Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[C:8](=[O:13])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6]2.[N+]([O-])([O-])=O.[Na+].[BrH:31]>O>[Br:31][CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[C:8](=[O:13])[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=1)[CH2:6]2
Reactant: Cc1cc(CN)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: Br
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1cc(CBr)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reaction time: 0.5 h
Yield: 70 %

Procedure:
5-Aminomethyl-7-methyl-2-(4-trifluoromethoxybenzyl)-2,3-dihydroisoindol-1-one (0.5 g, 1.43 mmol) was dissolved in a solution of water (10 mL) and 48% HBr (1 mL). The solution was chilled in an ice bath. A solution of sodium nitrate (0.17 g, 2.4 mmol) in water (5 mL) was added dropwise. A white solid formed. The reaction was allowed to stand for 30 minutes, and then the water was decanted off. The solid was chromatographed on silica gel, eluting with methylene chloride, to give 0.42 g (70% yield) of the title compound as a white solid. 1H NMR (300.132 MHz, CDCl3) δ 7.23-7.15 (m, 4H), 7.35-7.30 (m, 2H), 4.76 (s, 2H), 4.48 (s, 2H), 4.22 (s, 2H), 2.75 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[N:24]1([C:30](Cl)=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19]([CH3:22])[CH2:18][CH2:17]2)[CH:10]2[CH2:11][CH2:12][N:13]([C:30]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:31])[CH2:14][CH2:15]2)=[N:4][CH:3]=1
Reactant: O=C(Cl)N1CCOCC1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Product: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCN(C(=O)N3CCOCC3)CC2)CC1

Procedure:
Prepared in a similar manner to Example 554 using 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea and 4-morpholinecarbonyl chloride
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([S:15][CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17][C:18](O)=[O:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:39][NH2:40]>CN(C)C=O.ClCCl>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([S:15][CH:16]([CH2:21][CH2:22][CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:17][C:18]([NH:40][OH:39])=[O:19])[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(SC(CCCCc2ccccc2)CC(=O)O)cc1OC1CCCC1
Reactant: C[Si](C)(C)ON
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(SC(CCCCc2ccccc2)CC(=O)NO)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A stirred solution of (±)-3-(3-cyclopentyloxy-4-methoxyphenyl)sulfanyl-7-phenylheptanoic acid (0.40 g, Example 4) in a mixture of dimethylformamide (0.07 ml) and dichloromethane (20 ml) was treated dropwise with a solution of oxalyl chloride in dichloromethane (1.17 ml, 2.0 M). After stirring at room temperature for a further 30 minutes the mixture was treated dropwise with O-(trimethylsilyl)hydroxylamine (0.57 ml). The resulting white suspension was stirred for 10 minutes then partitioned between hydrochloric acid (50 ml, 1N) and ethyl acetate (50 ml). The aqueous layer was extracted twice with ethyl acetate (50 ml). The combined organic phases were washed with water (50 ml), then with brine (50 ml), then dried over magnesium sulphate and then evaporated to give the title compound (0.26 g) as a white foam. NMR (CDCl3): δ1.60 (m,8H), 1.86 (m,6H), 2.35 (br d,2H), 2.60 (br t,2H), 3.30 (m,1H), 3.80 (s,3H), 3.73 (m,1H), 6.76 (d,1H), 6.95 (d,2H), 7.10-7.30 (m,5H). Mass spectrum (FAB): m/z 444 (M+H)+.
Reaction SMILES: [OH-].[K+].CS(C)=O.[NH:7]1[CH:11]=[N:10][N:9]=[N:8]1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:24]=[C:23]([CH2:25][CH:26]([CH3:28])[CH3:27])[S:22][C:21]=2[S:29]([NH:32][C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:31])=[O:30])=[CH:16][CH:15]=1>O>[CH2:25]([C:23]1[S:22][C:21]([S:29]([NH:32][C:33]([CH3:34])([CH3:35])[CH3:36])(=[O:30])=[O:31])=[C:20]([C:17]2[CH:16]=[CH:15][C:14]([CH2:13][N:8]3[N:9]=[N:10][CH:11]=[N:7]3)=[CH:19][CH:18]=2)[CH:24]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: c1nnn[nH]1
Reactant: CC(C)Cc1cc(-c2ccc(CBr)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)Cc1cc(-c2ccc(Cn3ncnn3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Reaction time: 0.08 h
Yield: 22.6 %

