Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4]([C:6]1[C:21](=[O:22])[N:20]([CH2:23][CH3:24])[C:9]2[N:10]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:12]=[CH:13][C:8]=2[C:7]=1Cl)=[O:5])C.[NH2:26][CH2:27][CH2:28][OH:29]>>[CH2:23]([N:20]1[C:9]2[N:10]=[C:11]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:12]=[CH:13][C:8]=2[C:7]([NH:26][CH2:27][CH2:28][OH:29])=[C:6]([C:4]([NH:26][CH2:27][CH2:28][OH:29])=[O:5])[C:21]1=[O:22])[CH3:24]
Reactant: CCOC(=O)c1c(Cl)c2cnc(-c3ccccc3)nc2n(CC)c1=O
Reactant: NCCO
Product: CCn1c(=O)c(C(=O)NCCO)c(NCCO)c2cnc(-c3ccccc3)nc21

Procedure:
To 2 g. (0.0056 mole) of 5-chloro-7,8-dihydro-8-ethyl-7-oxo-2-phenylpyrido[2,3-d]pyrimidine-6-carboxylic acid ethyl ester (prepared by the method of the first paragraph of Example 3) was added 20 ml. of 2-aminoethanol and this mixture was heated at reflux for 1.5 hours. The reaction mixture was chilled in ice and the product collected on a filter and recrystallized from ethanol to give 1.7 g. of product.--m.p. 250°-253° C.
Reaction SMILES: [C:1]1(/[C:7](/[C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25](O)=[O:26])=[CH:19][CH:18]=2)=[C:8](/[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)\[CH2:9][CH3:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:28]1([CH3:38])[CH:33]=[CH:32][CH:31]=[C:30]([S:34]([NH2:37])(=[O:36])=[O:35])[CH:29]=1>>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([NH:37][S:34]([C:30]3[CH:31]=[CH:32][CH:33]=[C:28]([CH3:38])[CH:29]=3)(=[O:35])=[O:36])=[O:26])=[CH:19][CH:18]=2)=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:9][CH3:10])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC/C(=C(\c1ccccc1)c1ccc(C=CC(=O)O)cc1)c1ccccc1
Reactant: Cc1cccc(S(N)(=O)=O)c1
Product: CCC(=C(c1ccccc1)c1ccc(C=CC(=O)NS(=O)(=O)c2cccc(C)c2)cc1)c1ccccc1

Procedure:
Prepared by coupling 1a and m-toluenesulfonamide (Synlett, 1997, 375) in accordance with Procedure 1, Method B described hereinabove. Yield (24%); 1H NMR (CDCl3) δ 7.86 (m, 2H), 7.50 (d, J=15.7 Hz, 1H), 7.42–7.07 (m, 14H), 6.86 (d, J=8.4 Hz, 2H), 6.27 (d, J=15.7 Hz, 1H), 2.47 (q, J=7.3 Hz, 2H), 2.41 (s, 3H), 0.93 (t, J=7.3 Hz, 3H); APcI m/z: 508 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(N(CC)CC)C.Cl[C:20]([O:22][CH3:23])=[O:21]>C(#N)C>[CH3:23][O:22][C:20](=[O:21])[NH:11][S:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])(=[O:10])=[O:9]
Reactant: NS(=O)(=O)c1ccccc1Cl
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)NS(=O)(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 25.0 g 2-chloro-benzenesulfonamide was added 75 mL acetonitrile and 45.2 mL (2.5 eq) triethylamine. The mixture was cooled with an ice bath and 15.1 mL methyl chloroformate was slowly added dropwise. The mixture was stirred overnight at room temperature and concentrated in vacuo. Water was added and de aqueous layer was washed two times with ether. Acidification of the aqueous layer with 2 M HCl led to formation of a white precipitate. The suspension was filtered, the residue was washed with H2O and dried in vacuo to yield 19.1 g of a white solid. 1H NMR (400 MHz, DMSO-d6) δ 3.58 (s, 3H), 7.52-7.61 (m, 1H), 7.62-7.72 (m, 2H), 8.10 (dd, J=8 and 1.5 Hz, 1H), 12.42 (br s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:15]=[CH:14][C:8]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[C:7]([CH3:16])[CH:6]=1)=O.[NH2:17][C:18](=[N:20][C:21]([NH2:23])=[S:22])[NH2:19]>C(O)C>[NH2:17][C:18](=[N:20][C:21]1[S:22][CH:2]=[C:3]([C:5]2[CH:15]=[CH:14][C:8]([CH2:9][NH:10][C:11](=[O:13])[CH3:12])=[C:7]([CH3:16])[CH:6]=2)[N:23]=1)[NH2:19]
Reactant: NC(=S)N=C(N)N
Reactant: CC(=O)NCc1ccc(C(=O)CCl)cc1C
Solvent: CCO
Product: CC(=O)NCc1ccc(-c2csc(N=C(N)N)n2)cc1C
Yield: 69.1 %

