Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:14][S:15][C:16]2[NH:20][C:19]3[CH:21]=[C:22]([F:30])[C:23]([N:25]4[CH:29]=[CH:28][N:27]=[CH:26]4)=[CH:24][C:18]=3[N:17]=2)=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].ClC1C=CC=C(C(OO)=[O:39])C=1.[K+].[Br-]>ClCCl>[CH3:1][C:2]1[C:3]([CH2:14][S:15]([C:16]2[NH:20][C:19]3[CH:21]=[C:22]([F:30])[C:23]([N:25]4[CH:29]=[CH:28][N:27]=[CH:26]4)=[CH:24][C:18]=3[N:17]=2)=[O:39])=[N:4][CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:11])([F:12])[F:13]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1c(OCC(F)(F)F)ccnc1CSc1nc2cc(-n3ccnc3)c(F)cc2[nH]1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Product: Cc1c(OCC(F)(F)F)ccnc1CS(=O)c1nc2cc(-n3ccnc3)c(F)cc2[nH]1
Yield: 46.4 %

Procedure:
The title compound (0.24 g, 45%) was prepared by the above general procedure using 2-[[3-methyl-4-(2,2,2-trifluoroethoxy)pyridin-2-yl]methylthio]-6-fluoro-5-(imidazol-1-yl)-1H-benzimidazole (0.5 g, 1.14 mmol) (obtained in example 2), m-chloroperbenzoic acid (50%, 0.47 g, 1.4 mmol) and dichloromethane (10 mL). mp 234-235° C.; IR (KBr) 3449, 1049 cm- 1; 1H NMR (CD3OD+CDCl3) δ 2.28 (s, 3H, CH3), 4.42 (q,J=6.3 Hz, 2H, OCH2CF3), 4.74 (ABq, J=9.6 Hz, Δv=6.2 Hz, 2H, SOCH2), 6.74 (d,J=5.6 Hz, 1H), 7.20 (m, 2H), 7.52 (d,J=10.8 Hz, 1H), 7.70 (d,J=7.6 Hz, 1H), 7.86 (s, 1H), 8.30 (d,J=5.6 Hz, 1H); Mass (m/z) 453 (M+).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:14])([F:13])[F:12])[NH:7][C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]#[N:16].Br[CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20]>>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([F:12])([F:13])[F:14])[N:7]([CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:6]=2[CH:5]=[CH:4][C:3]=1[C:15]#[N:16]
Reactant: N#Cc1ccc2[nH]c(C(F)(F)F)nc2c1Cl
Reactant: CC(C)(C)OC(=O)CBr
Product: CC(C)(C)OC(=O)Cn1c(C(F)(F)F)nc2c(Cl)c(C#N)ccc21

Procedure:
Synthesized as described in Example 200A from 4-chloro-2-(trifluoromethyl)-1H-benzimidazole-5-carbonitrile and 1,1-dimethylethyl bromoacetate: MS (APCI) m/z 360 (M+1).
Reaction SMILES: N1[CH:5]=[N:4][C:3](SCCO)=N1.[C:10]1([C:16]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:17]2[CH:21]=[N:20][C:19]([CH2:22][CH2:23][CH2:24][OH:25])=[N:18]2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:32]1([C:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:17]2[CH:21]=[N:20][C:19]([CH2:22][CH2:23][CH2:24][O:25][C:5]3[CH:15]=[C:10]([C:16]#[N:17])[CH:11]=[CH:3][N:4]=3)=[N:18]2)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: OCCSc1nc[nH]n1
Reactant: OCCCc1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Product: N#Cc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1

Procedure:
By a method similar to that in Reference Example 17 and using, instead of 2-(1H-1,2,4-triazol-3-ylthio)ethanol, 3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propan-1-ol obtained in Reference Example 26, the title compound was obtained as a white powder (314 mg, 88%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH2:8][CH:7]([C:16]([OH:18])=[O:17])[C:6]2=1.[CH2:19](Cl)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11]1[CH2:10][CH2:9][CH2:8][CH:7]([C:16]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:17])[C:6]2=1
Reactant: ClCc1ccccc1
Reactant: COc1ccc2[nH]c3c(c2c1)C(C(=O)O)CCC3
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2[nH]c3c(c2c1)C(C(=O)OCc1ccccc1)CCC3

