Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[CH:6]([NH2:7])[CH2:5][CH2:4][CH:3]([NH2:8])[CH2:2]1.C1(S([N:18]2[C:22]3=[N:23][CH:24]=[CH:25][CH:26]=[C:21]3[C:20]([C:27]3[CH:32]=[CH:31][N:30]=[C:29](Cl)[N:28]=3)=[CH:19]2)(=O)=O)C=CC=CC=1>>[NH:18]1[C:22]2=[N:23][CH:24]=[CH:25][CH:26]=[C:21]2[C:20]([C:27]2[CH:32]=[CH:31][N:30]=[C:29]([NH:7][C@H:6]3[CH2:5][CH2:4][C@H:3]([NH2:8])[CH2:2][CH2:1]3)[N:28]=2)=[CH:19]1
Reactant: NC1CCC(N)CC1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: N[C@H]1CC[C@H](Nc2nccc(-c3c[nH]c4ncccc34)n2)CC1

Procedure:
Using the procedure of example 1, trans-1,4-cyclohexyldiamine (277 mg) was reacted with compound 1f (300 mg) to provide compound 42 (86 mg, 34%). 1H NMR (400 MHz, CD3OD) δ 8.90 (d, J=8.0 Hz, 1H), 8.25 (d, J=5.6 Hz, 1H), 8.17 (s, 1H), 8.12 (d, J=8.0 Hz, 1H), 7.22 (m, 1H), 6.95 (d, J=5.6 Hz, 1H), 3.85 (m, 1H), 2.78 (m, 1H), 2.18 (m, 2H), 2.20 (m, 2H), 1.40 (m, 4H). MS (ESI) m/z: 309 (M+H)+.
Reaction SMILES: CCCCCC.[C:7]([O:11][C:12](=[O:25])[NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1Br)([CH3:10])([CH3:9])[CH3:8].[CH:26](=[O:28])[CH3:27].[Cl-].[NH4+]>C1COCC1.O>[C:7]([O:11][C:12](=[O:25])[NH:13][C:14]1[CH:19]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:17]=[CH:16][C:15]=1[CH:26]([OH:28])[CH3:27])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC=O
Reactant: CC(C)(C)OC(=O)Nc1cc(C(F)(F)F)ccc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: CC(O)c1ccc(C(F)(F)F)cc1NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 58.3 %

Procedure:
At −78° C. under nitrogen 1.6 M butyllithium solution in hexane (13.8 ml, 20 mmol) were added dropwise to (2-Bromo-5-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (3.4 g, 10 mmol) in THF (60 ml). The reaction was stirred for 15 minutes at −78° C. and acetaldehyde (881 mg, 20 mmol) was added dropwise. After stirring for 15 minutes at −78° C. saturated aqueous ammonium chloride solution was added and the reaction was allowed to warm to room temperature. The reaction was diluted with water and extracted twice with diethyl ether. The combined organic layers were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and the solvent was evaporated to yield the crude product which was purified by column chromatography (heptane:ethyl acetate=7:3). The product was isolated as a yellow viscous oil (1.78 g, 58%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[CH:7]1.[CH2:20]([CH:22]([CH2:26][CH2:27][CH2:28][CH3:29])[C:23](Cl)=[O:24])[CH3:21]>>[NH2:19][C:10]1[C:9]2[N:8]=[CH:7][N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:23](=[O:24])[CH:22]([CH2:20][CH3:21])[CH2:26][CH2:27][CH2:28][CH3:29])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CCCCC(CC)C(=O)Cl
Reactant: NCCCCn1cnc2c(N)nc3ccccc3c21
Product: CCCCC(CC)C(=O)NCCCCn1cnc2c(N)nc3ccccc3c21

