Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([CH2:22][OH:23])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClS([N:28]=[C:29]=[O:30])(=O)=O.O>C(Cl)Cl>[C:29]([O:23][CH2:22][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][O:11][C:12]1[C:16]2[CH:17]=[C:18]([Cl:21])[CH:19]=[CH:20][C:15]=2[O:14][N:13]=1)(=[O:30])[NH2:28]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC(CO)COc1noc2ccc(Cl)cc12
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NC(COC(N)=O)COc1noc2ccc(Cl)cc12
Yield: 85.5 %

Procedure:
To a suspension of 3.43 g of 3-(2-tert-butoxycarbonylamino-3-hydroxypropoxy)-5-chloro-1,2-benzoisoxazole in 34 ml of methylene chloride is added 1.70 g of chlorosulfonyl isocyanate at -45° to -40° C., and the temperature thereof is elevated to 0° C., after which they are subjected to reaction at the same temperature for one hour. To the reaction mixture is added 10 ml of water and they are subjected to reaction at 20°-25° C. for one hour, after which methylene chloride is removed by distillation under reduced pressure. The crystals obtained are collected by filtration, to obtain 3.30 g of 3-(3-carbamoyloxy-2-tert-butoxycarbonylaminopropoxy)-5-chloro-1,2-benzoisoxazole.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].O.Cl>CO>[CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)c1ccc(-c2ccnc(C)c2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cc(-c2ccc(C(=O)O)cc2)ccn1
Yield: 44.7 %

Procedure:
Ethyl 4-(2-methyl-4-pyridyl)benzoate (185 mg) was dissolved in methanol (7.5 ml) and 1.0M NaOH (3.75 ml) and heated at 60° C. for 3 hours. The resulting mixture was reduced to low volume then water (10 ml) added, the solution neutralised to pH 7 with 10M HCl, the resulting precipitate filtered and dried over P2O5 to give 4-(2-methyl-4-pyridyl)benzoic acid as a light brown solid (73 mg); mp 293-294° C.; 1H NMR (300 MHz, DMSO-d6) δ=2.52 (s,3H), 7.53 (d,1H), 7.62 (s,1H), 7.89 (d,2H), 8.04 (d,2H), 8.52 (d1H) ppm. MS: m/z 214 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([NH:19][C:20](=[O:24])[CH2:21][CH2:22]Br)[C:14]=1[CH3:25].[CH2:26]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:27].C(OCC)(=O)C>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([NH:19][C:20](=[O:24])[CH2:21][CH2:22][N:31]2[CH2:32][CH2:33][N:28]([CH2:26][CH3:27])[CH2:29][CH2:30]2)[C:14]=1[CH3:25]
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1NC(=O)CCBr
Reactant: CCN1CCNCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCN1CCN(CCC(=O)Nc2c(C)[nH]c(/C=C3\C(=O)Nc4ccc(F)cc43)c2C)CC1
Temperature: 25 °C
Yield: 32 %

Procedure:
N-{5-[5-fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrol-3-yl}-3-bromo-propionamide (548 mg, 1.0 eq) was dissolved in 4 ml of DMF, stirred at room temperature to obtain a solution. To the solution was added 4-ethylpiperazine (850 mg, 4.0 eq). The reaction mixture was heated to 50° C. and reacted for 4 h. Once the reaction was completed as indicated by TLC, the reaction solution was added to 200 ml of ethyl acetate. Solid product was formed, collected by filtration, washed with ethyl acetate, dried, and purified by column chromatograph to obtain the target compound of 312 mg (yield 32%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([OH:20])=[O:19])=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[CH:22](=[N+:29]([CH3:31])[CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([OH:20])=[O:19])=[C:12]2[CH:22]([N:29]([CH3:31])[CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: C[N+](C)=Cc1ccccc1
Agent: [Cl-]
Product: CN(C)C(c1ccccc1)c1c(C(=O)O)[nH]c2ccc(OCc3ccccc3)cc12

