Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[C:11]2=[CH:12][CH:13]=[CH:14][N:10]2[CH:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]=2[O:6]1)C.C(=O)([O-])[O-].[K+].[K+].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33].O>C1C=CC=CC=1>[CH2:35]([O:34][C:32]([N:2]([CH2:4][CH:5]1[C:11]2=[CH:12][CH:13]=[CH:14][N:10]2[CH:9]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]=2[O:6]1)[CH3:1])=[O:33])[CH3:36]
Reactant: CN(C)CC1Oc2ccccc2C(c2ccccc2)n2cccc21
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)N(C)CC1Oc2ccccc2C(c2ccccc2)n2cccc21
Temperature: 65 °C

Procedure:
To a mixture of 11-dimethylaminomethyl-5-phenyl-5H,11H-pyrrolo[2,1-c][1,4]benzoxazepine 9.92 g) and potassium carbonate (4.28 g) in 150 ml of benzene was added ethyl chloroformate (5.9 ml). This was heated at 65° C. for 6 hours, then added to water and extracted with ethyl ether (4×). The combined organics were washed with water, dried and concentrated to give 10.5 g of an oil which was used without further purification.
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH2:5][N:6]1[CH:15]=[C:9]2[N:10]=[CH:11][C:12]([Cl:14])=[CH:13][C:8]2=[N:7]1)[C:3]#[N:4].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[S:24])=[CH:21][CH:20]=1>>[Cl:14][C:12]1[CH:11]=[N:10][C:9]2=[CH:15][N:6]([CH2:5][C:2]([NH:1][C:23](=[S:24])[C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=3)([C:3]#[N:4])[CH3:16])[N:7]=[C:8]2[CH:13]=1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1cc2ncc(Cl)cc2n1
Product: CC(C#N)(Cn1cc2ncc(Cl)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, 2-amino-3-(6-chloro-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (35 mg, described in Example 155) and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (13 mg, 20%). MS (ES): M/Z [M+H]=440. 1H NMR: (400 MHz, CHLOROFORM-d): 1.96 (s, 3H), 4.86 (d, J=14.0 Hz, 1H), 5.01 (d, J=14.0 Hz, 1H), 7.71-7.83 (m, 2H), 7.83-7.92 (m, 2H), 8.02 (dd, J=2.1, 0.9 Hz, 1H), 8.12 (s, 1H), 8.43 (d, J=0.7 Hz, 1H) and 8.56 (d, J=2.1 Hz, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −42.2 (s, 3F).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][CH:13]([NH2:17])[CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:7]1.[CH3:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1.C([O-])(O)=O.[Na+].Cl>ClCCl.C(OCC)(=O)C.C(N(CC)CC)C>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[O:5][CH:6]1[CH2:7][CH2:8][N:9]([CH2:12][CH:13]([NH:17][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([CH3:22])=[CH:24][CH:25]=2)[CH:14]([CH3:15])[CH3:16])[CH2:10][CH2:11]1
Reactant: CC(C)C(N)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)NC(CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)C(C)C)cc1
Reaction time: 2 h

Procedure:
The product of step (iii) (0.2 g) was dissolved in dichloromethane (5 ml), triethylamine (0.126 ml) and 4-methylbenzoyl chloride (0.097 ml) were added. After 2 hours at room temperature, ethyl acetate and aqueous NaHCO3 solution were added, the organic phase separated and the solvent removed to leave an oil. Purification by reverse phase HPLC (with a gradient eluent system (25% MeCN/NH4OAcaq (0.1%) to 95% MeCN//NH4OAcaq (0.1%)) gave a gum. Addition of 1.0M ethereal hydrogen chloride solution gave the titled product as a solid (0.104 g).