Procedure:
A mixture of N-(4-chloroacetyl-2-methylbenzyl)acetamide (3.6 g) and (diaminomethylene)thiourea (2.3 g) in ethanol (100 ml) was refluxed for 2 hours under stirring. The reaction mixture was evaporated in vacuo and the residue was suspended in water and resultant mixture was adjusted to pH 8.0 with 20% potassium carbonate aqueous solution and the precipitate was collected by filtration. The precipitate was dissolved in a mixture of ethyl acetate and tetrahydrofuran, washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was recrystallized from ethanol to give 2-(diaminomethyleneamino)-4-(4-acetylaminomethyl-3-methylphenyl)thiazole (3.15 g).
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]1[C:9]2[N:10]([CH3:14])[C:11](=[O:13])[O:12][C:8]=2[CH:7]=[C:6]([N:15]2[CH2:19][C@H:18]([C:20]([O:22]C)=O)[O:17][C:16]2=[O:24])[CH:5]=1>CO>[F:3][C:4]1[C:9]2[N:10]([CH3:14])[C:11](=[O:13])[O:12][C:8]=2[CH:7]=[C:6]([N:15]2[CH2:19][C@H:18]([C:20]([NH:2][CH3:1])=[O:22])[O:17][C:16]2=[O:24])[CH:5]=1
Reactant: CN
Reactant: COC(=O)[C@H]1CN(c2cc(F)c3c(c2)oc(=O)n3C)C(=O)O1
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2cc(F)c3c(c2)oc(=O)n3C)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
A solution of methylamine in methanol (2M, 5 ml) is added to solid methyl (5R)-3-(4-fluoro-3-methyl-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate (EXAMPLE 86, Step 9, 0.250 g, 0.806 mmol) and the suspension stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and the residue purified by PTLC (10% methanol/dichloromethane) to give product as a white solid (0.049 g, 19%); MS for C13H12FN3O5 m/z 310 (M+H)+; 1H NMR (DMSO-d6, 300 Mhz) δ 8.40 (m, 1H), 7.49 (d, 1H), 7.42 (dd, 1H), 5.07 (dd, 1H), 4.26 (t, 1H), 4.02 (dd, 1H), 3.42 (s, 3H), 2.65 (d, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[C:12]2=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:19]=O.[NH:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[CH:16]=[CH:15][C:14]([CH2:19][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:13]([OH:17])[C:12]2=[O:18])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)n2cccc(O)c2=O)cc1
Reactant: C=O
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)n2ccc(CN3CCCC3)c(O)c2=O)cc1
Reaction time: 0.5 h