Procedure:
The preparation was carried out in accordance with general synthesis instructions 4 from 5-benzyloxy-1H-indole-2-carboxylic acid and benzylidene-dimethyl-ammonium chloride, which had been prepared in accordance with example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[C:17]([NH:19][C@@H:20]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][CH2:33][CH2:34][F:35])=[CH:27][CH:26]=2)[C:21]([OH:23])=O)=[O:18])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:36][CH:37]1[CH2:42][C:41]([CH3:44])([CH3:43])[NH:40][C:39]([CH3:46])([CH3:45])[CH2:38]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>ClCCl>[F:35][CH2:34][CH2:33][CH2:32][O:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][C@H:20]([NH:19][C:17]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][N:11]2[S:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)(=[O:10])=[O:9])=[O:18])[C:21](=[O:23])[NH:36][CH:37]2[CH2:38][C:39]([CH3:46])([CH3:45])[NH:40][C:41]([CH3:44])([CH3:43])[CH2:42]2)=[CH:26][CH:27]=1
Reactant: CC1(C)CC(N)CC(C)(C)N1
Reactant: O=C(O)[C@H](Cc1ccc(OCCCF)cc1)NC(=O)[C@@H]1CCCCN1S(=O)(=O)c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC1(C)CC(NC(=O)[C@H](Cc2ccc(OCCCF)cc2)NC(=O)C2CCCCN2S(=O)(=O)c2cccc(F)c2)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26 %

Procedure:
(S)-2-{[(S)-1-(3-Fluoro-benzenesulfonyl)-piperidine-2-carbonyl]-amino}-3-[4-(3-fluoro-propoxy)-phenyl]-propionic acid (80 mg, 0.16 mmol), 4-amino-2,2,6,6-tetramethylpiperidine (25 mg, 0.16 mmol), 1-hydroxybenzotriazole (30 mg, 0.22 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (39 mg, 0.20 mmol) were mixed in dichloromethane (2 mL). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with dichloromethane and washed twice with a saturated aqueous sodium bicarbonate solution, and the organic fraction dried over magnesium sulfate. After filtration and subsequent concentration, the resulting oil was chromatographed (dichloromethane/methanol, 9/1) on silica gel to produce 27 mg (27%) of the title compound. MS: m/e 649.33 (M+H). 1H NMR (300 MHz, d6-DMSO): δ0.70-2.20 (m, 27H), 2.80 (m, 2H), 3.20 (m, 1H), 3.65 (d, 1H, J=12 Hz), 4.00 (m, 3H), 4.30 (q, 1H, J=6 Hz), 4.50 (m, 2H), 4.65 (t, 1H, J=6 Hz), 6.90 (d, 2H, J=9 Hz), 7.15 (d, 2H, J=9 Hz), 7.50 (m, 4H), 8.00 (m, 2H).
Reaction SMILES: I[C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.[F:10][CH:11]=[CH:12][SnH3]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd].CN(C)C=O>[F:10][C:11]([C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1)=[CH2:12]
Reactant: O=c1[nH]cc(I)c(=O)[nH]1
Reactant: FC=C[SnH3]
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: C=C(F)c1c[nH]c(=O)[nH]c1=O
Temperature: 100 °C
Yield: 31.6 %