Procedure:
KOH (112.2 mg, 2.00 mmol, crushed pellets) was added to DMSO (10 mL, dried over 4A molecular sieve) and stirred for 5 min. Tetrazole (28.0 mg, 0.4 mmol) was added to the mixture, which was then stirred for 2 h. 3-(4-Bromomethylphenyl)-5-iso-butyl-N-tert-butylthiophene-2-sulfonamide (130 mg, 0.292 mmol, see step (b) above) was added, the mixture was cooled briefly and stirred for an additional hour before water (50 mL) was added. The reaction mixture was extracted with ethyl acetate (250 mL) and the extract was washed with water (2×50 mL) and brine (50 mL). The organic phase was dried over MgSO4 and the solvent was removed in vacuo. The residue was purified on column chromatography using hexane:acetone (3:1) as eluent to give the sub-title compound (28.6 mg, 0.066 mmol, 23% yield).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[Cl:8][C:9]1[N:14]=[C:13](Cl)[C:12]([Cl:16])=[CH:11][N:10]=1.C(=O)([O-])[O-].[Na+].[Na+]>CCO>[Cl:8][C:9]1[N:14]=[C:13]([NH:7][C:4]2[CH:3]=[C:2]([CH3:1])[O:6][N:5]=2)[C:12]([Cl:16])=[CH:11][N:10]=1
Reactant: Cc1cc(N)no1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Nc2nc(Cl)ncc2Cl)no1

Procedure:
The mixture 5-methylisoxazol-3-amine (98 mg, 1.0 mmol), 2,4,5-trichloropyrimidine (344 μL, 3.0 mmol), and sodium carbonate (106 mg, 1.0 mmol) in 3 mL of EtOH was heated at 60° C. overnight. The reaction mixture was concentrated and then partitioned between EtOAc and brine. The collected organic extracts were dried (Na2SO4), concentrated in vacuo, and purified with silica gel chromatography (MeOH/DCM: 1/9) to afford N-(2,5-dichloropyrimidin-4-yl)-5-methylisoxazol-3-amine; ESMS m/z 245.0 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][O:12][C:13]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:14]=1[C:15](Cl)=[O:16]>N1C=CC=CC=1>[C:4]([C:3]1[CH:6]=[CH:7][C:8]([CH3:10])=[CH:9][C:2]=1[NH:1][C:15](=[O:16])[C:14]1[C:18]([CH3:22])=[CH:19][CH:20]=[CH:21][C:13]=1[O:12][CH3:11])#[N:5]
Reactant: COc1cccc(C)c1C(=O)Cl
Reactant: Cc1ccc(C#N)c(N)c1
Solvent: c1ccncc1
Product: COc1cccc(C)c1C(=O)Nc1cc(C)ccc1C#N
Temperature: 0 °C
Reaction time: 48 h
Yield: 76.9 %

Procedure:
2-Amino-4-methyl-benzonitrile (15.4 g, 0.117 mol) was dissolved in 100 mL pyridine and cooled to 0° C. To this mixture was added dropwise 2-methoxy-6-methylbenzoyl chloride (24 g, 0.13 mol, 1.1 equiv). During the addition the temperature did not exceed 2° C. The reaction was stirred at room temperature for 48 hours. The mixture was poured into 400 mL ice water, and the precipitate was collected by filtration and washed with water. The crude product was dissolved in 600 mL CH2Cl2, and the solution was washed twice with 500 mL of a 1 N HCl solution and once with 400 mL of a saturated aq. NaCl solution. The CH2Cl2 layer was dried over Na2SO4, filtered, and concentrated to dryness to yield 25.44 g (0.09 mol, 77.6%) of N-(2-cyano-5-methyl-phenyl)-2-methoxy-6-methyl-benzamide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.Cl[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH2:16]([O:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][N:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1)[CH2:17][CH2:18][CH3:19]
Reactant: O=C1CCNCC1
Reactant: CCCCOCCCCCCCl
Product: CCCCOCCCCCCN1CCC(=O)CC1

