Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=O)=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].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.[CH2:53]([CH2:55][NH2:56])[OH:54]>CN(C=O)C>[C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:56][CH2:55][CH2:53][OH:54])=[O:17])=[CH:18][CH:19]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(C(=O)O)cc2)s1
Reactant: NCCO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)Nc1nc(C)c(-c2ccc(C(=O)NCCO)cc2)s1
Reaction time: 5 h

Procedure:
To 4-(2-acetylamino-4-methyl-thiazol-5-yl)-benzoic acid (Example 74b) (0.1 g, 0.36 mmol) in DMF (1 ml) is added HATU (0.14 g, 0.36 mmol) followed by DIPEA (0.07 ml, 0.36 mmol) and ethanolamine (0.022 ml, 0.36 mmol). After 5 hours, the reaction mixture is filtered and the precipitated product is washed with ethanol and dried under vacuum to give the titled compound.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:10]C(=O)C)[CH2:4][C:5]1[CH:9]=[CH:8][S:7][CH:6]=1.[ClH:14]>>[ClH:14].[NH2:10][C@H:3]([CH2:4][C:5]1[CH:9]=[CH:8][S:7][CH:6]=1)[CH2:2][OH:1]
Reactant: CC(=O)N[C@@H](CO)Cc1ccsc1
Agent: Cl
Product: N[C@@H](CO)Cc1ccsc1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 1.4 g of N-[(1R)-2-hydroxy-1-(3-thienylmethyl)ethyl]acetamide in 17.6 cm3 of aqueous 6N hydrochloric acid is heated with stirring at a temperature in the region of 100° C. for 2 hours. The reaction mixture is then concentrated under reduced pressure (2 kPa) at a temperature in the region of 40° C. to give a greenish oil, which crystallizes from 60 cm3 of acetone. The crystals are filtered off on a sinter funnel, washed with acetone and then dried in an oven under vacuum (10 Pa) at a temperature in the region of 50° C. 0.92 g of (2R)-2-amino-3-(3-thienyl)-1-propanol hydrochloride is obtained in the form of an off-white solid. 1H NMR spectrum (400 MHz, (CD3)2SO-d6, δ in ppm): 2.93 (mt: 2H); from 3.25 to 3.50 (mt: 2H); 3.53 (broad d, J=11 Hz: 1H); 5.37 (unres. mult.: 1H); 7.07 (broad d, J=5 Hz: 1H); 7.35 (mt: 1H); 7.53 (dd, J=5 and 3 Hz: 1H); 8.18 (unres. mult.: 3H)
Reaction SMILES: C([O:3][C:4](=[O:29])[CH:5]([C:27]#[N:28])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:9][CH:8]=1)C.O.[OH-].[Li+].CO>O.O1CCCC1>[C:27]([CH:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=2)=[CH:11][CH:12]=1)[C:4]([OH:29])=[O:3])#[N:28]
Reactant: CCOC(=O)C(C#N)Cc1ccc(OCCc2ccc(OS(C)(=O)=O)cc2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CS(=O)(=O)Oc1ccc(CCOc2ccc(CC(C#N)C(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
A mixture of 2-cyano-3-{4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl}propanoic acid ethyl ester (described in Example 7) (0.9 g; 2.16 mmole), lithium hydroxide hydrate (0.12 g; 2.86 mmole), methanol (5 ml), water (5 ml) and tetrahydrofuran (10 ml) was stirred for 30 minutes at room temperature. Water was added and the mixture was washed with diethyl ether. The water phase was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase was dried (sodium sulfate), filtered and evaporated in vacuo. The crude product was purified by crystallization in diisopropyl ether to give 0.56 g (yield 67%) of 2-cyano-3-{4-[2-(4-methanesulfonyloxyphenyl)ethoxy]phenyl}propanoic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=O.S(Cl)(Cl)=O.[C:18]([O:26][CH2:27][CH3:28])(=[O:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21].[Mg+2].[Cl-].[Cl-]>C(#N)C.Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([CH3:13])([CH3:12])[C:9]([CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:18]([O:26][CH2:27][CH3:28])=[O:25])=[O:11]
Reactant: CC(C)(C(=O)O)c1ccccc1Cl
Reactant: CCOC(=O)CC(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Mg+2]
Solvent: O=S(Cl)Cl
Solvent: CC#N
Product: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1ccccc1Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 74.5 %