Procedure:
5-iodouracil (340 mg, 1.43 mmol), the (fluorovinyl)stannane (600 mg, 1.8 mmol, prepared above in step C), tetrakis(triphenylphosphine)palladium(O) (approximately 20 mg) and dimethylformamide (4 mL) are combined and heated at 100° C. for 2 hours under an atmosphere of nitrogen. The reaction is then cooled to room temperature and the solvent removed under high vacuum. The residue is purified by flash chromatography (8% methanol/methylene chloride). The fraction containing the product is azeotroped with methylene chloride and then slurried in methylene chloride/ether. The solid is collected by filtration and then recrystallized from water (3 mL) to provide after filtration a light tan solid (60.5 mg). The filtrate is concentrated under vacuum and the residue is purified by radial chromatography (6% methanol/methylene chloride) to provide an additional 10 mg to provide a total of 70.5 mg (45%) of title compound. This is combined with 70 mg from another similar run and then purified again by radial chromatography (6% methanol/methylene chloride) to provide 91 mg of title compound as a buff colored solid after drying under high vacuum; mp 235°-238° C.
Reaction SMILES: CN.[F:3][C:4]([F:29])([F:28])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[N:17]2C(=O)C3C(=CC=CC=3)C2=O)=[N:9][CH:10]=1>C(O)C>[F:28][C:4]([F:3])([F:29])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH:13]2[NH2:17])=[N:9][CH:10]=1
Reactant: O=C1c2ccccc2C(=O)N1C1CCCC1Cc1ccc(C(F)(F)F)cn1
Agent: CN
Solvent: CCO
Product: NC1CCCC1Cc1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methanamine (40% aq, 3 ml, 34.7 mmol) was added to a solution of 2-(2-{[5-(trifluoromethyl)pyridin-2-yl]methyl}cyclopentyl)-2,3-dihydro-1H-isoindole-1,3-dione (0.316 g, 0.84 mmol) in ethanol (5 ml). The reaction was stirred at room temperature for 24 hours and then further methanamine (40% aq, 3 ml, 34.7 mmol) was added. The reaction was stirred for 24 hours at room temperature and then re-suspended in ethanol (5 ml) and methanamine (40% aq, 3 ml, 34.7 mmol). The reaction stirred for 72 hours at room temperature. The reaction mixture was concentrated in vacuo and was then purified by reverse phase preparative HPLC (eluted with acetonitrile/water with 0.1% ammonia) and then purified by column chromatography (basic silica, 50-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [OH:1][CH:2]([C:8]1[CH:18]=[CH:17][C:11]([CH:12]=[CH:13][C:14]([OH:16])=O)=[CH:10][CH:9]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].P(C#N)(OCC)(OCC)=O.C(N(CC)CC)C.[NH2:36][CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>CN(C)C=O>[OH:1][CH:2]([C:8]1[CH:9]=[CH:10][C:11]([CH:12]=[CH:13][C:14](=[O:16])[NH:36][CH2:37][C:38]2[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=2)=[CH:17][CH:18]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)CC(O)c1ccc(C=CC(=O)O)cc1
Reactant: NCc1cccnc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CC(O)c1ccc(C=CC(=O)NCc2cccnc2)cc1

Procedure:
Finally, 82 mg of 4-[1-hydroxy-2-(methoxycarbonyl)ethyl]cinnamic acid was dissolved in 37 μl 3-(aminomethyl)pyridine and 1 ml dimethylformamide, and then treated with 55 μl diethyl cyanophosphate and 50 μl triethylamine on ice for 1 hour to give methyl 3-hydroxy-3-[4-[2-[N-(3-pyridylmethyl)carbamoyl]ethenyl]phenyl]propionate of interest (17 mg, 15%) as an amorphous solid.
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[CH:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].C(N(CC)CC)C>C(OCC)(=O)C>[C:1]([NH:8][CH2:9][C:10](=[O:16])[CH2:11][CH2:12][C:13]([O:15][CH:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:19]([O:21][C:22]([CH3:25])([CH3:23])[CH3:24])=[O:20])=[O:14])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)CCC(=O)O
Reactant: CC(C)(C)OC(=O)C(Br)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NCC(=O)CCC(=O)OC(C(=O)OC(C)(C)C)c1ccccc1
Yield: 77.9 %

Procedure:
This compound was prepared from 5-(Boc-amino)-4-oxopentanoic acid (1.97 g; 8.5 mmol), the product of 6a (2.35 g; 8.7 mmol), and triethylamine (0.88 g; 8.7 mmol) in ethyl acetate (30 mL) as described in Example 1a. The crude product was purified by flash chromatography on a 65×55 mm silica gel 60 column eluted with ethyl acetate-hexane (1:2) (1100 mL) collecting 18×50 mL fractions. After evaporation of fractions 3-8, 2.79 g (78%) product was obtained (amber oil).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25]([OH:27])=O)=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28][NH:29][CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=2)[C:13]([CH2:24][C:25](=[O:27])[N:29]([CH3:28])[CH2:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)=[CH:12][N:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CNCCc1ccccn1
Reactant: COc1cc2c(CC(=O)O)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Product: COc1cc2c(CC(=O)N(C)CCc3ccccn3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC

