Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[CH:12][C:11]=1[O:24][CH3:25].[OH-].[Na+].O>C1COCC1>[CH3:25][O:24][C:11]1[CH:12]=[C:13]([CH2:16][N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[CH:14]=[CH:15][C:10]=1[CH2:9][OH:8]
Reactant: COC(=O)c1ccc(CN2CCN(C)CC2)cc1OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(CN2CCN(C)CC2)ccc1CO
Reaction time: 1 h
Yield: 97.7 %

Procedure:
To 200 mL of a suspension of 5.21 g of LAH in THF cooled with ice was added dropwise, under argon flow, 50 mL of a solution of 25.5 g of 2-methoxy-4-[(4-methylpiperazin-1-yl)methyl]benzoic acid methyl ester in THF. The mixture was stirred under ice cooling for 1 hour and further stirred at room temperature for 22 hours. To the reaction mixture cooled with ice, 25 mL of a 10% NaOH water was added dropwise. After 30-minute stirring, the mixture was filtered through Celite. The filtrate was washed with 150 mL of THF and then was concentrated. To the residue, 50 mL of saturated brine and 300 mL of dichloromethane were added, and the organic layer was separated. The organic layer was concentrated. The residue was purified by silica gel column chromatography (CHCl3/methanol system) to give 22.4 g of the title compound (98% yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C@@:9]1([OH:27])[C@@H:22]([OH:23])[CH2:21][C@:20]2([CH2:24][CH3:25])[C@H:11]([CH2:12][CH2:13][C:14]3[C:19]2=[CH:18][CH:17]=[C:16]([OH:26])[CH:15]=3)[CH2:10]1.[H-].[Na+].Cl.Cl[CH2:32][C:33]1[C:34]([CH3:39])=[N:35][CH:36]=[CH:37][CH:38]=1.[Cl-].[NH4+]>CN(C)C=O.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C@@:9]1([OH:27])[C@@H:22]([OH:23])[CH2:21][C@:20]2([CH2:24][CH3:25])[C@H:11]([CH2:12][CH2:13][C:14]3[C:19]2=[CH:18][CH:17]=[C:16]([O:26][CH2:32][C:33]2[C:34]([CH3:39])=[N:35][CH:36]=[CH:37][CH:38]=2)[CH:15]=3)[CH2:10]1
Reactant: CC[C@@]12C[C@H](O)[C@](O)(c3c(F)cccc3F)C[C@H]1CCc1cc(O)ccc12
Reactant: Cc1ncccc1CCl
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@@]12C[C@H](O)[C@](O)(c3c(F)cccc3F)C[C@H]1CCc1cc(OCc3cccnc3C)ccc12
Reaction time: 8 h
Yield: 44.8 %

Procedure:
A mixture of the compound of Example 35 (35 mg, 0.093 mmol), sodium hydride 60% (20 mg, 0.5 mmol) and 3-chloromethyl-2-methyl-pyridine hydrochloride (23 mg, 0.13 mmol) in 3 mL of dimethylformamide (DMF) was stirred overnight. Saturated aqueous ammonium chloride solution (5 mL) and water (15 mL) were added and the mixture extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated to a oil (35 mg). The residue was purified by flash chromatography using a 50% to 80% ethyl acetate/hexanes eluant to afford 20 mg (44%) of the title compound as an oil, which was crystallized from hexanes to give a white solid. Melting point: 80–83° C. Mass spectrum: (m/e) 461(M+−H2O, +ion).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([O:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH:3]=1.ClC1C=C(Cl)N=[C:23]([C:28]2C=CC=[CH:30][CH:29]=2)N=1.ClC1C=C(Cl)N=C(CCCCCCCCCC)N=1>>[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:23][CH2:28][CH2:29][CH3:30])[N:5]=[C:4]([O:14][CH2:15][CH2:16][CH:17]([CH3:18])[CH3:19])[CH:3]=1
Reactant: Clc1cc(Cl)nc(-c2ccccc2)n1
Reactant: CC(C)CCOc1cc(Cl)nc(-c2ccccc2)n1
Agent: CCCCCCCCCCc1nc(Cl)cc(Cl)n1
Product: CCCCCCCCCCc1nc(Cl)cc(OCCC(C)C)n1