Procedure:
1-(6-Butoxyhexyl)-4-piperidone is prepared from 4-piperidone and 1-chloro-6-butoxyhexane essentially as described above in Example 38, Scheme C, step a.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH2:12][O:13][CH:14]2[CH:19]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[O:38][CH3:39])=[CH:22][CH:21]=3)[CH2:18][CH2:17][N:16]([C:40]([O:42][CH2:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)=[O:41])[CH2:15]2)=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[C:7]2[CH3:11].[H-].[Na+].Cl[CH2:53][CH2:54][CH2:55][O:56][CH3:57].C(=O)([O-])O.[Na+]>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[C:3]([CH2:12][O:13][CH:14]2[CH:19]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][CH2:29][O:30][CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=4[O:38][CH3:39])=[CH:24][CH:25]=3)[CH2:18][CH2:17][N:16]([C:40]([O:42][CH2:43][C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[O:41])[CH2:15]2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[CH:8]=[C:7]2[CH3:11]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3c(C)c[nH]c3c2Br)cc1
Reactant: COCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: COCCCn1cc(C)c2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)c(Br)c21
Reaction time: 0.17 h

Procedure:
The solution of 0.208 g benzyl 3-(7-bromo-3-methyl-1H-indol-6-ylmethoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 2.0 ml of N,N-dimethylformamide is cooled to 0° C., admixed with 0.023 g of sodium hydride dispersion (60%) and stirred over 10 minutes. The mixture is admixed successively with 0.126 ml of 1-chloro-3-methoxypropane and 0.011 g of tetrabutylammonium iodide and subsequently stirred at room temperature over 18 h. The reaction mixture is poured onto 1M sodium hydrogencarbonate solution (30 ml) and extracted with tert-butyl methyl ether (2×30 ml). The organic phases are washed with water (30 ml) and brine (30 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a slightly yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.17 (1:2 EtOAc-heptane); Rt=6.60.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4](=[CH2:13])[CH:5](OC(=O)C)[CH2:6][CH2:7][CH3:8].[CH2:15]([O:22][NH2:23])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[C:4]([CH2:13][NH:23][O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH:5][CH2:6][CH2:7][CH3:8]
Reactant: NOCc1ccccc1
Reactant: C=C(C(=O)OC)C(CCC)OC(C)=O
Solvent: C1CCOC1
Product: CCCC=C(CNOCc1ccccc1)C(=O)OC
Yield: 212.7 %

Procedure:
A mixture of 3-acetoxy-2-methylenehexanoic acid methyl ester (4.00 g, 20 mmol) and O-benzylhydroxylamine (7.39 g, 60 mmol) in THF (30 mL) is allowed to react at RT under N2 for 2 days. The reaction mixture is concentrated on Rotavap under reduced pressure (20 mbar) until no further solvent distills. The residue liquid is dissolved in ethyl acetate (75 mL) and washed with saturated aqueous sodium bicarbonate solution (50 mL). The ethyl acetate layer is concentrated on Rotavap under reduced pressure (20 mbar) until no further solvent distills to afford a colorless liquid (11.2 g).
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:15][Si](Cl)(C)C>CO>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([F:14])=[CH:7][C:3]=1[C:4]([O:6][CH3:15])=[O:5]
Reactant: C[Si](C)(C)Cl
Reactant: O=C(O)c1cc(F)cc([N+](=O)[O-])c1F
Solvent: CO
Product: COC(=O)c1cc(F)cc([N+](=O)[O-])c1F
Yield: 72.5 %

