Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.[N+:16]([O-])([OH:18])=[O:17].O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:10]=[CH:11][C:12]([OH:15])=[C:13]([N+:16]([O-:18])=[O:17])[CH:14]=2)=[N:4][CH:3]=1
Reactant: Oc1ccc(Oc2ncc(Cl)cn2)cc1
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(Oc2ncc(Cl)cn2)ccc1O
Yield: 53.5 %

Procedure:
A solution of 4-(5-chloro-2-pyrimidyloxy)phenol (1.4 g) in acetic acid (20 ml) was treated with fuming nitric acid (0.5 g) at 25° C. After 4 hours the mixture was poured into water and extracted with chloroform (2×100 ml). The chloroform extracts were dried (Mg2O4) and evaporated to a yellow solid which was chromatographed on silica gel (40 g). Elution with chloroform gave 4-(5-chloro-2-pyrimidyloxy)-2-nitrophenol (0.9 g) as pale yellow crystals.
Reaction SMILES: [OH-].[K+].[CH2:3]1[CH2:9][C:7](=[O:8])[NH:6][CH2:5][CH2:4]1.Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH:20]=[CH2:21].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.ClCCl>[CH2:21]([N:6]1[CH2:5][CH2:4][CH2:3][CH2:9][C:7]1=[O:8])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[CH2:11]
Reactant: C=CCCCCCCCCCBr
Reactant: O=C1CCCCN1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: C=CCCCCCCCCCN1CCCCC1=O
Reaction time: 6 h
Yield: 45.8 %

Procedure:
This example illustrates a synthesis of N-(10,11-Oxidoundecyl)-2-piperidone (inventive compound no. 1618). A mixture of potassium hydroxide (1.55 g, 25 mmol, pellets ground in mortar and pestle) and tetrabutylammonium bromide (1.61 g, 5.0 mmol) was stirred in dry tetrahydrofuran (10 mL). A solution of d-valerolactam (2.5 g, 25 mmol) and 1-bromo-10-undecene (Lancaster, 5.9 g, 25 mmol) in tetrahydrofuran (15 mL) was added by syringe pump over 1 hour. After stirring for a further 6 hours. Water (60 mL) and dichloromethane (60 mL) was added to the reaction mixture. The layers were separated and the aqueous layer was extracted with dichloromethane (2×50 mL). The combined organic layers were washed with water (50 mL) and saturated salt solution (50 mL) and then dried with sodium sulfate. The residue was further purified by chromatography using silica and 30% hexane, ethyl acetate to yield 2.88 g (46% yield) of N-(10-Undecenyl)-2-piperidone (inventive compound no. 1616) as a colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:15][CH:14]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37].[O:38]1[CH2:40][CH2:39]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[OH:38][CH2:39][CH2:40][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:14]=[CH:15][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:17][CH:18]=3)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:36][CH3:37]
Reactant: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1O
Reactant: C1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)c4c(C)n(C)n(-c5ccccc5)c4=O)cc3)ccnc2cc1OCCO
Yield: 14.8 %

Procedure:
The title compound was prepared according to the procedure described in Example 15 by using N-(4-((7-hydroxy-6-methoxyquinolin-4-yl)oxy)phenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (5 g, 10 mmol), oxirane (5.8 mL, 100 mmol) and K2CO3 (2.74 g, 2 mmol) in DMF/H2O (24 mL/6 mL). The crude product was purified by a silica gel column chromatography (DCM/MeOH=30/1) to give the title compound as a pale white solid (0.8 g, 15%).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:30])[NH:17][C:18]2[S:26][C:21]3[CH2:22][NH:23][CH2:24][CH2:25][C:20]=3[C:19]=2[C:27]([NH2:29])=[O:28])=[CH:11][CH:10]=1.S([O-])([O-])(=O)=O.[Mg+2].[Cl:37][CH2:38][CH:39]=O.C([BH3-])#N.[Na+]>CO.O1CCCC1.C(O)(=O)C.C(=O)(O)[O-].[Na+]>[Cl:37][CH2:38][CH2:39][N:23]1[CH2:24][CH2:25][C:20]2[C:19]([C:27]([NH2:29])=[O:28])=[C:18]([NH:17][C:16]([NH:15][C:12]3[CH:11]=[CH:10][C:9]([Cl:8])=[CH:14][CH:13]=3)=[O:30])[S:26][C:21]=2[CH2:22]1
Reactant: O=CCCl
Reactant: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCNC2
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Agent: [BH3-]C#N
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCN(CCCl)C2
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.8 %