Procedure:
As described in Example 1, 94 mg of [1-(tert-butoxycarbonylamino-methyl)-6,7-dimethoxy-isoquinolin-4-yl]-acetic acid was coupled with methyl-(2-pyridin-2-yl-ethyl)-amine to give 78 mg of (6,7-dimethoxy-4-{[methyl-(2-pyridin-2-yl-ethyl)-carbamoyl]-methyl}-isoquinolin-1-ylmethyl)-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C27H34N4O5+H 495.6; found 495.1.
Reaction SMILES: FC(F)(F)C(O)=O.[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[N:18]([CH2:19][CH2:20][O:21][C:22]4[CH:29]=[C:28]([CH:30]5[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]5)[CH:27]=[CH:26][C:23]=43)[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9].[CH3:36][C:37]([CH3:39])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.C(Cl)Cl.C(=O)([O-])O.[Na+]>[CH:8]([N:11]1[C:15]([C:16]2[N:25]=[C:24]3[C:23]4[CH:26]=[CH:27][C:28]([CH:30]5[CH2:35][CH2:34][N:33]([CH:37]([CH3:39])[CH3:36])[CH2:32][CH2:31]5)=[CH:29][C:22]=4[O:21][CH2:20][CH2:19][N:18]3[CH:17]=2)=[N:14][CH:13]=[N:12]1)([CH3:10])[CH3:9]
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3CCNCC3)cc1OCC2
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)N1CCC(c2ccc3c(c2)OCCn2cc(-c4ncnn4C(C)C)nc2-3)CC1
Reaction time: 0.17 h
Yield: 7.9 %

Procedure:
A suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-8-piperidin-4-yl-4,5-dihydro-6-oxa-1,3a-diaza-benzo[e]azulene trifluoro acetate (250 mg, 0.51 mmol) in DCE (5 mL) was added acetone (0.06 mL, 0.77 mmol) and 4 Å molecular sieves was stirred under an atmosphere of argon for 10 min before adding sodium triacetoxy borohydride (216 mg, 1.02 mmol) and stirring for 18 h at RT. Further acetone (0.06 mL) and sodium triacetoxyborohydride (216 mg) were added and stirring continued for a further 24 h. The reaction mixture was diluted with DCM and saturated aqueous sodium hydrogen carbonate and the organic layer washed with water followed by brine and then dried (MgSO4), filtered and concentrated in vacuo. The resultant solid was subjected to RPHPLC (gradient 20 to 70% methanol in water+0.1% HCO2H) to give 357 as a yellow solid (17 mg, 8%). LCMS: RT=2.81 min, [M+H]+=421. 1H NMR 400 MHz (DMSO-d) δ: 8.37-8.26 (1 H, m), 7.90-7.89 (2 H, m), 7.05 (1 H, dd, J=8.33, 1.81 Hz), 6.89 (1 H, d, J=1.73 Hz), 5.89-5.88 (1 H, m), 4.49-4.48 (4 H, m), 2.91 (2 H, d, J=10.95 Hz), 2.76-2.75 (1 H, m), 2.46 (1 H, s), 2.26 (2 H, t, J=11.38 Hz), 1.78 (2 H, d, J=12.43 Hz), 1.64 (2 H, td, J=12.20, 3.68 Hz), 1.48 (6H, d, J=6.60 Hz), 1.01 (6 H, d, J=6.57 Hz)
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].CCOCC.[CH3:12][N:13]([CH3:18])[S:14](Cl)(=[O:16])=[O:15]>C(N(CC)CC)C>[CH3:4][C:3]([NH2:6])([CH3:5])[CH2:2][NH:1][S:14]([N:13]([CH3:18])[CH3:12])(=[O:16])=[O:15]
Reactant: CC(C)(N)CN
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CN(C)S(=O)(=O)NCC(C)(C)N
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.4 %

