Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH:8]C(OC(C)(C)C)=O)[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:3]=1.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:8][C:6]1[N:5]=[C:4]([C:16]([O:18][CH3:19])=[O:17])[CH:3]=[C:2]([Br:1])[CH:7]=1
Reactant: COC(=O)c1cc(Br)cc(NC(=O)OC(C)(C)C)n1
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(Br)cc(N)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
7.23 g of methyl 4-bromo-6-t-butoxycarbonylamino-pyridine-2-carboxylate was dissolved in 30 ml of chloroform, and then 15 ml of trifluoroacetic acid was added thereto, followed by stirring at room temperature for 1 hour. After concentrating the reaction mixture, the residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. The residue was purified by a silica gel column chromatography (eluent: chloroform to chloroform/methanol=20/1) to give the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[C:11]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12]>>[NH2:8][C:5]1[CH:6]=[CH:7][C:2]([N:21]2[CH2:20][CH2:19][N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:23][CH2:22]2)=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(N)cn2)CC1

Procedure:
Intermediate B-11 was prepared by the general procedure for intermediate B-2, by using 2-chloro-5-nitropyridine and 1-BOC-piperazine as starting materials. LCMS (ESI) calcd for [M+1]+ 279.2. found 279.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[CH2:26][CH:25]([N:30](C)[C:31](=O)C(F)(F)F)[CH2:24]5)=[O:20])[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CO.O1CCCC1>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH2:18][C:19]([C:21]4[CH:22]=[C:23]5[C:27](=[CH:28][CH:29]=4)[CH2:26][CH:25]([NH:30][CH3:31])[CH2:24]5)=[O:20])[CH:12]=[N:11][C:10]=3[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CN(C(=O)C(F)(F)F)C1Cc2ccc(C(=O)Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CNC1Cc2ccc(C(=O)Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)cc2C1
Temperature: 60 °C
Reaction time: 3 h
Yield: 104 %

Procedure:
A mixture of the compound (70 mg) obtained in Example 15, potassium carbonate (53 mg), water (0.5 ml), methanol (1 ml) and tetrahydrofuran (1 ml) was stirred at 60° C. for 3 hr. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound (60 mg) as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[N:6][CH:7]=1.O1[CH2:22][CH2:21][O:20][CH2:19]C1>CCCC[N+](CCCC)(CCCC)CCCC.[I-].[O-2].[Mn+4].[O-2]>[CH3:19][O:20][C:21]1[CH:22]=[CH:11][C:10]([C:2]2[CH:3]=[N:4][C:5]([NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=3)=[N:6][CH:7]=2)=[CH:9][CH:14]=1
Reactant: OCc1ccc(Nc2ncc(Br)cn2)cc1
Reactant: C1COCCO1
Agent: [Mn+4]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Product: COc1ccc(-c2cnc(Nc3ccc(C=O)cc3)nc2)cc1
Temperature: 130 °C

Procedure:
To a solution of [4-(5-bromo-pyrimidin-2-ylamino)-phenyl]-methanol 15 (0.94 mmol) in dioxane (2 mL) is added manganese (IV) oxide (4.7 mmol) and TBAI (0.06 mmol). The reaction mixture is heated in a microwave oven at 130° C. for 30 min. Purification by silica gel chromatography using hexane:EtOAc=1:1 affords 4-[5-(4-methoxy-phenyl)-pyrimidin-2-ylamino]-benzaldehyde 16. 1H NMR (400 MHz, d6-DMSO) δ 10.45 (s, 1H), 9.85 (s, 1H), 8.72 (s, 2H), 7.96 (d, J=8.4 Hz, 2H), 7.85 (d, J=8.4 Hz, 2H). MS (m/z) (M+1)+: 278.0, 280.0.
Reaction SMILES: [CH2:1]([O:3][P:4]([C:9]1[CH:10]=[C:11]([C:14]2[S:15][C:16](I)=[CH:17][C:18]=2[P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])[S:12][CH:13]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].C([Sn](CCCC)(CCCC)[C:33]1[S:37][C:36]([C:38]2[S:39][CH:40]=[CH:41][C:42]=2[P:43]([O:48][CH2:49][CH3:50])([O:45][CH2:46][CH3:47])=[O:44])=[CH:35][C:34]=1[P:51]([O:56][CH2:57][CH3:58])([O:53][CH2:54][CH3:55])=[O:52])CCC.[Cu]C#N.[F-].[K+]>C1(C)C=CC=CC=1>[CH2:22]([O:21][P:19]([C:18]1[CH:17]=[CH:16][S:15][C:14]=1[C:11]1[S:12][C:13]([C:40]2[S:39][C:38]([C:36]3[S:37][CH:33]=[C:34]([P:51]([O:56][CH2:57][CH3:58])([O:53][CH2:54][CH3:55])=[O:52])[CH:35]=3)=[C:42]([P:43]([O:45][CH2:46][CH3:47])([O:48][CH2:49][CH3:50])=[O:44])[CH:41]=2)=[C:9]([P:4]([O:6][CH2:7][CH3:8])([O:3][CH2:1][CH3:2])=[O:5])[CH:10]=1)([O:24][CH2:25][CH3:26])=[O:20])[CH3:23]
Reactant: CCOP(=O)(OCC)c1csc(-c2sc(I)cc2P(=O)(OCC)OCC)c1
Reactant: CCCC[Sn](CCCC)(CCCC)c1sc(-c2sccc2P(=O)(OCC)OCC)cc1P(=O)(OCC)OCC
Agent: N#C[Cu]
Agent: [F-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOP(=O)(OCC)c1csc(-c2sc(-c3sc(-c4sccc4P(=O)(OCC)OCC)cc3P(=O)(OCC)OCC)cc2P(=O)(OCC)OCC)c1
Yield: 82 %