Procedure:
Following a procedure similar to that of Example 34C but using 37.2 g. of 6-methoxy-1,2,3,4-tetrahydrocarbazole-4-carboxylic acid, 19.5 g. of benzyl chloride and 16.8 g. of sodium carbonate in 300 ml. of dry dimethylformamide there was obtained 40.3 g. of the title compound; m.p. 81°-83°C. (ethyl alcoholpentane).
Reaction SMILES: C([N:8]1[C@@H:13]2[C@H:14]([C:16]([OH:19])([CH3:18])[CH3:17])[CH2:15][C@@:9]1([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C@H:10]([O:20][CH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[C:24]([C:32]([F:35])([F:34])[F:33])[CH:23]=1)[CH2:11][CH2:12]2)C1C=CC=CC=1>[Pd]>[F:30][C:28]([F:29])([F:31])[C:26]1[CH:27]=[C:22]([CH2:21][O:20][C@@H:10]2[CH2:11][CH2:12][C@@H:13]3[NH:8][C@@:9]2([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH2:15][C@H:14]3[C:16]([OH:19])([CH3:18])[CH3:17])[CH:23]=[C:24]([C:32]([F:33])([F:34])[F:35])[CH:25]=1
Reactant: CC(C)(O)[C@@H]1C[C@@]2(c3ccccc3)[C@H](OCc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC[C@@H]1N2Cc1ccccc1
Agent: [Pd]
Product: CC(C)(O)[C@@H]1C[C@]2(c3ccccc3)N[C@H]1CC[C@H]2OCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (1R*,2R*,5S*,6R*)-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-6-(1-hydroxy-1-methylethyl)-1-phenyl-8-azabicyclo[3.2.1]octane (Example 35; 56 mg 0.10 mmol), 10% palladium on charcoal (200 mg, 0.2 mmol) ethanol (10 ml) was stirred under hydrogen atmosphere (1 atm) at +60° C. for 2 hours. The reaction mixture was cooled to room temperature, flushed with nitrogen gas and filtered through a pad of Celite™. The filtrate was concentrated to give the title compound. The hydrochloride salt of the title compound was prepared by treatment with ethereal HCl and recrystallised from ethyl acetate:iso-hexane.
Reaction SMILES: C=O.[CH3:3][NH:4][C:5]([NH:7][N+:8]([O-:10])=[O:9])=[NH:6].C(N(CC)CC)C.[O:18]1[CH2:23]COC[CH2:19]1>C1(C)C=CC=CC=1>[CH3:3][N:4]1[C:5](=[N:7][N+:8]([O-:10])=[O:9])[NH:6][CH2:23][O:18][CH2:19]1
Reactant: CNC(=N)N[N+](=O)[O-]
Reactant: C1COCCO1
Agent: C=O
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CN1COCNC1=N[N+](=O)[O-]

Procedure:
30.5 g of paraformaldehyde are added, at room temperature, to a mixture of 20 g of N-methyl-N′-nitroguanidine, 17 g of triethylamine, 100 ml of dioxane and 100 ml of toluene, and the mixture is refluxed for 16 hours and subsequently evaporated in vacuo. The residue is purified by column chromatography [silica gel; dichloromethane/methanol (95:5)], giving the title compound which melts at 137 to 139°.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[N:9][N:10]([C:11]3[N:16]=[C:15]([C:17]4[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][CH:22]=4)[CH:14]=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.C[Sn](C)(C)[C:32]1[CH:37]=[N:36][CH:35]=[C:34]([CH3:38])[N:33]=1>CN(C)C(=O)C>[CH3:38][C:34]1[N:33]=[C:32]([C:2]2[N:7]=[CH:6][C:5]3[CH:8]=[N:9][N:10]([C:11]4[N:16]=[C:15]([C:17]5[CH2:18][CH2:19][N:20]([C:23]([O:25][C:26]([CH3:28])([CH3:29])[CH3:27])=[O:24])[CH2:21][CH:22]=5)[CH:14]=[CH:13][CH:12]=4)[C:4]=3[CH:3]=2)[CH:37]=[N:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cccc(-n3ncc4cnc(Cl)cc43)n2)CC1
Reactant: Cc1cncc([Sn](C)(C)C)n1
Solvent: CC(=O)N(C)C
Product: Cc1cncc(-c2cc3c(cn2)cnn3-c2cccc(C3=CCN(C(=O)OC(C)(C)C)CC3)n2)n1
Temperature: 145 °C
Yield: 72.3 %

