Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][NH2:4].[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[NH:4][CH2:3][CH2:2][CH2:1][NH2:5]
Reactant: NCCCN
Reactant: c1ccncc1
Product: NCCCNc1ccccn1
Yield: 76 %

Procedure:
To a solution of propane-1,3-diamine (310 ml, 3.63 mol) in dry pyridine (75 ml) kept under an atmosphere of nitrogen 2-bromopyridine (70 ml, 0.73 mol) was added. The reaction mixture was heated at reflux for 18 h, cooled and the volatiles evaporated in vacuo. To the residue was added tetrahydrofuran (1 l) and the precipitate was filtered off and washed with tetrahydrofuran (0.5 l). The solvent was evaporated in vacuo and the residue purified by distillation at 95-97° C. and 2×10-2 mbar affording 83.37 g (76%) of N-(pyridin-2-yl)propane-1,3-diamine.
Reaction SMILES: N1C=CC=CC=1.O1CCOCC1.[F:13][C:14]([F:47])([F:46])[C:15]1[CH:16]=[C:17]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[CH2:18][N:19]([CH3:38])[C:20]([C:22]1[C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:24][C:25]([CH2:28][C:29](=O)[NH2:30])=[N:26][CH:27]=1)=[O:21]>>[F:47][C:14]([F:13])([F:46])[C:15]1[CH:16]=[C:17]([CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=1)[CH2:18][N:19]([CH3:38])[C:20]([C:22]1[C:23]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[N:24][C:25]([CH2:28][C:29]#[N:30])=[N:26][CH:27]=1)=[O:21]
Reactant: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(CC(N)=O)nc1-c1ccccc1
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(=O)c1cnc(CC#N)nc1-c1ccccc1
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 0.50 g (1.01 mmol) in 2-carbamoylmethyl-4-phenyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide and 0.17 ml pyridine in 10 ml dioxane 0.15 ml (1.06 mmol) trifluoraceticanhydrid were added and the resulting reaction mixture was stirred for 1 hr. at 50°. The reaction mixture was poured on Ice/H2O and extracted three times with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH 30:1) to give 0.25 g (51%) 2-cyanomethyl-4-phenyl-pyrimidine-5-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as a colorless solid, m.p. 114-116°.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)=[CH:11][NH:10]2)[CH:4]=1.[CH2:20]([SH:22])[CH3:21].[H-].[Na+].O>CN(C=O)C>[CH2:20]([S:22][C:3]1[N:8]=[CH:7][N:6]=[C:5]([N:9]2[C:13](=[O:14])[C:12]([N:15]3[CH:19]=[CH:18][N:17]=[N:16]3)=[CH:11][NH:10]2)[CH:4]=1)[CH3:21]
Reactant: CCS
Reactant: O=c1c(-n2ccnn2)c[nH]n1-c1cc(Cl)ncn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cc(-n2[nH]cc(-n3ccnn3)c2=O)ncn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
200 mg (0.7 mmol) of the compound from Example 52A are suspended in 1.1 ml DMF under argon. 61 mg (1.0 mmol) ethanethiol are added. 35 mg (0.8 mmol, 60% strength in mineral oil) sodium hydride are added cautiously, while cooling with ice. The mixture is stirred at RT for 2.5 h. 1 ml water is subsequently added dropwise and the mixture is subsequently stirred at RT for 15 min. The clear reaction solution obtained is purified directly by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions are combined, the mixture is concentrated and the residue is dried under a high vacuum.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([OH:11])=O)=[N:7][CH:8]=1.[B-](F)(F)(F)F.CN(C(O[N:25]1[C:30](=O)[CH:29]=[CH:28]C=C1)=[N+](C)C)C.CCN(C(C)C)C(C)C.C1(N)CC1>CN(C=O)C>[CH:30]1([NH:25][C:9]([C:6]2[CH:5]=[CH:4][C:3]([CH2:2][OH:1])=[CH:8][N:7]=2)=[O:11])[CH2:28][CH2:29]1
Reactant: CN(C)C(On1ccccc1=O)=[N+](C)C
Reactant: O=C(O)c1ccc(CO)cn1
Agent: F[B-](F)(F)F
Agent: NC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CC1)c1ccc(CO)cn1