Procedure:
A solution of 2-(2-chlorophenyl)-2-methylpropanoic acid (2.55 g, 12.8 mmol) in thionyl chloride (50.0 mL, 685 mmol) was heated at 95° C. for 2 hours. The solution was concentrated in vacuo, azeotroped using toluene (2×100 mL), and dried in vacuo to give the crude acid chloride. A mixture of diethyl malonate (1.94 mL, 12.8 mmol) and MgCl2 (1.22 g, 12.8 mmol) in ACN (50 mL) was cooled to 0° C. TEA (3.75 mL, 27.0 mmol) was added slowly, and the mixture was stirred at 25° C. for 2 hours. A solution of the acid chloride in ACN (50 mL) was added, and the mixture was heated at 50° C. for 2 days. The solution was diluted with 10% HCl (aq) (200 mL) and extracted with EtOAc (3×100 mL). The combined organic layers were washed with 2N NaOH (aq) (3×200 mL) and then with brine (75 mL). The organic layer was dried over MgSO4, concentrated, and purified by flash column chromatography (silica, 0-100% DCM in hexane) to give diethyl 2-(2-(2-chlorophenyl)-2-methylpropanoyl)malonate (3.25 g). MS m/e=341 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([Cl:17])[CH:16]=[C:11]2[C:10]([CH2:18]N(C)C)=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22]C(OCC)=O>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[C:12]2=[N:13][CH:14]=[C:15]([Cl:17])[CH:16]=[C:11]2[C:10]([CH2:18][Cl:22])=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C)Cc1cn(C(=O)OC(C)(C)C)c2ncc(Cl)cc12
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)n1cc(CCl)c2cc(Cl)cnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.1 %

Procedure:
To 5-chloro-3-dimethylaminomethyl-pyrrolo[2,3-b]pyridine-1-carboxylic acid tert-butyl ester (141, 4.20 g, 13.6 mmol) in 100 mL of toluene, ethyl chloroformate (1.48 mL, 15.5 mmol) was added under nitrogen. The reaction was stirred at room temperature for 2 hours, then concentrated under vacuum and combined with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate was concentrated under vacuum. The resulting material was purified by silica gel column chromatography eluting with 25% ethyl acetate in hexane to provide the desired compound (142, 1.60 g).
Reaction SMILES: [I-].[Na+].C[Si](Cl)(C)C.[C:8]12([CH2:18][NH:19][C:20](=[O:30])[C:21]3[C:26]([Br:27])=[CH:25][N:24]=[C:23]([O:28]C)[CH:22]=3)[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2>C(#N)C.O>[C:8]12([CH2:18][NH:19][C:20](=[O:30])[C:21]3[C:26]([Br:27])=[CH:25][N:24]=[C:23]([OH:28])[CH:22]=3)[CH2:9][CH:10]3[CH2:11][CH:12]([CH2:13][CH:14]([CH2:16]3)[CH2:15]1)[CH2:17]2
Reactant: COc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Br)cn1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(O)ncc1Br
Temperature: 60 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
Sodium iodide (0.48 g) was added to a solution of trimethylsilylchloride (0.41 ml) in acetonitrile (30 ml) and the mixture was stirred for 1 hour. N-(1-Adamantylmethyl)-5-bromo-2-methoxyisonicotinamide (0.94 g) (Example 35(i)) was then added and the reaction mixture was heated at 60° C. under nitrogen for 3 hours. The reaction mixture was diluted with water (150 ml) and the resultant solid was collected by filtration and dried by means of ethanol/toluene azeotrope. The solid was triturated with diethyl ether and collected by filtration to afford the sub-titled compound (0.70 g).
Reaction SMILES: [Na].[C:2]([O:6][CH3:7])(=[O:5])[CH2:3][SH:4].C1(S(O[CH:18]=[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])[C:20]#[N:21])(=O)=O)C=CC=CC=1.O>CO>[NH2:21][C:20]1[C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH3:29])=[CH:18][S:4][C:3]=1[C:2]([O:6][CH3:7])=[O:5]
Reactant: COc1ccccc1C(C#N)=COS(=O)(=O)c1ccccc1
Reactant: COC(=O)CS
Agent: [Na]
Solvent: O
Solvent: CO
Product: COC(=O)c1scc(-c2ccccc2OC)c1N