Procedure:
At room temperature, 0.0564 g (0.1 mmol) of 4,3′-bis(diethoxyphosphoryl)-5′-iodo-[2,2′]-bithiophene and 0.0092 g (0.008 mmols) of commercially available tetrakistriphenylphosphine palladium were dissolved in 2 ml of toluene, to which 0.0709 g (0.1 mmol) of 5-(tributylstannyl)-4,3′-bis(diethoxyphosphoryl)-[2,2′]-bithiophene and 0.0018 g (0.02 mmols) of commercially available copper(I) cyanide were added at room temperature. Thereafter, the reaction mixture was heated and stirred under reflux for 2.5 hours. After the reaction, the reaction mixture was cooled down to room temperature, to which a potassium fluoride aqueous solution added, followed by stirring for 1 hour. The resulting solid was removed by celite filtration and the filtrate was extracted with ethyl acetate. The organic phase was washed with a saturated saline solution and dried over anhydrous sodium sulfate. The solvent was removed by distilling off under reduced pressure, and the resulting crude product was purified with a PTLC plate (developed with ethyl acetate and ethyl acetate:hexane=15:1) to obtain the specified substance in the form of an orange oil at a yield of 0.0717 g (yield: 82%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[CH3:26])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[OH-:27].[K+].C(P(C(C)(C)C)C1C=CC=CC=1C1C(C(C)C)=CC(C(C)C)=CC=1C(C)C)(C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([C@H:8]([C:5]2[CH:6]=[CH:7][C:2]([OH:27])=[CH:3][CH:4]=2)[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[C:14]([CH3:18])[CH:13]=2)=[O:11])=[C:20]([CH3:26])[CH:21]=1
Reactant: Cc1cc(C(=O)C[C@@H](c2ccc(Br)cc2)c2ccc(Cl)cc2C)ccn1
Reactant: [OH-]
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C(C)(C)C)C(C)(C)C)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc(C(=O)C[C@@H](c2ccc(O)cc2)c2ccc(Cl)cc2C)ccn1

Procedure:
In analogy to example 363, step 1, from (S)-3-(4-bromo-phenyl)-3-(4-chloro-2-methyl-phenyl)-1-(2-methyl-pyridin-4-yl)-propan-1-one (example 282, step 1) in presence of potassium hydroxide, 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl and tris(dibenzylidene-acetone)dipalladium(0) was prepared the title compound as a light yellow foam, MS (ESI+): m/z=366.1 ([M+H]+).
Reaction SMILES: Br.Br[CH2:3][C:4]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=O.Cl.[NH:13]=[C:14]1[CH2:18][CH2:17][CH2:16][NH:15]1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[N:9]1[CH:10]=[CH:11][C:6]([C:4]2[N:13]=[C:14]3[CH2:18][CH2:17][CH2:16][N:15]3[CH:3]=2)=[CH:7][CH:8]=1
Reactant: O=C(CBr)c1ccncc1
Reactant: N=C1CCCN1
Agent: Br
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: c1cc(-c2cn3c(n2)CCC3)ccn1
Temperature: 80 °C