Procedure:
5-Hydroxymethyl-pyridine-2-carboxylic acid (0.23 g, 1.5 mmol) was dissolved in DMF (3 ml) and activated with TPTU (0.45 g, 1.5 mmol), Hünig's base (0.51 ml, 3.0 mmol) and reacted with cyclopropyl amine (0.12 ml, 1.65 mmol) for 1 h at r.t during which a precipitate was formed. Solvent was removed and the residue dissolved in acetonitrile/water and purified by prep.RP(C18)HPLC: 60 mg;
Reaction SMILES: C([O:4][CH2:5][C@@:6]([NH:26]C(=O)C)([CH3:25])[CH2:7][CH2:8][C:9]1[O:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:12][CH:13]=1)(=O)C.O1CCCC1.CO.O.[OH-].[Li+]>O>[NH2:26][C@:6]([CH3:25])([CH2:7][CH2:8][C:9]1[O:10][C:11]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][CH:13]=1)[CH2:5][OH:4]
Reactant: CC(=O)N[C@](C)(CCc1ccc(CCCCCc2ccccc2)o1)COC(C)=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: C[C@](N)(CO)CCc1ccc(CCCCCc2ccccc2)o1
Temperature: 50 °C
Reaction time: 4 h
Yield: 94.6 %

Procedure:
To a solution of (2R)-1-acetoxy-2-acetylamino-2-methyl-4-[5-(5-phenylpentyl)furan-2-yl]butane (99.7 mg, 0.25 mmol) obtained in Example (6a) in a mixed solvent of tetrahydrofuran (0.5 ml) and methanol (0.5 ml) were added successively water (0.5 ml) and lithium hydroxide monohydrate (0.1037 g, 2.47 mmol), and the resulting mixture was stirred at 50° C. for 4 hours. After cooling, water was added to the reaction mixture, and the resulting mixture was extracted with dichloromethane. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After filtration, the solvent was removed in vacuo, and the residue was purified by chromatography on a basic silica gel column (NH type) using a mixed solvent of dichloromethane and methanol (100:1) as the eluent to afford (2R)-2-amino-2-methyl-4-[5-(5-phenylpentyl)furan-2-yl]butan-1-ol (74.6 mg, yield: 95%).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH3:12])[CH:8]=2)[NH:3]1.[N+:14]([O-])([OH:16])=[O:15].C([O-])([O-])=O.[K+].[K+]>S(=O)(=O)(O)O>[CH3:1][C:2]1([CH3:13])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([N+:14]([O-:16])=[O:15])=[C:7]([CH3:12])[CH:8]=2)[NH:3]1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2c(c1)CCC(C)(C)N2
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1cc2c(cc1[N+](=O)[O-])NC(C)(C)CC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 2,2,6-trimethyl-1,2,3,4-tetrahydroquinoline (0.66 g, 3.8 mmol) in 10 mL of concentrated sulfuric acid was cooled to 0° C. in an ice bath. To this solution was added dropwise 1.0 mL 90% fuming nitric acid. The resulting mixture was stirred at 0° C. for 30 min., poured onto 150 mL of ice-water, neutralized to pH=7 with K2CO3 and extracted with CH2Cl2 (3×200 mL). The combined organic layers were washed with water (2×300 mL), saturated aqueous NaHCO3 (300 mL) and brine (300 mL). The solution was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Silica gel, 15 to 20% ethyl acetate/hexane gradient elution) to give 2,2,6-trimethyl-7-nitro-1,2,3,4-tetrahydro-quinoline. 1H NMR (500 MHz, CDCl3): 8.03 (s, 1H), 7.05 (s, 1H), 2.85 (td, J=6.6, 1.1 Hz, 2H), 2.17 (s, 3H), 1.76 (t, J=6.6 Hz, 2H), 1.35 (s, 6H).
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][CH:17]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=3)[CH:16]3[CH2:32]C(O)C[CH:15]3[C:14]=2[CH:13]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl.CCOC(C)=O>[CH3:8][O:9][CH2:10][O:11][C:12]1[CH:21]=[CH:20][C:19]2[O:18][CH:17]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=3)[CH:16]3[CH2:32][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6][CH:15]3[C:14]=2[CH:13]=1
Reactant: CC(=O)OC(C)=O
Reactant: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(O)CC32)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COCOc1ccc(C2Oc3ccc(OCOC)cc3C3CC(OC(C)=O)CC32)cc1
Yield: 82.7 %