Procedure:
The compound of Example 24 is prepared analogously to the compound of Example 3, with 4,6-dichloro-2-phenylpyrimidine being replaced by 4,6-dichloro-2-decylpyrimidine.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=1)([CH2:6][OH:7])[CH2:4][OH:5].C1CCCCC=1>[Pd].O>[NH2:15][C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:3]([CH2:4][OH:5])([CH2:6][OH:7])[CH2:2][OH:1])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccc(NC(CO)(CO)CO)cc1
Agent: [Pd]
Solvent: O
Solvent: C1=CCCCC1
Product: Nc1ccc(NC(CO)(CO)CO)cc1
Yield: 58.1 %

Procedure:
7.3 g (0.03 mol) of 2-hydroxymethyl-2-(4-nitrophenylamino)propane-1,3-diol (5) were placed in a mixture of alcohol, water, and cyclohexene in proportions of 30 ml/15 ml/3 ml. 3 g of 10% Pd/C catalyst were added and the mixture was refluxed for 2 hours until decolorized. The medium was filtered while hot and the catalyst was washed with alcohol. The filtrate was concentrated to dryness and then taken up in 10 ml of ethanol, and the precipitate formed was filtered off and washed with alcohol and then with isopropyl ether. After drying, 3.7 g of a white powder were obtained, the elemental analysis of which gave the following results:
Reaction SMILES: C(O)C.C([O:8][C:9](=O)[CH2:10][CH2:11][N:12]([C:16]1[C:21]([NH2:22])=[CH:20][N:19]=[C:18]([Cl:23])[N:17]=1)[CH:13]([CH3:15])[CH3:14])(C)(C)C>C(O)(=O)C>[Cl:23][C:18]1[N:19]=[CH:20][C:21]2[NH:22][C:9](=[O:8])[CH2:10][CH2:11][N:12]([CH:13]([CH3:15])[CH3:14])[C:16]=2[N:17]=1
Reactant: CC(C)N(CCC(=O)OC(C)(C)C)c1nc(Cl)ncc1N
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)N1CCC(=O)Nc2cnc(Cl)nc21
Yield: 79.4 %

Procedure:
A mixture of 50 mL of ethanol, 1 mL of acetic acid and 1.4 g of the 3-[(5-amino-2-chloro-pyrimidin-4-yl)-isopropyl-amino]-propanoic acid tert-butyl ester (V-43), prepared in the previous step, was heated at reflux overnight, and then concentrated under reduced pressure. The residue was taken up in dichloromethane and washed successively with 10% sodium bicarbonate solution, water and then dried over anhydrous sodium sulfate. The mixture was filtered and then concentrated under reduced pressure. Trituration of the residue with ether, provided 0.85 g of 2-chloro-9-isopropyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VI-43).
Reaction SMILES: [F:1][CH:2]([F:9])[CH:3]1[NH:7][C:6](=[O:8])[CH2:5][CH2:4]1.FCC1NC(=[O:17])CC1>>[NH2:7][CH:3]([CH:2]([F:9])[F:1])[CH2:4][CH2:5][C:6]([OH:17])=[O:8]
Reactant: O=C1CCC(CF)N1
Reactant: O=C1CCC(C(F)F)N1
Product: NC(CCC(=O)O)C(F)F