Procedure:
To a slurry of compound A4 (200 mg, 0.431 mmol) and magnesium sulfate (2 g) in methanol (4 mL) and tetrahydrofuran (2 mL) was added two drops of glacial acetic acid and 2-chloroacetaldehyde (45% in water, 0.340 mL, 1.95 mmol). After stirring at room temperature for 5 min, sodium cyanoborohydride (271 mg, 4.31 mmol) was added and the reaction mixture was stirred for an additional 16 h at room temperature. After this time, the reaction was diluted with saturated aqueous sodium bicarbonate (100 mL), sonicated, and filtered. The filter cake was washed with water (50 mL) and triturated with methylene chloride to afford compound B1 as a white solid (176 mg, 99%): 1H NMR (300 MHz, DMSO-d6) δ 10.94 (s, 1H), 10.19 (s, 1H), 7.57-7.29 (m, 5H), 6.87 (bs, 1H), 3.76 (t, J=6.6 Hz, 2H), 3.57 (s, 2H), 2.87-2.71 (m, 6H). MS (M+H) 413.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.[O-]CC.[Na+].C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([NH:40][C:41](=[O:49])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[NH2:48])=[N:38][CH:39]=1>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:6]=1[C:7]([NH:48][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[C:41]([NH:40][C:37]1[CH:36]=[CH:35][C:34]([Cl:33])=[CH:39][N:38]=1)=[O:49])=[O:9]
Reactant: COCOc1cc(C(C)C)ccc1C(=O)O
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Agent: CC[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCOc1cc(C(C)C)ccc1C(=O)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reaction time: 0.25 h

Procedure:
To a stirring solution of 2-methoxymethyloxy-4-isopropylbenzoic acid (3.0 g, 13.4 mmol) in THF (50 mL) was added sodium ethoxide (0.91 g, 13.4 mmol). After 15 min, the solvent was removed in vacuo and the residue was suspended in dichloromethane (50 mL). To this mixture was added a couple drops of DMF followed by oxalyl chloride (1.7 g, 13.4 mmol). After another 30 min, the solvent was removed in vacuo and the residue was again suspended in dichloromethane (150 mL). To this mixture was added pyridine (2.9 g, 36.5 mmol), followed by N-(5-chloropyridin-2-yl)-2-aminobenzamide (3.02 g, 12.2 mmol). After stirring for 2 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate (400 mL) and water (200 mL). The organic phase was washed twice with 1 M citric acid, once with brine, twice with saturated aq sodium bicarbonate and once with brine. The organic phase was then dried with MgSO4 and filtered. To this solution was added silica gel (about 10 g) and the solvent was removed in vacuo. The resulting dry pack was loaded onto the top of a silica gel column loaded with 10% ethyl acetate in hexanes and eluted with a gradient of 10% ethyl acetate in hexanes through 30% ethyl acetate in hexanes. The clean product containing fractions were combined and concentrated in vacuo to give 2.18 g (39%) of off white solid. Another set of fractions which contained a small amount of impurity were combined and concentrated in vacuo to give 2.09 g (about 38%) of an off white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[CH:30]=[CH:29][C:24]([C:25]([O:27]C)=[O:26])=[CH:23][CH:22]=3)=[O:20])[CH3:16])[C:10]=2[OH:31])[CH:5]=[C:6]([CH3:8])[CH:7]=1.CO.[OH-].[Na+].Cl>O>[CH3:8][C:6]1[CH:5]=[C:4]([C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15](=[N:17][NH:18][C:19]([C:21]3[CH:22]=[CH:23][C:24]([C:25]([OH:27])=[O:26])=[CH:29][CH:30]=3)=[O:20])[CH3:16])[C:10]=2[OH:31])[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: COC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3cc(C)cc(C)c3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(=NNC(=O)c1ccc(C(=O)O)cc1)c1nn(C)c(-c2cc(C)cc(C)c2)c1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 27.9 %