Procedure:
Add acetic anhydride (53 mg, 0.52 mmol) to a solution of alcohol 25 (200 mg, 0.52 mmol), Et3 N (0.14 mL, 1.03 mmol), and DMAP (6 mg, 0.052 mmol) in CH2Cl2 (5 mL) and stir the reaction at room temperature for 1 hour. Dilute the solution with EtOAc and wash with H2O, saturated aqueous sodium bicarbonate and brine. Dry (Na2SO4), filter and concentrate the solution in vacuo. Purify the product by flash chromatography (10 g SiO2, 40 mL/min, 0-40% EtOAc/Hexanes over 20 minutes and then 40% EtOAc/Hexanes for 13 minutes) to afford acetate 42 (183 mg, 0.43 mmol, 83%) as a yellow oil. HRMS(FAB+) calcd for C24H28O7: 428.1835; found: 428.1833 (M+).
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]=O.Cl.[CH3:11][NH:12][CH3:13]>O>[CH3:11][N:12]([CH2:8][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][C:1]1=[O:7])[CH3:13]
Reactant: C=O
Reactant: O=C1CCCCC1
Reactant: CNC
Agent: Cl
Solvent: O
Product: CN(C)CC1CCCCC1=O

Procedure:
To cyclohexanone (259 mL) was added formaldehyde (37.2 mL of a 37% aqueous solution) and dimethylamine hydrochloride (40.8 g). The stirred mixture was slowly heated and refluxed for 1 h. After cooling to ambient temperature H2O was added, and the mixture was extracted twice with Et2O. The aqueous layer was made basic by addition of 50% aqueous NaOH (27.5 mL), and subsequently extracted twice with DCM. The combined organic phases were dried over Na2SO4 and evaporated under reduced pressure to give 66.6 g of a light-yellow liquid. 1H NMR (400 MHz, CDCl3) δ 1.34-1.47 (m, 1H), 1.60-1.78 (m, 2H), 1.81-1.92 (m, 1H), 1.98-2.09 (m, 1H), 2.16-2.55 (m, 5H), 2.21 (s, 6H), 2.69 (dd, J=13 and 6 Hz, 1H).
Reaction SMILES: COC1C=CC(C(C2C=CC(OC)=CC=2)[N:10]2[C:14]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19][C:20]4[CH:29]=[C:28]([N:30]5[CH2:35][CH2:34][N:33]([CH2:36][C:37]6[CH2:42][CH2:41][C:40]([CH3:44])([CH3:43])[CH2:39][C:38]=6[C:45]6[CH:50]=[CH:49][C:48]([Cl:51])=[CH:47][CH:46]=6)[CH2:32][CH2:31]5)[CH:27]=[CH:26][C:21]=4C(OC)=O)C=3N=C2)=CC=1.[CH3:60][N:61]([CH3:64])[CH:62]=[O:63].C(Cl)(=O)C(Cl)=O>ClCCl>[Cl:51][C:48]1[CH:47]=[CH:46][C:45]([C:38]2[CH2:39][C:40]([CH3:44])([CH3:43])[CH2:41][CH2:42][C:37]=2[CH2:36][N:33]2[CH2:32][CH2:31][N:30]([C:28]3[CH:27]=[CH:26][C:21]4[C:62](=[O:63])[N:61]5[CH:64]=[N:10][C:14]6[CH:15]=[CH:16][CH:17]=[C:18]([C:60]=65)[O:19][C:20]=4[CH:29]=3)[CH2:35][CH2:34]2)=[CH:50][CH:49]=1
Reactant: CN(C)C=O
Reactant: COC(=O)c1ccc(N2CCN(CC3=C(c4ccc(Cl)cc4)CC(C)(C)CC3)CC2)cc1Oc1cccc2c1ncn2C(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC1(C)CCC(CN2CCN(c3ccc4c(c3)Oc3cccc5ncn(c35)C4=O)CC2)=C(c2ccc(Cl)cc2)C1
Reaction time: 1 h

