Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[C:15](Br)=[C:14]([C:17]([F:20])([F:19])[F:18])[N:13]=[C:12]([O:21][CH3:22])[C:11]=1[Br:23])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1([Li])C=CC=CC=1.C1CCCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(OCC)C>[Br:23][C:11]1[C:12]([O:21][CH3:22])=[N:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][C:10]=1[CH2:9][O:8][Si:1]([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:3])[CH3:2]
Reactant: COc1nc(C(F)(F)F)c(Br)c(CO[Si](C)(C)C(C)(C)C)c1Br
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: COc1nc(C(F)(F)F)cc(CO[Si](C)(C)C(C)(C)C)c1Br
Reaction time: 0.08 h

Procedure:
To a solution of the compound from Step E above (2.68 g, 3.41 mmol) in tetrahydrofuran (50 mL) at −78° C. was added 2.0M phenyllithium in cyclohexane (1.70 mL, 3.41 mmol). After the reaction was stirred for 5 min, 10% citric acid in THF was added. The mixture was diluted with ethyl ether, washed sequentially with water and saturated brine, dried over sodium sulfate and concentrated. The residue was purified by flash chromatography (silica gel; 10 to 15% ethyl acetate/hexanes gradient elution) to yield the title compound. 1H NMR (400 MHz, CDCl3) δ 7.52 (s, 1H), 4.74 (s, 2H), 4.08 (s, 3H), 0.99 (s, 9H), 0.17 (s, 6H). LC/MS: 400/402 (M+H and M+H+2).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([S:11]([O-:13])=[O:12])[S:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[Li+].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1.C(OC([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)=O)(C)(C)C>>[ClH:1].[Br:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][S:11]([C:9]2[S:10][C:6]3[CH:5]=[CH:4][N:3]=[C:2]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)[C:7]=3[CH:8]=2)(=[O:13])=[O:12])=[CH:18][CH:17]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=S([O-])c1cc2c(Cl)nccc2s1
Agent: [Li+]
Product: Cl
Product: O=S(=O)(Cc1ccc(Br)cc1)c1cc2c(N3CCNCC3)nccc2s1

Procedure:
Lithium 4-chlorothieno[3,2-c]pyridine-2-sulfinate (0.42 mmol) was treated with 4-bromobenzylbromide (0.59 mmol) as described in Method P above and then reacted further with tert-butyl-piperazine-1-carboxylate as described in Method Q. The BOC protecting group was removed using Method R. Yield 0.024 g (12% over three steps). White solid. 1H NMR (300 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.18 (d, J=5.5 Hz, 1H), 8.02 (s, 1H), 7.69 (d, J=5.5 Hz, 1H), 7.53 (d, J=8.5 Hz, 2H), 7.17 (d, J=8.5 Hz, 2H), 4.95 (s, 2H), 3.62-3.68 (m, 4H), 3.27-3.32 (m, 4H); MS (ESI+) for C18H18BrN3O2S2. C1 H m/z 454 (M+H)+. HPLC 90%, RT 1.24 min (YMC ODS AQ, 33×3 mm, 20-50% acetonitrile in 1.5 min).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[C:9]([O:12][CH2:13][CH2:14]Br)(=[O:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:13]([O:12][C:9](=[O:11])[CH2:10][NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:14]
Reactant: CC(=O)OCCBr
Reactant: Nc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)CNc1ccc(Cl)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 85.6 %

Procedure:
4-Chloroaniline (2.0 g) was dissolved in acetonitrile (20 mL), and bromoethyl acetate (2.1 g) and potassium carbonate (2.2 g) were added thereto, followed by stirring at 60° C. for 2 days. The reaction mixture was filtered through a Celite pad, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:chloroform=2:1), to thereby give the title compound (2.3 g).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([O:15][C@H:16]2[O:21][CH2:20][CH2:19][N:18](CC3C=CC=CC=3)[C@H:17]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH2:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1>[Pd].C(O)(C)C.C(OCC)(=O)C>[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([C@@H:13]([O:15][C@H:16]2[O:21][CH2:20][CH2:19][NH:18][C@H:17]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1.[F:36][C:2]([F:1])([F:35])[C:3]1[CH:4]=[C:5]([C@H:13]([O:15][C@H:16]2[O:21][CH2:20][CH2:19][NH:18][C@H:17]2[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH3:14])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: C=C(O[C@H]1OCCN(Cc2ccccc2)[C@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C[C@@H](O[C@H]1OCCN[C@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: C[C@H](O[C@H]1OCCN[C@H]1c1ccccc1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 48 h