Reaction SMILES: [CH3:1][N:2]1[C@@H:19]2[CH2:20][C:7]3[CH:8]=[CH:9][C:10]([O:22][CH3:23])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:16][CH2:17][C@:18]2([OH:21])[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:15].CCN(C(C)C)C(C)C.C1CCC(N=C=NC2CCCCC2)CC1.[C:48]([O:52][C:53](=[O:60])[CH2:54][CH2:55][CH2:56][C:57](O)=[O:58])([CH3:51])([CH3:50])[CH3:49]>C(#N)C.CN(C1C=CN=CC=1)C.C(O)(C(F)(F)F)=O>[CH3:23][O:22][C:10]1[CH:9]=[CH:8][C:7]2[CH2:20][C@H:19]3[N:2]([CH3:1])[CH2:3][CH2:4][C@:5]45[C:6]=2[C:11]=1[O:12][C@H:13]4[C:14]([O:15][C:57](=[O:58])[CH2:56][CH2:55][CH2:54][C:53]([O:52][C:48]([CH3:50])([CH3:49])[CH3:51])=[O:60])=[CH:16][CH2:17][C@@:18]35[OH:21]
Reactant: CC(C)(C)OC(=O)CCCC(=O)O
Reactant: COc1ccc2c3c1O[C@H]1C(=O)CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c3c1O[C@H]1C(OC(=O)CCCC(=O)OC(C)(C)C)=CC[C@@]4(O)[C@@H](C2)N(C)CC[C@]314
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.3 %

Procedure:
A suspension of oxycodone free base (100 mg, 0.317 mmol) in 1.5 mL of anhydrous acetonitrile was stirred for 20 min with DIEA (0.2 mL 1.15 mmol). DMAP (63 mg, 0.516 mmol) and DCC (112 mg, 0.545 mmol) were then added to the stirred suspension. After 5 min 1-2 (150 mg, 0.8 mmol) was added, the mixture stirred for 16 h at rt, and the resulting orange suspension concentrated to an oil under reduced pressure. The concentrated mixture was stirred with 6 mL of acetone for 10 min, and the precipitated DCU removed by filtration. The filtrate was concentrated to give a brown oil. HPLC analysis of the oil indicated that the primary reaction product was 1-3. The concentrated oil was subjected to reverse phase C-18 silica gel chromatography using a gradient of 25–40% acetonitrile in 0.07% aqueous TFA as eluent. Evaporation of the eluent from the fraction containing 1-3 gave 82 mg (53% yield) of a colorless oil which was greater than >99% pure 1-3 (HPLC).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:26])([C@@H:14]([CH2:21][CH:22](OC)O)[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1.[S:27]1[CH:31]=[N:30][N:29]=[C:28]1[NH2:32].C(Cl)Cl.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(OCC)(=O)C.Cl[Ti](OC(C)C)(OC(C)C)OC(C)C.CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][N:11]3[C:20]=2[CH:19]=[C:18]2[C@@:13]([CH3:26])([C@@H:14]([CH2:21][CH2:22][NH:32][C:28]4[S:27][CH:31]=[N:30][N:29]=4)[CH2:15][CH2:16][CH2:17]2)[CH2:12]3)=[CH:4][CH:3]=1
Reactant: COC(O)C[C@H]1CCCC2=Cc3c(-c4ccc(F)cc4)ncn3C[C@@]21C
Reactant: Nc1nncs1
Agent: CC(C)O[Ti](Cl)(OC(C)C)OC(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: C[C@]12Cn3cnc(-c4ccc(F)cc4)c3C=C1CCC[C@@H]2CCNc1nncs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a stirred mixture of 2-((5aR,6R)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)-1-methoxyethanol (18 mg, 0.05 mmol), 1,3,4-thiadiazol-2-amine (10 mg, 0.1 mmol), and anhydrous methylene chloride (0.5 mL) was added chlorotriisopropoxytitanium solution (1 M in hexanes, 0.2 mL, 0.2 mmol) at RT under nitrogen. The mixture was stirred at RT for 15 min before sodium triacetoxyborohydride (106 mg, 0.5 mmol) was added. The mixture was stirred at RT for 1 hr and quenched by the addition of saturated aqueous sodium bicarbonate solution (3 mL). The aqueous layer was separated and extracted with ethyl acetate (3×2 mL). The combined organic solutions were dried (Na2SO4) and concentrated. Prep TLC (silica gel, 50% acetone in ethyl acetate) gave N-(2-((5aR,6R)-1-(4-fluorophenyl)-5a-methyl-5,5a,6,7,8,9-hexahydroimidazo[1,5-b]isoquinolin-6-yl)ethyl)-1,3,4-thiadiazol-2-amine (6 mg, 0.015 mmol, 30% yield) as a solid.