Procedure:
A solution of EXAMPLE 44G (4.5 g) in anhydrous dichloromethane (100 ml) was cooled in an ice bath and catalytic N,N-dimethylformamide was added. This was followed by the dropwise addition of a solution of oxalyl dichloride (1.231 ml) in anhydrous methylene chloride (5 ml). The ice bath was removed and the reaction stirred for 1 hour. The reaction was quenched by the addition of ice (ca. 150 ml) and saturated sodium bicarbonate solution (100 ml). The mixture further diluted with saturated aqueous sodium bicarbonate solution (200 ml) and methylene chloride (200 ml). The crude product was isolated by concentration of the organic layer and the residue was purified on silica gel, eluting with a 0, 10, 25, 100% ethyl acetate in methylene chloride step gradient.
Reaction SMILES: [I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[NH:9][C:4]=2[CH:3]=1.[F:13][C:14]1[CH:21]=[C:20]([F:22])[C:19]([F:23])=[CH:18][C:15]=1[CH2:16]Br>>[I:1][C:2]1[CH:12]=[N:11][C:5]2[NH:6][CH2:7][C:8](=[O:10])[N:9]([CH2:16][C:15]3[CH:18]=[C:19]([F:23])[C:20]([F:22])=[CH:21][C:14]=3[F:13])[C:4]=2[CH:3]=1
Reactant: O=C1CNc2ncc(I)cc2N1
Reactant: Fc1cc(F)c(CBr)cc1F
Product: O=C1CNc2ncc(I)cc2N1Cc1cc(F)c(F)cc1F
Yield: 55 %

Procedure:
7-Iodo-3,4-dihydro-1H-pyrido[2,3-b]pyrazin-2-one (1.0 g) was reacted with 2,4,5 trifluorobenzyl bromide as in General Procedure 1 to give the title compound as a pale yellow solid (55% yield). M.p. 227-228° C., LCMS: m/z=420.00 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 4.26 (s, 2H), 4.89 (bs, 1H), 5.06 (s, 2H), 6.91-7.00 (m, 2H), 7.16 (s, 1H), 7.91 (s, 1H).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH:7]([C:10]1[C:15](=[O:16])[NH:14][C:13](=[O:17])[NH:12][C:11]=1[O:18][C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([CH3:27])[CH:26]=1)[C:22]#[N:23])([CH3:9])[CH3:8].[CH2:28](I)[CH3:29].C(OCC)(=O)C>CN(C=O)C>[CH2:28]([N:12]1[C:11]([O:18][C:19]2[CH:20]=[C:21]([CH:24]=[C:25]([CH3:27])[CH:26]=2)[C:22]#[N:23])=[C:10]([CH:7]([CH3:9])[CH3:8])[C:15](=[O:16])[NH:14][C:13]1=[O:17])[CH3:29]
Reactant: Cc1cc(C#N)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCn1c(Oc2cc(C)cc(C#N)c2)c(C(C)C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 27.8 %

Procedure:
Potassium carbonate (24 mg, 0.172 mmol, 1.0 eq.) was added to 3-(5-isopropyl-2,6-dioxo-1,2,3,6-tetrahydro-pyrimidin-4-yloxy)-5-methyl-benzonitrile (103) (59 mg, 0.207 mmol, 1.2 eq.) in 2.0 mL DMF. The reaction mixture was stirred at room temperature for 10 minutes, then ethyl iodide (14 μL, 0.172 mmol) was added. The reaction mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction mixture, which was then washed with brine. The organic layer was concentrated and purified (silica gel, 20-80% EtOAc/hexane), followed by reverse phase HPLC (MeCN/water) to give a white powder (15 mg, 28%). LC-MS shows 314.1 (M+1). 1H NMR (300 MHz, CDCl3): δ 9.17 (br, 1H), 7.25 (s, 1H), 7.08 (s, 1H), 7.00 (s, 1H), 3.77 (t, 2H), 2.69 (m, 1H), 2.42 (s, 3H), 1.2 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:11][C@@H:10](I)[C@@H:9]2[CH2:13][C@H:6]1[C:7](=[O:14])[O:8]2)=[O:4].C[Si]([SiH]([Si](C)(C)C)[Si](C)(C)C)(C)C.N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:11][CH2:10][C@@H:9]2[CH2:13][C@H:6]1[C:7](=[O:14])[O:8]2)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](I)[C@@H]2C[C@H]1C(=O)O2
Agent: C[Si](C)(C)[SiH]([Si](C)(C)C)[Si](C)(C)C
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CC[C@@H]2C[C@H]1C(=O)O2
Temperature: 25 °C
Yield: 71 %