Procedure:
A mixture of 1.50 g (2.9 mmol) of 2-(R)-(1-(3,5-bis(trifluoromethyl)phenyl)ethenyloxy)-3-(S)-phenyl-4-benzyl morpholine (from Example 68) and 750 mg 10% palladium on carbon catatlyst in 25 mL of 3:2 v/v isopropanol/ethyl acetate was stirred under an atmosphere of hydrogen for 48 hours. The catalyst was filtered onto a pad of Celite; the reaction flask and filter pad were rinsed with 500 mL of ethyl acetate. The filtrate was concentrated in vacuo. Flash chromatography on 60 g of silica gel using 2:1 v/v hexanes/ether, then 2:1 v/v hexanes/ether afforded 106 mg of 2-(R)-(1-(S)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl morpholine and 899 mg of 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-phenyl morpholine, both as oils (84% total yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[CH2:17](O)[CH2:18][OH:19]>C1C=CC=CC=1.CCOC(C)=O.CC1C=CC(S(O)(=O)=O)=CC=1.O>[O:19]1[C:2]2([CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:8])[CH2:3]2)[O:1][CH2:17][CH2:18]1
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC2(C1)OCCO2
Reaction time: 20 h
Yield: 101.4 %

Procedure:
A solution of benzyl 3-oxopyrrolidine-1-carboxylate (11.2 g, 51.09 mmol), ethylene glycol (2.4 g, 38.67 mmol) and TsOH.H2O (10 mg) in benzene (100 mL) was heated at reflux using Dean-Stork condenser. After 20 h, the reaction mixture was cooled, diluted with EtOAc (100 mL), washed with water (2×25 mL), brine (25 mL), dried (MgSO4), filtered and concentrated to give yellow oil. Flash column chromatography purification on silica gel column with 1:4 followed by 3:7 EtOAc:hexanes provided desired product (10.32 g, 100%) as colorless liquid. 1H NMR (500 MHz, CDCl3) δ: 7.38-7.28 (5H, m), 5.13 (2H, s), 3.99-3.92 (4H, m), 3.58-3.54 (2H, m), 3.45 (2H, d, J=10.7 Hz), 2.07-2.02 (2H, m).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:12]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13].C(N(CC)C(C)C)(C)C.FC(F)(F)C(O)=O>CN1CCCC1=O>[C:12]([C:16]1[CH:17]=[CH:18][C:19]([CH2:20][NH:21][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:22][CH:23]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: Clc1ncnc2ccccc12
Reactant: CC(C)(C)c1ccc(CN)cc1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccc(CNc2ncnc3ccccc23)cc1
Temperature: 160 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
To a solution of 4-chloro-quinazoline described in Preparation Example X-1 (8 mg, 0.049 mmol) in 1-methyl-2-pyrrolidone (0.5 mL) were added 4-tert-butyl-benzylamine (10 μl, 0.059 mmol) and N,N-diisopropylethylamine (17 μl, 0.098 mmol), and the solution was stirred for 5 hours at 160° C. The reaction mixture was directly purified by reverse phase high performance liquid chromatography (acetonitrile-water mobile phase (containing 0.1% trifluoroacetic acid) was used), and the title compound (16.5 mg, 0.041 mmol, 72%) was obtained as a trifluoroacetic acid salt.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:15]=[C:16](I)[C:3]=12.[CH3:27][N:28]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[N:29]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:6][N:5]=[C:4]2[N:14]([CH2:18][CH2:19][N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[N:15]=[C:16]([C:31]3[CH:30]=[N:29][N:28]([CH3:27])[CH:32]=3)[C:3]=12
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CN1CCN(CCn2nc(I)c3c(Cl)c(-c4ccccc4)nnc32)CC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1CCN(CCn2nc(-c3cnn(C)c3)c3c(Cl)c(-c4ccccc4)nnc32)CC1