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[C:25]([O:29][C:30]([NH:32][C:33]1([C:48]([OH:50])=O)[CH2:38][CH2:37][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:35][CH2:34]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].C(N(C(C)C)C(C)C)C.[NH2:60][CH:61]([C:67]1[CH:72]=[CH:71][C:70]([Cl:73])=[CH:69][CH:68]=1)[CH2:62][NH:63][C:64](=[O:66])[CH3:65]>CN1C(=O)CCC1>[C:64]([NH:63][CH2:62][CH:61]([NH:60][C:48]([C:33]1([NH:32][C:30](=[O:31])[O:29][C:25]([CH3:27])([CH3:26])[CH3:28])[CH2:34][CH2:35][N:36]([C:39]2[C:40]3[CH:47]=[CH:46][NH:45][C:41]=3[N:42]=[CH:43][N:44]=2)[CH2:37][CH2:38]1)=[O:50])[C:67]1[CH:68]=[CH:69][C:70]([Cl:73])=[CH:71][CH:72]=1)(=[O:66])[CH3:65]
Reactant: CC(=O)NCC(N)c1ccc(Cl)cc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCN(c2ncnc3[nH]ccc23)CC1
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: CN1CCCC1=O
Product: CC(=O)NCC(NC(=O)C1(NC(=O)OC(C)(C)C)CCN(c2ncnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 65 h
Yield: 81.7 %

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (89 mg, 0.23 mmol) was added in one portion to a stirred solution of 4-(tert-butoxycarbonylamino)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidine-4-carboxylic acid (Intermediate 1) (80 mg, 0.22 mmol) and N-ethyldiisopropylamine (0.046 mL, 0.27 mmol) in NMP (3 mL). The mixture was treated with N-(2-amino-2-(4-chlorophenyl)ethyl)acetamide (Intermediate 83) (52 mg, 0.24 mmol). The solution was stirred for 65 hours at room temperature. The mixture was partitioned between ethyl acetate and water. The organic layer was washed twice with water. The organic solution was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica using gradient elution (1% methanol/DCM to 15% methanol/DCM). Product containing fractions were combined to give tert-butyl 4-(2-acetamido-1-(4-chlorophenyl)ethylcarbamoyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-4-ylcarbamate (100 mg, 81%) as colourless solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:4]=1[C:21]1[O:22][CH:23]=[CH:24][N:25]=1.[O:26]1[C:30]2[CH:31]=[CH:32][C:33]([C:35](Cl)=[O:36])=[CH:34][C:29]=2[O:28][CH2:27]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:35]([C:33]3[CH:32]=[CH:31][C:30]4[O:26][CH2:27][O:28][C:29]=4[CH:34]=3)=[O:36])=[C:4]([C:21]3[O:22][CH:23]=[CH:24][N:25]=3)[N:5]2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:10][CH:9]=1
Reactant: NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1c(-c2ncco2)n(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial, 3-(aminomethyl)-7-chloro-2-(oxazol-2-yl)-1-phenylquinolin-4(1H)-one (intermediate A) (20 mg, 0.057 mmol), benzo[d][1,3]dioxole-5-carbonyl chloride (12 mg, 0.065 mmol) and N,N-(dimethylamino)pyridine (DMAP) (1.0 mg, 0.085 mmol) were combined with methylene chloride (1.5 mL) to give a brown solution. N,N-diisopropylethylamine (37 mg, 0.050 mL, 0.28 mmol) was added. The reaction mixture was stirred overnight at room temperature. In the morning, LC/MS indicated complete conversion to the desired product. The reaction mixture was diluted with 10 mL methylene chloride, then the organic solution was washed with water. The organic phase was dried over Na2SO4, filtered, then concentrated over silica gel. The silica gel-supported crude product was loaded onto a 25 gram SiliCycle column. Flash chromatography (50% ethyl acetate-hexanes ramped to 75% ethyl acetate-hexanes) afforded benzo[1,3]dioxole-5-carboxylic acid (7-chloro-2-oxazol-2-yl-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-amide as a brown oil. 1H NMR (300 MHz, chloroform-d) δ ppm 8.36 (d, J=8.67 Hz, 1H) 7.50 (d, J=0.94 Hz, 1H) 7.34-7.42 (m, 4H) 7.30 (dd, J=8.67, 1.88 Hz, 1H) 7.15-7.26 (m, 6H) 7.05 (d, J=0.94 Hz, 1H) 6.77 (d, J=1.88 Hz, 1H) 6.70 (d, J=8.10 Hz, 1H) 5.91 (s, 2H) 4.37 (s, 2H). MS calcd. for C27H18ClN3O5 [(M+H)+] 499.9, obsd. 500.0.
