Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[CH:12]=[CH:13][C:14]([C:16](O)([CH3:18])[CH3:17])=[CH:15][C:4]=2[N:3]=1.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:17]=[C:16]([C:14]1[CH:13]=[CH:12][C:5]2=[C:6]3[C:11](=[C:2]([NH2:1])[N:3]=[C:4]2[CH:15]=1)[N:10]=[CH:9][CH:8]=[CH:7]3)[CH3:18]
Reactant: CC(C)(O)c1ccc2c(c1)nc(N)c1ncccc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C=C(C)c1ccc2c(c1)nc(N)c1ncccc12

Procedure:
A solution of 2-(5-aminobenzo[f][1,7]naphthyridin-8-yl)propan-2-ol (from the previous step) (1.0 eq.) and p-TsOH (2 eq.) in toluene (0.01 M) was stirred at 90° C. for 6 hours. The reaction was quenched by saturated NaHCO3 and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4 and concentrated en vacuo to obtain a crude residue. The crude material was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give 8-(prop-1-en-2-yl)benzo[f][1,7]naphthyridin-5-amine as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[N:7]([CH2:13][C:14]([OH:16])=O)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:17]#[N:18].CCN=C=NCCCN(C)C.Cl.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[C:37]([NH:39][NH2:40])=O.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C(#N)C.C1COCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([CH2:11][CH3:12])[N:7]([CH2:13][C:14]3[O:16][C:37]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=4)=[N:39][N:40]=3)[C:6]=2[CH:5]=[CH:4][C:3]=1[C:17]#[N:18]
Reactant: CCc1nc2c(Cl)c(C#N)ccc2n1CC(=O)O
Reactant: NNC(=O)c1ccccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC#N
Product: CCc1nc2c(Cl)c(C#N)ccc2n1Cc1nnc(-c2ccccn2)o1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 16.9 %

Procedure:
(4-Chloro-5-cyano-2-ethyl-1H-benzimidazol-1-yl)acetic acid (0.017 g, 0.065 mmol) and EDCl (0.014 mg, 0.072 mmol) were combined in acetonitrile (3 mL) and stirred at rt for 3 min. 2-Pyridinecarbohydrazide (0.0094 g, 0.068 mmol) was added next and the resulting mixture was stirred for 60 min. To this solution was added THF (THF 3 mL) followed by tosyl chloride (0.015 g, 0.078 mmol) and P-BEMP (0.148 g, 0.325 mmol, 2.2 mmol/g resin load). The reaction vessel was sealed and heated to 100° C. in a microwave for 5 min. The resin was filtered away and washed with CH2Cl2 (×2). The concentrated filtrate was purified (SiO2, 25% EtOAc/hexanes) to afford the title compound (0.004 g): MS (APCl) m/z 365 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[N:25]=[C:24]([O:26][C@H:27]3[C@H:31]4[O:32][CH2:33][C@@H:34]([OH:35])[C@H:30]4[O:29][CH2:28]3)[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[C:5]2=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=1.Br[C:45]1[CH:50]=[CH:49][C:48]([NH:51][S:52]([CH3:57])(=[N:54][CH2:55][CH3:56])=[O:53])=[CH:47][CH:46]=1>>[OH:35][C@H:34]1[C@H:30]2[O:29][CH2:28][C@@H:27]([O:26][C:24]3[N:23]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:41])[CH3:42])[C:5]4=[N:6][C:7]([C:8]5[CH:13]=[CH:12][C:11]([C:45]6[CH:46]=[CH:47][C:48]([NH:51][S:52]([CH3:57])(=[N:54][CH2:55][CH3:56])=[O:53])=[CH:49][CH:50]=6)=[CH:10][CH:9]=5)=[C:2]([Cl:1])[CH:3]=[C:4]4[N:25]=3)[C@H:31]2[O:32][CH2:33]1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)OC1(C)C
Reactant: CCN=S(C)(=O)Nc1ccc(Br)cc1
Product: CCN=S(C)(=O)Nc1ccc(-c2ccc(-c3nc4c(cc3Cl)nc(O[C@@H]3CO[C@H]5[C@@H]3OC[C@H]5O)n4COCC[Si](C)(C)C)cc2)cc1