Procedure:
A stirred suspension of 10q (35.6 mmoles) of 4-(bromoacetyl) pyridine hydrobromide and 12.9 q (107 mmoles) of 2-imino-pyrrolidine hydrochloride in 100 ml of dry dimethylformamide was treated with 18.9 q (178 mmoles) of anhydrous sodium carbonate. This suspension was heated at 80° C. overnight in an oil bath. The solvent was removed in vacuo, the residue dissolved in water and extracted with chloroform. The organic layer was washed three times with water, dried over anhydrous potassium carbonate and stripped in vacuo. The residue was chromatographed on silica and eluted with 10-15% methanol in methylene chloride acetone (85:15). This fraction was stripped in vacuo and the solid residue recrystallized twice from ethyl acetate to afford the desired titled compound, mp 140-141° C., 1HNMR (250 MHz, CDCl3) δ8 62 (2H,d), 7.60(2H,d), 7.34(lH,s), 4.04(2H,t), 2.95 (2H,t), 2.64(2H,q).
Reaction SMILES: C([Li])CCC.[F:6][C:7]([F:22])([F:21])[C:8]1[N:9]=[CH:10][N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:12]=1.Cl[C:24]1[CH:29]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[C:32]([Cl:37])[CH:31]=2)[N:27]=[CH:26][N:25]=1>C1COCC1.CC(OC)(C)C.[Cl-].[Cl-].[Zn+2].C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:37][C:32]1[CH:31]=[C:30]([C:28]2[CH:29]=[C:24]([C:10]3[N:11]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[CH:12]=[C:8]([C:7]([F:21])([F:6])[F:22])[N:9]=3)[N:25]=[CH:26][N:27]=2)[CH:35]=[CH:34][C:33]=1[Cl:36]
Reactant: C[Si](C)(C)CCOCn1cnc(C(F)(F)F)c1
Reactant: Clc1cc(-c2ccc(Cl)c(Cl)c2)ncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1cc(-c2ccc(Cl)c(Cl)c2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
n-Butyl lithium (2.5M solution in hexane, 0.11 ml, 0.27 mmol) was added dropwise to a cold (−78° C.) stirred solution of 4-trifluoromethyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole (0.067 g, 0.25 mmol) in THF (5 ml) and the mixture was stirred at this temperature under a nitrogen atmosphere for 30 minutes. After this time, ZnCl2 (1M solution in Et2O, 0.58 ml, 0.58 mmol) was added in one portion and the solution was allowed to warm to room temperature. 4-Chloro-6-(3,4-dichloro-phenyl)-pyrimidine (0.05 g, 0.19 mmol) and Pd(PPh3)4 (0.045 g, 0.01 mol) were added sequentially and the resulting mixture was heated to reflux and stirred for a further 4 hours. After this time the mixture was diluted with TBME (100 ml) and washed with 1M HCl (50 ml). The layers were separated and the aqueous extracted with TBME (50 ml). The organic layers were combined, dried (MgSO4), filtered and concentrated. The resulting residue was purified using a Biotage Isolera (10 g silica column eluting with 100% heptane to 20% ethyl acetate/80% heptane) to afford the title compound (0.064 g, 68% yield) as a white solid. δH (250 MHz, CDCl3) 9.26 (d, J=1.22 Hz, 1H), 8.60 (d, J=1.37 Hz, 1H), 8.37 (d, J=2.13 Hz, 1H), 8.06 (dd, J=2.13, 8.53 Hz, 1H), 7.52-7.75 (m, 2H), 6.13 (s, 2H), 3.65 (dd, J=7.77, 8.68 Hz, 2H), 0.79-1.05 (m, 2H), −0.03 (s, 9H). Tr=2.66 min m/z (ES+) (M+H+) 489, 491.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.CCN(CC)CC.[CH:17]([N:20]1[C:24]([C:25]2[N:34]=[C:33]3[N:27]([CH2:28][CH2:29][O:30][C:31]4[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][C:32]=43)[CH:26]=2)=[N:23][CH:22]=[N:21]1)([CH3:19])[CH3:18]>C(Cl)Cl>[CH:17]([N:20]1[C:24]([C:25]2[N:34]=[C:33]3[C:32]4[CH:35]=[C:36]([S:39]([N:6]5[CH2:7][CH2:8][CH:3]([N:2]([CH3:9])[CH3:1])[CH2:4][CH2:5]5)(=[O:41])=[O:40])[CH:37]=[CH:38][C:31]=4[O:30][CH2:29][CH2:28][N:27]3[CH:26]=2)=[N:23][CH:22]=[N:21]1)([CH3:19])[CH3:18]
Reactant: CN(C)C1CCNCC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)N3CCC(N(C)C)CC3)ccc1OCC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of dimethyl-piperidin-4-yl-amine (45 mg, 0.35 mmol) and NEt3 (83 μL, 0.59 mmol) in DCM (15 mL) at 0° C. was added a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (93 mg, 0.12 mmol) in DCM (5 mL) and the resulting mixture warmed to RT after 10 min then stirred for 1 h. The reaction mixture was diluted with DCM, washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 0-16% MeOH in EtOAc) then freeze-dried from MeCN/H2O affording 131 (29 mg, 52%) as a white solid. LCMS: RT 2.83 min [M+H]+ 486.3. 1H NMR (DMSO, 400 MHz): δ 8.79 (1H, d, J=2.42 Hz), 8.00 (1H, s), 7.93 (1H, d, J=0.62 Hz), 7.63 (1H, dd, J=10.74, 2.40 Hz), 7.26 (1H, d, J=8.62 Hz), 5.72-5.71 (1H, m), 4.61-4.60 (4H, m), 3.60-3.57 (2H, m), 2.40-2.39 (2H, m), 2.15-2.05 (1H, m), 2.10 (6H, s), 1.77-1.73 (2H, m), 1.49 (6H, d, J=6.62 Hz), 1.46-1.37 (2H, m)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]1[CH:13]=[C:14]([OH:19])[CH:15]=[CH:16][C:17]=1[F:18]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:19][C:14]1[CH:15]=[CH:16][C:17]([F:18])=[C:12]([F:11])[CH:13]=1)[CH:5]=[O:6]
Reactant: Oc1ccc(F)c(F)c1
Reactant: O=Cc1ccc(F)c(Cl)c1
Product: O=Cc1ccc(Oc2ccc(F)c(F)c2)c(Cl)c1