Procedure:
Nitrogen was bubbled through a suspension of 4-chloro-3-iodo-1-(2-(4-methylpiperazin-1-yl)ethyl)-5-phenyl-1H-pyrazolo[3,4-c]pyridazine (75 mg, 0.16 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (37 mg, 0.18 mmol) and K3PO4 (99 mg, 0.47 mmol) in DMF (1.2 mL) and water (0.4 mL) for 20 min. 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (13 mg, 0.016 mmol) was added and the tube sealed and heated using microwave irradiation to 60° C. for 30 min. The crude reaction mixture was filtered and purified by preparative HPLC to provide Compound Ic (42 mg).
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([C:17](O)=[O:18])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(OCC)=O.[CH2:33]([NH:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:34][CH2:35][CH3:36]>C1(C)C=CC=CC=1>[CH2:33]([N:37]([CH2:38][CH2:39][CH2:40][CH3:41])[C:17]([C:9]1[N:8]=[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:16]2[C:11]([CH:10]=1)=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:18])[CH2:34][CH2:35][CH3:36]
Reactant: CCCCNCCCC
Reactant: O=C(O)c1cc2ccccc2c(-c2ccccc2)n1
Agent: CCOC(=O)Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCN(CCCC)C(=O)c1cc2ccccc2c(-c2ccccc2)n1
Yield: 41.5 %

Procedure:
Operations are carried out as for Example 7, starting from 2.5 g of 1-phenyl isoquinoline 3-carboxylic acid, 1.15 g of triethylamine, 1.24 g of ethyl chloroformate and 1.66 g of dibutylamine in 100 ml of toluene. After chromatography and recrystallization in petroleum ether, 1.5 g of N,N-dibutyl 1-phenyl isoquinoline 3-carboxamide melting at 62° C. is obtained.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:39])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([N:36]([CH3:38])[CH3:37])=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:38][N:36]([CH3:37])[C:33]1[N:32]=[CH:31][C:30]([C:26]2[CH:25]=[C:24]([C:22]3[CH2:21][C:20](=[O:39])[NH:19][C:9]4[CH:10]=[C:11]([C:15]([F:16])([F:18])[F:17])[C:12]([CH3:14])=[CH:13][C:8]=4[N:7]=3)[CH:29]=[CH:28][CH:27]=2)=[CH:35][CH:34]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccc(N(C)C)nc3)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccc(N(C)C)nc3)c1)=N2

Procedure:
The title compound was prepared from (2-{3-[3-(6-dimethylamino-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M197) (298 mg, 0.53 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (198 mg, 83%).
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][C:11](B3OC(C)(C)C(C)(C)O3)=[CH:12][C:7]=2[N:6]=[CH:5]1)([CH3:3])[CH3:2].[NH2:22][C:23]1[C:32]2[C:27](=[C:28](Br)[CH:29]=[CH:30][CH:31]=2)[N:26]=[N:25][C:24]=1[C:34]([NH2:36])=[O:35]>>[NH2:22][C:23]1[C:32]2[C:27](=[C:28]([C:11]3[CH:10]=[CH:9][C:8]4[N:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=[N:6][C:7]=4[CH:12]=3)[CH:29]=[CH:30][CH:31]=2)[N:26]=[N:25][C:24]=1[C:34]([NH2:36])=[O:35]
Reactant: NC(=O)c1nnc2c(Br)cccc2c1N
Reactant: CC(C)n1cnc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Product: CC(C)n1cnc2cc(-c3cccc4c(N)c(C(N)=O)nnc34)ccc21