Procedure:
1-(4′-Methylbenzenesulfonyl)-3-hydroxypyridin-2(1H)-one (7) (250 mg, 0.94 mmol) and formaldehyde (200 mg, 2.07 mmol) are combined in aqueous ethanol (10 mL) and stirred for 30 minutes. Pyrrolidine (149 mg, 2.07 mmol) is then added and the reaction stirred for 12 hours. The solvent is removed by evaporation and the residue dissolved in methanol (5 mL) and purified via prep HPLC eluting with water/acetonitrile to afford the desired product. 1H NMR (300 MHz, DMSO) δ 1.87 (m, 2H), 1.99 (m, 2H), 2.44 (s, 3H), 3.09 (m, 2H), 3.40 (m, 2H), 4.19 (s, 2H), 6.51 (d, J=7.5 Hz, 1H), 7.51 (d, J=8.4 Hz, 1H), 7.76 (d, J=7.5 Hz, 1H), 7.98 (d, J=8.1 Hz, 1H), 9.93 (broad s, 1H); 19F NMR (252 MHz, DMSO) δ 88.4; 13C NMR (75 MHz, DMSO) δ 21.5, 22.7, 50.5, 53.7, 108.7, 118.6, 119.4, 128.4, 129.7, 130.1, 133.1, 146.8, 147.7, 156.2; ES MS (M+1) 349.25; HRMS Calcd. For C17H20N2O4S, 348.42. Found (M+1) 349.42.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH:11]=[CH2:12])[N:5]=1)[CH3:2].C[N+]1([O-])CC[O:19]CC1.[OH2:23]>C(O)(C)(C)C.CC(C)=O.CC(=O)OCC.O=[Os](=O)(=O)=O>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4]1[N:5]=[C:6]([CH:11]([OH:19])[CH2:12][OH:23])[CH:7]=[C:8]([CH3:10])[CH:9]=1)[CH3:14]
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=Cc1cc(C)cc(N(CC)CC)n1
Reactant: O
Agent: O=[Os](=O)(=O)=O
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Solvent: CC(C)(C)O
Product: CCN(CC)c1cc(C)cc(C(O)CO)n1

Procedure:
A solution of diethyl-(4-methyl-6-vinyl-pyridin-2-yl)-amine (457 mg, 2.40 mmol), N-methyl-morpholine-N-oxide (885 mg), and OsO4 (5 mg, 20 μmol, 200 μL of a 2.5% solution in tert.-butanol) in acetone (16 mL) and water (2 mL) is stirred at rt for 18 h. The mixture is diluted with EA (200 mL) and washed with water (50 mL). The org. extract is dried over MgSO4, filtered and concentrated to give crude 1-(6-diethylamino-4-methyl-pyridin-2-yl)ethane-1,2-diol (550 mg) as a brown oil; LC-MS: tR=0.55 min, [M+1]+=225.03. 1H NMR (CDCl3): δ 1.20 (t, J=7.0 Hz, 6H), 2.27 (s, 3H), 3.51 (q, J=7.0 Hz, 4H), 3.71 (dd, J=11.3, 5.8 Hz, 1H), 3.75 (s br, 1H), 3.88 (dd, J=11.0, 3.8 Hz, 1H), 4.62 (t, J=4.8 Hz, 1H), 6.22 (s, 1H), 6.33 (s, 1H). A solution of the above crude 1-(6-diethylamino-4-methyl-pyridin-2-yl)-ethane-1,2-diol (550 mg, 2.45 mmol) and NaIO4 (857 mg, 4.01 mmol) in THF (18 mL) and water (3 mL) is stirred at rt for 7 h before another portion of NaIO4 (524 mg, 2.45 mmol) is added. Stirring is continued for 16 h. The mixture is diluted with EA, washed with water, dried over MgSO4, filtered and concentrated to give crude 6-diethylamino-4-methyl-pyridine-2-carbaldehyde (427 mg) as a green oil; LC-MS: tR=0.55 min, [M+1]+=193.01; 1H NMR (CDCl3): δ 1.22 (t, J=7.0 Hz, 6H), 2.34 (s, 3H), 3.60 (q, J=7.0 Hz, 4H), 6.49 (s, 1H), 7.04 (s, 1H), 9.89 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[N+:37]([O-])=O)=[S:29])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.Cl.C(O)C.N>[Fe].CO.O>[NH2:37][C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[NH:30][C:28]([NH:27][CH2:26][CH2:25][N:22]1[CH2:21][CH2:20][CH:19]([NH:18][C:10]2[N:9]([CH2:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=2)[CH2:24][CH2:23]1)=[S:29]
Reactant: O=[N+]([O-])c1ccccc1NC(=S)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Agent: [Fe]
Agent: Cl
Agent: N
Solvent: CCO
Solvent: CO
Solvent: O
Product: Nc1ccccc1NC(=S)NCCN1CCC(Nc2nc3ccccc3n2Cc2ccc(F)cc2)CC1

