Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:25][C:14]3=[N:15][CH:16]=[CH:17][C:18]([N:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[C:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:26]([C:28]1[NH:29][C:30]([CH3:35])=[C:31]([CH:33]=O)[N:32]=1)[CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[NH:25][C:14]3=[N:15][CH:16]=[CH:17][C:18]([N:19]4[CH2:20][CH2:21][N:22]([CH2:35][C:30]5[N:29]=[C:28]([CH2:26][CH3:27])[NH:32][C:31]=5[CH3:33])[CH2:23][CH2:24]4)=[C:13]3[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc(-c2nc3c(N4CCNCC4)ccnc3[nH]2)cc1
Reactant: CCc1nc(C=O)c(C)[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCc1nc(CN2CCN(c3ccnc4[nH]c(-c5ccc(C(C)(C)C)cc5)nc34)CC2)c(C)[nH]1
Reaction time: 18 h
Yield: 33.3 %

Procedure:
2-(4-tert-Butyl-phenyl)-7-piperazin-1-yl imidazo[4,5-b]pyridine (7) (50 mg, 0.15 mmol) and 2-ethyl-5-methyl-1H-imidazole-4-carbaldehyde (21 mg, 0.15 mmol) were dissolved in NMP (4 ml) with sodium triacetoxyborohydride (64 mg, 0.30 mmol). The reaction mixture was allowed to stir for 18 hours under nitrogen. It was judged complete by MS, and purified by HPLC Method E to yield the title product 8 (23 mg (33%), 0.05 mmol). 1H NMR (DMSO-d6): δ 8.09 (d, J=8.3 Hz, 3H), 7.59 (d, J=8.3 Hz, 2H), 6.80 (s, 1H), 3.80-4.00 (m, 8H), 2.84 (q, J=7.7 Hz, 2H), 2.25 (s, 3H), 1.31 (m, 12H). The product 8 was determined to be 96% pure by analytical HPLC. MS (ESI-POS): [M+H]+=458; MS(ESI-NEG):[M−H]−=456.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([NH2:25])[CH:16]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N1CCC(OC2C=C(C(F)(F)F)C=C(N[C:51]([C:53]3[C:54]([F:59])=[N:55][CH:56]=[CH:57][CH:58]=3)=[O:52])C=2)CC1)(OC(C)(C)C)=O>>[C:1]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH2:13][O:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([NH:25][C:51]([C:53]2[C:54]([F:59])=[N:55][CH:56]=[CH:57][CH:58]=2)=[O:52])[CH:16]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1cc(N)cc(C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2cc(NC(=O)c3cccnc3F)cc(C(F)(F)F)c2)CC1
Product: CC(C)(C)OC(=O)N1CCCC1COc1cc(NC(=O)c2cccnc2F)cc(C(F)(F)F)c1

Procedure:
1-Boc-2-{3-[(2-Fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxymethyl}-pyrrolidine was prepared from 1-Boc-2-(3-amino-5-trifluoromethyl-phenoxymethyl)-pyrrolidine by a procedure similar to that described in the preparation of 1-Boc-4-{3-[(2-fluoro-pyridine-3-carbonyl)-amino]-5-trifluoromethyl-phenoxy}-piperidine.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([NH:23][CH3:24])=[CH:21][CH:20]=1.C([O-])(=O)C.[Na+]>O1CCCC1.O>[Cl:1][C:2]1[N:11]=[C:10]([N:23]([C:22]2[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=2)[CH3:24])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1
Reactant: CNc1ccc(OC)cc1
Reactant: COc1cc2nc(Cl)nc(Cl)c2cc1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(N(C)c2nc(Cl)nc3cc(OC)c(OC)cc23)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 43.2 %

Procedure:
A mixture of 2,4-dichloro-6,7-dimethoxyquinazoline (100 mg, 0.386 mmol), 4-methoxy-N-methylaniline (55 mg, 0.401 mmol) and sodium acetate (60 mg, 0.732 mmol) in tetrahydrofuran (5 mL) and water (2.5 mL) was stirred at room temperature for 48 h. The reaction mixture was evaporated to dryness and the residue was crystallized using ethanol/water and isolated as white solid (60 mg, 60%). 1H NMR (CDCl3): 8.19 (s, 1H), 7.32-7.26 (m, 2H), 7.09-7.07 (m, 2H), 6.16 (s, 1H), 4.03 (s, 3H), 3.87 (s, 3H), 3.75 (s, 3H), 3.32 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:27])C=1>ClCCl.ClCCl.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([S:17]([CH3:18])=[O:27])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Solvent: ClCCl
Solvent: CCCCCC
Product: CS(=O)c1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reaction time: 0.03 h
Yield: 73.4 %