Procedure:
According to the general method of Example 14, 1-(4-aminobutyl)-1H-imidazo[4,5-c]quinolin-4-amine and 2-ethylhexanoyl chloride were combined to provide N1-[4-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-2-ethylhexanamide as a tan powder, m.p. 163.0-164.0° C. 1H NMR (300 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.03 (d, J=8.1 Hz, 1H), 7.79 (m, 1H), 7.61 (dd, J=8.1, 1.2 Hz 1H), 7.44 (dt, J=7.5, 1.2 Hz, 1H), 7.26 (dt, J=7.5, 1.2 Hz, 1H), 6.63 (s, 2H), 4.61 (t, J=6.9 Hz, 2H), 3.12-3.05 (m, 2H), 1.94-1.82 (m, 3H), 1.49-1.03 (m, 10H), 0.76 (t, J=7.2 Hz, 3H), 0.67 (t, J=7.2 Hz, 3H); MS (EI) m/e 381.2533 (381.2529 calcd for C22H31N5O).
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:9]=[N+:8]([O-:10])[C:7]([CH3:11])=[CH:6][CH:5]=1.S(=O)(=O)(O)O.[N+:17]([O-])([O-:19])=[O:18].[K+].C(=O)([O-])[O-].[K+].[K+]>>[F:3][C:4]1[CH:9]=[N+:8]([O-:10])[C:7]([CH3:11])=[CH:6][C:5]=1[N+:17]([O-:19])=[O:18]
Reactant: Cc1ccc(F)c[n+]1[O-]
Reactant: O=[N+]([O-])[O-]
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc([N+](=O)[O-])c(F)c[n+]1[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
The reaction was carried out in a flask vented to a gas scrubber containing aqueous sodium hydroxide solution. The product of Step 5, 5-fluoro-2-picoline-N-oxide (1.0 g, 7.86 mmol) was cooled to 0° C. and concentrated sulfuric acid (4.2 mL) was slowly added, with stirring. Solid potassium nitrate (1.27 g, 12.5 mmol) was then added to this mixture at 0° C., in small portions over a 45 minute period. The reaction mixture was allowed to warm to ambient temperature and was stirred at ambient temperature for 1 hour. Not all of the potassium nitrate had dissolved and the reaction mixture was heated at 50° C. for 0.5 hours and then at 100° C. for 18 hours. The homogeneous reaction solution was poured over ice and the resultant aqueous solution was adjusted to pH 9 with solid potassium carbonate. The aqueous solution was then extracted with 3×80 mL of methylene chloride. The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give 1.084 g (80% yield) of the title compound as a yellow solid, m.p. 107°-108° C.; MS DCI-NH3M/Z: 190 (M+NH4)+ 10%, 173 (M+H)+ 30%, 157 (M-O)+ 50%; 1H NMR (CDCl3) d 2.48 (s, 3H), 8.05 (d, 1H, J=9.0 Hz), 8.31 (d, 1H, J=6.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][OH:11])[CH:9]=1)=[O:4].[I:13][C:14]1[CH:19]=[CH:18][C:17](O)=[CH:16][N:15]=1>>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:12])=[C:8]([CH2:10][O:11][C:17]2[CH:16]=[N:15][C:14]([I:13])=[CH:19][CH:18]=2)[CH:9]=1)=[O:4]
Reactant: Oc1ccc(I)nc1
Reactant: COC(=O)c1cc(CO)c(C)o1
Product: COC(=O)c1cc(COc2ccc(I)nc2)c(C)o1

Procedure:
Compound (54) was prepared from compound (16) and 2-iodo-5-hydroxy-pyridine in a manner analagous to that described in Example 5(a). LC/MS System A: Rt=3.52 mins, m/z=374 ((M+H) for C13H12INO4)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@@H:13]1[O:15][CH2:14]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:23]([NH2:27])[CH2:24][CH2:25][CH3:26]>>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C@H:13]([OH:15])[CH2:14][NH:27][CH2:23][CH2:24][CH2:25][CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)[C@H]1CO1)OCc1ccccc1
Reactant: CCCCN
Product: CCCCNC[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Yield: 81 %