Procedure:
A mixture of 3.7 parts of N-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}ethyl]-N'-(2-nitrophenyl)thiourea, 7 parts of iron-powder, 0.25 parts of concentrated hydrochloric acid, 48 parts of ethanol and 15 parts of water is stirred and refluxed for 1 hour. The reaction mixture is alkalized with methanol saturated with ammonia. The whole is filtered and the filtrate is evaporated, yielding 3.5 parts of N-(2-aminophenyl)-N'-[2-{4-[1-(4-fluorophenylmethyl)-1H-benzimidazol-2-ylamino]-1-piperidinyl}-ethyl]thiourea as a residue.
Reaction SMILES: P(Br)(Br)[Br:2].[CH3:5][O:6][C:7](=[O:35])[C:8]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33]O)=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[CH:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[CH:11]=1>C(Cl)Cl>[CH3:5][O:6][C:7](=[O:35])[C:8]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][Br:2])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)=[CH:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: BrP(Br)Br
Reactant: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(CO)cc2)cc1
Solvent: ClCCl
Product: COC(=O)C(=Cc1cc(OC)cc(OC)c1)c1ccc(Oc2ccc(CBr)cc2)cc1
Reaction time: 1 h
Yield: 99 %

Procedure:
A solution of PBr3 (4.8 mL of 1.0 M in CH2Cl2) was added dropwise to 12 (5.0 g, 11.9 mmol) dissolved in CH2Cl2 (20 mL) at temperature with good stirring. After 1 h, the solution was extracted with water (2×60 mL) and brine (20 mL). The organic phase was dried over anhydrous magnesium sulfate, filtered through a small bed of silica gel (20 g) and solvent was evaporated. The resulting tacky syrup was dried under high vacuum for 48 h at room temperature to yield the title compound (5.7 g, 99%): mp 79-81° C.; 1H NMR (400 MHz, DMSO-d6) δ 7.73 (s, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.22 (d, J=8.4 Hz, 2H), 7.07 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 2H), 6.42 (t, J=2.4 Hz, 1H), 6.28 (d, J=2.0 Hz, 2H), 4.73 (d, J=4.8 Hz, 2H), 3.68 (s, 3H), 3.58 (s, 6H); Anal. (C25H23BrO5) C: calculated, 61.12; found, 62.26; H: calculated 4.80; found 4.88.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[Li].[C:11]1([C:17]#[CH:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CON(C)[C:22](=[O:35])[C:23]1[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=1>O1CCCC1>[CH3:30][O:29][C:27]1[CH:28]=[C:23]([C:22](=[O:35])[C:18]#[C:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:24]=[C:25]([O:33][CH3:34])[C:26]=1[O:31][CH3:32]
Reactant: COc1cc(C(=O)N(C)OC)cc(OC)c1OC
Reactant: C#Cc1ccccc1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Product: COc1cc(C(=O)C#Cc2ccccc2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.9 %