Procedure:
To a solution of compound 34b (1.24 g, 1.0 eq.) in toluene (12 mL) was added tris(trimethylsilyl)silane (1.48 mL, 1.2 eq.) with stirring, followed addition of 1,1′-azobis(cyclohexanecarbonitrile) (AIBN) (98 mg, 0.1 eq.). The reaction mixture was stirred at 90° C. for 1.5 hrs. The solution was cooled down to room temperature, quenched with 5% citric acid solution, and extracted with EtOAc (50 mL). Organics were washed sequentially with H2O (30 mL), saturated NaHCO3 aqueous solution (30 mL), and brine (30 mL), and concentrated under reduced pressure to yield a colourless oil. Crude material was purified by chromatography on silica gel (petroleum ether/EtOAc) to yield compound 34c as white crystals in 71% yield. 1H NMR (CDCl3, 400 MHz) δ 1.68-1.73 (m, 4H), 2.05-2.18 (m, 2H), 2.82-2.85 (m, 2H), 3.60 (s, 3H), 4.71 (m, 1H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH3:12][N:13]([C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)[NH2:14]>C(Cl)(Cl)Cl>[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[C:1]([NH:14][N:13]([C:15]1[O:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)[CH3:12])=[O:11])([OH:6])=[O:5]
Reactant: CN(N)c1nc2ccccc2o1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: ClC(Cl)Cl
Product: CN(NC(=O)c1ccccc1C(=O)O)c1nc2ccccc2o1
Reaction time: 8 h

Procedure:
A suspension of 5.2 g. of phthalic anhydride in 75 ml. of chloroform is stirred and treated with 5.7 g. of 2-(1-methylhydrazino)benzoxazole. A clear yellow solution results and the temperature drops several degrees, then rises to 33+ C. After about 15 min. precipitation of a solid begins. An additional 200 ml. of chloroform is added and the mixture is stirred overnight. The solid is filtered, washed with chloroform and dried to give 8.6 g. of product, m.p. 140°-142°.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:15]=2[Cl:23])[CH2:10]1)(C)(C)C.FC(F)(F)C(O)=O.Cl>ClCCl.O1CCOCC1>[Cl:23][C:15]1[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:14]=1[N:11]1[CH2:12][CH2:13][C@H:9]([CH2:8][NH2:7])[CH2:10]1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CCN(c2ccc([N+](=O)[O-])cc2Cl)C1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC[C@H]1CCN(c2ccc([N+](=O)[O-])cc2Cl)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A solution of [(R)-1-(2-chloro-4-nitrophenyl)pyrrolidin-3-yl]methylcarbamic acid tert-butyl ester (560 mg) in dichloromethane (2 mL) was mixed with trifluoroacetic acid (2 mL; alternatively a solution of HCl in dioxane or propanole-2 can be used) and stirred at room temperature for 5 hours. The reaction mixture was partitioned between dichloromethane and sodium carbonate solution. The organic phase was dried and concentrated. The product with the molecular weight of 255.71 (C11H14ClN3O2) was obtained in this way; MS (ESI): 256 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[Se:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:11][I:12]>C(Cl)(Cl)Cl>[I-:12].[CH3:1][C:2]1[Se:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N+:6]=1[CH3:11]
Reactant: Cc1nc2ccccc2[se]1
Reactant: CI
Solvent: ClC(Cl)Cl
Product: Cc1[se]c2ccccc2[n+]1C
Product: [I-]
Temperature: 80 °C
Yield: 94.2 %