Procedure:
11 mmol of sodium are dissolved in 100 ml of methanol. After cooling the reaction mixture using an ice bath, 4.5 mmol of methyl thioglycolate and then 3.7 mmol of the compound obtained in Step B are added. After 2 hours' reaction, 100 ml of water are added, bringing about the formation of a precipitate, which is filtered off and then dried, allowing the to expected product to be isolated.
Reaction SMILES: [N:1]1([S:7]([NH2:10])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])=O.[NH4+].C(=O)([O-])[O-].[K+].[K+].[CH3:21][O:22][CH2:23][CH2:24]Br>CO>[CH3:21][O:22][CH2:23][CH2:24][NH:10][S:7]([N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:9])=[O:8]
Reactant: COCCBr
Reactant: NS(=O)(=O)N1CCCCC1
Agent: O=C([O-])[O-]
Agent: O=C[O-]
Agent: [K+]
Solvent: CO
Product: COCCNS(=O)(=O)N1CCCCC1
Yield: 53 %

Procedure:
To a slurry of the piperidine sulfonamide from part F (420 mg, 0.8 mmol) in methanol (15 mL) was added ammonium formate (147 mg, 2.3 mmol). The system was purged with nitrogen for 10 minutes. The nitrogen stream was removed and palladium on carbon (80 mg of 10 weight % on activated carbon, 50% water) was added. The reaction was refluxed for forty five minutes, cooled, filtered through Celite under nitrogen, and concentrated in vacuo. The residue was dissolved in dry dimethylformamide (5 mL) and potassium carbonate (150 mg, 1.07 mmol) and 2-bromoethyl methyl ether (100 uL, 1.07 mmol) were added. The reaction was stirred at thirty five degrees Celsius for thirty hours and then concentrated in vacuo. The residue was taken up in ethyl acetate and filtered through Celite. The filtrate washed with water two times, saturated sodium chloride solution, dried over Na2SO4, filtered, and concentrated in vacuo. The product was recrystallized (methanol) to give the N-methoxyethyl piperidine sulfonamide as an off-white solid (190 mg, 53%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[C@H:10]([C:20]([OH:22])=[O:21])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.Cl[CH2:29]Cl.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:29][O:21][C:20]([C@H:10]1[C@@H:11]([C:13]2[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=2)[CH2:12][N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:9]1)=[O:22]
Reactant: ClCCl
Reactant: O=C(O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 96 %