Procedure:
When in the procedure of Example 5 500 mg of 5-difluoromethyl-2-pyrrolidone is substituted for 5-fluoromethyl-2-pyrrolidone, 4-amino-4-difluoromethylbutyric acid is obtained.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:6][C:5]=1[OH:14].[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl.CO>[CH2:15]([NH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]([CH3:11])([CH3:13])[CH3:12])=[CH:6][C:5]=1[OH:14])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)c1ccc(CN)c(O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)c1ccc(CNCc2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.216 g (1.0 mmol) of the product of Example 1 and 0.108 g (0.1 mmol) of benzaldehyde suspended in 5 mL of 1,2-dichloroethane was added 0.5 mL acetic acid and 1 g of finely powdered 4 Å molecular sieves. The reaction mixture was stirred under a nitrogen atmosphere at room temperature overnight, then 1.12 g (5 mmol) of sodium triacetoxyborohydride was added. The reaction was then stirred an addition day at room temperature, then diluted with CH2Cl2 and MeOH. The mixture was filtered through a pad of Celite filter aid eluted with CH2Cl2, and the filtrate was washed with saturated aq. NaHCO3. The organic layer was the separated, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified on a flash chromatography column eluted with CH2Cl2-MeOH—NH4HO (97:2:1) to afford the title compound.
Reaction SMILES: [C:1]([C:4]1[CH:33]=[CH:32][C:7]2[NH:8][C:9]([C:11]3[CH:12]=[C:13]([C:29](O)=[O:30])[CH:14]=[C:15]([C:18]4[CH:23]=[C:22]([S:24](=[O:27])(=[O:26])[NH2:25])[CH:21]=[CH:20][C:19]=4[OH:28])[C:16]=3[OH:17])=[N:10][C:6]=2[CH:5]=1)(=[NH:3])[NH2:2].[NH2:34][CH2:35][CH2:36][S:37]([O-:40])(=[O:39])=[O:38].[Li+]>>[C:1]([C:4]1[CH:33]=[CH:32][C:7]2[NH:8][C:9]([C:11]3[CH:12]=[C:13]([C:29]([NH:34][CH2:35][CH2:36][S:37]([OH:40])(=[O:39])=[O:38])=[O:30])[CH:14]=[C:15]([C:18]4[CH:23]=[C:22]([S:24](=[O:27])(=[O:26])[NH2:25])[CH:21]=[CH:20][C:19]=4[OH:28])[C:16]=3[OH:17])=[N:10][C:6]=2[CH:5]=1)(=[NH:3])[NH2:2]
Reactant: NCCS(=O)(=O)[O-]
Reactant: N=C(N)c1ccc2[nH]c(-c3cc(C(=O)O)cc(-c4cc(S(N)(=O)=O)ccc4O)c3O)nc2c1
Agent: [Li+]
Product: N=C(N)c1ccc2[nH]c(-c3cc(C(=O)NCCS(=O)(=O)O)cc(-c4cc(S(N)(=O)=O)ccc4O)c3O)nc2c1

Procedure:
Proceeding as in Example 17, but substituting 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoylbiphenyl-3-carboxylic acid (20 mg, 40 μmol), prepared as in Reference 10, and lithium 2-aminoethanesulfonate, prepared as in Reference 4, gave 2-{[5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-6,2′-dihydroxy-5′-sulfamoyl-biphenyl-3-carbonyl]-amino}-ethanesulfonic acid as a yellow solid, Compound 111. RP-HPLC (1-90S) RT=2.21 min; 1H NMR (400 MHz, d6-DMSO, selected signals): δ 9.36* (2H, s), 8.98* (2H, s), 8.74 (1H, J=1.6 Hz), 8.74 (1H, d, J=2.0 Hz), 8.49* (1H, br t, J=5.0 Hz), 8.17 (1H, s), 7.85 (1H, d, J=8.4 Hz), 7.81 (1H d, J=2.0 Hz), 7.75 (1H, dd, J=8.4 Hz, 0.8 Hz), 7.70 (1H, dd, J=2.4 Hz), 7.67 (1H, dd, J=8.4, 2.4 Hz); 7.16* (2H, br s), 7.07 (1H, d, J=8.4 Hz); m/z (LCMS-ESI): Q+ 575 (M+H); Q− 573 (M−H).
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH:40][C:41]([C:43]([F:46])([F:45])[F:44])=[O:42].[F:47][CH:48]([F:77])[CH2:49][NH:50][C:51]1[N:52]=[C:53]2[CH2:75][CH:74]([CH3:76])[NH:73][CH2:72][C:54]2=[N:55][C:56]=1[N:57]1[CH2:62][CH2:61][CH:60]([O:63][C:64]2[CH:69]=[CH:68][C:67]([F:70])=[CH:66][C:65]=2[F:71])[CH2:59][CH2:58]1>CN(C=O)C>[CH:1]1([C:4]([N:73]2[CH:74]([CH3:76])[CH2:75][C:53]3[C:54](=[N:55][C:56]([N:57]4[CH2:62][CH2:61][CH:60]([O:63][C:64]5[CH:69]=[CH:68][C:67]([F:70])=[CH:66][C:65]=5[F:71])[CH2:59][CH2:58]4)=[C:51]([NH:50][CH2:49][CH:48]([F:77])[F:47])[N:52]=3)[CH2:72]2)=[O:6])[CH2:3][CH2:2]1.[C:41]([OH:42])([C:43]([F:46])([F:45])[F:44])=[O:40]
Reactant: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1
Reactant: O=C(O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC1Cc2nc(NCC(F)F)c(N3CCC(Oc4ccc(F)cc4F)CC3)nc2CN1C(=O)C1CC1
Reaction time: 2 h