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using 1-isopropyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole and 4-amino-8-bromocinnoline-3-carboxamide. 1H NMR (400 MHz, CD3OD) δ ppm 1.70 (d, J=8 Hz, 6 H), 7.61 (dd, J=8, 4 Hz, 1 H), 7.76 (dd, J=8, 4 Hz, 1 H), 7.78-7.84 (m, 1 H), 7.85-7.92 (m, 1 H), 7.93 (m, 1 H), 8.30 (dd, J=8, 4 Hz, 1 H), 8.37 (s, 1 H); ESI-MS m/z [M+H]+ 347.3.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:15]=[C:16]([CH3:19])[C:17]=1[OH:18])[NH2:14]>>[Cl:10][C:11]1[CH:12]=[C:13]([NH:14][C:2]2[N:7]=[C:6]([NH:14][C:13]3[CH:15]=[C:16]([CH3:19])[C:17]([OH:18])=[C:11]([Cl:10])[CH:12]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:15]=[C:16]([CH3:19])[C:17]=1[OH:18]
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: Cc1cc(N)cc(Cl)c1O
Product: Cc1cc(Nc2ncc(F)c(Nc3cc(C)c(O)c(Cl)c3)n2)cc(Cl)c1O

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-fluoropyrimidine with 3-chloro-4-hydroxy-5-methylaniline gave N2,N4-bis-(3-chloro-4-hydroxy-5-methylphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 20.55 min.; purity: 99%; MS (m/e): 410 (MH+);
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:25]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH:38]=O)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26]>C(Cl)Cl>[C:25]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]/[CH:38]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCCCC=O
Solvent: ClCCl
Product: COC(=O)/C=C/CCCCCNC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
A solution of 35.28 g (105.5 mmole) methyl (triphenylphosphoranylidene)acetate in 70 mL methylene chloride was added to a solution of 11.36 g (52.76 mmoles) of (7) in 20 mL methylene chloride. After 2 h at room temperature, the solution was concentrated in vacuo to remove most of the solvent and the residue was diluted with ether. The solid was removed by filtration and the filtrate was concentrated and the residue chromatographed (Flash, hexane - ethyl acetate 7:3). The product fraction amounted to 10.7 g of a colorless oil (8).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]3[CH:14]([C:15](=[O:18])[NH:16][N:17]=2)[CH2:13]3)=[CH:7][CH:6]=1)(=O)C.CO.[OH-].[Na+].Cl>O>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:12]3[CH:14]([C:15](=[O:18])[NH:16][N:17]=2)[CH2:13]3)=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(C2=NNC(=O)C3CC23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1ccc(C2=NNC(=O)C3CC23)cc1
Yield: 93.1 %

Procedure:
25 g (103 millimoles) of 2-(p-acetylaminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one (see Example 7c), 215 ml of methanol and 215 ml of 10 N sodium hydroxide solution are refluxed for 3 hours. The methanol is then stripped off under reduced pressure. 500 ml of water are added to the residue and the mixture is brought to pH 4 with dilute hydrochloric acid. After filtering off the product and drying it under reduced pressure at 50° C., 19.3 g (93% of theory) of 2-(p-aminophenyl)-3,4-diaza-bicyclo[4.1.0]hept-2-en-5-one are isolated as almost colorless crystals, of melting point 230°-231° C. after recrystallization from methanol.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20]Cl)=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1.Cl.Cl.[CH3:28][NH:29][CH2:30][CH:31]([C:33]1[NH:37][N:36]=[CH:35][CH:34]=1)[OH:32].C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:11](=[O:23])[C:12]3[S:19][C:18]([CH2:20][N:29]([CH2:30][CH:31]([OH:32])[C:33]4[NH:37][N:36]=[CH:35][CH:34]=4)[CH3:28])=[C:17]([CH3:22])[C:13]=3[N:14]([CH3:16])[CH:15]=2)=[O:9])=[CH:4][CH:3]=1
Reactant: CNCC(O)c1ccn[nH]1
Reactant: Cc1c(CCl)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CN(C)CC(O)c2ccn[nH]2)sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c12
Temperature: 60 °C
Reaction time: 48 h