Procedure:
2,5-Difluoro-3-nitrobenzoic acid (2.00 g, 9.847 mmol) was dissolved in MeOH (60 mL). TMSCl (6.220 mL, 49.24 mmol) was added, and the reaction mixture was stirred at reflux for 4 hours. The reaction mixture was concentrated to about 20 mL, and the crystals produced were filtered and dried under high vacuum providing methyl 2,5-difluoro-3-nitrobenzoate (1.55 g, 72.4%) as a crystalline solid.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][C@@H:8]([CH:18]([CH3:20])[CH3:19])[C:9]([N:11]1[CH2:15][CH2:14][C:13]([F:17])([F:16])[CH2:12]1)=O.O.[OH-].[Na+]>C1COCC1>[F:17][C:13]1([F:16])[CH2:14][CH2:15][N:11]([CH2:9][C@@H:8]([NH2:7])[CH:18]([CH3:19])[CH3:20])[CH2:12]1
Reactant: CC(C)[C@H](N)C(=O)N1CCC(F)(F)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@H](N)CN1CCC(F)(F)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
To a 1M solution of LAH in THF (9.89 mL, 9.89 mmol) was (S)-2-amino-1-(3,3-difluoropyrrolidin-1-yl)-3-methylbutan-1-one (1.02 g, 4.95 mmol) dropwise added (over approximately 60 min) as a solution in THF under a nitrogen atmosphere. The mixture was stirred at rt for 30 min and heated at 70° C. over night. The reaction was cooled to 0° C. Water (0.5 mL) was slowly added, followed by 15% aq. NaOH (0.5 mL), THF (10 mL) and additional water (2 mL). The reaction mixture was warmed to rt and stirred for 1 h. The mixture was filtered and the solid washed with THF. The filtrate was dried (Na2SO4) and concentrated under reduced pressure to give the title compound (0.67 g, 70.6%). The obtained crude product was used without further purification. 1H NMR (400 MHz, CH3OD) δ 0.87-0.99, 1.52-1.65, 2.12-2.48, 2.59-2.87, 2.92-3.07, 3.31-3.67.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:4][N:3]=1.[CH2:13]([NH2:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[OH-].[NH4+].N1C=CC=NC=1>C(Cl)Cl.CO.C(Cl)(Cl)Cl.O.C(O)C>[CH2:13]([NH:25][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:4][N:3]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: OCCCNc1ccnc(Cl)n1
Reactant: CCCCCCCCCCCCN
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: c1cncnc1
Solvent: CCO
Product: CCCCCCCCCCCCNc1nccc(NCCCO)n1
Yield: 84.4 %

Procedure:
A mixture of 2-chloro-4-(3-hydroxypropylamino)pyrimidine (37 g, 0.2 m), n-dodecylamine (81.5 g, 0.44 m), ethanol (2.5 l) and water (250 ml) is heated under reflux until thin layer chromatography (silica gel; 7.5 parts by volume chloroform, 0.5 parts by volume concentrated ammonium hydroxide, and 2.0 parts by volume methanol) indicates absence of the pyrimidine starting material. After concentration of the mixture, the residue is taken up in methylene chloride, and filtered from some n-dodecylamine hydrochloride. The organic solution is washed with water, dried and concentrated, and the residue is chromatographed on silica gel using a chloroform-ethanol eluant system (0-10% by volume of ethanol) to yield 56 g of 2-n-dodecylamino-4-(3-hydroxypropylamino)pyrimidine, m.p. 58°-59° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[NH:12][C:11](=[O:13])[CH2:10][NH:9][C:8](=[O:14])[C:7]=2[CH:15]=1.[H-].[Na+].[CH2:20](I)[CH2:21][CH3:22]>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([O:16][CH3:17])=[CH:5][C:6]2[N:12]([CH2:20][CH2:21][CH3:22])[C:11](=[O:13])[CH2:10][NH:9][C:8](=[O:14])[C:7]=2[CH:15]=1
Reactant: CCCI
Reactant: COc1cc2c(cc1OC)C(=O)NCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN1C(=O)CNC(=O)c2cc(OC)c(OC)cc21
Reaction time: 0.17 h
Yield: 37.6 %