Procedure:
From the reaction of (1.48 g, 5.0 mmol) of N-benzyloxycarbonyl 3(S)-amino-1,2-(S)-epoxy-4-phenylbutane and (7.314 g, 100.0 mmol) of n-butylamine, one obtains 1.50 g (80%) of N-[3(S)-benzyloxycarbonylamino-2(R)-hydroxy-4-phenylbutyl]-N-butylamine, mp 125-128° C., FAB MS, Spectrum: MH+ =371.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][NH2:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)CC)C.Cl[CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl>[CH:21]([S:22]([NH:11][CH2:10][CH2:9][NH:8][C:1](=[O:2])[O:3][C:4]([CH3:5])([CH3:6])[CH3:7])(=[O:24])=[O:23])=[CH2:20]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)(C)OC(=O)NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CS(=O)(=O)NCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of N-Boc ethylenediamine (1.24 g, 7.74 mmol) in methylene chloride (35 ml) at −10 C, was added triethylamine (2.37 ml, 17.0 mmol). 2-chloro-1-ethanesulfonyl chloride (0.809 mL, 7.74 mmol). After 4 hr at −10 C the cold bath was removed and the reaction was stirred for 12 hr at room temperature. The reaction was quenched by the addition of Na2CO3 (sat aq.) and extracted with methylene chloride. The organic extracts were dried (MgSO4) and the solvent evaporated in vacuo to afford the title compound as an oil which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@@H:14]([OH:32])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:31]=[CH:30][C:24]([C:25]([O:27]CC)=[O:26])=[CH:23][CH:22]=3)[CH2:17][CH2:16]2)=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.CO.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[C@@H:14]([OH:32])[CH:15]2[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:30][CH:31]=3)[CH2:17][CH2:16]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1ccc(N2CCC([C@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc(N2CCC([C@H](O)c3ccccc3-c3ccc(Cl)cc3)CC2)cc1
Temperature: 25 °C

Procedure:
(S)-Ethyl 4-(4-((4′-chlorobiphenyl-2-yl)(hydroxy)methyl)piperidin-1-yl)benzoate (INTERMEDIATE 11B, 150.0 mg, 0.33 mmol) was dissolved in THF (6.0 ml) and methanol (1.4 ml). A solution of LiOH (40.6 mg) in water (1.4 ml) was added. The solution was heated at 50° overnight. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure. The residue was diluted with water (5 ml), acidified with 1N aq. HCl (2.0 ml), and extracted with DCM (2×5 ml). The extract was dried (MgSO4), filtered through cotton, and evaporated under vacuum to provide the title product as a substantially separated enantiomer (155 mg, yield: almost quantitative) 1H NMR (400 MHz, DICHLOROMETHANE-d2) δ ppm 0.79-0.94 (m, 1 H) 0.98-1.12 (m, 1 H) 1.14-1.40 (m, 4 H) 2.04 (m, 1 H) 2.67 (td, J=12.51, 2.78 Hz, 1 H) 2.78 (td, 1 H) 3.74 (d, 1 H) 3.91 (m, 1 H) 4.48 (d, 1 H) 6.81 (d, 2 H) 7.17-7.29 (m, 3 H) 7.31-7.49 (m, 4 H) 7.61 (dd, 1 H) 7.84-7.93 (m, 2 H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][CH3:31])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38](O)=[O:39])[CH:33]=1)C1C=CC=CC=1.[N:41]1([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH2:28]([N:27]1[C:23]([C:12]2[C:13]([OH:15])=[CH:14][C:9]([OH:8])=[C:10]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([N:49]4[CH2:50][CH2:51][CH:46]([N:41]5[CH2:45][CH2:44][CH2:43][CH2:42]5)[CH2:47][CH2:48]4)=[O:39])[CH:33]=3)[CH:11]=2)=[N:24][N:25]=[N:26]1)[CH2:29][CH2:30][CH3:31]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Product: CCCCn1nnnc1-c1cc(-c2cccc(C(=O)N3CCC(N4CCCC4)CC3)c2)c(O)cc1O