Procedure:
A mixture of 30.7 g (0.35 mol) of 1,2-diamino-2-methylpropane, 150 ml of ether and 50 ml of triethylamine was cooled to 0° C. and 20 g (0.14 mol) of dimethylsulfamoyl chloride was added slowly. The reaction mixture was stirred for 30 minutes and evaporated to dryness. The residue was mixed with water, basified with K2CO3 and evaporated to dryness. Acetone was added and the mixture was filtered. Evaporation of the filtrate gave a solid which was recrystalized from toluene to give 16.5 g (60.3%) of product, mp 77°-78° C. The NMR and IR were consistent with the assigned structure.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([CH2:15][O:16][CH2:17][C:18]3([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[CH:8]2)=[N:3]1.[C:30]([BH3-])#N.[Na+].C=O.C(O)(=O)C>C(#N)C.C(O)(=O)C>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([C:5]([CH2:15][O:16][CH2:17][C:18]3([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH2:19][CH2:20][N:21]([CH3:30])[CH2:22][CH2:23]3)=[CH:6][C:7]([C:11]([F:13])([F:12])[F:14])=[CH:8]2)=[N:3]1
Reactant: Cn1cc2cc(C(F)(F)F)cc(COCC3(c4ccccc4)CCNCC3)c2n1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CN1CCC(COCc2cc(C(F)(F)F)cc3cn(C)nc23)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2-methyl-7-(((4-phenylpiperidin-4-yl)methoxy)methyl)-5-(trifluoromethyl)-2H-indazole (58 mg, 0.144 mmol) and sodium cyanoborohydride (18 mg, 0.288 mmol) in acetonitrile (1 mL) at room temperature was added formalin (50 μL). To this was added 1 drop of acetic acid. After 5 min, a second drop of acetic acid was added and the reaction stirred at room temperature for 15 min. The reaction was concentrated and loaded onto a strong cation exchange cartridge in methanol. The cartridge was washed with several volumes of methanol which were discarded. The product was eluted with 2 M ammonia in methanol and concentrated to give 15 mg (25%). 1H-NMR (CDCl3, 500 MHz) δ 7.97 (s, 1H), 7.85 (s, 1H), 7.41 (m, 2H), 7.34 (m, 2H), 7.22 (m, 1H), 4.82 (s, 2H), 4.21 (s, 3H), 3.58 (s, 2H), 2.60 (m, 2H), 2.20-2.33 (m, 4H), 2.22 (s, 3H), 2.06 (m, 2H); 13C-NMR (CDCl3, 126 MHz) δ 147.6, 135.1, 129.3, 128.3, 127.4, 126.1, 125.5, 124.9 (q, J=272 Hz), 124.2 (q, J=32 Hz), 120.7, 118.7, 117.5 (q, J=4.8 Hz), 79.9, 68.7, 52.1, 46.2, 40.9, 40.7, 32.4. Mass spec.: 418.15 (MH)+. Accurate mass spec.: m/z 418.2019 [MH]+, Δ=0.7 ppm.
Reaction SMILES: [NH:1]([C:16]([O:18][CH2:19][CH:20]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:17])[C@H:2]([C:13](O)=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.ON1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C.[NH2:62][C@H:63]([C:71]([OH:73])=[O:72])[CH2:64][S:65][S:66][C:67]([CH3:70])([CH3:69])[CH3:68].Cl>ClCCl>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][C@@H:2]([C:13](=[O:14])[NH:62][C@H:63]([C:71]([OH:73])=[O:72])[CH2:64][S:65][S:66][C:67]([CH3:70])([CH3:68])[CH3:69])[NH:1][C:16](=[O:17])[O:18][CH2:19][CH:20]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]3[C:21]2=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:5]1
Reactant: CC(C)(C)SSC[C@H](N)C(=O)O
Reactant: O=C(N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O)OCC1c2ccccc2-c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)SSC[C@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 57.3 %