Procedure:
A solution of cyclopropanecarboxylic acid (1.6 mg, 0.018 mmol), DIPEA (7.0 mg, 0.054 mmol), and HATU (6.9 mg, 0.018 mmol) in DMF (181 μL) was stirred at room temperature for 10 min followed by the addition of N-(2,2-difluoroethyl)-3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-7-methyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (10 mg, 0.018 mmol). The resulting reaction mixture was stirred for 2 h. The crude reaction mixture was diluted in DMF, filtered through a hydrophilic PTFE 0.45 μm filter (Millipore® Millex-LCR), and purified via HPLC Method A to give the title compound as a TFA salt (5 mg) as a white solid. 1H NMR (400 MHz, methanol-d4, mixture of rotamers) 6 ppm 0.80-1.01 (m, 4H), 1.13 (d, J=6.6 Hz, 1.4H), 1.27 (d, J=6.3 Hz, 1.6H), 1.91-2.04 (m, 2H), 2.06-2.20 (m, 2H), 2.56-2.60 (m, 0.5H), 2.66-2.70 (m, 0.5H), 3.02 (br s, 2H), 3.13-3.15 (m, 0.5H), 3.16-3.20 (m, 0.5H), 3.34-3.46 (m, 2H), 3.72-3.87 (m, 2H), 4.04 (d, J=18.2 Hz, 1H), 4.41-4.58 (m, 2H), 5.02 (d, J=17.4 Hz, 1.4H), 5.15-5.19 (m, 0.6H), 5.90-6.23 (m, 1H), 6.84-6.91 (m, 1H), 6.99 (ddd, J=11.4, 8.6, 3.0 Hz, 1H), 7.18 (td, J=9.2, 5.3 Hz, 1H); ESI-MS m/z [M+H]+ 507.9.
Reaction SMILES: [CH2:1]([C:5]1[CH2:10][CH2:9][CH2:8][C:7](=[O:11])[CH:6]=1)[CH2:2][CH2:3][CH3:4].C([N-]C(C)C)(C)C.[Li+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23].C(CC1C(=O)C=C(C)CC1)(OCC)=O>C1COCC1>[C:22]([CH2:21][CH:8]1[C:7](=[O:11])[CH:6]=[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:10][CH2:9]1)([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)CBr
Reactant: CCCCC1=CC(=O)CCC1
Agent: CC(C)[N-]C(C)C
Agent: CCOC(=O)CC1CCC(C)=CC1=O
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCCC1=CC(=O)C(CC(=O)OCC)CC1
Yield: 83.5 %