Procedure:
A mixture of N-(4-chlorobenzyl)-2-(chloromethyl)-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide (100 mg, 0.25 mmol), 2-(methylamino)-1-(1H-pyrazol-5-yl)ethanol dihydrochloride Preparation 97)(67 mg, 0.38 mmol) and diisopropylethylamine (201 μL, 1.14 mmol) in dry DMF (5 mL) was heated to 60° C., becoming a solution. The reaction was stirred for 48 hours at that temperature. After cooling to room temperature, the solution was diluted with water (15 mL). The resulting milky suspension was stirred vigorously for 30 minutes, and then left standing overnight at room temp. The mixture was filtered, and the collected solid was washed with water and dried in vacuo, leaving a white solid. Recrystallization from acetonitrile (5 mL, dissolved with warming and then cooled to 0° C. overnight) gave the title compound (63 mg) as a white solid.
Reaction SMILES: CN(C)CCN1C2C=CC=CC=2C2C1=CC=CC=2.[N+]([O-])(O)=O.[CH3:23][N:24]([CH3:43])[CH2:25][CH2:26][N:27]1[C:39]2[CH:38]=[CH:37][C:36]([N+:40]([O-])=O)=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2>C(O)(=O)C>[CH3:23][N:24]([CH3:43])[CH2:25][CH2:26][N:27]1[C:39]2[CH:38]=[CH:37][C:36]([NH2:40])=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2
Reactant: CN(C)CCn1c2ccccc2c2cc([N+](=O)[O-])ccc21
Agent: CN(C)CCn1c2ccccc2c2ccccc21
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: CN(C)CCn1c2ccccc2c2cc(N)ccc21
Temperature: 0 °C

Procedure:
23.7 g. (0.1 mol) 9-(β-dimethylaminoethyl)-carbazole (prepared in the manner described by O. Eisleb, Ber. dtsch. chem. Ges., 74, 1433/1941) in 100 ml. glacial acetic acid were placed in a 500 ml. three-necked flask equipped with a stirrer, thermometer and dropping funnel and placed in an ice-bath. A solution of 8.28 ml. (0.2 mol) anhydrous nitric acid in 50 ml. glacial acetic acid was added dropwise thereto at 15° - 20°C. The reaction mixture was further stirred for an hour at 20° - 25°C. and then poured into 500 ml. ice-water. The precipitated green crystals were filtered off with suction, well washed with water and dried at 80°C. in a drying cabinet. There were obtained 32.4 g. (94% of theory) 9-(β-dimethylaminoethyl)-3-nitrocarbazole which melted, with decomposition, at 190°C.
Reaction SMILES: C([O:3][C:4]([CH:6]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:7]([NH:9][C@H:10]([CH2:21][OH:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])=[O:5])C.CO.[OH-].[K+].Cl>C1COCC1.O>[C:4]([CH:6]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:7]([NH:9][C@H:10]([CH2:21][OH:22])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)=[O:8])([OH:5])=[O:3]
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)N[C@H](CO)Cc1c[nH]c2ccccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)C(Cc1ccccc1)C(=O)N[C@H](CO)Cc1c[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 20 h
Yield: 96.9 %

Procedure:
To an ice-cooled and stirred solution of N-(2-ethoxycarbonyl-3-phenylpropionyl)-(L)-tryptophanol (15 g) in THF (40 ml)-methanol (30 ml) was added dropwise a solution of KOH (2.5 g) in water (10 ml). After stirring at 4° C.--room temperature for 20 hours, the reaction mixture was acidified with 1N HCl, diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with brine and dried (MgSO4). The organic solvent was evaporated off to yield N-(2-carboxy-3-phenylpropionyl)-(L)-tryptophanol (13.5 g, 97%) as crystals. Recrystallization from ethyl acetate-hexane gave pale yellow crystals having melting point of 130° to 131° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.[NH2:17][CH2:18][CH2:19][N:20]1[CH2:24][CH2:23][NH:22][C:21]1=[O:25].C1(C)C=CC=CC=1>ClCCl>[CH3:1][C:2]1[C:3]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH:17][CH2:18][CH2:19][N:20]2[CH2:24][CH2:23][NH:22][C:21]2=[O:25])=[N:6][CH:7]=1
Reactant: Cc1cnc(S(C)(=O)=O)nc1-c1cccs1
Reactant: NCCN1CCNC1=O
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: Cc1cnc(NCCN2CCNC2=O)nc1-c1cccs1
Temperature: 200 °C