Procedure:
A solution of tert-butyl 4-[6-(6-chloropyrazolo[4,3-c]pyridin-1-yl)-2-pyridyl]-3,6-dihydro-2H-pyridine-1-carboxylate (200 mg, 0.486 mmol) and palladium(0)tetrakis(triphenylphosphine) (56 mg, 0.049 mmol) in N,N-dimethylacetamide 5.0 mL was added trimethyl-(6-methylpyrazin-2-yl)stannane (250 mg, 0.971 mmol). The reaction mixture heated at 145° C. for 40 min in microwave. The reaction mixture was filtered through celite and concentrated. The crude product was diluted with EtOAc then washed with water. The organic layers was dried with sodium sulfate, filtered, and concentrated in vacuum. The crude product was purified by flash chromatography (EtOAc/Heptane eluted at 65% EtOAc) to give the desired product 165 mg 72% yield.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[S-:10][C:11]#[N:12].[K+]>>[Br:1][C:2]1[C:3]([S:10][C:11]#[N:12])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: N#C[S-]
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [K+]
Product: N#CSc1nc(Cl)ncc1Br
Yield: 80 %

Procedure:
In 100 ml of formid acid, a reaction of 23.0 g of 5-bromo-2,4-dichloropyrimidine and 10.0 g of potassium thiocyanate was conducted at room temperature (20° C.) for 4 hours in a similar manner as Synthesis Example 1. Then, the reaction mixture was treated in a similar procedure as Synthesis Example 1, there was obtained a 80.0% yield of 5-bromo-2-chloro-4-thiocyanopyrimidine, m.p. 166.5°-170° C.
Reaction SMILES: C(OC(=O)[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[CH:21]=[C:22]([CH:30]([CH3:32])[CH3:31])[CH:23]=[C:24]4[C:29]=3[N:28]=[CH:27][CH:26]=[CH:25]4)[CH:15]=2)=[CH:8][CH:7]=1)(C)C>CCOC(C)=O>[CH:30]([C:22]1[CH:23]=[C:24]2[C:29](=[C:20]([C:16]3[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=3)[CH2:13][O:12][C:9]3[CH:10]=[CH:11][C:6]([C:9]([OH:12])([CH3:10])[CH3:8])=[CH:7][CH:8]=3)[CH:21]=1)[N:28]=[CH:27][CH:26]=[CH:25]2)([CH3:32])[CH3:31]
Reactant: CC(C)OC(=O)c1ccc(OCc2cccc(-c3cc(C(C)C)cc4cccnc34)c2)cc1
Solvent: CCOC(C)=O
Product: CC(C)c1cc(-c2cccc(COc3ccc(C(C)(C)O)cc3)c2)c2ncccc2c1

Procedure:
Prepared according to the procedure described in EXAMPLE 11 but using the previous ester from step 1 as the starting material. Flash chromatography (Hex:EtOAc 0 to 70% gradient) afforded the compound as a foam.
Reaction SMILES: [C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[NH2:17][OH:18].[OH-].[Na+]>CCO>[C:1]1([CH:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[N:17][OH:18])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=CC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: ON=CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of diphenylacetaldehyde (51) (4.0 g, 20.3 mmol) in EtOH (50 mL) were sequentially added hydroxylamine hydrochloride (1.41 g, 20.3 mmol) and 2 N NaOH (aq. 5 mL). The reaction was stirred at room temperature overnight followed by removal of EtOH under reduced pressure. The residue was washed with water (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure to give 52 (4.0 g, 93%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH2:27][CH2:28][CH:29](C(OCC)=O)[C:30]([O:32]CC)=[O:31])[CH:6]=[CH:7][C:8]=1[C:9]1[S:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[C:13]([C:18]1([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:20][CH2:19]1)[N:12]=2>>[F:2][C:3]1[CH:4]=[C:5]([CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[CH:6]=[CH:7][C:8]=1[C:9]1[S:10][C:11]2[C:16]([N:17]=1)=[CH:15][CH:14]=[C:13]([C:18]1([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:20][CH2:19]1)[N:12]=2
Reactant: CCOC(=O)C(CCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1)C(=O)OCC
Agent: Cl
Product: O=C(O)CCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 120 °C