Procedure:
Place lithium hexamethyldisilazane (3 mL of a 1M solution in tetrahydrofuran, 3 mmol) and tetrahydrofuran (10 mL) under an argon atmosphere and cool to 0° C. Add phenylacetylene (0.33 mL, 3 mmol) and stir at 0° C. for 30 minutes. Add N-methoxy-N-methyl-(3,4,5-trimethoxy)benzamide (0.76 g, 3 mmol), remove the cooling bath and stir at room temperature for 1 hour. Partition between ethyl ether and saturated aqueous sodium chloride, separate the organic phase and dry (MgSO4). Filter and evaporate the solvent in vacuo. Pour onto silica gel and elute with 20% ethyl acetate/hexane to yield a crude solid. Recrystallize (hexane/ethyl acetate) to yield 0.31 g of the title compound; mp 94°-96° C.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@H:10]([C:16]([NH:18][C@H:19]([C:32]([NH:34][C@H:35]([C:43]([NH:45][CH2:46][C:47]([OH:49])=[O:48])=[O:44])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:42])[NH2:41])=[O:33])[CH2:20][CH2:21][C:22](=[O:31])[O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[NH2:14])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].CC(OC([NH:57][C@H:58]([C:61](OCC1C=CC([N+]([O-])=O)=CC=1)=[O:62])[CH2:59][OH:60])=O)(C)C>FC(F)(F)C([O-])=O>[NH2:57][C@H:58]([C:59]([NH:1][C@H:2]([C:7]([NH:9][C@H:10]([C:16]([NH:18][C@H:19]([C:32]([NH:34][C@H:35]([C:43]([NH:45][CH2:46][C:47]([OH:49])=[O:48])=[O:44])[CH2:36][CH2:37][CH2:38][NH:39][C:40](=[NH:41])[NH2:42])=[O:33])[CH2:20][CH2:21][C:22](=[O:31])[O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:17])[CH2:11][CH2:12][C:13](=[O:15])[NH2:14])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:60])[CH2:61][OH:62]
Reactant: N=C(N)NCCC[C@H](NC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](N)CC(N)=O)C(=O)NCC(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])C(F)(F)F
Product: N=C(N)NCCC[C@H](NC(=O)[C@H](CCC(=O)OCc1ccccc1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](N)CO)C(=O)NCC(=O)O

Procedure:
Likewise under the conditions of Example II-2 and from 806 g of H-Asn-Gln-Glu(OBzl)-Arg-Gly-OH and 366 g of Boc-Ser-ONb, the product is obtained, monitored by NMR and TLC with a yield of 688 g (77%) and in trifluoroacetate form.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:12]2([CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][CH2:13]2)[CH2:11]1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].[N:31]#CBr>C(Cl)(Cl)Cl>[C:18]([N:15]1[CH2:16][CH2:17][C:12]2([C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N+:1]([O-:3])=[O:2])[CH2:11]2)[CH2:13][CH2:14]1)#[N:31]
Reactant: N#CBr
Reactant: CN1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC2(CC1)CN(c1ccccc1[N+](=O)[O-])c1ccccc12

Procedure:
A solution of 18.23 g of 1-(2-nitrophenyl)-1'-methylspiro[indoline-3,4'-piperidine] of Example 15 in 100 ml of chloroform is added dropwise over 50 minutes to a rapidly stirred slurry of 11.65 g of potassium carbonate and 8.94 g of cyanogen bromide in 100 ml of chloroform under nitrogen. After heating at reflux for 2.75 hours, the cooled product is washed with 10% sodium hydroxide and water, dried over anhydrous magnesium sulfate and concentrated to yield a crude solid which is chromatographed on silica gel (650 g) using ether-chloroform and is then recrystallized from ether-dichloromethane to yield a solid, mp 148°-150° C. of 1'-cyano-1-(2-nitrophenyl)spiro[indoline-3,4'-piperidine].
Reaction SMILES: Br[C:2]1[C:7]2[N:8]([CH3:23])[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][NH:18]4)[CH3:12])=[N:10][C:6]=2[CH:5]=[CH:4][C:3]=1[F:24].[C:25]1(B(O)O)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.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>[F:24][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([C@@H:11]([NH:13][C:14]3[N:22]=[CH:21][N:20]=[C:19]4[C:15]=3[N:16]=[CH:17][NH:18]4)[CH3:12])[N:8]([CH3:23])[C:7]=2[C:2]=1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: OB(O)c1ccccc1
Reactant: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(Br)c2n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c(-c3ccccc3)c2n1C
Temperature: 140 °C
Yield: 74.5 %