Procedure:
The reaction of 3-n-butyl-2-cyclohexen-1-one (3.0 g, 19.7 mmoles) in 10 ml of THF with lithium diisopropylamide (2.17 mmoles) followed by ethyl bromoacetate (3.96 g, 23.6 mmoles) in 10 ml of THF, at -78° C. under argon, was conducted in a similar manner to the synthesis of 6-(carbethoxymethyl)-3-methyl-2-cyclohexen-1-one described in Example II, and a yield of 3.92 g (83%) of 6-(carbethoxymethyl)-3-n-butyl-2-cyclohexen-1-one was obtained.
Reaction SMILES: [NH2:1][OH:2].O.C(N(CC)CC)C.Cl[C:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:13]>C(OCC)(=O)C>[O:14]([C:12]([NH:1][OH:2])=[O:13])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NO
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(NO)Oc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To an aqueous solution comprising 48 g of a 50% hydroxylamine aqueous solution and 50 ml of deionized water were successively added 30 g of triethylamine and 400 ml of ethyl acetate under cooling, and then, 94 g of phenyl chloroformate was added dropwise to the mixture at 0° C. or lower over 1.5 hours. Thereafter, the mixture was stirred at room temperature for 1.5 hours. After the reaction, an organic layer was collected by separation and washed with a saturated saline solution. After drying over anhydrous sodium sulfate, the solvent was removed. Cyclohexane was added to the residue to crystallize the reaction product, and the crystal was washed with chloroform and dried to obtain white colored N-phenoxycarbonyl hydroxylamine which is an intermediate. Yield: 31 g, Melting point: 108° C.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[CH2:8])=[CH:5][CH:4]=1)=O.[CH2:11]([O:13][CH:14]([O:24][CH2:25][CH3:26])[CH2:15][NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH3:12].[BH4-].[Na+]>C(Cl)Cl.C(O)C.O>[CH:7]([C:6]1[CH:9]=[CH:10][C:3]([CH2:1][NH:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:16][CH2:15][CH:14]([O:13][CH2:11][CH3:12])[O:24][CH2:25][CH3:26])=[CH:4][CH:5]=1)=[CH2:8]
Reactant: C=Cc1ccc(C=O)cc1
Reactant: CCOC(CNCCCCCCN)OCC
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: C=Cc1ccc(CNCCCCCCNCC(OCC)OCC)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Formylstyrene, 1c (2.98 g, 22.5 mmol) and 2c (5.00 g, 21.5 mmol) were weighed into a 250 mL 3-neck RB flask and ethanol (90 mL) added forming a colourless solution. The flask was then attached to two B19 stoppers (side-arms) and a B24 double-layer coil condenser (centre-socket) and this in turn connected to a nitrogen-vacuum manifold. The apparatus was flushed with nitrogen and the reaction mixture stirred overnight at room temperature. Next day 3-(diethylenetriamino)propyl-functionalised silica gel (1.85 g, 1.23 mmol/g loading) was added to the reaction mixture which was stirred at room temperature under nitrogen for a period of 6 hours in order to scavenge the excess 4-formylstyrene. Sodium borohydride (1.22 g, 32.2 mmol) was then added to the reaction mixture which was then stirred at room temperature for a period of 65 hours under nitrogen. Water (100 mL) was then added to the reaction mixture via syringe in order to quench the reaction. The reaction mixture was then stirred for 30 minutes at room temperature before the ethanol was stripped from the mixture in vacuo using a rotary evaporator to yield a white emulsion. CH2Cl2 (100 mL) was added to this residue and the resultant mixture transferred to a 250 mL-separating funnel. Water (10 mL) was added to the funnel which was then shaken and the layers partitioned and the lower organic layer decanted off. The aqueous layer was discarded and the organic layer then extracted with a further 2×100 mL portions of brine. The layers were partitioned and the lower organic layer collected and dried over anhydrous MgSO4 for a period of 1 hour. The drying mixture was filtered and the collected solid washed with 3×20 mL portions of CH2Cl2. The filtrate and washings were combined and stripped to dryness in vacuo using a rotary evaporator for a period of 1 hour to yield a very pale yellow oil. This was then further dried in vacuo (0.25 torr) at room temperature for a period of 20 hours. Yield: 6.82 g (91%, pale yellow oil). NMR (CDCl3) δ 1.21 (t, 6H, —CH3), 1.32 (bm, 4H, —CH2—), 1.48 (bm, 4H, —CH2—), 2.61 (triplet of doublets, 4H, hexamethylene bridge >NCH2—), 2.71 (d, 2H, 2,2-diethoxyethyl NCH2—), 3.54 (m, 2H, HA of OC(HA)(HB)—), 3.69 (m, 2H, HB of OC(HA)(HB)—), 3.76 (s, 2H, >NCH2Ar), 4.59 (t, 1H, —CH(OR)2), 5.20 (d, 1H, ═C—H), 5.72 (d, 1H, ═C—H), 6.70 (dd, 1H, ═C—H), 7.26 (d, 2H, ArH), 7.36 (d, 2H, ArH).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]([C:23]1[CH2:28][CH2:27][CH2:26][CH:25](Br)[C:24]=1O)=[O:22])[CH3:19]>CC(O)C.[Cl-].[Zn+2].[Cl-]>[CH2:18]([O:20][C:21]([CH:23]1[C:24]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:25]=2[CH2:26][CH2:27][CH2:28]1)=[O:22])[CH3:19]
Reactant: CCOC(=O)C1=C(O)C(Br)CCC1
Reactant: c1ccc(COCCNc2ccccc2)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CC(C)O
Product: CCOC(=O)C1CCCc2c1c1ccccc1n2CCOCc1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 71.1 %