Procedure:
In reactor bottle, hydrochloric acid, 5N aq. (3 mL) was added to diethyl 2-(2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)ethyl)malonate (0.257 g, 0.48 mmol), and the mixture heated to 120° C. for 6 h. The crude reaction mixture was concentrated in vacuo and purified by silica gel chromatography to afford 4-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)butanoic acid. MS (ESI) m/z: calculated: 432.1; Observed: 433.0 (M++1).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[OH:17])[C:6]1=[O:18])(=[O:3])[CH3:2].[CH2:19]([O:26][C:27]1[CH:28]=[C:29]([CH2:35][CH2:36]N=C([O-])C(Cl)(Cl)Cl)[CH:30]=[CH:31][C:32]=1[O:33][CH3:34])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:1]([O:4][C@@H:5]1[CH2:9][C:8](=[O:10])[N:7]([C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[O:17][CH2:36][CH2:35][C:29]2[CH:30]=[CH:31][C:32]([O:33][CH3:34])=[C:27]([O:26][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:28]=2)[C:6]1=[O:18])(=[O:3])[CH3:2]
Reactant: COc1ccc(CCN=C([O-])C(Cl)(Cl)Cl)cc1OCc1ccccc1
Reactant: CC(=O)O[C@@H]1CC(=O)N([C@@H]2CCCC[C@H]2O)C1=O
Solvent: ClCCl
Product: COc1ccc(CCO[C@@H]2CCCC[C@H]2N2C(=O)C[C@@H](OC(C)=O)C2=O)cc1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85.9 %

Procedure:
To a chilled (0° C.) solution of (3R)-1-((1R,2R)-2-hydroxylcyclohex-1-yl)-2,5-dioxopyrrolidin-3-yl acetate (15.0 g, 58.7 mmol) in anhydrous dichloromethane (100 mL) was added tetrafluoroboric acid diethyl ether complex (3.2 mL). The resultant reaction mixture was stirred at 0° C. for 20 minutes before adding a solution of 2-(3-benzyloxy-4-methoxy-phenyl)-ethyl-2,2,2-trichloroacetimidate (24.8 g, 61.6 mmol, 1.05 equiv.) in dichloromethane (100 mL) via an addition funnel over 30 minutes. The reaction mixture was stirred at 0° C. until the reaction was judged complete by HPLC analysis. The reaction mixture was quenched with water (250 mL). The organic layer was separated from the aqueous layer and subsequently washed with dilute NaHCO3 (5% wt solution, 2×100 mL), and water (5×100 mL). The organic layer was dried (anhydrous MgSO4), filtered, and concentrated under reduced pressure to ˜100 mL solution. The solution was cooled at −20° C. for 24 hours and the precipitate (trichloroacetamide) was removed by filtration. The filtrate was further concentrated to a volume of ˜40 mL. This process was repeated three times until the bulk of the by-product (trichloroacetamide) was removed. After the third filtration, the filtrate was concentrated in vacuo to give (1R,2R)-1-{2-[2-(3-benzyloxy-4-methoxy-phenyl)ethoxy]cyclohexyl}-2,5-dioxopyrrolidin-3-(R)-yl acetate as a pale yellow syrup (25 g, 86% yield).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]([CH3:38])[CH2:13][C:14]1[C:15]([C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=[O:37])[CH:33]=[C:34]([CH3:36])[CH3:35])[CH:26]=2)=[N:16][N:17]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[CH:18]=1)C(=O)OC(C)(C)C>Cl>[CH3:35][C:34]([CH3:36])=[CH:33][C:32]([NH:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([C:15]2[C:14]([CH2:13][N:12]([CH3:38])[CH2:11][CH2:10][NH:2][CH3:1])=[CH:18][N:17]([CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[N:16]=2)[CH:26]=1)=[O:37]
Reactant: CC(C)=CC(=O)Nc1cccc(-c2nn(C3CCCCO3)cc2CN(C)CCN(C)C(=O)OC(C)(C)C)c1
Agent: Cl
Product: CNCCN(C)Cc1cn(C2CCCCO2)nc1-c1cccc(NC(=O)C=C(C)C)c1
Yield: 26.8 %