Procedure:
To a solution of 723 mg (3.06 mmol) of 7,8-dimethoxy-3,4-dihydro-1H-1,4-benzodiazepine-2,5-dione (XVIIab), in 6 ml of anhydrous DMF, add under an inert atmosphere 134 mg (3.37 mmol) of 60% NaH in oil. After 10 minutes at room temperature, add dropwise 328 μl (3.37 mmol) of n-PrI. Allow to stand at room temperature for 3 hours. Add 40 ml of a water-ice mixture. Filter the precipitate and wash twice with 1 ml of EtOH and 3 ml of Et2O. One obtains 320 mg of the abovenamed product in the form of a white powder. Yield: 65%. 1H-NMR (DMSO, 200 MHz): d 0.66–0.73 (m, 3H, CH2CH3), 1.27–1.39 (m, 2H, CH2CH3), 3.30–4.22 (m, 10H, CH2+CH2+2×OCH3), 6.97 (s, 1H Ar), 7.13 (s, 1H Ar), 8.56 (s, 1H, NH).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([C@@:7]1([NH:12][C:13]([C@@H:15]2[CH2:19][C@@H:18]([OH:20])[CH2:17][NH:16]2)=[O:14])[CH2:9][C@H:8]1[CH:10]=[CH2:11])=[O:6])[CH3:3].[C:21]([O:25][C:26]([NH:28][C@@H:29]([CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH:38]=[CH2:39])[C:30](O)=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1.C(#N)C.O.C(OCC)(=O)C>[C:21]([O:25][C:26]([NH:28][C@@H:29]([CH2:33][O:34][CH2:35][CH2:36][CH2:37][CH:38]=[CH2:39])[C:30]([N:16]1[CH2:17][C@H:18]([OH:20])[CH2:19][C@H:15]1[C:13]([NH:12][C@:7]1([C:5]([O:4][CH2:2][CH3:3])=[O:6])[CH2:9][C@H:8]1[CH:10]=[CH2:11])=[O:14])=[O:31])=[O:27])([CH3:24])([CH3:23])[CH3:22]
Reactant: C=C[C@@H]1C[C@]1(NC(=O)[C@@H]1C[C@@H](O)CN1)C(=O)OCC
Reactant: C=CCCCOC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: C=CCCCOC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@H](O)C[C@H]1C(=O)N[C@]1(C(=O)OCC)C[C@H]1C=C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(1R,2S)-ethyl-1-((2S,4R)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate hydrochloride salt (WO2005095403) (0.770 g, 2.45 mmol), (S)-2-(tert-butoxycarbonylamino)-3-(pent-4-enyloxy)propanoic acid (WO2004094452) (0.68 g, 2.50 mmol) and HATU (1.025 g, 2.696 mmol) in toluene (18 mL) and ACN (2 mL) was added DIEA (d 0.742) (1.281 mL, 7.352 mmol) at 0° C. The reaction warmed to rt and stirred at rt for 1 hr. Ethyl acetate (30 mL) and water (20 mL) was added. The organic layer was separated and washed with brine, dried over sodium sulfate. After removal of solvent, the residue was purified by chromatography (Ethyl acetate) to give (1R,2S)-ethyl 1-((2S,4R)-1-((S)-2-(tert-butoxycarbonylamino)-3-(pent-4-enyloxy)propanoyl)-4-hydroxypyrrolidine-2-carboxamido)-2-vinylcyclopropanecarboxylate as white wax solid (0.92 g, 71.7%). MS: Calcd.: 523; Found: [M+H]+ 524.
Reaction SMILES: [Br:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH2:19])[CH:13]=1.C(Cl)Cl.CO.[NH4+].[OH-]>>[Br:1][C:2]1[N:6]2[N:7]=[C:8]([NH:19][CH2:18][C:14]3[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NCc1cccnc1
Reactant: Clc1ccc2ncc(Br)n2n1
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Brc1cnc2ccc(NCc3cccnc3)nn12