Procedure:
The title compound is prepared from (3R,3aR,6R,6aR)-6-(6-chloro-5-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazo[4,5-b]pyridin-2-yloxy)hexahydrofuro[3,2-b]furan-3-ol and N-(4-bromophenyl)-N′-ethyl-methanesulfonimidamide following a procedure analogous to that described for Intermediate 3 (Step 3). LC (method 1): tR=1.10 min; Mass spectrum (ESI+): m/z=700 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[Al+3:10].[Cl-].[Cl-].[Cl-]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([Al:10]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[CH:4][CH:3]=1
Reactant: [Al+3]
Reactant: Cc1ccc([Mg]Br)cc1
Agent: [Cl-]
Product: Cc1ccc([Al](c2ccc(C)cc2)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.9 %

Procedure:
To a solution of 4-methylphenylmagnesium bromide (9 mL, 9 mmol, 1.0 M in THF) was added a solution of AlCl3 (6 mL, 3 mmol, 0.5 M in THF) at 0° C. The mixture was stirred at room temperature for 15 hours. The solution was removed from the solids by cannula and the solvent was evaporated under a strong stream of dry nitrogen gas. The residue was washed twice with n-hexane (10 mL each) and filtered in an enclosed system (Schlenk filtration) to avoid exposure of the moisture sensitive organometallic product to the atmosphere. The filtered solid was dried under reduced pressure affording the title product (0.81 g, 72%).
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5]Br)[CH3:2].[CH2:7]([NH:14][C:15](=[O:37])[N:16]([C:18]1[CH:19]=[C:20]([C:24]2[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:26][C:25]=2[OH:36])[CH:21]=[CH:22][CH:23]=1)[CH3:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[CH2:1]([O:3][CH2:4][CH2:5][O:36][C:25]1[CH:26]=[C:27]([CH2:30][CH2:31][C:32]([O:34][CH3:35])=[O:33])[CH:28]=[CH:29][C:24]=1[C:20]1[CH:21]=[CH:22][CH:23]=[C:18]([N:16]([CH3:17])[C:15]([NH:14][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:37])[CH:19]=1)[CH3:2]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2O)c1
Reactant: CCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCOCC)c1

Procedure:
In a manner similar to that of Example (25a), by reaction of 500 μL (4.43 mmol, 5.4 eq) of 2-bromoethyl ethyl ether and 350 mg (0.82 mmol, 1 eq) of methyl 3-[3′-(3-heptyl-1-methylureido)-2-hydroxybiphenyl-4-yl]propanoate (prepared in Example 15f) in 10 ml of methyl ethyl ketone in the presence of 500 mg (3.61 mmol, 4.4 eq) of potassium carbonate at 90° C. for 12 hours, methyl 3-[2-(2-ethoxyethoxy)-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate is obtained in oil form and is used in the following reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:5]=[C:6](/[CH:10]=[N:11]/[S@:12]([C:14]([CH3:17])([CH3:16])[CH3:15])=[O:13])[CH:7]=[CH:8][CH:9]=1.[CH3:20][Mg]Br>C1COCC1>[F:19][C:2]([F:1])([F:18])[O:3][C:4]1[CH:5]=[C:6]([C@H:10]([NH:11][S@:12]([C:14]([CH3:16])([CH3:15])[CH3:17])=[O:13])[CH3:20])[CH:7]=[CH:8][CH:9]=1
Reactant: C[Mg]Br
Reactant: CC(C)(C)[S@](=O)/N=C/c1cccc(OC(F)(F)F)c1
Solvent: C1CCOC1
Product: C[C@@H](N[S@@](=O)C(C)(C)C)c1cccc(OC(F)(F)F)c1
Temperature: -76 °C
Yield: 50.2 %