Procedure:
2-Methylbenzoselenazole (10.1 g ) was dissolved in 100 ml of chloroform, then 10.0 g of methyl iodide was added to the solution, and the mixture was heated in an autoclave at 80° C. for 5 days. The crystals resulting from the reaction were taken out by filtration, washed with ether and dried to give 16.4 g of 2,3-dimethyl-benzoselenazolium iodide (yield 94%).
Reaction SMILES: CS(O)(=O)=O.CS(O)(=O)=O.[NH2:11][C:12]1[C:19](=[O:20])[N:15]2[CH2:16][CH2:17][CH2:18][N:14]2[C:13]=1[NH2:21].[NH2:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:30])=[C:27]([OH:29])[CH:28]=1.N.OO>O.C(O)C>[NH2:21][C:13]1[N:14]2[CH2:18][CH2:17][CH2:16][N:15]2[C:19](=[O:20])[C:12]=1/[N:11]=[C:24]1/[C:23]([NH2:22])=[CH:28][C:27](=[O:29])[C:26]([CH3:30])=[CH:25]/1
Reactant: Nc1c(N)n2n(c1=O)CCC2
Reactant: Cc1ccc(N)cc1O
Agent: CS(=O)(=O)O
Agent: N
Agent: OO
Solvent: O
Solvent: CCO
Product: CC1=C/C(=N\c2c(N)n3n(c2=O)CCC3)C(N)=CC1=O

Procedure:
0.58 mmol of 2,3-diamino-6,7-dihydro-1H,5H-pyrazolo[1,2-a]pyrazol-1-one dimethane sulphonate was dissolved in a mixture of water and ethanol (7.5 ml/1.5 ml). This solution was admixed with 0.58 mmol of 5-amino-2-methyl phenol, then with 1.8 ml of concentrated aqueous ammonia, then with 9 ml of hydrogen peroxide.
Reaction SMILES: CN1C=CC=C1[CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH:19][C:20]([C:22]3[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:21])[CH:15]=2)[CH2:10]1.FC(F)(F)C1C=CC(C2C(C(O)=O)=CC=CC=2)=CC=1.C1(C(C2C=CC=CC=2)CN2CCC3C(=CC=[C:70]([NH:75][C:76](C4C(C5C=CC(C(F)(F)F)=CC=5)=CC=CC=4)=[O:77])C=3)C2)C=CC=CC=1.C1(CCC2C3C(=CC(NC(C4C(C5C=CC(C(F)(F)F)=CC=5)=CC=CC=4)=O)=CC=3)CC[NH:109]2)C=CC=CC=1.N1CCC(N2CCC3C(=CC=C(NC(C4C(C5C=CC(C(F)(F)F)=CC=5)=CC=CC=4)=O)C=3)C2)CC1>>[CH3:70][NH:75][C:76](=[O:77])[NH:109][CH2:7][CH2:8][N:9]1[CH2:10][CH2:11][C:12]2[C:17](=[CH:16][CH:15]=[C:14]([NH:19][C:20]([C:22]3[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)=[CH:24][CH:25]=[CH:26][CH:27]=3)=[O:21])[CH:13]=2)[CH2:18]1
Reactant: O=C(Nc1ccc2c(c1)CCNC2CCc1ccccc1)c1ccccc1-c1ccc(C(F)(F)F)cc1
Reactant: Cn1cccc1CCN1CCc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2C1
Reactant: O=C(Nc1ccc2c(c1)CCN(CC(c1ccccc1)c1ccccc1)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: O=C(Nc1ccc2c(c1)CCN(C1CCNCC1)C2)c1ccccc1-c1ccc(C(F)(F)F)cc1
Agent: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Product: CNC(=O)NCCN1CCc2cc(NC(=O)c3ccccc3-c3ccc(C(F)(F)F)cc3)ccc2C1