Procedure:
To a solution of 2-methylsulfanylpyrimidine-5-carboxylic acid (4-fluorophenyl)amide (2.00 g, 7.60 mmol) in dichloromethane (76 mL) was added m-CPBA (67%, 2.02 g, 7.84 mmol) in one portion. Solid precipitate appeared within 2 min, and after 10 min the solution was diluted with 2/1 dichloromethane/hexane (60 mL). The solids were collected by filtration and washed with 50% dichloromethane/hexane to afford, after drying, 1.558 g (73% yield) of the titled sulfoxide. A second crop was obtained by concentrating the filtrate and triturating the solids first with hot 2/1 dichloromethane/hexane, and then after filtration by a second trituration with acetone. An additional 0.22 g (10%) of titled product was obtained, and was shown by 1H NMR to be contaminated with 10% sulfone.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7](S)[S:8][C:4]=2[C:3]=1[Cl:12].S(Cl)([Cl:15])=O>CN(C)C=O>[Cl:15][C:7]1[S:8][C:4]2[C:3]([Cl:12])=[C:2]([Cl:1])[CH:11]=[CH:10][C:5]=2[N:6]=1
Reactant: Sc1nc2ccc(Cl)c(Cl)c2s1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Clc1nc2ccc(Cl)c(Cl)c2s1
Temperature: 25 °C
Reaction time: 4 h
Yield: 41.9 %

Procedure:
To a suspension of 300 mg (1.270 mmol) 6,7-dichloro-benzothiazole-2-thiol in 1.4 mL (19.05 mmol) thionyl chloride was added dropwise 32.3 □L N,N-dimethylformamide dry at room temperature. The mixture was stirred at room temperature for 4 h. The solvent was removed in vacuo. The residue was purified with flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate to provide 127 mg (41.9%) of the title compound as a yellow solid. MS(m/e): 239 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([OH:7])=O.CCN(C(C)C)C(C)C.Cl.Cl.[NH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])[CH2:30][CH2:29]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[C:5]([NH:26][CH2:27][CH:28]1[CH2:33][CH2:32][N:31]([CH2:34][CH2:35][NH:36][S:37]([C:40]([F:43])([F:42])[F:41])(=[O:39])=[O:38])[CH2:30][CH2:29]1)=[O:7]
Reactant: NCC1CCN(CCNS(=O)(=O)C(F)(F)F)CC1
Reactant: O=C(O)c1cc(Br)cc(C(F)(F)F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NCC1CCN(CCNS(=O)(=O)C(F)(F)F)CC1)c1cc(Br)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-bromo-5-(trifluoromethyl)benzoic acid (0.1 g, 0.37 mmol) in CH2Cl2 (4 mL) was added DIPEA (0.3 mL, 1.8 mmol), N-(2-(4-(aminomethyl)piperidin-1-yl)ethyl)-1,1,1-trifluoromethanesulfonamide dihydrochloride salt (0.1 g, 0.3 mmol) and HATU (0.17 g, 0.4 mmol). The reaction mixture was stirred at room temperature for 2 h. The organic layer was washed with sat. NaHCO3 aq. (8 mL), dried over Na2SO4, and concentrated to give crude product as gummy solid. Purification of the crude material was done using High Throughput Purification System (HiTOPs).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7](O)=[O:8])=[CH:5][N:4]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:18][C:11]=23)[N:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.C1COCC1.[NH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1>>[CH3:1][C:2]1[C:6]([C:7]([N:44]2[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]2)=[O:8])=[CH:5][N:4]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]3[N:16]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:24])([CH3:25])[CH3:26])[CH:17]=[CH:18][C:11]=23)[N:3]=1
Reactant: C1CCNCC1
Reactant: Cc1nn(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1nn(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cc1C(=O)N1CCCCC1
Reaction time: 2 h
Yield: 101.3 %