Procedure:
In a round-bottomed flask, (S)-2-methyl-propane-2-sulfinic acid 1-(3-trifluoromethoxyphenyl)-meth-(E)-ylideneamide (424 mg, 1.45 mmol) was dissolved in THF (2.9 ml). The light yellow solution was cooled to −76° C. and methylmagnesium bromide (3.0 M in diethyl ether, 0.86 ml, 2.58 mmol) was added dropwise. The reaction mixture was allowed to warm slowly to room temperature overnight then quenched with saturated aqueous NH4Cl and extracted with EtOAc (2×). The combined organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/hexanes (gradient: 0-10% EtOAc) to give 225 mg (50%) of (S)-2-methyl-propane-2-sulfinic acid [(R)-1-(3-trifluoromethoxy-phenyl)-ethyl]-amide as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.33-7.41 (m, 1H), 7.24-7.28 (m, 1H), 7.22 (s, 1H), 7.13 (dd, J=8.1, 1.0 Hz, 1H), 4.62 (q, J=6.7 Hz, 1H), 1.55 (d, J=6.6 Hz, 3H), 1.22 (s, 9H). Also isolated 161 mg (36%) of (S)-2-methyl-propane-2-sulfinic acid [(S)-1-(3-trifluoromethoxy-phenyl)ethyl]-amide as a colorless oil. 1H NMR (CDCl3, 400 MHz): δ (ppm) 7.35-7.43 (m, 1H), 7.28-7.33 (m, 1H), 7.21 (s, 1H), 7.11-7.18 (m, 1H), 4.58 (qd, J=6.4, 2.9 Hz, 1H), 1.53 (d, J=6.6 Hz, 3H), 1.25 (s, 9H).
Reaction SMILES: I[C:2]1[CH:25]=[CH:24][C:5]([O:6][CH:7]2[CH2:12][CH2:11][CH:10]([C:13]([N:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[O:14])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][C:27]1=[O:32].C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.[Cu]>[CH:21]([N:18]1[CH2:19][CH2:20][N:15]([C:13]([C@H:10]2[CH2:11][CH2:12][C@H:7]([O:6][C:5]3[CH:24]=[CH:25][C:2]([N:26]4[CH2:31][CH2:30][CH2:29][CH2:28][C:27]4=[O:32])=[CH:3][CH:4]=3)[CH2:8][CH2:9]2)=[O:14])[CH2:16][CH2:17]1)([CH3:23])[CH3:22]
Reactant: CC(C)N1CCN(C(=O)C2CCC(Oc3ccc(I)cc3)CC2)CC1
Reactant: O=C1CCCCN1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CC(C)N1CCN(C(=O)[C@H]2CC[C@H](Oc3ccc(N4CCCCC4=O)cc3)CC2)CC1

Procedure:
To a mixture of 1.04 g (4.09 mmol) of cis-(4-isopropyl-piperazin-1-yl)-(4-hydroxy-cyclohexyl)-methanone, 1.50 g (6.82 mmol) of 4-iodephenol, 1.25 g (4.77 mmol) of triphenylphisphine in 5 ml THF, 1.1 g (4.78 mmol) of di-tert-butyl azodicarboxylate was added at 0° C., and stirred for 12 h at room temperature. After evaporation, the residue was purified by column chromatography on silica gel eluting with cyclohexane and ethyl acetate=from 100:0 to 2:1. The combined product fractions were evaporated to dryness to yield 0.67 g (14% yields, about 67% purity) of [4-(4-iodo-phenoxy)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone. A mixture 100 mg (0.15 mmol) of [4-(4-iodo-phenoxy)-cyclohexyl]-(4-isopropyl-piperazin-1-yl)-methanone, 87 mg (0.88 mmol) of 2-piperidone, 41 mg (0.3 mmol) of potassium carbonate and 37 mg (0.58 mmol) of copper was stirred at 175 degree for 6 hr. The mixture was diluted with AcOEt, filtered through celite. The filtrate was washed with saturated NaHCO3 solution and brine, dried over MgSO4, and evaporated. The residue was purified by column chromatography on silica eluting with cyclohexane and ethyl acetate=from 100:0 to 1:3. The combined product fractions were evaporated to dryness to yield 30 mg (32%) of the title compound. MS (m/e): 428.3 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[CH:10][C:9]=2[CH3:16])[CH2:5][C:4](=[O:17])[C:3]=1[C:18](=[O:21])[CH2:19][CH3:20].C(OC(=O)C)(=O)C.[N+:29]([O-])([OH:31])=[O:30]>C(O)(=O)C>[OH:17][C:4]1[CH2:5][CH:6]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([CH3:15])=[C:10]([N+:29]([O-:31])=[O:30])[C:9]=2[CH3:16])[CH2:7][C:2](=[O:1])[C:3]=1[C:18](=[O:21])[CH2:19][CH3:20]
Reactant: O=[N+]([O-])O
Reactant: CCC(=O)C1=C(O)CC(c2c(C)cc(C)cc2C)CC1=O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCC(=O)C1=C(O)CC(c2c(C)cc(C)c([N+](=O)[O-])c2C)CC1=O
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 43.6 %