Reaction SMILES: [N-]1C=CN=C1.CO.[C:8]([C:15]1NC=CN=1)([C:10]1NC=CN=1)=[O:9].ClCCl.[O:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>>[OH:9][C:8]1[CH:10]=[C:25]([CH:26]=[CH:27][CH:15]=1)[CH2:24][OH:23]
Reactant: C1CCOC1
Reactant: O=C(c1ncc[nH]1)c1ncc[nH]1
Agent: c1c[n-]cn1
Solvent: ClCCl
Solvent: CO
Product: OCc1cccc(O)c1

Procedure:
Scheme 20 Example 4 illustrates the preparation of carbamates in which an alkyloxycarbonylimidazole 20.8 is employed. In this procedure, a carbinol 20.5 is reacted with an equimolar amount of carbonyl diimidazole 20.11 to prepare the intermediate 20.8. The reaction is conducted in an aprotic organic solvent such as dichloromethane or tetrahydrofuran. The acyloxyimidazole 20.8 is then reacted with an equimolar amount of the amine R′NH2 to afford the carbamate 20.7. The reaction is performed in an aprotic organic solvent such as dichloromethane, as described in Tet. Lett., 42, 2001, 5227, to afford the carbamate 20.7.
Reaction SMILES: [O:1]=[C:2]1[CH2:8][C:7](=[O:9])[N:6]([C:10]2[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[CH:12][CH:11]=2)[C:5]2[CH:19]=[CH:20][C:21]3[C:26]([C:4]=2[NH:3]1)=[CH:25][CH:24]=[CH:23][CH:22]=3.[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31].C1(NC(C2C=CC(N3C(=O)CC(=O)NC4C5C(C=CC3=4)=CC=CC=5)=CC=2)=O)C=CC=CC=1>>[Cl:27][C:28]1[CH:35]=[CH:34][CH:33]=[CH:32][C:29]=1[CH2:30][NH:31][C:14]([C:13]1[CH:12]=[CH:11][C:10]([N:6]2[C:7](=[O:9])[CH2:8][C:2](=[O:1])[NH:3][C:4]3[C:26]4[C:21]([CH:20]=[CH:19][C:5]2=3)=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][CH:17]=1)=[O:16]
Reactant: NCc1ccccc1Cl
Reactant: O=C1CC(=O)N(c2ccc(C(=O)O)cc2)c2ccc3ccccc3c2N1
Agent: O=C1CC(=O)N(c2ccc(C(=O)Nc3ccccc3)cc2)c2ccc3ccccc3c2N1
Product: O=C1CC(=O)N(c2ccc(C(=O)NCc3ccccc3Cl)cc2)c2ccc3ccccc3c2N1
Yield: 15 %

Procedure:
By using 4-[2,4-dioxo-3,4-dihydro-1H-naphtho[2,1-b][1,4]diazepin-5(2H)-yl]benzoic acid obtained in Example 102, (4), and 2-chlorobenzylamine, the title compound (yield 15%) was obtained in the same manner as that of Example 102, (5).