Procedure:
The title compound was prepared by a procedure similar to that described for D4 starting from 3-chloro-4-fluorobenzaldehyde and 3,4-difluorophenol.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[N:3]=[C:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]([O:11][CH2:12][CH3:13])=[O:10].C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)(=O)C.O.C(OCC)(=O)C>[CH3:1][N:2]([CH3:14])[NH:3][CH:4]1[CH2:8][CH2:7][CH2:6][CH:5]1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)C1CCCC1=NN(C)C
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)C1CCCC1NN(C)C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The crude ethyl 2-(2,2-dimethylhydrazono)cyclopentanecarboxylate (6.91 mmol) was dissolved in acetic acid (10 mL) and water (10 mL). Sodium cyanoborohydride was added and the reaction was stirred at 25° C. for 16 h. The mixture was neutralized with saturated aqueous sodium bicarbonate solution until pH=8 was reached and was diluted with ethyl acetate (30 mL). After shaking, both layers were passed through a plug of Celite. The organic layer was further washed with saturated aqueous sodium bicarbonate solution (10 mL), saturated aqueous brine solution (10 mL), then dried over magnesium sulfate, filtered, and concentrated in vacuo to afford the crude product, ethyl 2-(2,2-dimethylhydrazinyl)cyclopentanecarboxylate as a clear oil, which was used directly in the next step without any further purification. LC-MS (ESI) calcd for C10H20N2O2 200.28, found 201.3 [M+H+].
Reaction SMILES: [O:1]1[C:3]2([CH2:8][CH2:7][O:6][CH2:5][CH2:4]2)[CH2:2]1.[NH4+:9].[OH-]>CO>[NH2:9][CH2:2][C:3]1([OH:1])[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: C1CC2(CCO1)CO2
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: NCC1(O)CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 41 %

Procedure:
4-Aminomethyl-tetrahydro-pyran-4-ol is prepared from 1,6-dioxa-spiro[2.5]octane. A MeOH (3.5 mL) solution of 1,6-dioxa-spiro[2.5]octane (0.19 g, 1.7 mmol) is added to concentrated aqueous NH4OH (4.3 mL) at 0° C. The reaction mixture is warmed to room temperature and stirred for 16 hours. The reaction mixture is concentrated under reduced pressure and purified by column chromatography (10% MeOH, 2% Et3N in DCM) to afford 90 mg (41%) of the desired product as a white solid.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH:6]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH3:20])=[O:18])[C:7]([O:9][CH3:10])=[O:8]>C(#N)C>[N:1]([CH:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:6][C:7]([O:9][CH3:10])=[O:8])[C:17]([O:19][CH3:20])=[O:18])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COC(=O)CCCCCCC(Br)C(=O)OC
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)CCCCCCC(N=[N+]=[N-])C(=O)OC