Procedure:
(b) 3-Hydroxy-5-mesityl-2-propionylcyclohex-2-en-1-one (1.3 g; 4.5 mmole) was added to acetic anhydride (3.0 g) at 5° C. A solution of fuming nitric acid (0.42 g) in a glacial acetic acid (0.27 g)/acetic anhydride (0.27 g) solution was added to the cooled, stirred mixture dropwise over a period of 5 minutes. The mixture was maintained at 5° C. over a period of 1 hour and then at room temperature over a period of 2 hours followed by heating at 50° C. for 10 minutes. The resultant cooled solution was then poured into ice water (100 ml) and extracted with diethyl etther. The organic phase was washed three times with saturated sodium bicarbonate solution and twice with water, then dried over anhydrous sodium sulfate. The solvent was removed by evaporation under reduced pressure using a rotary evaporator and the resultant yellow solid recrystallized from ethanol to give 3-hydroxy-5-(2,4,6-trimethyl-3-nitrophenyl)-2-propionylcyclohex-2-en- 1-one (0.65 g; 43.6%) as a yellow solid mp 174° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9](C(OCC)=O)[N:8]([O:16][CH3:17])[C:7]=2[CH:18]=1.[ClH:19]>>[ClH:19].[Cl:19][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[CH:9][N:8]([O:16][CH3:17])[C:7]=2[CH:18]=1
Reactant: CCOC(=O)c1nc2ccc(CO)cc2n1OC
Agent: Cl
Product: COn1cnc2ccc(CCl)cc21
Reaction time: 1 h
Yield: 79.2 %

Procedure:
(a-5) A mixture of 4.2 parts of ethyl 6-(hydroxymethyl)-1-methoxy-1H-benzimidazole-2-carboxylate and 60 parts of concentrated hydrochloric acid was stirred for 1 hour at reflux temperature. The reaction mixture was concentrated and the residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 3.1 parts (79.2%) of 6-(chloromethyl)-1-methoxy-1H-benzimidazole monohydrochloride; mp. 158° C. (int. 33).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9]([CH3:16])([CH2:10][C:11](=[O:15])[NH:12][N:13]=3)[CH2:8][CH2:7][C:6]=2[CH:17]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20]>C1(C)C=CC=CC=1>[CH2:22]([O:21][C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]3[C:9]([CH3:16])([CH2:10][C:11](=[O:15])[NH:12][N:13]=3)[CH2:8][CH2:7][C:6]=2[CH:17]=1)=[O:20])[CH3:23]
Reactant: CC12CCc3cc(N)ccc3C1=NNC(=O)C2
Reactant: CCOC(=O)Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)Nc1ccc2c(c1)CCC1(C)CC(=O)NN=C21