Procedure:
A mixture of (2-benzyloxy-ethyl)-phenyl-amine (21; prepared according to Example 3(c)) (8.0 g, 26 mmol) and 3-bromo-2-hydroxy-cyclohex-1-enecarboxylic acid ethyl ester (4; prepared according to Example 1(d)) (3.2 g, 13 mmol) was stirred under N2 at 50° C. for 3 h and the reaction turned brown. The resulting mixture was dissolved in propan-2-ol (30 mL) and dry zinc chloride (10.6 g, 78 mmol) was added. The mixture was heated to reflux under N2 for 16 h and then concentrated in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed with 2 N HCl (100 mL), water (2×100 mL) and aqueous potassium carbonate solution (2×100 mL) then dried and concentrated in vacuo. The crude material was purified by silica gel chromatography eluting with petrol (A) and ethyl acetate (B) (2.5-40% B, 17 CV, 330 g, 100 mL/min) to give 3.49 g (72%) of 9-(2-benzyloxy-ethyl)-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid ethyl ester (25) as an oil. The structure was confirmed by 13C NMR (75 MHz, CDCl3) δC 14.2, 20.5, 21.8, 26.5, 38.6, 42.9, 60.4, 68.7, 73.2, 106.4, 108.8, 118.7, 120.7, 127.4, 127.5, 128.3, 136.2, 136.9, 137.8, 175.0.
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15](O)[C:14]([C:23]3C=CO[CH:24]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S(CC2C(C(OC)=O)=C(OS(C(F)(F)F)(=O)=O)C(CC)=CC=2)(=O)=O)C=CC=CC=1.[CH3:58][N:59]1[C:63](B2OC(C)(C)C(C)(C)O2)=[CH:62][CH:61]=[N:60]1>>[C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:63]3[N:59]([CH3:58])[N:60]=[CH:61][CH:62]=3)[C:14]([CH2:23][CH3:24])=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Agent: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1OS(=O)(=O)C(F)(F)F
Product: CCc1ccc(CS(=O)(=O)c2ccccc2)c(C(=O)OC)c1-c1ccnn1C

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 6-(benzenesulphonylmethyl)-3-ethyl-2-(trifluoromethanesulphonyloxy)benzoate (Intermediate 127) and 1-methyl-1H-pyrazole-5-boronic acid pinacol ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:15]1([CH:21]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:22]2[CH2:25][CH:24](S(C)(=O)=O)[CH2:23]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(#N)C>[CH:21]([N:22]1[CH2:25][CH:24]([O:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[CH2:23]1)([C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Oc1cccc(F)c1
Reactant: CS(=O)(=O)C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Fc1cccc(OC2CN(C(c3ccccc3)c3ccccc3)C2)c1
Temperature: 75 °C
Yield: 29.1 %