Procedure:
To methyl 4-[(2-{1-[5-(3,5-dimethylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethylidene}hydrazino)carbonyl]benzoate (0.015 mmol, 6.5 mg), methanol (1 mL) was added, and 1 M aqueous sodium hydroxide (5 eq., 0.077 mL) was added at room temperature. After 20 minutes of stirring at room temperature and 1.5 hours of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (5 eq., 0.077 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump, and the residue was further purified by silica gel thin layer chromatography (chloroform/methanol=10/1). After addition of chloroform/n-hexane, the precipitated solid was recovered by filtration and dried to give the desired product as a yellow solid (1.7 mg, yield 27%).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[C:5]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[C@H:48]12[CH2:54][C@H:53]1[CH2:52][C@@H:51]([CH2:55][NH:56][C:57]1[CH:62]=[N:61][C:60]([C:63]([F:66])([F:65])[F:64])=[CH:59][N:58]=1)[NH:50][CH2:49]2.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([C:8]([N:50]2[C@H:51]([CH2:55][NH:56][C:57]3[CH:62]=[N:61][C:60]([C:63]([F:66])([F:64])[F:65])=[CH:59][N:58]=3)[CH2:52][C@H:53]3[C@H:48]([CH2:54]3)[CH2:49]2)=[O:10])[C:5]([C:11]2[N:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:4][CH:3]=1
Reactant: FC(F)(F)c1cnc(NC[C@@H]2C[C@@H]3C[C@@H]3CN2)cn1
Reactant: Cc1ccc(-c2ncccn2)c(C(=O)O)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(-c2ncccn2)c(C(=O)N2C[C@H]3C[C@H]3C[C@H]2CNc2cnc(C(F)(F)F)cn2)n1
Reaction time: 16 h

Procedure:
To a solution of 6-methyl-3-(2-pyrimidinyl)-2-pyridinecarboxylic acid D19 (66.2 mg) in dry DCM (0.5 ml) at room temperature DIPEA (0.038 ml, 0.220 mmol) was added followed by TBTU (38.9 mg, 0.121 mmol). The mixture dissolved completely in about 10 minutes. After 30 minutes N-[(1S,4S,6S)-3-azabicyclo[4.1.0]hept-4-ylmethyl]-5-(trifluoromethyl)-2-pyrazinamine D31 (30 mg) dissolved in dry DCM (0.5 ml) was added dropwise. The reaction mixture was left reacting for 16 hours. The reaction mixture was taken up with DCM (10 mls) and NaHCO3 saturated solution (15 mls). The aqueous layer was back extracted with DCM (2×10 mls). The combined organic layers were washed with brine (1×10 mls). The organic was dried Na2SO4, filtered and concentrated to get crude material. The crude product was purified by silica —NH chromatography (Biotage SP—column size 11 g, using EtOAc 100% as eluent). The product recovered was not pure so it was purified again by C18 Phase [Snap 60 g, eluting with water (HCOOH 0.5%): Acetonitrile (HCOOH 0.5%)=95:5 to 5:95]. It was recovered the title compound E4 (25 mg). UPLC: (Acid Final_QC): rt=0.86 minutes, peaks observed: 470 (M+1). C23H22F3N7O requires 469. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.86-8.79 (m, 2 H), 8.51-8.47 (m, 1 H), 8.41-8.37 (m, 1 H), 8.13-7.81 (m, 2 H), 7.52-7.38 (m, 2 H) 4.24-4.12 (m, 1 H) 3.82-3.66 (m, 2 H), 3.64-3.55 (m, 1 H), 2.69 (s, 3 H), 2.68-2.61 (m, 1 H), 2.46-2.39 (m, 1 H), 1.20-1.02 (m, 2 H), 0.99-0.89 (m, 1 H), 0.68-0.59 (m, 1 H), 0.23-0.16 (m, 1 H).
Reaction SMILES: [C:1]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:9]([O:16][CH3:17])(=[O:15])[CH2:10][C:11]([O:13][CH3:14])=[O:12]>CC(O)(C)C>[CH3:14][O:13][C:11]([CH:10]([C:9]([O:16][CH3:17])=[O:15])[C@@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][C:1](=[O:8])[CH2:2]1)=[O:12]
Reactant: O=C1C=CCCCC1
Reactant: COC(=O)CC(=O)OC
Solvent: CC(C)(C)O
Product: COC(=O)C(C(=O)OC)[C@@H]1CCCCC(=O)C1
Temperature: 30 °C
Reaction time: 72 h
Yield: 74.7 %