Procedure:
A mixture of [(S)-1-(7-bromo-6-fluoro-1-methyl-1H-benzoimidazol-2-yl)ethyl]-(9H-purin-6-yl)amine, (0.10 g, 0.26 mmol), phenylboronic acid (0.041 g, 0.33 mmol), tetrakis(triphenylphosphine)palladium(0) (0.015 g, 0.01 mmol) and caesium carbonate (0.17 g, 0.51 mmol) in dioxane (3 mL) and water (1.5 mL) was placed in a sealed tube and degassed with nitrogen for 5 minutes, then heated for 45 minutes at 140° C. by microwave irradiation. The resulting mixture was loaded onto an Isolute® SCX-2 cartridge then washed with MeOH and the product eluted with 2M NH3/MeOH and concentrated in vacuo. The residue was purified by chromatography (SiO2, 0-10% (2M ammonia in methanol) in DCM) then by preparative HPLC (Phenomenex Gemini 5 μm C18 on a 78 min gradient 20-98% 0.1% HCO2H in acetonitrile/water). The relevant fractions were concentrated to approximately ⅓ volume and partitioned between DCM (3×) and saturated aqueous NaHCO3. The combined DCM extracts were dried (Na2SO4) and concentrated in vacuo to give 431 as a white solid (0.075 g, 76%). LCMS (Method K): RT 3.21 min [M+H]+ 388.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.98 (1H, s), 8.26-8.11 (2H, m), 7.93-7.86 (1H, m), 7.64 (1H, dd, J=8.82, 4.74 Hz), 7.54-7.39 (5H, m), 7.15-7.08 (1H, m), 5.82-5.71 (1H, m), 3.21 (3H, s), 1.65 (3H, d, J=6.74 Hz). Signals split due to presence of tautomers
Reaction SMILES: [C:1](Cl)(=O)[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[CH3:10][CH:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([NH2:24])[CH:18]=2)=[N:15][NH:14][C:13](=[O:25])[CH2:12]1.ClC1C=CC=CC=1>C(O)(=O)C>[CH3:10][CH:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]3[N:23]=[C:1]([C:2]4[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=4)[NH:24][C:19]=3[CH:18]=2)=[N:15][NH:14][C:13](=[O:25])[CH2:12]1
Reactant: O=C(Cl)c1ccncc1
Reactant: CC1CC(=O)NN=C1c1ccc(N)c(N)c1
Solvent: Clc1ccccc1
Solvent: CC(=O)O
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3ccncc3)[nH]c2c1
Reaction time: 2 h

Procedure:
A mixture of 17 g of isonicotinoyl chloride, 21.8 g of 5-methyl-6-(3,4-diaminophenyl)-4,5-dihydropyridazin-3-one ("IIa"; m.p. 195°-196°) and 400 ml of chlorobenzene is boiled for 2 hours. After having been cooled, the usual working up is carried out and, initially, an oily mixture of 5-methyl-6-(3-amino-4-isonicotinamidophenyl)- and 5-methyl-6-(3-isonicotinamido-4-aminophenyl)-4,5-dihydropyridazin-3-one is obtained, which is dissolved in 400 ml of acetic acid and boiled for 3 hours. After having been cooled, 5-methyl-6-[2-(4-pyridyl)-5-benzimidazolyl]-4,5-dihydropyridazin-3-one ("M"), dihydrate, m.p.195°-198° (decomposition) is obtained. Dihydrochloride-dihydrate, m.p. 224°-227°. Methanesulphonate, m.p. 282°-285°.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]1[CH:35]=[C:34]([O:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:33]=[CH:32][C:29]=1[CH2:30][NH2:31]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:31][CH2:30][C:29]1[CH:32]=[CH:33][C:34]([O:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)=[CH:35][C:28]=1[F:27]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: NCc1ccc(Oc2ccccc2)cc1F
Product: O=C(N1CCc2ccc(Cl)c(NCc3ccc(Oc4ccccc4)cc3F)c2CC1)C(F)(F)F