Procedure:
Sodium azide (4.87 g, 75 mmol) was added to a solution of dimethyl 2-bromoazelate (5.9 g, 20 mmol) prepared according to Auguston, M, et al; Acta Chim. Acad. Sci. Hung; 46:85 (1965) in acetonitrile, and the mixture was heated at reflux temperature for 4 h. The solvent was removed in vacuo, dichloromethane (80 ml) was added to the residue, and the mixture was washed with water. The organic phase was dried over sodium sulfate and the solvent was removed in vacuo to give the title compound as an oil.
Reaction SMILES: CO[C:3](=[O:25])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[CH:26]([NH2:29])([CH3:28])[CH3:27]>>[F:24][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([CH2:11][NH:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:29][CH:26]([CH3:28])[CH3:27])=[O:25])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)N
Reactant: COC(=O)c1ccc(NCc2c(-c3cccc(F)c3)noc2C)nc1
Product: Cc1onc(-c2cccc(F)c2)c1CNc1ccc(C(=O)NC(C)C)cn1
Yield: 33 %

Procedure:
As described for example 168, 6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-nicotinic acid methyl ester (85 mg, 0.25 mmol) was converted using isopropylamine instead of 2,2,2-trifluoroethylamine to the title compound (30 mg, 33%) which was obtained as an off white foam. MS: m/e=369.1 [M+H]+.
Reaction SMILES: [CH2:1]([C:3]([CH2:17][CH3:18])([P:13]([OH:16])([OH:15])=[O:14])[C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)[CH3:2].B#B>C1COCC1>[CH2:17]([C:3]([CH2:1][CH3:2])([P:13]([OH:15])([OH:16])=[O:14])[C:4]1[CH:12]=[CH:11][C:7]([CH2:8][OH:9])=[CH:6][CH:5]=1)[CH3:18]
Reactant: CCC(CC)(c1ccc(C(=O)O)cc1)P(=O)(O)O
Agent: B#B
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(CO)cc1)P(=O)(O)O
Temperature: 25 °C

Procedure:
4-(Diethyl phosphonomethyl)benzoic acid (66 mmol) was suspended in anhydrous THF (75 mL) under a nitrogen atmosphere. The reaction was cooled in an ice bath while diborane 1M in THF (72.6 mmol ) was added dropwise to the acid. Once the addition was complete the reaction was allowed to gradually warm to room temperature over several hours. The reaction was quenched by the careful addition of H2O (50 mL), then most of the THF was removed on a rotatory evaporator. The residue was partitioned between dichloromethane (100 mL) and H2O (100 mL). The layers were separated and the aqueous later extracted a second time with dichloromethane (100 mL). The combined organic layers were washed with H2O (100 mL), dried (MgSO4), and concentrated to give the product as a clear oil.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7](N)[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.COC1C=CC(COC(N=[N+]=[N-])=O)=CC=1>>[C:4]1([CH2:7][C:8]([OH:10])=[O:9])[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: N[C@@H](C(=O)O)c1ccccc1
Agent: COc1ccc(COC(=O)N=[N+]=[N-])cc1
Product: O=C(O)Cc1ccccc1

Procedure:
D-2-Phenylglycine and p-methoxybenzyloxycarbonylazide are reacted according to the procedure of example 1(a) to yield D-2-[[[(4-methoxyphenyl)methoxyphenyl)methoxy]carbonyl]amino]-phenylacetic acid.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=O)/[CH:4]=[CH:5]/[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[F:13].[C:17]1([NH:23][NH2:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(O)C>C(OCC)(=O)C>[C:17]1([N:23]2[CH:5]([C:6]3[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=3[F:13])[CH2:4][C:3]([C:2]([F:16])([F:15])[F:1])=[N:24]2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(/C=C/c1ccc(F)cc1F)C(F)(F)F
Reactant: NNc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Fc1ccc(C2CC(C(F)(F)F)=NN2c2ccccc2)c(F)c1
Temperature: 110 °C
Reaction time: 2 h