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]([NH2:13])=[O:12])[CH:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1)(=O)=O.CCN(C(C)C)C(C)C.[CH3:29][NH:30][CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O1CCOCC1>[CH3:29][N:30]([CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:5]1[N:10]=[C:9]([C:11]([NH2:13])=[O:12])[CH:8]=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]=1
Reactant: CNCCc1ccccc1
Reactant: CS(=O)(=O)c1nc(C(N)=O)cc(-c2ccccc2)n1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCc1ccccc1)c1nc(C(N)=O)cc(-c2ccccc2)n1
Temperature: 85 °C
Yield: 51.7 %

Procedure:
2-Methanesulfonyl-6-phenylpyrimidine-4-carboxamide (70 mg, 0.25 mmol), 1,4-dioxane (4 mL), DIPEA (0.3 mL, 2.0 mmol) and N-methylphenethylamine (82 mg, 0.6 mmol) were added to a 8 mL vial. The vial was sealed and heated at 85° C. for two days. The reaction mixture was allowed to cool to room temperature, and the solvent then removed by centrifugal evaporation. The residue was purified by preparative HPLC to afford 43 mg of 2-(N-methylphenethylamino)-6-phenylpyrimidine-4-carboxamide. 1H NMR (CDCl3, 300 MHz) δ 8.14 (m, 2H), 7.74 (s, 1H), 7.67 (br s, 1H), 7.47 (m, 3H), 7.25 (m, 5H), 5.79 (br s, 1H), 3.95 (t, J=6.9 Hz, 2H), 3.21 (s, 3H), 2.97 (t, J=6.9 Hz, 2H). HPLC ret. time 3.25 min, 10-100% CH3CN, 5 min run. ESI-MS m/z 333.3 (M+H)+.
Reaction SMILES: [H-].[Na+:2].Cl[C:4]1[CH:16]=[C:15](Cl)[CH:14]=[CH:13][C:5]=1[CH2:6][C:7]1[N:8]=[N:9][CH:10]=[CH:11][CH:12]=1.[CH3:18][OH:19]>>[CH3:18][O-:19].[Na+:2].[CH3:18][O:19][CH:6]([C:7]1[N:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[C:5]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:4]=1
Reactant: CO
Reactant: Clc1ccc(Cc2cccnn2)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Product: COC(c1ccccc1)c1cccnn1
Product: C[O-]

Procedure:
A solution of sodium methoxide was prepared by the addition of sodium hydride (0.72 g.) to methanol (25 ml.). (±) 3-α-Chlorobenzylpyridazine (prepared as described in Example 2) (4.1 g.) was heated at reflux in this solution for 2 hours and the mixture was evaporated to dryness. The residue was dissolved in a mixture of diethyl ether and water and the ethereal layer was separated, dried over sodium sulphate and evaporated to give a brown oil. Distillation of this oil gave (±) 3-α-methoxybenzylpyridazine (1.8 g.), b.p. 140°-180° C./0.2-0.4 mm.Hg.