Procedure:
A solution of Fmoc-Trp-OH (5 g, 11.72 mmol) and N-hydroxysuccinimide (1.35 g, 11.72 mmol) in dichloromethane (23 ml) was cooled to 0° C., after which 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC.HCl, 2.25 g, 11.72 mmol) was added and the reaction solution was stirred at room temperature for 5.5 hours. The reaction solution was cooled to 0° C., after which N,N-diisopropylethylamine (2.05 ml, 11.72 mmol) and H-Cys(StBu)-OH (2.45 g, 11.72 mmol) were added and the reaction solution was stirred at room temperature for 14 hours. Dichloromethane and 1 M hydrochloric acid were added to the reaction mixture, followed by extraction with dichloromethane. The organic layer was washed with 25 wt % brine and dried over sodium sulfate. The resulting solution was concentrated under reduced pressure, and the concentration residue was purified by reverse-phase silica gel column chromatography (0.1% aqueous formic acid solution/0.1% formic acid-acetonitrile solution) to afford (5S,8R)-5-((1H-indol-3-yl)methyl)-1-(9H-fluoren-9-yl)-12,12-dimethyl-3,6-dioxo-2-oxa-10,11-dithia-4,7-diazatridecane-8-carboxylic acid (Compound SP602, Fmoc-Trp-Cys(StBu)-OH) (4.15 g, 57%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([C:15]#[N:16])[CH:9]=1.Br[C:18]([CH3:22])([CH3:21])[CH:19]=[O:20]>C1COCC1>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:18]([CH3:22])([CH3:21])[CH:19]=[O:20])=[C:10]([C:15]#[N:16])[CH:9]=1
Reactant: CC(C)(Br)C=O
Reactant: N#Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C=O)Oc1ccc(Cl)cc1C#N
Temperature: 4 °C
Yield: 94.7 %

Procedure:
Anhydrous potassium carbonate (2.76 g) was added to a stirred solution of 4-chloro-2-cyanophenol (1.53 g) and 2-bromo-2-methyl propanal (2.26 g) in THF (50 ml) and the mixture heated at reflux for 5 hours. The mixture was then cooled to 4° C., the suspended solid removed by filtration and the filtrate evaporated to give a yellow oil which crystallised on standing. The solid was triturated with hexane and collected by filtration to give 2-(4-chloro-2-cyanophenoxy)-2-methylpropanal (2.11 g), m.p. 85°-88° C.; NMR: 1.52(6H,s), 6.79(1H,d,J=8 Hz), 7.42(1H,dd,J=8,2.5 Hz), 7.57(1H,d,J=2.5 Hz), 9.80(1H,s).
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]1.[C:10]1(=O)[O:15][C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C(N(C(C)C)C(C)C)C.C1(C)C=CC=CC=1>O>[C:10]1(=[O:15])[N:2]([CH:3]2[CH2:8][CH2:7][CH:6]([OH:9])[CH2:5][CH2:4]2)[C:13](=[O:14])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12
Reactant: O=C1OC(=O)c2ccccc21
Reactant: NC1CCC(O)CC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1c2ccccc2C(=O)N1C1CCC(O)CC1

Procedure:
75.5 g (0.5 Mol) of 4-aminocyclohexanolhydrochloride and 74.0 g (0.5 Mol) of phthalic acid anhydride are mixed with 65 g (0.5 Mol) of ethyl-diisopropyl-amine and 1000 ml of toluene and boiled for 36 hours with a water separator. Then water is added, the toluene phase is separated off and the aqueous phase is extracted several times with chloroform. The organic phases are combined, dried and concentrated. The concentration residue is recrystallised from isopropanol.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH:13]2[C:10]([C:15](OC(C3C=CC=CC=3)C3C=CC=CC=3)=[O:16])([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Li+].[BH4-].[Na+].CO>O1CCCC1>[CH2:1]([N:8]1[CH2:14][CH:13]2[C:10]([CH2:15][OH:16])([CH2:11][CH2:12]2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C12CCC1CN(Cc1ccccc1)C2
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Product: OCC12CCC1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 15 h
Yield: 76 %

Procedure:
13 g of 3-benzyl-1-diphenylmethoxycarbonyl-3-azabicyclo[3.2.0]heptane was dissolved in 100 ml of tetrahydrofuran, and 2.8 g of lithium chloride was added thereto. After 2.5 g of sodium borohydride was added little by little, 30 ml of methanol was slowly added thereto and the resulting mixture was stirred at room temperature for 15 hours. The reaction mixture was concentrated under reduced pressure, mixed with ice water, and extracted with ethyl acetate. After the extract was mixed with 10% hydrochloric acid and stirred vigorously, the aqueous layer was separated. This aqueous layer was adjusted to pH 8 by the addition of a 10% aqueous solution of sodium hydroxide, and then extracted with ethyl acetate. After the extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography (using a 4:1 mixture of n-hexane and acetone as the eluent) to obtain 5.4 g of 3-benzyl-1-hydroxymethyl-3-azabicyclo[3.2.0]heptane.