCC(C3)C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3-carboxylate (340 mg, 1.18 mmol) in tetrahydrofuran (8 ml)-methanol (4 ml) was added 1N sodium hydroxide (8 ml), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was neutralized with 1N hydrochloric acid and then concentrated. The resulting white solid was washed with chloroform and then filtrated. The filtrate was dried over magnesium sulfate and the solvent was evaporated, to give 2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3-carboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[O-:14].[K+].Br[CH2:17][CH2:18][OH:19].CN(P(N(C)C)N(C)C)C.Cl>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[C:5]([O:12][CH3:13])[C:4]=1[O:14][CH2:17][CH2:18][OH:19]
Reactant: COc1cc([N+](=O)[O-])cc(OC)c1[O-]
Reactant: OCCBr
Agent: CN(C)P(N(C)C)N(C)C
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])cc(OC)c1OCCO

Procedure:
A slurry of potassium 2,6-dimethoxy-4-nitrophenolate [Collins, R. P. and Davis, M. J. Chem. Soc. (1961), 1986] (38 g, 160 mmol) in DMF (600 ml) was treated with 2-bromoethanol (25 ml, 353 mmol) and hexamethylphosphorus triamide (31 ml, 176 mmol) and the reaction heated at 115° for 6 h. After cooling, the reaction was poured onto 1M hydrochloric acid (1.5 l) and extracted with ethyl acetate (5×500 ml). The organics were washed with 1M sodium hydroxide (4×700 ml), brine (200 ml) and drfied (MgSO4). Concentration in vacuo gave 3,5-dimethoxy-4-(2-hydroxyethoxy)nitrobenzene as an off white solid (31 g) δH (CDCl3) 7.52 (2H, s), 4.21 (2H, t, J 2.9 Hz), 3.94 (3H, s), 3.76 (2H, m) and 2.94 (1H, br s). MS (ES+) 266 (MNa+, 50%), 244 (MH+, 100%). A mixture of this nitrobenzene (750 mg, 3.16 mmol) and 10% palladium on carbon (75 mg) in ethanol (50 ml) was degassed and then subjected to an atmosphere of hydrogen (balloon) for 16 h. at 200. Dichloromethane was added and the solution filtered and solvent removed in vacuo to give 3,5-dimethoxy-4-(2-hydroxyethoxy)aniline as a grey solid (620 mg) after trituration with diethyl ether. δH (CDCl3+DMSO) 5.84 (2H, s), 3.87-3.84 (2H, m), 3.64 (6H, s) and 3.52-3.49 (2H, m). MS (ES+) 214 (MH+, 100%.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][NH:8][CH2:9]2)([O-:3])=[O:2].[N+:14]([O-])([OH:16])=[O:15].[OH-].[Na+].ClCCl>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][NH:8][CH2:9]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc2c1CCNC2
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=[N+]([O-])c1cc2c(c([N+](=O)[O-])c1)CCNC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
5-Nitro-1,2,3,4-tetrahydroisoquinoline (1.0 g, 5.6 mmol) in conc. sulfuric acid (3 ml) was treated with conc. nitric acid (1 ml) and the mixture stirred at room temperature for 1 h. The mixture was cooled, basified with 40% aqueous NaOH and work-up with dichloromethane gave the title compound (1.14 g).
Reaction SMILES: COS(OC)(=O)=O.CN(C)C[N:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH:13]=[CH:12]1.[C-]#[N:22].[K+].[CH2:24]1[CH2:28]OCC1>>[NH:11]1[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[C:13]([CH2:28][C:24]#[N:22])=[CH:12]1
Reactant: [C-]#N
Reactant: C1CCOC1
Reactant: CN(C)Cn1ccc2cccnc21
Agent: [K+]
Solvent: COS(=O)(=O)OC
Product: N#CCc1c[nH]c2ncccc12
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 56 %

Procedure:
A solution of dimethylsulfate (32.7 g; 0.25 mol) in THF (50 mL) was added dropwise while stirring to the solution of dimethyl-(1H-pyrrolo[2,3-b]-pyridinyl-methyl)-amine (42 g; 0.24 mol) in THF (800 mL). After the addition was complete, the mixture was heated at 80° C. for 10 minutes then cooled to ambient temperature. The solvent was decanted and the residual gum was triturated with acetone/methanol (1:1 mixture) while warming. The solid formed was collected by filtration. The solid was then dissolved in water (500 mL). Potassium cyanide (22 g; 0.32 mol) was added. The mixture was stirred at ambient temperature for 15 minutes, heated to reflux for 30 minutes, then cooled to ambient temperature. After 2 hours, the solid was collected by filtration and washed with water then dried to give 21 g (56% yield) of the title compound as an off-white solid, m.p. 141°-142° C. which was used for the reaction described in step 3.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[C:11](=[O:20])[CH:10]2[CH2:21][CH2:22][CH:23]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[OH:24])=[CH:5][CH:4]=1.[OH:32][CH:33]([CH:47]([OH:54])[CH:48]([OH:53])[CH:49]([OH:52])[CH2:50][OH:51])[CH2:34][NH:35][CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][C:44](O)=[O:45])=[CH:39][CH:38]=1>>[F:19][C:16]1[CH:15]=[CH:14][C:13]([N:12]2[C:11](=[O:20])[CH:10]([CH2:21][CH2:22][CH:23]([C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[OH:24])[CH:9]2[C:6]2[CH:7]=[CH:8][C:3]([CH2:2][NH:1][C:44](=[O:45])[CH2:43][C:40]3[CH:39]=[CH:38][C:37]([CH2:36][NH:35][CH2:34][CH:33]([OH:32])[CH:47]([OH:54])[CH:48]([OH:53])[CH:49]([OH:52])[CH2:50][OH:51])=[CH:42][CH:41]=3)=[CH:4][CH:5]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)Cc1ccc(CNCC(O)C(O)C(O)C(O)CO)cc1
Reactant: NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1
Product: O=C(Cc1ccc(CNCC(O)C(O)C(O)C(O)CO)cc1)NCc1ccc(C2C(CCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1

Procedure:
The synthesis was carried out analogously to Example XVe), starting [lacuna] 70 mg of 4-(4-aminomethylphenyl)-1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-azetidin-2-one and 110 mg of {4-[(2,3,4,5,6-pentahydroxyhexylamino)-methyl]-phenyl}acetic acid. This gave the product of molecular weight 733.82 (C40H45F2N3O8+); MS (ESI) 734.32 (M +H+).