Reaction SMILES: [CH:1](=[N:3][OH:4])[CH3:2].ClN1C(=O)CCC1=O.[C:13]([C:15]1[CH:21]2[CH2:22][CH:18]([CH2:19][N:20]2[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17][CH:16]=1)#[CH:14].C(N(CC)CC)C>C(Cl)(Cl)Cl.N1C=CC=CC=1>[CH3:2][C:1]1[CH:14]=[C:13]([C:15]2[CH:21]3[CH2:22][CH:18]([CH2:19][N:20]3[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:17][CH:16]=2)[O:4][N:3]=1
Reactant: C#CC1=CCC2CC1N(C(=O)OC(C)(C)C)C2
Reactant: CC=NO
Agent: O=C1CCC(=O)N1Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1cc(C2=CCC3CC2N(C(=O)OC(C)(C)C)C3)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of acetaldoxime (65 mg, 1.1 mmol) in 15 mL of chloroform were added 2 drops of pyridine, followed by N-chlorosuccinimide (146 mg, 1.1 mmol). After stirring the cloudy mixture for 1 h at ambient temperature, tert-butyl 4-ethynyl-6-azabicyclo[3.2.1]oct-3-ene-6-carboxylate (233 mg, 1.00 mmol) was added in 2 mL of chloroform, followed by drop-wise addition of triethylamine (0.175 mL, 1.25 mmol). The mixture was stirred at ambient temperature for 4 h and then concentrated to dryness under reduced pressure. The residue was chromatographed on a silica gel column, with a gradient of 2:1 hexane/ethyl acetate to 2:1 ethyl acetate/hexane, to give first recovered starting material, then tert-butyl 4-(3-methyl-5-isoxazolyl)-6-azabicyclo[3.2.1]oct-3-ene-6-carboxylate (100 mg, 40%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH3:10])=[N+:7]([O-:9])[CH:8]=1.[N+:11]([O-])([OH:13])=[O:12]>>[CH3:1][O:2][C:3]1[C:4]([N+:11]([O-:13])=[O:12])=[CH:5][C:6]([CH3:10])=[N+:7]([O-:9])[CH:8]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C)[n+]([O-])c1
Product: COc1c[n+]([O-])c(C)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 1 h
Yield: 87 %

Procedure:
21.2 g of 5-methoxy-2-methylpyridine 1-oxide are metered into 35 ml of 65% strength nitric acid and warmed to 60° C. in a manner such that the temperature of the reaction mixture does not rise above 80° C. The mixture is stirred at 80° C. for 1 hour, a further 13 ml of 100% strength nitric acid are added to bring the reaction to completion and the mixture is stirred at 60°-70° C. for a further 2 hours. For working up, the mixture is poured onto 300 g of ice. The yellow precipitate which separates out is filtered off over a suction filter, washed with water and dried. The dry solid is boiled up with 200 ml of methylene chloride, filtered off and dried. Further TLC-pure product is isolated by concentration of the filtrate. 22.3 g (87% of theory) of 5-methoxy-2-methyl-4-nitropyridine 1oxide of m.p. 201°-202° C. are obtained as yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=O)[CH:9]([CH3:13])[N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[S:22])[CH:9]([CH3:13])[N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:6]=2[CH:20]=1
Reactant: CC1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=O
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: CC1N=C(c2ccccc2)c2cc(Cl)ccc2NC1=S
Yield: 28.5 %

Procedure:
A stirred mixture of 7-chloro-1,3-dihydro-3-methyl-5-phenyl-2H-1,4 -benzodiazepin-2-one (10 g, 0.035 mol) in pyridine (300 ml), treated with P2S5 (8.0 g, 0.036 mol) was refluxed, under N2, for 2 hours then concentrated in vacuo. To remove the remaining pyridine the residue was combined with toluene twice with concentration after each addition. The remaining material was mixed with cold NaHCO3 and extracted twice with CH2Cl2. At this point a precipitate thought to be undissolved product formed between the two layers. This was filtered and washed with CH2Cl2 and H2O . The NaHCO3 layer was extracted with CH2Cl2 again. The combined CH2Cl2 extracts were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was crystallized from EtOAc-Skelly B to give 3.0 g of the subtitled intermediate, mp 250°. The precipitate was also recrystallized from EtOAc-Skelly B to give 3.01 g of additional subtitled intermediate, mp 255°.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C(C[C:11]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])=[CH:15][CH:14]=[C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])C=1CC(O)=O)(O)=O.[C:35](=[O:37])=O.C([O:41][CH2:42][CH3:43])(=O)C>C1COCC1>[OH:41][CH2:42][C:43]1[C:13]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])=[CH:14][CH:15]=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[CH3:23])[C:11]=1[CH2:35][OH:37]
Reactant: CCOC(C)=O
Reactant: Cc1ccccc1-c1ccc(-c2ccccc2C)c(CC(=O)O)c1CC(=O)O
Reactant: O=C=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc(-c2ccccc2C)c(CO)c1CO
Temperature: 0 °C

Procedure:
250 ml of THF are slowly added to 10.13 g (267.3 mmol) of lithium aluminium hydride, then 71.5 g (190.9 mmol) of 1,2-dicarboxymethyl-3,6-di-o-tolylbenzene, dissolved in 450 ml of THF, are slowly added at such a rate that the temperature does not rise above 40° C. If necessary, the mixture is cooled using dry ice. When the addition is complete, the suspension is heated under reflux for 2 h. When the conversion is complete, a mixture of 120 ml of ethyl acetate and 340 ml of THF is slowly added with cooling at 0° C. (reaction of the excess lithium aluminium hydride with ethyl acetate). When quenching is complete, 300 ml of ethanol are carefully added, and the mixture is subjected to aqueous work-up. 200 ml of water are added, the precipitate is filtered off with suction, and the mother liquor is evaporated a little, extracted with ethyl acetate and dichloromethane, dried over MgSO4 and evaporated, giving 61 g of crude product, which can be employed directly in the next transformation.