Procedure:
5-Methyl-2-(methylsulfonyl)-4-(thiophen-2-yl)pyrimidine (0.1 g, 0.39 mmol) and 1-(2-aminoethyl)imidazolidin-2-one (0.06 g, 047 mmol) were added to a microwave tube along with toluene (1 mL). The tube was capped and heated to 200° C. for 10 min in a Personal Chemistry microwave. The mixture was diluted with dichloromethane and purified by flash chromatography using a gradient of 2 to 10% methanol in dichloromethane to obtain an off-white solid. Yield=0.03 g. MS (M+H)+ 304.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[C:13](=[O:14])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:11]([C:22]3[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[CH:10]=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].N>O>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:2]2[CH:3]=[C:4]([N:8]3[C:13](=[O:14])[C:12]([C:15]4[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=4)=[C:11]([C:22]4[CH:27]=[CH:26][C:25]([S:28]([CH3:31])(=[O:30])=[O:29])=[CH:24][CH:23]=4)[CH:10]=[N:9]3)[CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:17]=1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(Br)c3)c(=O)c2-c2ccc(F)cc2)cc1
Agent: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)c1ccc(-c2cnn(-c3cccc(-c4ccc(F)cc4)c3)c(=O)c2-c2ccc(F)cc2)cc1

Procedure:
The title compound was prepared according to the method of Example 4, starting with 2-(3-bromophenyl)-4-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (Example 166) in place of 2-benzyl-4-bromo-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone and substituting cesium fluoride for sodium carbonate (yield: 0.62 g, 62%). mp 222-225° C. 1H NMR (300 MHz, DMSO d6) δ 3.24 (s, 3H), 7.16 (m, 2H), 7.36 (m, 3H), 7.53 (m, 2H), 7.64 (m, 2H), 7.73-7.81 (m, 3H), 7.93 (m, 3H), 8.27 (s, 1H). MS (DCI/NH3) m/z 515 (M+H)+, 532 (M+NH4)+. Anal. calc. for C29H21F2N2O3S.0.25 H2O: C, 67.10; H, 3.98; N, 5.35. Found: C, 66.93; H, 3.99; N, 5.17.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH2:11])=[CH:4][CH:3]=1.[CH:12]([CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[NH:11][CH2:12][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:22]=[CH:23][C:24]([C:25]([O:27][CH3:28])=[O:26])=[CH:29][CH:30]=3)[CH2:16][CH2:15]2)=[CH:6][CH:7]=1
Reactant: COC(=O)c1ccc(CN2CCC(C=O)CC2)cc1
Reactant: N[C@@H]1C[C@H]1c1ccc(I)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)c1ccc(CN2CCC(CN[C@@H]3C[C@H]3c3ccc(I)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.5 %

Procedure:
To a solution of trans-2-(4-iodophenyl)cyclopropanamine (420 mg, 1.621 mmol) in methanol (7 mL) were added methyl 4-((4-formylpiperidin-1-yl)methyl)benzoate (466 mg, 1.783 mmol), sodium cyanoborohydride (204 mg, 3.24 mmol), and acetic acid (0.028 mL, 0.486 mmol), and the mixture was stirred at room temperature for 18 h. The mixture was then quenched with saturated NaHCO3 aqueous solution (2 ml) and concentrated. The residue was treated with water (4 mL) and extracted with DCM (3×). The extract was dried (Na2SO4) and concentrated. The residue was purified using column chromatography (silica gel, 0 to 10% MeOH/EtOAc) to give 241 mg of product as pale yellow solid. MS: (M+H)+=505.3 1H NMR (400 MHz, METHANOL-d4) δ ppm 0.97-1.16 (m, 2H), 1.19-1.38 (m, 2H), 1.46-1.63 (m, 1H), 1.71-1.92 (m, 3H), 2.00-2.10 (m, 2H), 2.29 (ddd, J=7.45, 4.42, 3.28 Hz, 1H), 2.56-2.65 (m, 2H), 2.86-2.98 (m, 2H), 3.56-3.66 (m, 2H), 3.89-3.98 (m, 3H), 6.80-6.92 (m, 2H), 7.43-7.62 (m, 4H), 7.94-8.05 (m, 2H).