Procedure:
##STR5## 4'-Trifluoromethylbiphenyl-2-carboxylic acid-{2- [2-(1-methyl-1H-pyrrol-2-yl)ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide; ##STR6## 4'-Trifluoromethylbiphenyl-2-carboxylic acid-{2-[2-(2H-[1,2,4]triazol-3-yl-ethyl]-1,2,3,4-tetrahydroisoquinolin-6-yl}-amide; ##STR7## 4'-Trifluoromethylbiphenyl-2-carboxylic acid-[2-(2,2-diphenylethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide; ##STR8## 4'-Trifluoromethylbiphenyl-2-carboxylic acid-[2-(2-pyridin-2-yl-ethyl-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide; ##STR9## 4'-Trifluoromethylbiphenyl-2-carboxylic acid-(2-phenylethyl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide; ##STR10## 4'-Trifluoromethylbiphenyl-2-carboxylic acid-(2-piperidin-4-yl-1,2,3,4-tetrahydroisoquinolin-6-yl)-amide; and ##STR11## 4'-Trifluoromethylbiphenyl-2-carboxylic acid-[2-(1-trifluoromethylacetyl-piperidin-4-yl)-1,2,3,4-tetrahydroisoquinolin-6-yl]-amide.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[C:16]2[C:7]([CH2:8][CH2:9][C:10]3[S:14][C:13]([NH2:15])=[N:12][C:11]=32)=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:18]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>>[N+:1]([C:4]1[CH:17]=[C:16]2[C:7]([CH2:8][CH2:9][C:10]3[S:14][C:13]([NH:15][S:24]([C:21]4[CH:20]=[CH:19][C:18]([C:28]5[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=5)=[CH:23][CH:22]=4)(=[O:26])=[O:25])=[N:12][C:11]=32)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(Cl)c1ccc(-c2ccccc2)cc1
Reactant: Nc1nc2c(s1)CCc1ccc([N+](=O)[O-])cc1-2
Product: O=[N+]([O-])c1ccc2c(c1)-c1nc(NS(=O)(=O)c3ccc(-c4ccccc4)cc3)sc1CC2

Procedure:
The title compound was prepared from 8nitro-4,5-dihydronaphtho[1,2-d][1,3]thiazol-2-amine (100 mg, synthesized according to METHOD I from 7-nitrotetralone) and 4-biphenylsulfonyl chloride (122 mg) as described in the synetic METHOD A to give a yellow powder (4.4 mg) with a purity of >90%: MS-ES (neg) m/z 462.4.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]([NH:12][C:13]3[CH:17]=[N:16][N:15]([CH3:18])[C:14]=3[C:19]([OH:21])=O)=[O:11])[C:7]([NH:22][C:23]3[CH:24]=[N:25][CH:26]=[N:27][CH:28]=3)=[N:6][CH:5]=2)[CH2:3][CH2:2]1.Cl.[O:30]1[CH2:34][CH2:33][CH2:32][NH:31]1>>[O:30]1[CH2:34][CH2:33][CH2:32][N:31]1[C:19]([C:14]1[N:15]([CH3:18])[N:16]=[CH:17][C:13]=1[NH:12][C:10]([C:8]1[C:7]([NH:22][C:23]2[CH:28]=[N:27][CH:26]=[N:25][CH:24]=2)=[N:6][CH:5]=[C:4]([CH:1]2[CH2:3][CH2:2]2)[N:9]=1)=[O:11])=[O:21]
Reactant: C1CNOC1
Reactant: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)O
Agent: Cl
Product: Cn1ncc(NC(=O)c2nc(C3CC3)cnc2Nc2cncnc2)c1C(=O)N1CCCO1

Procedure:
The product was obtained starting from 4-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyrazine-2-carbonyl]-amino}-2-methyl-2H-pyrazole-3-carboxylic acid (50 mg, 131 μmol; example 236, step 3) and isoxazolidine hydrochloride (17 mg, 145 μmol) according to the method described in example 64, step 6 after purification by preparative HPLC using an acetonitrile/water gradient as yellow solid (9 mg, 16%).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH3:21])([CH2:12][CH2:13][O:14]C1CCCCO1)[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>Cl>[CH2:1]([NH:8][C:9]([CH3:21])([CH2:12][CH2:13][OH:14])[CH2:10][OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CO)(CCOC1CCCCO1)NCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(CO)(CCO)NCc1ccccc1

Procedure:
The crude 2-benzylamino-2-methyl-4-((tetrahydro-2H-pyran-2-yl)oxy)butanol (10D, 80.1 g, 0.273 mol) was dissolved in 3N HCl (128 mL). After 5 min the mixture was washed with Et2O (200 mL). The aqueous solution was concentrated by rotary evaporation to give a thick oil which was cooled and basified with excess 50% NaOH. The oily amine which formed was extracted with Et2O (3×200 mL). The Et2O extends were combined and concentrated to give 63.6 g of a thick oil. Distillation gave 49.8 g (94%) of 2-benzylamino-2-methyl-1,4-butanediol as a pale yellow oil (bp 168°-170°/0.35 mm) (C,H,N)