Procedure:
A solution of 3-methyl-1-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazole-4-carboxylic acid (0.040 g, 0.00011 mol) (1:1 of AcOH) and N,N-carbonyldiimidazole (0.035 g, 0.00021 mol) in THF (1 mL, 0.01 mol) was stirred for 1.2 h, after which time piperidine (32 μL, 0.00032 mol) was added. After another 2 h, another portion of piperidine (15 μL) was added and the resulting mixture was stirred overnight. The reaction mixture was then partitioned between ethyl acetate and water, and washed sequentially with sat. NaHCO3 and brine. The organic phase was dried and evaporated to give 49 mg of the crude product as an orange oil/glass. The crude product was chromatographed with 75-100% ethyl acetate/hexanes, sample in DCM. Collected 25 mg of the purified product as a colorless glass/oil (50% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:13])=[O:12])[CH:8]=2)[NH:3]1.[N:15]1([CH2:20][CH2:21][O:22][C:23]2[CH:24]=[C:25]3[C:29](=[CH:30][CH:31]=2)[NH:28][C:27]([CH:32]=O)=[CH:26]3)[CH2:19][CH2:18][CH2:17][CH2:16]1.N1CCCCC1>C(O)C>[O:1]=[C:2]1[C:10](=[CH:32][C:27]2[NH:28][C:29]3[C:25]([CH:26]=2)=[CH:24][C:23]([O:22][CH2:21][CH2:20][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:31][CH:30]=3)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([S:11]([NH2:14])(=[O:12])=[O:13])[CH:8]=2)[NH:3]1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: NS(=O)(=O)c1ccc2c(c1)CC(=O)N2
Solvent: CCO
Solvent: C1CCNCC1
Product: NS(=O)(=O)c1ccc2c(c1)C(=Cc1cc3cc(OCCN4CCCC4)ccc3[nH]1)C(=O)N2
Temperature: 90 °C
Yield: 79.9 %

Procedure:
A mixture of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid amide (28 mg, 0.13 mmol), 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde (34 mg, 0.13 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 90° C. for 2 hours. The reaction was cooled at 0° C. for overnight. The precipitate was collected by vacuum filtration, washed with cold ethanol and dried to give 47 mg (80%) of the title compound as an orange solid.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:37])(=[N:34][C:35]#[N:36])=[O:33])=[CH:28][CH:27]=2)=[O:25])=[O:15])=[N:11][CH:12]=1>O>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[NH:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([S:32]([CH3:37])(=[N:34][C:35](=[O:2])[NH2:36])=[O:33])=[CH:28][CH:27]=2)=[O:25])=[O:15])=[N:11][CH:12]=1
Reactant: CS(=O)(=NC#N)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Reactant: O=S(=O)(O)O
Solvent: O
Product: CS(=O)(=NC(N)=O)c1ccc(C(=O)Nc2ccc(Cl)cc2C(=O)Nc2ccc(Cl)cn2)cc1
Temperature: 27.5 °C
Reaction time: 3 h
Yield: 45 %

Procedure:
Sulfuric acid (0.5 mL) was cooled to 5-10° C. To this was added product of Example 15 (150 mg, 0.38 mmol) and reaction mixture was stirred at 25-30° C. for 3 hr. Above reaction mixture was slowly poured in chilled water. Precipitated product was filtered and washed with water. Drying afforded 70 mg of titled compound in 45% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[N:10][C:9]=2[CH:17]2[CH2:19][CH2:18]2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:21][C:22]1[O:26][N:25]=[C:24]([C:27]2([NH2:31])[CH2:30][CH2:29][CH2:28]2)[N:23]=1>>[CH3:21][C:22]1[O:26][N:25]=[C:24]([C:27]2([NH:31][C:14]([C:12]3[CH:11]=[N:10][C:9]([CH:17]4[CH2:19][CH2:18]4)=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:13]=3)=[O:16])[CH2:30][CH2:29][CH2:28]2)[N:23]=1
Reactant: O=C(O)c1cnc(C2CC2)c(-c2cccc(Cl)c2)n1
Reactant: Cc1nc(C2(N)CCC2)no1
Agent: Cl
Product: Cc1nc(C2(NC(=O)c3cnc(C4CC4)c(-c4cccc(Cl)c4)n3)CCC2)no1