Procedure:
Under an atmosphere of argon, 11.0 mg (0.02 mmol, S/C=100) of Ru[(S,S)-Msdpen] (hexamethylbenzene), 111 μL (1.0 mmol) of 2-cycloheptenone, 114 μL (1.0 mmol) of dimethyl malonate, and 1 mL of 2-methyl-2-propanol were placed in a 20 mL Schlenk tube and stirred at 30° C. for 72 hours. This solution was purified by flash column chromatography (hexane/acetone=90/10, SiO2) to give 181 mg (75% yield) of the title compound. The optical rotation [α]D27 was +45.2 (c 1.76, CHCl3). This was reacted with (2R,3R)-butanediol in the presence of a catalytic amount of p-toluenesulfonic acid so as to be converted into a ketal derivative. The 13C NMR spectrum of this derivative was measured, and the optical purity was determined from the ratio of the integrals of the peaks of two diastereomers, with the result that it was >99% ee.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:34])[C:18](=[O:33])[NH:19][N:20]=2)[CH2:9]1)=O)(C)(C)C.[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH:8]1[CH2:9][CH:10]([NH:12][C:13]2[CH:14]=[C:15]3[C:24](=[CH:25][C:26]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:23][CH2:22][C:21]2[N:16]3[C@@H:17]([CH3:34])[C:18](=[O:33])[NH:19][N:20]=2)[CH2:11]1
Reactant: C[C@H]1C(=O)NN=C2COc3cc(-c4ccccc4)c(NC4CN(C(=O)OC(C)(C)C)C4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H]1C(=O)NN=C2COc3cc(-c4ccccc4)c(NC4CNC4)cc3N21
Yield: 100 %

Procedure:
A solution of 3-(4(S)-methyl-3-oxo-7-phenyl-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-ylamino)-azetidine-1-carboxylic acid tert-butyl ester (enantiomer 2, SFC (Table 1, Method 1), Rt=4.333 min., 0.252 g, 0.54 mmol) in TFA (4 mL) and DCM (24 mL) was stirred at ambient temperature for 3 h. The solvent was removed in vacuo to give 6-(azetidin-3-ylamino)-4(S)-methyl-7-phenyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (Example #1-2, Enantiomer 2, SFC (Table 1, Method 1), Rt=5.572 min, 0.261 g, 100%) as yellow solid. LC/MS (Table 1, Method 5) Rt=2.117 min.; MS m/z: 364 [M+H]+
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1>>[O:12]1[CH2:13][CH2:14][N:9]([C:2]2[N:3]=[N:4][C:5]([N:9]3[CH2:14][CH2:13][O:12][CH2:11][CH2:10]3)=[CH:6][CH:7]=2)[CH2:10][CH2:11]1
Reactant: Clc1ccc(Cl)nn1
Reactant: C1COCCN1
Product: c1cc(N2CCOCC2)nnc1N1CCOCC1
Yield: 80 %

Procedure:
3,6-Dichloropyridazine (25.0 g, 0.168 mol) was dissolved in morpholine (120 mol), for reflux condition for 24 hours. After cooling, the deposited crystal was filtered, to give 3,6-dimorpholinopyridazine in white crystal (33.7 g as a yield of 80%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([SH:18])=[CH:14][CH:13]=2)=[N:4][N:5]([CH3:11])[C:6]=1[O:7][CH:8]([F:10])[F:9].[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:33]Cl)=[C:24]([CH:32]=1)[O:25][CH:26]([CH3:31])[C:27]([O:29][CH3:30])=[O:28].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:33][S:18][C:15]2[CH:16]=[CH:17][C:12]([C:3]3[C:2]([Cl:1])=[C:6]([O:7][CH:8]([F:9])[F:10])[N:5]([CH3:11])[N:4]=3)=[CH:13][CH:14]=2)=[C:24]([CH:32]=1)[O:25][CH:26]([CH3:31])[C:27]([O:29][CH3:30])=[O:28]
Reactant: Cn1nc(-c2ccc(S)cc2)c(Cl)c1OC(F)F
Reactant: COC(=O)C(C)Oc1cc(Cl)ccc1CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)Oc1cc(Cl)ccc1CSc1ccc(-c2nn(C)c(OC(F)F)c2Cl)cc1