Procedure:
(3S,4S)-1-Benzyl-4-(4-chloro-phenyl)-pyrrolidine-3-carboxylic acid (7.0 g, 22.0 mmol) were dissolved in methanol (75 mL) and at ambient temperature treated with sulfuric acid 97% (2.4 mL). The reaction mixture was stirred at 60° C. for 18 h. At 0° C. dichloro methane (150 mL) was added followed by aqueous sodium carbonate 10% (150 mL) (final pH 11) under vigorous stirring. The phases were separated. The aqueous phase was washed with dichloro methane, the combined organic phases with water and brine and then dried on sodium sulfate. After filtration and evaporation of the solvent the title product was obtained as a light brown oil (7.0 g, 96%) which was directly used in the next step. ES-MS m/e: 330.8 (M+H+).
Reaction SMILES: N1(CCN2CCC(N[C:17]([C:19]3[NH:20][C:21]4[C:26]([CH:27]=3)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=4)=[O:18])CC2)CCCCCC1.Cl.Cl.Cl.[NH2:36][CH:37]1[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][N:45]2[CH:50]3[CH2:51][CH2:52][CH:46]2[CH2:47][CH:48]([OH:53])[CH2:49]3)[CH2:39][CH2:38]1>>[OH:53][CH:48]1[CH2:49][CH:50]2[N:45]([CH2:44][CH2:43][N:40]3[CH2:41][CH2:42][CH:37]([NH:36][C:17]([C:19]4[NH:20][C:21]5[C:26]([CH:27]=4)=[C:25]([O:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:24]=[CH:23][CH:22]=5)=[O:18])[CH2:38][CH2:39]3)[CH:46]([CH2:52][CH2:51]2)[CH2:47]1
Reactant: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12
Reactant: NC1CCN(CCN2C3CCC2CC(O)C3)CC1
Agent: Cl
Product: CC(C)COc1cccc2[nH]c(C(=O)NC3CCN(CCN4C5CCC4CC(O)C5)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-Isobutoxy-1H-indole-2-carboxylic acid 80 (preparation see Example 8) and amine 24.
Reaction SMILES: [NH:1]([C:3]1[N:4]=[N:5][C:6]([C:9]2[CH:10]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:13][CH:14]=2)=[CH:7][N:8]=1)[NH2:2].[CH:19]([O-])([O-])OCC>CCCCCC>[F:16][C:15]([F:18])([F:17])[C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:6]2[CH:7]=[N:8][C:3]3[N:4]([CH:19]=[N:2][N:1]=3)[N:5]=2)[CH:10]=1
Reactant: NNc1ncc(-c2cccc(C(F)(F)F)c2)nn1
Reactant: CCOC([O-])[O-]
Solvent: CCCCCC
Product: FC(F)(F)c1cccc(-c2cnc3nncn3n2)c1

Procedure:
A mixture of one gram of 3-hydrazino-6-(α,α,α-trifluoro-m-tolyl)-1,2,4-triazine and 15 ml. of ethyl orthoformate is refluxed for 4 hours, cooled and poured into hexane. The solid is collected by filtration and washed with ethanol giving the desired product, m.p. 229°-232° C.
Reaction SMILES: C([O:4][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]([CH3:15])[CH:6]=1)(=O)C>[OH-].[K+]>[CH3:15][C:7]1[CH:6]=[C:5]([OH:4])[C:14]2[C:9]([CH:8]=1)=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: CC(=O)Oc1cc(C)cc2ccccc12
Agent: [K+]
Agent: [OH-]
Product: Cc1cc(O)c2ccccc2c1
Yield: 27.7 %

Procedure:
Crude 1-acetoxy-3-methylnaphthalene (84 g, 0.42 mole) was boiled with 10% ethanolic potassium hydroxide (300 cm3) for 3 hours. Ethanol was distilled off and the residue dissolved in water and extracted with toluene to remove neutral products. The aqueous alkaline solution was carefully acidified with dilute hydrochloric acid and the liberated 3-methyl-l-naphthol extracted with ether. The ether extract was washed with water, dried and filtered. Ether solvent was removed leaving 3-methyl-l-naphthol (18.4 g) as clear colorless crystals.
Reaction SMILES: [OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O.[NH2:17][C:18]([C:20]1[NH:21][C:22](=[O:38])[N:23]([CH:25]2[CH2:30][CH2:29][N:28]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:27][CH2:26]2)[CH:24]=1)=O.ClCCl.C(=O)(O)[O-].[Na+]>ClC(Cl)C>[C:18]([C:20]1[NH:21][C:22](=[O:38])[N:23]([CH:25]2[CH2:26][CH2:27][N:28]([C:31]([O:33][C:34]([CH3:36])([CH3:35])[CH3:37])=[O:32])[CH2:29][CH2:30]2)[CH:24]=1)#[N:17]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(C(N)=O)[nH]c2=O)CC1
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(n2cc(C#N)[nH]c2=O)CC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
(Methoxycarbonylsulfamoyl)triethylammonium hydroxide, inner salt (179.7 mg, 0.754 mmol) was added to a solution of tert-butyl 4-[4-(aminocarbonyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]piperidine-1-carboxylate (78 mg, 0.251 mmol) in dichloroethane (5 mL) and was heated to 50° C. After 1 h, the reaction was worked up with dichloromethane and saturated sodium bicarbonate. The organic extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→5% methanol {1% ammonium hydroxide}/dichloromethane) gave the title compound (40 mg). MS 237.04 (M+1-tert butyl)
Reaction SMILES: CO.C(N)CCC.[S:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][N:18]2C(=O)[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]2=[O:28])[S:9]1>C1(C)C=CC=CC=1>[S:8]1[CH2:12][CH2:11][CH:10]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:28])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[S:9]1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCC1CCSS1
Solvent: Cc1ccccc1
Solvent: CCCCN
Solvent: CO
Product: O=C(NCCCCCC1CCSS1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.8 %