Procedure:
The title compound was synthesized in analogy to Example 1e, using 6-(3-chloro-phenyl)-5-cyclopropyl-pyrazine-2-carboxylic acid and 1-(5-methyl-1,2,4-oxadiazol-3-yl)-cyclobutanamine hydrochloride (CAN 1170897-128-5) as starting materials, and isolated (43 mg, 58%) as white solid; MS (EI): 410.2 (M+H).
Reaction SMILES: [CH:1]1[N:9]2[C:4]([C:5]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[O:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[CH:3][CH:2]=1.C1C(=O)N([Br:33])C(=O)C1>C(Cl)Cl.[O-]S([O-])(=S)=O.[Na+].[Na+]>[Br:33][C:1]1[N:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]3([CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[C:4]2=[CH:3][CH:2]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1cccc12
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)Oc1ccccc1-n1c(Br)ccc12
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
To tert-butyl spiro[piperidine-4,4′-pyrrolo[2,1-c][1,4]benzoxazine]-1-carboxylate (13.2 g, 38.8 mmol) in CH2Cl2 (125 mL) at 0° C. was added NBS (7.25 g, 40.7 mmol) in CH2Cl2 (25 mL) dropwise over 10 min. The mixture was stirred at 0° C. for 5 min before it was diluted with 200 mL of 0.5M Na2S2O3. The aqueous phase was removed and the organic phase was washed with 200 mL of brine. The organic phase was separated, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (0-30% EtOAc/hexanes) to give tert-butyl 1-bromospiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-carboxylate. ESI-MS m/z calc. 418.1, found 419.0 (M+1)+; Retention time: 2.29 minutes (3 min run).
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[CH3:11][O:12][CH2:13][CH2:14][CH2:15][C:16]1[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:19]2[CH:29]=[CH:30][CH:31]=[C:32]([C:33](OC)=[O:34])[C:18]=2[N:17]=1>O1CCCC1>[CH3:11][O:12][CH2:13][CH2:14][CH2:15][C:16]1[N:20]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[C:19]2[CH:29]=[CH:30][CH:31]=[C:32]([CH2:33][OH:34])[C:18]=2[N:17]=1
Reactant: COCCCc1nc2c(C(=O)OC)cccc2n1COCC[Si](C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: C1CCOC1
Product: COCCCc1nc2c(CO)cccc2n1COCC[Si](C)(C)C
Temperature: -10 °C
Reaction time: 1 h

Procedure:
35 ml of diisobutylaluminium hydride (1.5M in toluene) are added dropwise at −70° C. to a solution of 4.95 g of methyl 2-(3-methoxypropyl)-1-(2-trimethylsilanylethoxymethyl)-1H-benzoimidazole-4-carboxylate in 200 ml of tetrahydrofuran. The reaction mixture is then stirred at −10° C. for 1 hour and subsequently partitioned between tert-butyl methyl ether and 2:1 water/1N potassium bisulphate solution—the organic phase is washed with saturated aqueous sodium bicarbonate solution and water, dried over sodium sulphate and concentrated by evaporation. The combined aqueous phases are reextracted with ethyl acetate (3×)—the combined organic phases are washed with saturated aqueous sodium bicarbonate solution and water, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a yellow oil from the residues by means of flash chromatography (SiO2 60F). Rf=0.21 (95:5 ethyl acetate-methanol); Rt=3.91.
Reaction SMILES: Br[C:2]1[N:6]([CH2:7][C:8]([F:11])([F:10])[F:9])[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[N:15]1([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>>[N+:12]([C:3]1[CH:4]=[N:5][N:6]([CH2:7][C:8]([F:11])([F:10])[F:9])[C:2]=1[N:18]1[CH2:19][CH2:20][CH2:21][N:15]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16][CH2:17]1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnn(CC(F)(F)F)c1Br
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Product: CC(C)(C)OC(=O)N1CCCN(c2c([N+](=O)[O-])cnn2CC(F)(F)F)CC1
Yield: 91 %

Procedure:
Following the procedure for Intermediate 22 starting from 5-bromo-4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazole and tert-butyl 1,4-diazepane-1-carboxylate gave tert-butyl 4-(4-nitro-1-(2,2,2-trifluoroethyl)-1H-pyrazol-5-yl)-1,4-diazepane-1-carboxylate as a pale yellow gum (197 mg, 91%). 1H NMR (400 MHz, CDCl3) δ 8.19-8.12 (m, 1H), 4.76-4.66 (m, 2H), 3.65-3.49 (m, 4H), 3.32-3.23 (m, 4H), 1.92-1.78 (m, 2H), 1.52-1.47 (m, 9H).
Reaction SMILES: [CH3:1][C:2]1([CH3:5])[CH2:4][NH:3]1.[SH:6][CH2:7][C:8]([O:10]C)=O>>[CH3:1][C:2]1([CH3:5])[NH:3][C:8](=[O:10])[CH2:7][S:6][CH2:4]1
Reactant: CC1(C)CN1
Reactant: COC(=O)CS
Product: CC1(C)CSCC(=O)N1
Reaction time: 2 h