Procedure:
This compound is prepared in a manner analogous to that of Step I of Example 1, using 0.58 gram (0.002 mole) of 4-(4-chloro-5-difluoromethoxy-1-methylpyrazol-3-yl)thiophenol, 0.32 gram (0.002 mole) of methyl 2-(5-chloro-2-chloromethylphenoxy)propanoate (prepared as in Steps A through D of Example 2), and 0.41 gram (0.003 mole) of potassium carbonate in 60 mil of N,N-di-methylformamide, yielding the title compound.
Reaction SMILES: [CH3:1][C:2]1([C:21]2[CH:22]=[C:23]([NH:27][S:28]([CH3:31])(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([C:8](=O)[CH2:9][C:10]1[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:19])[CH:11]=1)[CH2:6]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH3:1][C:2]1([C:21]2[CH:22]=[C:23]([NH:27][S:28]([CH3:31])(=[O:29])=[O:30])[CH:24]=[CH:25][CH:26]=2)[CH:7]2[CH:3]1[CH2:4][N:5]([CH2:8][CH2:9][C:10]1[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH3:19])[CH:11]=1)[CH2:6]2
Reactant: Cn1cc(CC(=O)N2CC3C(C2)C3(C)c2cccc(NS(C)(=O)=O)c2)c2ccccc21
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cn1cc(CCN2CC3C(C2)C3(C)c2cccc(NS(C)(=O)=O)c2)c2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.5 %

Procedure:
To a solution of N-(3-{6-methyl-3-[2-(1-methyl-1H-indol-3-yl)acetyl]-3-azabicyclo[3.1.0]hex-6-yl}phenyl)methanesulfonamide (Preparation 117, 55 mg, 0.126 mmol) in anhydrous tetrahydrofuran (1 ml) under a nitrogen atmosphere at 0° C. was added dropwise lithium aluminium hydride (1.0M solution in tetrahydrofuran, 0.26 ml, 0.26 mmol) and the reaction mixture was stirred at room temperature for 3 h. The rapidly stirred reaction mixture was treated sequentially with water (0.26 ml), sodium hydrogen carbonate (250 mg) and ethyl acetate (10 ml). After 30 min, the reaction mixture was filtered and concentrated in vacuo to afford a colourless oil. This was purified by preparative HPLC (condition 8) to give a pale yellow oil which was partitioned between dichloromethane (10 ml) and aqueous potassium carbonate solution (4% w:v, 5 ml). The layers were separated and the organic layer was washed with water (3 ml), dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound as a colourless oil (28 mg, 52%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([NH:11][C:12]([O:14]CC[Si](C)(C)C)=O)[CH2:9][N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:7]1)=[O:5])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Cl:46][C:47]1[S:51][C:50](C(O)=O)=[CH:49][CH:48]=1.CN1CCOCC1.ClC(OCC(C)C)=O>C(#N)C.C1COCC1>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([NH:11][C:12]([C:50]2[S:51][C:47]([Cl:46])=[CH:48][CH:49]=2)=[O:14])[CH2:9][N:8]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC(=O)OCC[Si](C)(C)C
Reactant: O=C(O)c1ccc(Cl)s1
Agent: CC(C)COC(=O)Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CN1CCOCC1
Solvent: CC#N
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1NC(=O)c1ccc(Cl)s1
Temperature: 50 °C
Reaction time: 18 h
Yield: 43.2 %

Procedure:
40.2 (3S,4R)-4-(2-Trimethylsilanylethoxycarbonylamino)-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (1.4 g; 3 mmol) is dissolved in acetonitrile (15 ml) and TBAF (1.372 g; 4 mmol) is added under an argon atmosphere. The mixture is stirred for 18 h at 50° C. 5-Chlorothiophene-2-carboxylic acid (1.272 g; 8 mmol) is dissolved in THF (10 ml), N-methyl morpholine (0.86 ml; 8 mmol) followed by isobutyl chloroformate (1.03 ml; 8 mmol) is added at 0° C. to this solution. After 30 min stirring at 25° C. this solution is added to the reaction mixture above. After 18 h at 25° C. additional 0.5 equivalents of activated 5-chloro-thiophene-2-carboxylic acid is added. The whole mixture is stirred for 3 d at 25° C., evaporated to dryness, dissolved in DCM/THF and washed with 1N aq. HCl solution, 10% aq. Na2CO3 solution. The organic phase is dried over Na2SO4. Flash chromatography over silica gel using DCM/MeOH/NH3 as eluent yielded 0.522 g (37.2%) (3S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester. Light brown oil. MS 403.5 [M+H+].
Reaction SMILES: Cl.[NH:2]1[CH2:21][CH2:20][CH2:19][C@H:3]1[C:4]([NH:6][C@H:7]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH3:8])=[O:5].[NH:22]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@H:23]([C:41](O)=[O:42])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:40])[NH:29][S:30]([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31].ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(Cl)(Cl)Cl.CO>[NH:22]([C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[C@H:23]([C:41]([N:2]1[CH2:21][CH2:20][CH2:19][C@H:3]1[C:4]([NH:6][C@H:7]([C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])[CH3:8])=[O:5])=[O:42])[CH2:24][CH2:25][CH2:26][NH:27][C:28](=[NH:40])[NH:29][S:30]([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31]
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Reactant: C[C@H](NC(=O)[C@@H]1CCCN1)C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N2CCC[C@H]2C(=O)N[C@@H](C)C(=O)OCc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 6 h
Yield: 75.6 %