Procedure:
To a solution of 3.9 g (0.035 mol) of 3-fluorophenol in 250 mL of acetonitrile, was added 6.3 g (0.045 mol) of K2CO3 followed by 12.25 g (0.039 mol) of 1-(diphenylmethyl)-3-methane sulfonyl azetidine, prepared according to the procedure of Example 1a, Step 4. The reaction mixture was heated at 75° C. for 18 h. The solvent was removed under vacuo, and the residue was taken up in a mixture of ether and water. The aqueous layer was extracted with ether, the combined extracts were dried over magnesium sulfate, and the solvent was removed under vacuo. The product was filtered through 500 mL of silica gel, eluted with 50% CH2Cl2/hexane then 15% ethyl acetate/hexane to give 3.4 g of the title compound: mp 81-82° C. 1H NMR (300 MHz, CDCl3) δ 3.17 (dd, 2H), 3.72 (dd, 2H), 4.46 (s, 1H), 4.77 (m, 1H), 6.48 (dd, 1H), 6.53 (dd, 1H), 6.63 (m, 1H), 7.22 (m, 3H), 7.29 (m, 4H), 7.31 (dd, 4H); MS (ES) m/z (relative intensity): 334 (M++H).
Reaction SMILES: [C:1]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]([S:20]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[CH:11]([C:31]([O:33][CH3:34])=[O:32])[CH2:10]1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B>O1CCCC1>[CH2:1]([N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][N:12]([S:20]([C:23]2[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=2)(=[O:22])=[O:21])[CH:11]([C:31]([O:33][CH3:34])=[O:32])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C1CN(C(=O)c2ccccc2)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Agent: B
Solvent: C1CCOC1
Product: COC(=O)C1CN(Cc2ccccc2)c2ccccc2CN1S(=O)(=O)c1ccc(OC)cc1
Reaction time: 1 h
Yield: 72.1 %

Procedure:
A mixture of 0.20 g (0.416 mmol) of methyl 1-(benzoyl)-4-(4-methoxybenzenesulfonyl)-2,3,4,5-tetrahydro-1H-[1 ,4]benzodiazepine-3-carboxylate and 4 ml of borane in tetrahydrofuran (1.0 M) was refluxed overnight and the solvent removed. To the residue was added 5 ml of CH2Cl2 and 5 ml of 2N HCl and the mixture stirred for 1 hour. The organic layer was separated and concentrated to dryness. The residue was chromatographed on thick layer silica gel plates with hexane-ethyl acetate (2:1) as solvent to give 0.140 g of a colorless oil; Mass spectrum (ES) 467.5 (M+H).
Reaction SMILES: Cl.[F:2][C:3]([F:7])([F:6])[CH2:4][NH2:5].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=1.C(N(CC)CC)C>C(#N)C>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=[N:5][CH2:4][C:3]([F:7])([F:6])[F:2])[CH:9]=1
Reactant: NCC(F)(F)F
Reactant: O=Cc1cccnc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: FC(F)(F)CN=Cc1cccnc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 84.6 %

Procedure:
To a solution of 2,2,2-Trifluoroethylamine hydrochloride (3.98 g, 29.4 mmol) in acetonitrile (9 mL) was added 3-pyridinecarboxaldehyde (Sigma-Aldrich) (2.1 g, 19.6 mmol) followed by triethylamine (4 ml, 29.43 mmol) at 0° C. The resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was filtered and the solids washed with acetonitrile. The filtrate was then concentrated in vacuo. The residue was taken up in ethyl ether, filtered and concentrated to afford 3.12 g (84%) of the tile compound as a white foam. 1H NMR (300 MHz, DMSO-d6) δ4.40 (m, 2H), 7.52 (m, 1H), 8.18 (m, 1H), 8.61 (s, 1H), 8.70 (dd, J=1.8, 4.8 Hz, 1H), 8.92 (d, J=1.8, 1H). MS (ESI, [M+H] +), 189.5.