Procedure:
2 ml of methanol and 2 ml of butylamine were added to 3 ml of a solution of 1.6 mmol of 2-[5-(1,2-dithiolan-3-yl)pentyl]isoindoline-1,3-dione (prepared as described in Example 58) in toluene, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then left to stand at room temperature for 2 days, after which the solvent was removed from the reaction mixture by evaporation under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extraction solution was washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and 5 ml of anhydrous tetrahydrofuran, 0.33 ml of triethylamine and 0.28 ml of benxoyl chloride were added to the residue. The mixture was then stirred at room temperature for 6 hours. At the end of this time, the solvent was removed from the reaction mixture by evaporation under reduced pressure, and water was added to the residue, after which it was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was subjected to silica gel column chromatography, using 1:8, 1:4 and 1:2 by volume mixtures of ethyl acetate and hexane as the eluent. The residue was then subjected to reverse phase preparative silica gel column chromatography, using 2:3 and 1:1 by volume mixtures of acetonitrile and water was eluent, and the acetonitrile was removed from the solution by evaporation under reduced pressure, after which the residue was extracted with ethyl acetate. The extraction solution was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The ethyl acetate was removed from the extraction solution by evaporation under reduced pressure, and the residue was dissolved in dioxane and then lyophilised, to obtain 56 mg of the title compound as a yellow amorphous substance, melting at 58 to 59° C.
Reaction SMILES: [H-].[Na+].Br[CH2:4][CH2:5][O:6][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:26]([P:37](=[O:46])([O:42][CH:43]([CH3:45])[CH3:44])[O:38][CH:39]([CH3:41])[CH3:40])[P:27](=[O:36])([O:32][CH:33]([CH3:35])[CH3:34])[O:28][CH:29]([CH3:31])[CH3:30].[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH:39]([O:38][P:37]([O:42][CH:43]([CH3:45])[CH3:44])([CH:26]([P:27]([O:32][CH:33]([CH3:35])[CH3:34])([O:28][CH:29]([CH3:30])[CH3:31])=[O:36])[CH2:4][CH2:5][O:6][C:7]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:46])([CH3:41])[CH3:40]
Reactant: CC(C)OP(=O)(CP(=O)(OC(C)C)OC(C)C)OC(C)C
Reactant: BrCCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)OP(=O)(OC(C)C)C(CCOC(c1ccccc1)(c1ccccc1)c1ccccc1)P(=O)(OC(C)C)OC(C)C
Temperature: 120 °C
Reaction time: 7 h
Yield: 77.4 %