Procedure:
At 0° C. the solution of 72 mg (0.231 mmol) of HCl.Pro-Ala-OBzl in 15 ml of anhydrous tetrahydrofuran was adjusted to pH 9, to which the pre-cold solution of 100 mg (0.234 mmol) of Boc-Arg(Tos)-OH, 31 mg (0.230 mmol) of 1-hydroxybenzotriazole and 48 mg (0.233 mmol) of dicyclohexylcarbodiimide in 20 ml of anhydrous tetrahydrofuran was added. The reaction mixture was stirred at 0° C. for 2 h and at room temperature for 6 h and TLC (chloroform/methanol, 30:1) indicated complete disappearance of HCl.Pro-Ala-OBzl. The resulted precipitates of N,N-dicyclohexylurea were filtrated and the filtrate was diluted with 80 ml of ethyl acetate. The solution obtained was washed successively with saturated NaCO3 in water (50 ml×3), saturated NaCl in water (50 ml×3) and KHSO4 in water (5%, 30 ml×3). The separated ethyl acetate layer was dried with anhydrous MgSO4, and then evaporated to provide 120 mg (75.6%) of the title compound as a colorless powder. Mp70–71.5° C., FAB-MS (m/e) 688[M+H]+.
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].[CH3:8][C:9](=[CH2:11])[CH3:10]>C(OC)(C)(C)C>[C:9]([O:7][CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=[CH2:1])([CH3:11])([CH3:10])[CH3:8]
Reactant: C=CCCCCO
Reactant: C=C(C)C
Solvent: COC(C)(C)C
Product: C=CCCCCOC(C)(C)C
Reaction time: 4 h
Yield: 75 %

Procedure:
200 g of hex-1-en-6-ol are dissolved in 250 ml of methyl tert-butyl ether, and 100 g of acidic ion exchanger (SPC 118H+) are added. Isobutylene is then passed in until the solution is saturated, and the reaction is monitored by thin layer chromatography, After 4 hours, the reaction is complete. Fractional distillation gives 243 g of 6-tert-butoxyhex-1-ene having a gas chromatographic purity of 98.5%; bp.: 66-67° C./32 mbar. Yield: 75% of theory.
Reaction SMILES: O.[N+](C1C=CC(C(Cl)=O)=CC=1)([O-])=O.N1CCOCC1.[N+:20]([C:23]1[CH:36]=[CH:35][C:26]([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:24]=1)([O-])=O>O1CCOCC1.[Pd]>[NH2:20][C:23]1[CH:36]=[CH:35][C:26]([C:27]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[O:28])=[CH:25][CH:24]=1
Reactant: O=C(c1ccc([N+](=O)[O-])cc1)N1CCOCC1
Agent: [Pd]
Agent: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: C1COCCN1
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc(C(=O)N2CCOCC2)cc1

Procedure:
The above dyes can be prepared by a conventional method. For example, the dye (1) given in Table 1, which is a red water-soluble dye, can be prepared as follows: One mole of 4-nitrobenzoyl chloride is allowed to react with 2 moles of morpholine in dioxane at a temperature below room temperature, so that 4-nitrobenzoylmorpholine (m.p. 108° 109° C.) is obtained. The thus obtained nitro compound is reduced in the presence of a 5%Pd-C catalyst to produce 4-aminobenzoylmorpholine. This is subjected to diazotization by a conventional method to produce a diazonium compound, which is then coupled with H-acid in an alkaline solution, followed by subjecting it to acidic precipitation, so that the dye (I) in Table 1 is obtained.