Procedure:
This product was synthesized using 2′,4′-bis-benzyloxy-5′-(1-butyl-1H-tetrazol-5-yl)-biphenyl-3-carboxylic acid and 4-(1-pyrrolidinyl)piperidine as described in general procedure D. LCMS: 491 [M+H].
Reaction SMILES: [NH2:1][C:2]([CH3:12])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][OH:4].[Na].Br[CH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[C:32]([N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[C:19]([NH:21][C@@H:22]([C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=1)[CH3:23])=[O:20]>CN(C=O)C.C1COCC1>[NH2:1][C:2]([CH3:12])([CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:3][O:4][CH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[C:32]([N:34]([CH3:39])[S:35]([CH3:38])(=[O:37])=[O:36])[CH:33]=1)[C:19]([NH:21][C@@H:22]([C:24]1[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=1)[CH3:23])=[O:20]
Reactant: CC(N)(CO)Cc1ccccc1
Reactant: C[C@@H](NC(=O)c1cc(CBr)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)c1cc(COCC(C)(N)Cc2ccccc2)cc(N(C)S(C)(=O)=O)c1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-amino-2-methyl-3-phenylpropan-1-ol I (28 mg, 0.17 mmol) in 0.5 nL DMF cooled to 0° C. was added sodium hexamethyldisylazide (0.17 mL, 0.17 mmol, 1 M in THF). The reaction mixture was stirred at 0° C. for 5 min and intermediate III 3-(bromomethyl)-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide (25 mg, 0.06 mmol) in 0.5 mL DMF was added dropwise. The reaction mixture was stirred at 0° C. for 0.5 h and purified by preparative HPLC (5%->95% CH3CN in water containing 0.1% TFA, C18 PRO YMC 20×150 mm) to afford 3-[(2-amino-2-methyl-3-phenylpropoxy)methyl]-N-[(1R)-1-(4-fluorophenyl)ethyl]-5-[methyl(methylsulfonyl)amino]benzamide. 1H NMR (400 MHz, d4-MeOH) δ 8.87 (d, J=8 Hz, 1H), 7.86-7.80 (m, 2H), 7.66 (s, 1H), 7.45-7.40 (m, 2H), 7.36-7.24 (m, 3H), 7.22-7.16 (m, 2H), 7.10-7.02 (m, 2H), 5.30-5.20 (m, 1H), 4.73-4.64 (m, 2H), 3.44 (A of AB, d, J=10 Hz, 1H), 3.39 (B of AB, d, J=10 Hz, 1H), 3.35 (s, 3H), 3.09 (A of AB, d, J=13.2 Hz, 1H), 2.94 (s, 3H), 2.87 (B of AB, d, J=13.2 Hz, 1H), 1.59 (d, J=7.2 Hz, 3H), 1.25 (s, 3H).
Reaction SMILES: C(O)(=O)[C@@H](C1C=CC=CC=1)O.[CH2:12]([N:15]1[C@@H:20]([CH3:21])[CH2:19][N:18]([C@H:22]([C:30]2[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=2)[C@H:17]([CH3:37])[CH2:16]1)[CH:13]=[CH2:14]>C(O)C>[CH2:12]([N:15]1[C@H:20]([CH3:21])[CH2:19][N:18]([C@@H:22]([C:30]2[CH:31]=[C:32]([OH:36])[CH:33]=[CH:34][CH:35]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Br:29])[CH:24]=2)[C@@H:17]([CH3:37])[CH2:16]1)[CH:13]=[CH2:14]
Reactant: C=CCN1C[C@@H](C)N([C@H](c2cccc(O)c2)c2cccc(Br)c2)C[C@@H]1C
Agent: O=C(O)[C@H](O)c1ccccc1
Solvent: CCO
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(Br)c2)C[C@H]1C
Yield: 21.9 %