Procedure:
Under a nitrogen atmosphere, 60% sodium hydride (200 mg), 1-bromo-2-triphenylmethoxyethane (1.84 g) and tetraisopropyl methylenebisphosphonate (1.72 g) were suspended in toluene (5 ml), and the resulting suspension was stirred at 120° C. for 7 hours. The reaction mixture was diluted with toluene, and then a saturated aqueous ammonium chloride solution was added thereto to decompose the excess sodium hydride. Then, ethyl acetate was added thereto to effect separation, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (chloroform:acetone) to obtain 1,1-bis(diisopropoxyphosphinoyl)-3-triphenylmethoxypropane (2.44 g, yield 77%).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1.P(Br)(Br)[Br:28]>C(Cl)Cl.C(Cl)Cl.CO>[Br:28][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:5][CH:4]=1
Reactant: BrP(Br)Br
Reactant: Cc1ccc(COc2ccn(CCc3ccc(CO)cc3)c(=O)c2)nc1
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(COc2ccn(CCc3ccc(CBr)cc3)c(=O)c2)nc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 100 mg (0.29 mmol) 1-[2-(4-hydroxymethyl-phenyl)-ethyl]-4-(5-methyl-pyridin-2-ylmethoxy)-1H-pyridin-2-one (example 13.1a) in 5.0 mL of DCM is added 21 μL (0.23 mmol) phosphorus tribromide. The mixture is stirred 2 h at RT, diluted with DCM/MeOH and extracted twice with water. The organic phase is dried over MgSO4, filtered and the solvent is evaporated to afford the product.
Reaction SMILES: C(=O)(OC(C)(C)C)N.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2([NH:22][C:23]([CH:25]3[N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30][C:27]4([CH2:29][CH2:28]4)[CH2:26]3)=[O:24])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)=[O:12]>>[CH2:28]1[C:27]2([CH2:30][CH2:31][NH:32][CH:25]([C:23]([NH:22][C:19]3([C:16]4[CH:17]=[CH:18][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:14][CH:15]=4)[CH2:20][CH2:21]3)=[O:24])[CH2:26]2)[CH2:29]1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3C(=O)OC(C)(C)C)CC4)CC2)cc1
Agent: CC(C)(C)OC(N)=O
Product: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3)CC4)CC2)cc1
Yield: 99.9 %

Procedure:
The title compound (D90) (310 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from tert-butyl 5-((1-(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (D55) (405 mg).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][CH2:8][C@H:7](OS(C)(=O)=O)[CH2:6]1)(=[O:3])[CH3:2].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C=O)C>[C:1]([O:4][C@@H:5]1[CH2:9][CH2:8][C@@H:7]([N:15]=[N+:16]=[N-:17])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC[C@H](OS(C)(=O)=O)C1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)O[C@@H]1CC[C@@H](N=[N+]=[N-])C1
Temperature: 80 °C
Reaction time: 3 h
Yield: 81.5 %

Procedure:
To a 8 ml DMF solution of 580 mg (2.61 mmol) of (1R,3S)-3-[(methylsulfonyl)oxy]cyclopentyl acetate, 203 mg (3.13 mmol) of sodium azide and 26 μl (0.13 mmol) of 15-crown-5-ether were added and stirred at 80° C. for 3 hours, followed by concentrating and then by diluting with 50 ml of diethyl ether. The residue was washed with 10 ml of saturated saline and then the solvent was distilled off to obtain 360 mg (82%) of the above-identified compound as a slightly brown oily substance.
Reaction SMILES: [B:1]([F:4])([F:3])[F:2].[C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([N+:18]([O-:20])=[O:19])=[CH:10][C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]1=2)#[N:6].C(O)(=[O:27])C>ClC1C=CC=CC=1>[C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]([N+:18]([O-:20])=[O:19])=[CH:10][C:9]2[CH:21]=[CH:22][CH:23]=[CH:24][C:8]1=2)(=[O:27])[NH2:6].[B:1]([F:4])([F:3])[F:2]
Reactant: CC(=O)O
Reactant: N#CN1c2ccccc2C=C([N+](=O)[O-])c2ccccc21
Agent: FB(F)F
Solvent: Clc1ccccc1
Product: NC(=O)N1c2ccccc2C=C([N+](=O)[O-])c2ccccc21

Procedure:
25 ml of a solution of 15% by weight of BF3 in acetic acid are allowed to flow rapidly into a suspension of 13.1 g (0.05 mole) of 5-cyano-10-nitro-5H-dibenz[b,f]azepine in 130 ml of chlorobenzene, while stirring, and a clear brownish solution is obtained of which the temperature increases to 35°. The crystallisation, which begins after a few minutes, is completed by stirring for one hour in an ice-bath. Suction-filtering is carried out, followed by washing with chlorobenzene and drying in vacuo at 40°, resulting in 19.2 of 5-carbamoyl-10-nitro-5H-dibenz[b,f]azepine in the form of a BF3 adduct. To liberate the end product the BF3 adduct is made into a slurry with 150 ml of water, stirred for 15 hours, suction-filtered and washed neutral with water. After drying, 5-carbamoyl-10-nitro-5H-dibenz[b,f]azepine, which is identical to the product obtained according to Example 21, is obtained.