Procedure:
Prepared from 3-bromo-6-chloroimidazo[1,2-b]pyridazine and pyridin-3-ylmethanamine according to general procedure 1 providing the intermediate (88 mg, 45%) as a white solid: Rf=0.66 (CH2Cl2/MeOH/NH4OH, 160:18:2); 1H NMR (500 MHz, CD3OD) δ 8.70 (d, J=1.9 Hz, 1H), 7.99-7.97 (m, 1H), 7.85-7.82 (m, 1H), 7.59 (d, J=9.7 Hz, 1H), 7.40 (s, 1H), 6.73 (d, J=9.7 Hz, 1H), 4.57 (s, 2H); ES-MS: (M+H)=304, 306 m/z.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.C1COCC1.C(N(CC)CC)C.[CH:25]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28][CH2:27][CH2:26]1>C(Cl)(Cl)Cl.CO.C(OCC)(=O)C>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([CH2:3][CH2:2][NH:1][S:30]([CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)(=[O:32])=[O:31])=[CH:5]1
Reactant: O=S(=O)(Cl)C1CCCC1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=S(=O)(NCCc1c[nH]c2ccccc12)C1CCCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Tryptamine (950 mg, 5.93 mmol) was initially introduced into abs. THF (30 ml), and triethylamine (0.82 ml, 5.93 mmol) was added at RT. Cyclopentanesulfonyl chloride (1.00 g, 5.93 mmol) was then swiftly added dropwise at RT and the mixture was stirred at RT for 1 d. A subsequent TLC in chloroform/methanol 20:1 showed only small amounts still of tryptamine. The mixture was concentrated i. vac., the residue obtained was taken up in ethyl acetate (20 ml) and the mixture was washed with saturated NaHCO3 solution (2×20 ml). A precipitate precipitated out of the solution, this was filtered off with suction, but according to TLC it was not the product. The organic phase was washed with saturated NaCl solution (2×20 ml), dried over Na2SO4 and concentrated i. vac.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][O:11][C:12](=[O:24])[C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=1[NH:20][C:21](=[O:23])[CH3:22]>>[CH3:10][O:11][C:12](=[O:24])[C:13]1[CH:18]=[C:17]([N+:6]([O-:9])=[O:7])[C:16]([Cl:19])=[CH:15][C:14]=1[NH:20][C:21](=[O:23])[CH3:22]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(Cl)cc1NC(C)=O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(Cl)cc1NC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3 mL conc. sulfuric acid and 0.40 mL of 90% nitric acid at 0° C. was added 2-acetylamino-4-chlorobenzoic acid methyl ester (1.5 g) in three portions over a period of 20 minutes. This was stirred at 0° C. for 30 minutes then allowed to warm to room temperature for an additional 1 hour. At this time the reaction was poured into 50 mL of an ice/water mixture and extracted with ethyl acetate (3×50 mL). The combined organics were washed sequentially with water (2×50 mL), 10% sodium bicarbonate (2×50 mL) and brine (50 mL) then dried over magnesium sulfate and concentrated in vacuo. Recrystallization of the crude product from methanol gave the title compound (1.02 g).
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][OH:33])[CH:27]=3)[CH:24]=2)[NH:19][CH:18]=1)=O)C1C=CC=CC=1.C(Cl)(=O)C>C(O)C>[OH:33][CH2:32][C:28]1[CH:27]=[C:26]([C:23]2[CH:24]=[C:25]3[C:20](=[CH:21][CH:22]=2)[NH:19][CH:18]=[C:17]3[CH2:16][C@H:12]2[CH2:13][CH2:14][CH2:15][NH:11]2)[CH:31]=[CH:30][CH:29]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1Cc1c[nH]c2ccc(-c3cccc(CO)c3)cc12
Solvent: CC(=O)Cl
Solvent: CCO
Product: OCc1cccc(-c2ccc3[nH]cc(C[C@H]4CCCN4)c3c2)c1
Yield: 63.8 %

Procedure:
3-(1-Benzyloxycarbonylpyrrolidin-2(R)-ylmethyl)-5-(3-hydroxymethylphenyl)-1H-indole (1.030 g, 2.316 mmol) (see Preparation 38) in ethanol was reduced using catalytic hydrogenation as described in Example 35 except that no acetyl chloride was used in the reaction. This gave the title compound as an off-white foam (453 mg). Found: C,72.36; H,6.76; N,8.20; C20H22N2O.3/8CH2Cl2 requires: C,72.35; H,6.78; N,8.28%.