Procedure:
A mixture of 8-amino-4a-methyl-4,4a,5,6-tetrahydrobenzo[h]-cinnolin-3[2H]-one and ethyl chloroformate in toluene is heated to afford the title compound.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]4[CH2:41][CH2:40][CH2:39][CH2:38][N:37]4[CH:42]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[N:35]=[C:36]4[CH2:41][CH2:40][CH2:39][CH2:38][N:37]4[CH:42]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3cn4c(n3)CCCC4)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3cn4c(n3)CCCC4)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(5,6,7,8-tetrahydro-imidazo-[1,2-a]pyridin-2-yl)-benzimidazol-1-yl)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][S:16]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][N:20]=1)(=[O:18])=[O:17]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([S:16]([CH3:15])(=[O:18])=[O:17])=[N:20][CH:21]=2)=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CS(=O)(=O)c1ccc(C(=O)O)cn1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Product: CS(=O)(=O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cn1

Procedure:
1 g of methyl 6-chloronicotinate was reacted via Procedure O to yield methyl 6-(methylsulfonyl)nicotinate. 1 g of methyl 6-(methylsulfonyl)nicotinate was hydrolyzed via Procedure M to give 6-(methylsulfonyl)nicotinic acid. 100 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 6-(methylsulfonyl)nicotinic acid via Procedure G. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-6-(methylsulfonyl)nicotinamide. MS (Q1) 388.1 (M)+.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([Cl:19])[C:10]=1[N+:20]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pt].C(#N)C>[CH2:1]([NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[C:11]([Cl:19])[C:10]=1[NH2:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1c(Cl)nc2ccccc2c1NCc1ccccc1
Agent: [Pt]
Solvent: CC#N
Product: Nc1c(Cl)nc2ccccc2c1NCc1ccccc1
Reaction time: 8 h
Yield: 96.1 %

Procedure:
N-Benzyl-2-chloro-3-nitroquinolin-4-amine (31.9 g, 0.102 mol), 5% platinum on carbon (3.2 g), and acetonitrile (325 mL) were added to a Parr vessel and shaken under hydrogen pressure (30 psi, 2.1×105 Pa) overnight. The mixture was filtered through a layer of CELITE filter agent, and the filtrate was concentrated under reduced pressure and further dried under high vacuum to provide 27.82 g of N4-benzyl-2-chloroquinoline-3,4-diamine, which was used without purification.
Reaction SMILES: [C:1]([C:5]([CH3:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[N:8]1[C:21]2[C:12](=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[CH:16]3)[CH:11]=[CH:10][CH:9]=1>>[OH:6][C:5]([C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[C:21]3[C:12](=[CH:13][CH:14]=2)[CH:11]=[CH:10][CH:9]=[N:8]3)[N:19]=1)([CH3:7])[C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)C(C)(C)C
Reactant: c1cnc2c(c1)ccc1cccnc12
Product: CC(C)(C)C(C)(O)c1ccc2ccc3cccnc3c2n1

Procedure:
The process of claim 1 wherein methyl t-butyl ketone is coupled with 1,10-phenanthroline to provide 2-[(1-hydroxy-1,2,2-trimethylpropyl)]-1,10-phenanthroline.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[O:4][N:3]=1.Cl.CC(OC)(C)C>C(O)C>[NH2:1][C:2]1[N:6]=[C:5]([CH:7]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:8]2)[O:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2nc(N)no2)C1
Agent: Cl
Solvent: COC(C)(C)C
Solvent: CCO
Product: Nc1noc(C2CCCNC2)n1
Temperature: 40 °C
Yield: 61.4 %