Procedure:
Using method similar to the General Procedure 5-3, couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.1 g, 2.5 mmol) with 2-fluoro-4-phenoxy-benzylamine (550 mg, 2.5 mmol). Purify by chromatography on silica gel eluting with hexane/EtOAc (9:1) and then SCX chromatography to obtain 7-chloro-6-(2-fluoro-4-phenoxy-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine. MS (ES+) m/z: 493 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][C:5]([C:7]1[N:8]=[CH:9][N:10]2[C:16]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=3[C:14](=[O:22])[N:13]([CH3:23])[CH2:12][C:11]=12)=[O:6])[C:2]#[CH:3].IN1C(=O)CCC1=O.[CH2:32]([NH:35][CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34]>C(O)(=O)C>[CH2:32]([N:35]([CH2:3][C:2]1[O:6][C:5]([C:7]2[N:8]=[CH:9][N:10]3[C:16]4[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=4[C:14](=[O:22])[N:13]([CH3:23])[CH2:12][C:11]=23)=[N:4][CH:1]=1)[CH2:36][CH2:37][CH3:38])[CH2:33][CH3:34]
Reactant: CCCNCCC
Reactant: C#CCNC(=O)c1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Agent: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: CCCN(CCC)Cc1cnc(-c2ncn3c2CN(C)C(=O)c2cc(F)ccc2-3)o1
Temperature: 25 °C
Reaction time: 39 h
Yield: 24.3 %

Procedure:
A solution of 3.12 g (0.010 mol) of 8-fluoro-5-methyl-6-oxo-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid prop-2-ynylamide in 200 ml of acetic acid was treated with 3.36 g (0.015 mol) of N-iodosuccinimide while gassing with argon. After stirring at room temperature for 39 hrs. the dark brown suspension obtained was completely freed from the solvents and dried azeotropically several times with toluene. The brown residue was dissolved in 100 ml of THF, treated with 11.9 ml (0.0865 mol) of dipropylamine and stirred at room temperature for 22 hrs. The brown solution obtained was completely freed from the solvents, the residue was partitioned between ethyl acetate and 1N aqueous hydrochloric acid and extracted. The aqueous-acidic phase was made basic and extracted with ethyl acetate. The organic phase was concentrated, the orange-brownish product was chromatographed over basic Alox (grade III) with dichloromethane/ethyl acetate 4:1 as the eluent and recrystallized from hot isopropyl ether. There was obtained 1.0 g (24%) of 3-(5-dipropylaminomethyl-oxazol-2-yl)-8-fluoro-5-methyl-5,6-dihydro-4H-imidazo[1,5-a][1,4]benzodiazepin-6-one as yellowish crystals; m.p. 123-125°.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([NH2:6])[CH:3]=[N:2]1.[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:12]([CH:16]=1)[C:13](O)=[O:14].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:12]([CH:16]=1)[C:13]([NH:6][C:4]1[CH:5]=[N:1][NH:2][CH:3]=1)=[O:14]
Reactant: Nc1cn[nH]c1
Reactant: O=C(O)c1cc(Br)ccc1OCc1ccccc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1cn[nH]c1)c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Neat 1H-pyrazol-4-amine (55.2 mg, 0.66 mmol) was added in one charge to a stirred solution of 5-bromo-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 5, method D; 170 mg, 0.55 mmol), EDC (318 mg, 1.66 mmol) and HOBT (254 mg, 1.66 mmol) in N,N-dimethylformamide (4 ml) in air at room temperature. The reaction mixture was stirred at room temperature overnight. Water (30 ml) was added, and the mixture was extracted with ethyl acetate (50 ml×2). The organic layers were combined, dried over MgSO4, and concentrated in vacuo. The residue was washed with ethyl acetate yield the title compound as a brown solid. 180 mg.