Procedure:
(R)-(-)-Mandelic acid (11.50g, 75.6 mmol) was added to a suspension of 28.55 g (68.7 mmol) of (±)-3-((αR*)-α-((2R*,5S*)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-bromobenzyl)phenol (Example 84, infra) in 450 mL of absolute ethanol. The mixture was heated to complete solution and then allowed to crystallize at room temperature. Crystals were collected and recrystallized from absolute ethanol. The crystalline mandelate salt was treated with excess 1N aqueous sodium hydroxide and then titrated to pH 8 with 6N hydrochloric acid. The precipitated free amine was recrystallized from absolute ethanol to give 6.25 g (44% of theoretical for one enantiomer) of (+)-3-((αS)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-bromobenzyl)-phenol as a white solid, mp 205°-206° C. [α]D20 =+20° (methanol, c=2). Calc. for C22H27BrN2O: C, 63.62; H, 6.55; N, 6.74; Br, 19.24. Found: C, 63.63; H, 6.57; N, 6.68; Br, 19.16.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:14])=[CH:10]/[C:11]([OH:13])=[O:12])[C@@:5]1([CH3:29])[C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1.COC[C@H]1[C@H](/C=C/C(/C)=C/C(OCC)=O)[C@@]1(C)C1C=CC2C(C)(C)CCC(C)(C)C=2C=1>>[CH3:1][O:2][CH2:3][C@H:4]1[C@H:6](/[CH:7]=[CH:8]/[C:9](/[CH3:14])=[CH:10]/[C:11]([OH:13])=[O:12])[C@@:5]1([CH3:29])[C:15]1[CH:24]=[CH:23][C:22]2[C:21]([CH3:26])([CH3:25])[CH2:20][CH2:19][C:18]([CH3:28])([CH3:27])[C:17]=2[CH:16]=1
Reactant: COC[C@@H]1[C@H](/C=C/C(C)=C/C(=O)O)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: CCOC(=O)/C=C(C)/C=C/[C@H]1[C@H](COC)[C@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Product: COC[C@H]1[C@H](/C=C/C(C)=C/C(=O)O)[C@@]1(C)c1ccc2c(c1)C(C)(C)CCC2(C)C
Yield: 93 %

Procedure:
Following a procedure similar to that for the preparation of Compound 20a but using Compound 18a as the starting material afforded the title compound (28 mg, 93% yield) as a white solid:
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH:5]1[CH2:7][CH2:6]1.[S:8]1[CH2:13][CH2:12][CH2:11][S:10][CH:9]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1(C)C=CC=CC=1.CN(C=O)C>[CH:7]1([CH2:6][C:9]2([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:8][CH2:13][CH2:12][CH2:11][S:10]2)[CH2:5][CH2:4]1
Reactant: CCOC(=O)C1SCCCS1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(CC2CC2)SCCCS1
Temperature: 0 °C
Yield: 85.9 %

Procedure:
To a suspension of NaH (95%, 2.8 g, 111 mmol) in dry toluene (120 mL) stirring at 0° C. was dropwise added, over 10 minutes, a solution of bromomethylcyclopropane (15 g, 111 mmol), and ethyl 1,3-dithiane-2-carboxylate (17.77 g, 92.58 mmol) in dry DMF (40 mL). The ice bath was removed and the solution was stirred overnight at rt. Water was added to the solution and the phases were separated. The organic phase was dried over MgSO4, then evaporated to give 19.6 g (50%) of ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate, which was used in the next step without purification. 1H NMR (CDCl3): δ 4.26 (2H, q, J=7.2 Hz), 3.30-3.23 (2H, m), 2.69-2.64 (2H, m), 2.16-2.11 (1H, m), 1.96 (2H, d, J=6.8 Hz), 1.91-1.81 (1H, m), 1.34 (3H, t, J=7.2 Hz), 0.93-0.86 (1H, m), 0.52-0.47 (2H, m), 0.20-0.16 (2H, m).
Reaction SMILES: C([O:8][C:9]1[CH:52]=[CH:51][C:12]([CH2:13][CH:14]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:15][C@@H:16]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[NH:17]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:11][CH:10]=1)C1C=CC=CC=1>CO.[Pd]>[OH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][CH:14]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:15][C@@H:16]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[NH2:17])=[CH:51][CH:52]=1
Reactant: CC(C)(C)OC(=O)C(Cc1ccc(OCc2ccccc2)cc1)C[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)C(Cc1ccc(O)cc1)C[C@H](N)C(=O)OC(C)(C)C
Reaction time: 12 h
Yield: 28.5 %