Reaction SMILES: COC1C=C(C=CC=1C[N:25]([C:36]1[CH:37]=[C:38]2[C:43](=[CH:44][CH:45]=1)[C:42]([CH2:46][C:47]1[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=1)=[N:41][NH:40][C:39]2=[O:53])[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=1)=[O:27])OCCCC(NCC1C=CC(C)=CC=1)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:53]=[C:39]1[C:38]2[C:43](=[CH:44][CH:45]=[C:36]([NH:25][C:26]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=3)=[O:27])[CH:37]=2)[C:42]([CH2:46][C:47]2[CH:48]=[N:49][CH:50]=[CH:51][CH:52]=2)=[N:41][NH:40]1
Reactant: COc1cc(OCCCC(=O)NCc2ccc(C)cc2)ccc1CN(C(=O)Nc1ccc(C)cc1)c1ccc2c(Cc3cccnc3)n[nH]c(=O)c2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)Nc2ccc3c(Cc4cccnc4)n[nH]c(=O)c3c2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4-{3-Methoxy-4-[1-(4-oxo-1-pyridin-3-ylmethyl-3,4-dihydro-phthalazin-6-yl)-3-p-tolyl-ureidomethyl]-phenoxy}-N-(4-methyl-benzyl)-butyramide of example 8 was suspended in a solution of 20% TFA in DCM (3 ml), and stirred at room temperature for 2 hours. The resin was filtered and the solution collected and dried up yielding 11 mg of title compound. [M+1]+=386; HPLC r.t. 4.72; 1H-NMR (DMSO-d6), diagnostic signals (ppm): 2.23 (s, 3H), 4.26 (s, 2H), 7.10 (d, 2H), 7.29 (m, 1H) 7.33 (d, 2H), 7.64 (m, 1H), 7.83 (dd, 1H), 7.89 (d, 1H), 8.40 (m, 2H), 8.56 (d, 1H), 8.70 (br. S, 1H), 9.22 (br. s, 1H), 12.38 (br. s, 1H).
Reaction SMILES: [C:1]1([C:7]2([C:13]#[N:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:15](#[N:18])[CH:16]=[CH2:17]>CO>[C:15]([CH2:16][CH2:17][N:10]1[CH2:9][CH2:8][C:7]([C:13]#[N:14])([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:12][CH2:11]1)#[N:18]
Reactant: C=CC#N
Reactant: N#CC1(c2ccccc2)CCNCC1
Solvent: CO
Product: N#CCCN1CCC(C#N)(c2ccccc2)CC1

Procedure:
4-Phenyl-4-cyanopiperidine (7 g, 37.6 mmol) and acrylonitrile (2.97 ml ,45.1 mmol) were stirred at room temperature in methanol (34 mL) for 18 hours monitoring the reaction by tlc until complete. The solvent was removed under vacuum and the residue chased with toluene (2x). This residual oil was used directly in the next step