Procedure:
In a 50 mL beaker are introduced (E)-1,1,1-trifluoro-4-(2,4-difluorophenyl)-3-buten-2-one(2.66 g, 11.2 mmol), monohydrated p-toluensulphonic acid (2.1 g, 11.2 mmol) and phenylhydrazine chlorhydrate (1.33 g, 12.3 mmol) and heated to 110° C. A small amount of ethyl alcohol can be used to facilitate the initial mixture. After approximately 2 h (control by CCF) the mixture is allowed to cool and it is diluted with ethyl acetate. It is then washed with a saturated solution of NaHCO3, dried with MgSO4, filtered and the solvent evaporated at low pressure. The crude thus obtained (3.9 g) is recrystallised with methanol (2 mL) to precipitate 3.67 g (65%) of the pyrazoline (±)-5: pf=83–84° C.; IR (KBr) μ max (cm−1) 1600, 1505, 1326; 1H-RMN (CDCl3) δ (ppm): 7.28–6.72 (m, 8H), 5.64 (dd, J=13 Hz, J=7.5 Hz, 1H), 3.8–3.6 (m, 1H), 2.94 (dd, J=17.2 Hz, J=7 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]=[C:10]([NH:12][CH:13]([CH:16](OCC)OCC)[CH2:14][OH:15])[CH2:9][N:8]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:6]=2[CH:30]=1>C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:16]=[C:13]([CH2:14][OH:15])[N:12]=[C:10]3[CH2:9][N:8]=[C:7]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:6]=2[CH:30]=1
Reactant: CCOC(OCC)C(CO)NC1=Nc2ccc(Cl)cc2C(c2ccccc2F)=NC1
Solvent: CC(=O)O
Product: OCc1cn2c(n1)CN=C(c1ccccc1F)c1cc(Cl)ccc1-2
Reaction time: 2 h
Yield: 49.1 %

Procedure:
A solution of 30 g of 7-chloro-2-(3,3-diethoxy-1-hydroxy-2-propyl-amino)-5-(2-fluorophenyl)-3H-1,4-benzodiazepine in 300 ml of glacial acetic acid was heated to reflux temperature for 5 h. After cooling the solvent was removed in a vacuum, the residue was taken up in 300 ml of ethanol, the solution was treated with 150 ml of 2N aqueous sodium hydroxide solution and left te stand at room temperature for 2 h. Then, about 200 ml of ethanol were distilled off at 30° C. in a vacuum. The solution remaining behind was extracted three times with chloroform. The chloroform extracts were washed with saturated sodium chloride solution, then dried over sodium sulphate and evaporated to dryness in a vacuum. The residue (20.5 g) was dissolved in chloroform and chromatographed over 500 g of silica gel. Byproducts (total 4.1 g) were eluted with chloroform containing 0.2% to 1.6% ethanol. 13.0 g of the desired product were eluted with chloroform containing 2.4 to 20% ethanol. After recrystallization from ethyl acetate/diethyl ether there were obtained 11.6 g of 8-chloro-6-(2-fluorophenyl)-4H-imidazo[1,2-a][1,4]benzodiazepine-2-methanol of m.p. 196-199.5° C. After repeated recrystallization from ethyl acetate the m.p. lay at 199-201° C.
Reaction SMILES: C(C1CCC(C)CC1[O:11][C:12]([CH:14]1[CH2:18][CH:17]([CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:16][N:15]1C(OC(C)(C)C)=O)=[O:13])(C)C.[ClH:33]>C1(C)C=CC=CC=1>[ClH:33].[CH:20]1([CH2:19][C@@H:17]2[CH2:16][NH:15][C@H:14]([C:12]([OH:13])=[O:11])[CH2:18]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC1CCC(C(C)C)C(OC(=O)C2CC(CC3CCCCC3)CN2C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(O)[C@@H]1C[C@H](CC2CCCCC2)CN1
Temperature: 25 °C
Yield: 48 %

Procedure:
4-Cyclohexylmethyl-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-(2-isopropyl-5-methyl-cyclohexyl)ester (Preparation 38, 316 mg, 0.70 mmol) was dissolved in toluene (2 ml). 6N hydrochloric acid (50 ml) was added and stirred at reflux for 72 hours. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (3×20 ml). The aqueous layer was concentrated by evaporation under reduced pressure to give the title compound as a white solid (80 mg, 48%).