Procedure:
Di-tert-butyl 4-[4-(benzyloxy)benzyl]-N-trityl-L-glutamate (499 mg, 0.72 mmol) were dissolved in methanol (20 ml). Palladium (10% on charcoal) (228 mg; 214 μmol) was added and the suspension was shaken under a hydrogen atmosphere for 12 h. The reaction mixture was filtered through a pad of celite, concentrated under reduced pressure and the residue was purified by silica gel column chromatography to yield 75 mg (28.7%) of the product.
Reaction SMILES: C1C(=O)N(O[C:9]([O:11][N:12]2[C:17](=[O:18])[CH2:16][CH2:15][C:13]2=[O:14])=[O:10])C(=O)C1.[NH2:19][C:20]1[CH:36]=[CH:35][C:23]([O:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[C:22]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH:21]=1>CN(C)C=O>[O:18]=[C:17]1[CH2:16][CH2:15][C:13](=[O:14])[N:12]1[O:11][C:9]([NH:19][C:20]1[CH:36]=[CH:35][C:23]([O:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:31])[CH3:32])=[C:22]([C:37]2[N:41]([CH3:42])[N:40]=[CH:39][CH:38]=2)[CH:21]=1)=[O:10]
Reactant: Cn1nccc1-c1cc(N)ccc1OCCNC(=O)OC(C)(C)C
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(NC(=O)ON2C(=O)CCC2=O)ccc1OCCNC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
N,N′-Disuccinimidyl carbonate (462 mg, 1.2 eq) was dissolved in 30 mL dimethylformamide and cooled to 0° C. To this was added the tert-butyl 2-(4-amino-2-(1-methyl-1H-pyrazol-5-yl)phenoxy)ethylcarbamate (500 mg, 1.81 mmol) dissolved in 10 mL dimethylformamide, drop-wise over 30 mins. The solution was removed from the ice bath and stirred at room temperature for 2 hr, then moved to an oil bath and stirred at 65° C. for 30 minutes. It was then removed from heating and allowed to cool to room temperature. It was used in the following step without purification. LCMS m/z (%)=474 (M+H, 100).
Reaction SMILES: Cl.[Na+].[C:3]1([S:9]([O-:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>>[C:3]1([S:9]([OH:11])=[O:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=S([O-])c1ccccc1
Agent: Cl
Agent: [Na+]
Product: O=S(O)c1ccccc1
Yield: 77 %

Procedure:
25% HCl was added dropwise to benzenesulfinic acid sodium salt (0.6 g), until the solid dissolved. This mixture was extracted with ethyl acetate (15 ml) dried (Na2SO4) and concentrated to give benzenesulfinic acid (0.4 g). To an ice-cooled mixture of benzenesulfinic acid (0.32 g, 2.23 mmol) and calcium chloride (0.25 g, 2.23 mmol) in dry CH2Cl2 a solution of (2RS,6S)-6-(4-fluorophenoxymethyl)-2-hydroxy-tetrahydropyran (0.42 g, 1.86 mmol) in dry CH2Cl2 (5 ml) was added. The reaction mixture was stirred for 4 h, filtered through celite and washed with CH2Cl2. The combined organic layers were washed with saturated aqueous Na2CO3, water, brine and dried (Na2SO4). The solvent was removed under vacuum and the residue was purified on a silica gel column using light petroleum-ethyl acetate (4:1) as eluent to afford pure (2RS,6S)-2-benzenesulfonyl-6-(4-fluorophenoxymethyl)-tetrahydropyran (0.5 g, 70%) as a viscous liquid. TLC:ethyl acetate-light petroleum (1:3), Rf=0.4. 1H NMR (CDCl3, 200 MHz): δ 1.5 (m, 2H), 1.75-2.0 (m, 2H), 2.2-2.4 (m, 1H), 2.6-2.8 (m, 1H), 3.75-3.9 (m, 2H), 4.65 (d, 1H), 4.85-5.0 (m, 1H), 6.7-7.0 (m, 4H), 7.5-7.7 (m, 3H), 7.95 (d, J=5.4 Hz, 2H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH:6]=[N:7][NH:8]2)([O-])=O.I[CH2:14][CH3:15]>>[CH2:14]([N:7]1[CH:6]=[C:5]2[C:9]([CH:10]=[CH:11][CH:12]=[C:4]2[NH2:1])=[N:8]1)[CH3:15]
Reactant: O=[N+]([O-])c1cccc2[nH]ncc12
Reactant: CCI
Product: CCn1cc2c(N)cccc2n1