Procedure:
tert-Butyl 3-(3-amino-1,2,4-oxadiazol-5-yl)piperidine-1-carboxylate 26 (0.33 g, 0.00123 mol) was dissolved in 2 mL ethanol. Hydrochloric acid in ethanol (2.5 M) (2.00 mL, 0.00493 mol) was added and the mixture was heated to 40° C. for 1 hour. 12 mL of MTBE was added and the product precipitated from solution. The solids were filtered and washed with 2×5 mL MTBE, and recrystallized 3 times from methanol:isopropanol to give 127 mg white solid. MS (ESI) m/z 168 [M+1]+. 1H NMR (DMSO-d6) δ 1.67-1.82 (m, 3H), 2.08-2.12 (d, 1H), 2.86-2.90 (t, 1H), 3.06-3.12 (t, 1H), 3.21-3.24 (d, 1H), 3.33 (s, 2H), 3.49-3.52 (d, 1H), 6.32 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[N:12]=[N:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.C([BH3-])#N.[Na+].Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[NH:12][NH:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nn3ccnnc3c2-c2ccncc2)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(-c2nn3c(c2-c2ccncc2)NNCC3)cc1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
To a suspension of 7-(4-fluorophenyl)-8-(pyridin-4-yl)pyrazolo[5,1-c][1,2,4]triazine (2.2 g) in methanol (20 ml) was added sodium cyanoborohydride (480 mg). The pH of the mixture was maintained at 3 to 4 for 2 hours with 1N hydrochloric acid. The procedure was repeated three additional times to completely finish the reduction. Then, the mixture was concentrated in vacuo and the residue was dissolved in 2N hydrochloric acid. The mixture was stirred at 80° C. for 30 minutes and cooled. The solution was neutralized with an aqueous saturated sodium bicarbonate solution. The separated solid was collected, washed with water and methanol and dried to give 7-(4-fluorophenyl)-8-(pyridin-4-yl)-1,2,3,4-tetrahydropyrazolo[5,1-c][1,2,4]triazine (2.06 g).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[N:5][N:6]([CH3:8])[N:7]=1.[CH3:9][NH2:10]>>[CH3:9][NH:10][CH2:2][C:3]1[N:4]=[N:5][N:6]([CH3:8])[N:7]=1
Reactant: Cn1nnc(CCl)n1
Reactant: CN
Product: CNCc1nnn(C)n1
Temperature: 45 °C
Reaction time: 16 h

Procedure:
To 5-(chloromethyl)-2-methyl-2H-tetrazole (136.8 mg, 1.032 mmol), was added methylamine (4.00 mL of 2M solution in THF, 8.00 mmol). This was stirred for 16 hours at 45° C. A white precipitate formed in the reaction and it was allowed to continue stirring for another 24 hours at room temperature before being concentrated in vacuo and successively azeotroped with THF, triethylamine, methanol, and then DCM. 1H NMR (600 MHz, CDCl3) δ 2.23 (s, 3H), 3.80 (s, 2H), 4.29 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[NH:15][C:14](=[O:16])[NH:13][C:12]2=[O:17])=[CH:2]1.Cl.Cl[CH2:20][CH2:21][CH2:22][N:23]([CH2:26][CH3:27])[CH2:24][CH3:25].CC[O-].[Na+]>C(O)C>[CH2:24]([N:23]([CH2:26][CH3:27])[CH2:22][CH2:21][CH2:20][N:13]1[C:12](=[O:17])[CH:11]([CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[NH:15][C:14]1=[O:16])[CH3:25]
Reactant: O=C1NC(=O)C(Cc2c[nH]c3ccccc23)N1
Reactant: CCN(CC)CCCCl
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCN(CC)CCCN1C(=O)NC(Cc2c[nH]c3ccccc23)C1=O
Reaction time: 20 h