Procedure:
2,2-Dimethylaziridine (35.5 g) was added dropwise with stirring at 100° C. to methyl mercaptoacetate (53 g) during 1.5 hours. After a further 2 hours at 100° C., the mixture was cooled and crystallized from ethyl acetate. Melting point: 151-152° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH2:21][N:22]3C(=O)[C:25]4=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]4[C:23]3=O)=[N:19][N:18]=[C:17]2[CH2:33][N:34]2C(=O)C3=CC=CC=C3C2=O)=[C:6]([CH:15]=1)C(C1C=CC=CC=1)=O.O.NN>C(O)C>[Br:1][C:2]1[CH:15]=[CH:6][C:5]2[N:16]3[C:17]([CH2:33][NH2:34])=[N:18][N:19]=[C:20]3[CH2:21][N:22]=[C:23]([C:24]3[CH:25]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:4]=2[CH:3]=1
Reactant: O=C(c1ccccc1)c1cc(Br)ccc1-n1c(CN2C(=O)c3ccccc3C2=O)nnc1CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: NCc1nnc2n1-c1ccc(Br)cc1C(c1ccccc1)=NC2

Procedure:
In the manner given in Example 22, 5-bromo-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone in ethanol is heated with hydrazine hydrate to give 8-bromo-1-(aminomethyl)-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24]([CH2:34][C:35]4[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=4)[CH2:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)[N:18]=3)=[CH:15][C:14]([CH2:43][N:44]3[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]3)=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].[CH:50]([N:53]([CH3:62])[C:54](N1C=C[N+](C)=C1)=[O:55])([CH3:52])[CH3:51].C(Cl)Cl.C(N(CC)CC)C>>[CH3:42][O:41][C:38]1[CH:39]=[CH:40][C:35]([CH2:34][N:24]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[C:19]2[N:20]=[C:21]([CH3:23])[N:22]=[C:17]([C:16]3[CH:15]=[C:14]([CH2:43][N:44]4[CH2:49][CH2:48][N:47]([C:54]([N:53]([CH:50]([CH3:52])[CH3:51])[CH3:62])=[O:55])[CH2:46][CH2:45]4)[CH:13]=[N:12][C:11]=3[NH:10][C:4]3[CH:5]=[N:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=3)[N:18]=2)=[CH:36][CH:37]=1
Reactant: CC(C)N(C)C(=O)n1cc[n+](C)c1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCNCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)N(C)C(C)C)CC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1

Procedure:
To a 50 mL round-bottomed flask was added 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(piperazin-1-ylmethyl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.350 g, 0.526 mmol), 1-(isopropyl(methyl)carbamoyl)-3-methyl-1H-imidazol-3-ium (0.479 g, 2.63 mmol), DCM (25 mL, 0.526 mmol), triethylamine (0.366 mL, 2.63 mmol). After 1 hour the mixture was washed with 1.0N HCl (2×5 mL) and brine, the organic layer was dried over sodium sulfate, filtered and concentrated under a vacuum to give 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)-N-isopropyl-N-methylpiperazine-1-carboxamide, which was treated with trifluoroacetic acid (5 mL, 67.3 mmol), trifluoromethanesulfonic acid (0.2 mL, 0.278 mmol). The solution was stirred at 80° C. for one hour. The dark solution was cooled down to room temperature and concentrated to slurry. The slurry was neutralized to pH 8 with NaHCO2. The precipitate was dissolved in DCM/MeOH and adsorbed onto a plug of silica gel and chromatographed through a silica gel column (40 g), eluting with a gradient of 5% to 10% 2 M NH3-MeOH in DCM, to provide 4-((5-(4-amino-6-methyl-1,3,5-triazin-2-yl)-6-(5-fluoro-6-methoxypyridin-3-ylamino)pyridin-3-yl)methyl)-N-isopropyl-N-methylpiperazine-1-carboxamide (0.033 g, 0.063 mmol, 26.7% yield). m/z (ESI, Positive ion) 525.2 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.07 (d, J=6.85 Hz, 6H) 2.44 (s, 3H) 2.64 (s, 3H) 2.97 (dd, J=5.38, 4.60 Hz, 4H) 3.09 (d, J=7.24 Hz, 1H) 3.25 (d, J=4.89 Hz, 4H) 3.95 (s, 3H) 4.12 (s, 2H) 7.83 (br. s., 1H) 7.96 (br. s., 1H) 8.33-8.37 (d, 1H) 8.40 (s, 1H) 8.44 (s, 1H) 8.87 (dd, J=2.15, 0.39 Hz, 1H) 12.01 (s, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9]([CH:24]([CH3:33])[CH2:25][S:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[CH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C.[C:38](Cl)(=[O:40])[CH3:39]>C1C=CC=CC=1>[C:38]([C:10](=[C:9]([NH:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH:24]([CH3:33])[CH2:25][S:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:11]([O:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=1)=[O:12])(=[O:40])[CH3:39]
Reactant: CC(=O)Cl
Reactant: CC(CSc1ccccc1)C(=CC(=O)OCc1ccc([N+](=O)[O-])cc1)NCc1ccccc1
Agent: CN(C)C
Solvent: c1ccccc1
Product: CC(=O)C(C(=O)OCc1ccc([N+](=O)[O-])cc1)=C(NCc1ccccc1)C(C)CSc1ccccc1