Procedure:
In accordance with Example 4 (Steps 1 and 2), 4-nitro-1H-indazole was used instead of 5-nitro-1H-indazole, and 2-iodoethane was used instead of ethyl bromide-d5 to obtain 2-ethyl-2H-indazol-4-amine.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.C(=O)([O-])[O-].[Na+].[Na+]>>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([CH2:4][CH2:5][CH2:6][C:7]#[N:8])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[CH:17][CH:18]=1
Reactant: Clc1ccc(CNCc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: N#CCCCN(Cc1ccc(Cl)cc1)Cc1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
Bis-(4-chlorobenzyl)amine hydrochloride [prepared by reducing N-(4-chlorobenzyl)-4-chlorobenzamide with lithium aluminium hydride in tetrahydrofuran] was basified using sodium carbonate in methylene dichlorlde solvent to give after rotary evaporation 3.16 g of the free base as an oil. This was then mixed with 4-bromobutyronitrile (1.19 ml), diisopropylethylamine (2.1 ml) and 25 ml of dry dimethylformamide and the mixture stirred at 80° C. under nitrogen for 24 hours. On cooling water (100 cm3) was added and then the mixture was extracted with 1×50 ml and 2×25 ml of methylene dichloride. The combined extracts were washed with water, dried (MgSO4), filtered and evaporated to give an oil. This was further purified by column chromatography (silica column eluted with toluene) to give 2.83 g of the title product as an oil. 2.8 g of the title compound was dissolved in 10 ml hot ethanol, acidified with 0.76 g (1 equiv) of oxalic acid, diluted with ether and cooled to give, after filtration, the 1:1-ethanedioate salt (1.78 g) as colourless crystals, mp 124°-6° (dec).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22]Br>CN(C=O)C.C(OCC)(=O)C>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH2:22][N:13]1[C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=2[C:6]2[C:14]1=[CH:15][CH:16]=[CH:17][C:5]=2[C:1]([O:3][CH3:4])=[O:2]
Reactant: Clc1ccccc1CBr
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2ccccc2Cl)CCCC1=O
Reaction time: 0.08 h
Yield: 53.5 %

Procedure:
40% Methanolic Triton B (2.42 mL, 5.3 mM) was slowly added dropwise to a solution of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (873.7 mg, 3.59 mM) in 10 mL of DMF at 25° C. After 5 minutes, 2-chlorobenzyl bromide (1.11 g, 5.39 mM) was added and the resultant mixture stirred at room temperature for 72 hours. The mixture was diluted with ethyl acetate, washed five times with H2O, once with saturated brine, dried over anhydrousmagnesium sulfate, filtered, and concentrated. The residue was purified by crystallization from ethyl acetate to afford 706.3 mg (53%) of the 9-[(2-chlorophenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a yellow solid. 1H NMR (DMSO-d6) δ7.6 (m, 2H), 7.4-7.1 (m, 4H), 6.5 (d, 1H, J=8 Hz), 5.6 (s, 2H), 3.8 (s, 3H), 2.9 (t, 2H, J=6 Hz), 2.4 (t, 2H, J=6 Hz), and 2.1 (m, 2H). IR (CDCl3, cm−1) 3050, 2950, 1725, 1655, 1462, 1446, 1435, 1288 and 1120. MS (ES) m/e 368, 370.