Procedure:
A mixture of 5-(indol-3-ylmethyl)hydantoin (10 g, 0.04 mole), 3-chloro-N,N-diethylpropylamine hydrochloride (8.2 g, 0.04 mole), NaOC2H5 (0.08 mole) and 500 ml of anhydrous C2H5OH was heated to reflux with stirring for 20 hours. The mixture was filtered and concentrated to dryness. The concentrate was dissolved in CHCl3, filtered and concentrated. The concentrate was crystallized and recrystallized from benzene-petroleum ether. The solid was again recrystallized from xylene and the solvated solid was dried in vacuum, yield 2.5 g, mp 90°.
Reaction SMILES: [NH2:1][C:2](=[NH:36])[N:3]1[CH2:8][CH2:7][CH2:6][C@@H:5]([CH2:9][NH:10][C:11]([CH2:13][C@H:14]([NH:25]C(OCC2C=CC=CC=2)=O)[C:15]([N:17]([CH2:21][C:22]([OH:24])=[O:23])[CH:18]2[CH2:20][CH2:19]2)=[O:16])=[O:12])[CH2:4]1.[ClH:37]>[Pd].C(O)C>[ClH:37].[NH2:25][C@@H:14]([CH2:13][C:11](=[O:12])[NH:10][CH2:9][C@@H:5]1[CH2:6][CH2:7][CH2:8][N:3]([C:2]([NH2:36])=[NH:1])[CH2:4]1)[C:15]([N:17]([CH2:21][C:22]([OH:24])=[O:23])[CH:18]1[CH2:20][CH2:19]1)=[O:16]
Reactant: N=C(N)N1CCC[C@@H](CNC(=O)C[C@H](NC(=O)OCc2ccccc2)C(=O)N(CC(=O)O)C2CC2)C1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N=C(N)N1CCC[C@@H](CNC(=O)C[C@H](N)C(=O)N(CC(=O)O)C2CC2)C1
Reaction time: 2 h

Procedure:
0.34 g of palladium/charcoal catalyst is added to a solution of 3.4 g of the product of Example 3 in 34 ml of ethanol and 6.8 ml of 1N hydrochloric acid and the reaction mixture is hydrogenated for 2 hours. Then, the catalyst is filtered off and the filtrate is evaporated. Colourless [[(S)-2-amino-3-[(S)-1-(amino-imino-methyl)-piperidin-3-ylmethylcarbamoyl]-propionyl]-cyclopropyl-amino]-acetic acid hydrochloride (1:1), MS (ion spray): 369.4 (M+H)+, is thus isolated.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([CH3:9])[C:5]([Cl:10])=[CH:4][N:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[N+:20]([O-:22])=[O:21].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(#N)C>[Cl:10][C:5]1[C:6]([CH3:9])=[C:7]2[N:8]=[C:16]([C:15]3[CH:18]=[CH:19][C:12]([OH:11])=[C:13]([N+:20]([O-:22])=[O:21])[CH:14]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: O=Cc1ccc(O)c([N+](=O)[O-])c1
Reactant: Cc1c(Cl)cnc(N)c1N
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: O
Product: Cc1c(Cl)cnc2[nH]c(-c3ccc(O)c([N+](=O)[O-])c3)nc12

Procedure:
2,3-Diamino-5-chloro-4-methylpyridine (prepared by a method similar to Example 206a) (3.2 g, 20.3 mmol), was dissolved in acetonitrile (150 ml). 4-Hydroxy-3-nitrobenzaldehyde (3.1 g) was added, followed by p-toluenesulfonic acid monohydrate (0.7 g) and the resulting mixture was heated to reflux overnight. The solvent was then removed in vacuo and the residue dissolved in a mixture of dichloromethane and methanol (1:1). To this solution was added silica gel and the solvents were evaporated in vacuo. The silica-supported product mixture was then applied to column chromatography, eluting with first dichloromethane and then a mixture of dichloromethane and methanol 4:1. This afforded the title compound of approx. 75% purity. This material was suspended in hot EtOAc and filtered while still hot. The collected solid was approx. 95% pure. An analytical sample was prepared by semi-preparative HPLC-C18.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=2)[NH2:12])=[CH:5][N:4]=1.[C:17](NC1C=CC=C(C2C=CC=CN=2)C=1)(=[O:19])[CH3:18]>>[C:17]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([C:6]2[CH:7]=[N:8][C:3]([N:2]([CH3:16])[CH3:1])=[N:4][CH:5]=2)[CH:10]=1)(=[O:19])[CH3:18]
Reactant: CN(C)c1ncc(-c2cccc(N)c2)cn1
Reactant: CC(=O)Nc1cccc(-c2ccccn2)c1
Product: CC(=O)Nc1cccc(-c2cnc(N(C)C)nc2)c1

Procedure:
2h is acetylated as described for 2g in Example 5 to yield 2i. Mp 183-188° C.