Procedure:
p-Nitrobenzyl 3-benzylamino-4-methyl-5-phenylthio-2-pentenoate (1.58 g; 3.51 mmole) was dissolved in tolune (5 ml), and trimethylamine (1.06 g; 10.5 mmole) was added thereto at 50° to 60° C. Acetyl chloride (630 mg; 8.0 mmole) was further added thereto all at once, and the resultant mixture was stirred for 10 minutes. Benzene (50 ml) was added to the reaction mixture, which was washed successively with a saturated sodium bicarbonate solution, water, dilute hydrochloric acid and an aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by silica gel column chromatography to give p-nitrobenzyl 2-acetyl-3-benzylamino-4-methyl-5-phenylthio-2-pentenoate.
Reaction SMILES: [NH2:1][C:2]1[CH:25]=[CH:24][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][C:16]3[CH:21]=[C:20]([CH3:22])[N:19]=[C:18]([NH2:23])[N:17]=3)[CH:10]=2)=[O:7])=[CH:4][CH:3]=1.CCO.[Cl:29][C:30]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]=[CH:32][CH:31]=1.Cl>O>[ClH:29].[NH2:23][C:18]1[N:17]=[C:16]([NH:15][C:11]2[CH:10]=[C:9]([NH:8][C:6](=[O:7])[C:5]3[CH:24]=[CH:25][C:2]([NH:1][C:30]4[C:39]5[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=5)[N:33]=[CH:32][CH:31]=4)=[CH:3][CH:4]=3)[CH:14]=[CH:13][CH:12]=2)[CH:21]=[C:20]([CH3:22])[N:19]=1
Reactant: Clc1ccnc2ccccc12
Reactant: Cc1cc(Nc2cccc(NC(=O)c3ccc(N)cc3)c2)nc(N)n1
Agent: Cl
Solvent: O
Solvent: CCO
Product: Cc1cc(Nc2cccc(NC(=O)c3ccc(Nc4ccnc5ccccc45)cc3)c2)nc(N)n1

Procedure:
To a solution of amine E4 (0.26 g, 0.63 mmol) in 1:2 EtOH:H2O (30 mL) were sequentially added 4-chloroquinoline (0.62 g, 3.78 mmol) and c.HCl (0.17 mL, 5.67 mmol), and the resulting mixture refluxed for 3 h (reaction progress followed by TLC, eluting with the top phase of a 5:4:1 mixture of n-BuOH:H2O:acetic acid; product Rf=0.43, yellow spot after staining with KMnO4). After this time, solvent was removed under reduced pressure, and the residue dried via three MeOH-azeotrope cycles. The residue was re-precipitated from MeOH:EtOAc to give Cpd. II as an amorphous lemon-yellow solid (0.27 g, 79%); mp 251-255° C. (powder-glue); 1H NMR (400 MHz, DMSO): δ 14.78 (v br s, 1H, quinolinyl-N+—H), 12.79 (v br s, 1H, pyrimidinyl-N+—H), 11.14 (s, 1H, ArNHAr), 10.64 (br s, 1H, ArC(O)NHAr), 10.52 (s, 1H, ArNHAr), 8.87 (d, J=8.44 Hz, 1H, ArH), 8.61 (d, J=6.94 Hz, 1H, ArH), 8.30-7.45 (m, 12H, ArH & ArNH2), 7.38 (t, J=8.07 Hz, 1H, ArH), 7.00 (d, J=6.94 Hz, 1H, ArH), 6.22 (s, 1H ArH), 2.29 (s, 3H, ArCH3); LCMS (APCI+): 463 (100%); HPLC: 95.4%.