Procedure:
A solution of tert-butyl methyl(2-(methyl((3-(3-(3-methylbut-2-enamido)phenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)amino)ethyl)carbamate (0.08 g, 0.000228 mol) in methanolic HCl (2 mL, 4M) was stirred for 1 hr at room temperature. The solution was concentrated under reduce pressure and triturated with diethyl ether to give 3-methyl-N-(3-(4-((methyl(2-(methylamino)ethyl)amino)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)phenyl)but-2-enamide (0.026 g, yield: 33%, HCl salt). 1H NMR (400 MHz, DMSO-d6): δ 8.02-7.80 (m, 2H), 7.60-7.50 (m, 1H), 7.44-7.35 (m, 1H), 7.30-7.21 (m, 1H), 5.90 (s, 1H), 4.50-4.20 (s, 2H), 3.30-3.00 (m), 2.60 (s, 3H), 2.52 (s, 3H), 2.15 (s, 3H), 1.88 (s, 3H) ppm. LCMS (ESI): RT=1.49 min, m/z=342.4 [M+H]+.
Reaction SMILES: [OH:1][CH:2]([C:4]1[CH:11]=[CH:10][C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)[CH3:3].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([Mg]Br)=[CH:15][CH:14]=1>C1COCC1>[NH2:9][CH:8]([C:16]1[CH:17]=[CH:18][C:13]([Cl:12])=[CH:14][CH:15]=1)[C:7]1[CH:10]=[CH:11][C:4]([CH:2]([OH:1])[CH3:3])=[CH:5][CH:6]=1
Reactant: CC(O)c1ccc(C#N)cc1
Reactant: Clc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CC(O)c1ccc(C(N)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The product of Step A (1.47 g, 10 mmol) was dissolved in THF (20 mL), cooled in an ice-bath and 4-chlorophenylmagnesium bromide (21.00 mL, 21.00 mmol, 1 M in THF) was added. The reaction aged at 50° C. for 4 h and then cooled to rt overnight. The solvent had evaporated overnight and the product was taken up in 2-methyltetrhydrofuran (20 mL) and an additional 1 eq of 4-chlorophenylmagnesium bromide was added. The reaction aged at rt for 3 h and was concentrated. The reaction was diluted with 15 mL MeOH. NaBH (378 mg, 10.00 mmol) was added and the reaction aged for 1 h. The reaction was concentrated, diluted with 2M HCl (aq) and extracted with EtOAc. The organic layer was collected, dried with Na2SO4, filtered and concentrated. The residue was purified somewhat by flash chromatography on silica gel gradient eluted with 0-10% MeOH/EtOAc affording title compound. HPLC/MS: 244.9 (M—NH2)+; Rt=2.09 min
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:26][NH:27][C:28]1[C:29]([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)=[N:30][CH:31]=[CH:32][CH:33]=1>C1COCC1.C(OCC)(=O)C>[CH3:26][NH:27][C:28]1[CH:33]=[CH:32][CH:31]=[N:30][C:29]=1[N:34]1[CH2:39][CH2:38][N:37]([C:11]([C:6]2[NH:7][C:8]3[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=3[CH:5]=2)=[O:13])[CH2:36][CH2:35]1
Reactant: CNc1cccnc1N1CCNCC1
Reactant: O=C(O)c1cc2cc(F)ccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNc1cccnc1N1CCN(C(=O)c2cc3cc(F)ccc3[nH]2)CC1
Reaction time: 2 h

Procedure:
5-Fluoroindole-2-carboxylic acid (98 mg) and 1,1'-carbonyldiimidazole (95 mg) are dissolved in dry THF (1 ml) and stirred for 2 hr at 20°-25°. The resulting solution is added via canula to a -10° cooled solution of 4-[3-(methylamino)-2-pyridinyl]piperazine (117 mg) in dry THF (1 ml). The reaction mixture is then allowed to reach 20°-25° overnight. The reaction mixture is then diluted with ethyl acetate, washed with saturated sodium bicarbonate and saline, dried over magnesium sulfate, and concentrated to give a solid, which is purified on a silica gel flash column eluting with hexane/ethyl acetate (1/1). The appropriate fractions are pooled and concentrated to give a solid. Recrystallization of the solid from ethyl acetate/ether gives the title compound, mp 194°-195°.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:25]/[O:26][C:27]2([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])[CH2:29][CH2:28]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][OH:24])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C1COCC1.CCOC(C)=O>[C:1]([O:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12](/[C:14](=[N:25]/[O:26][C:27]2([C:30]([O:32][CH:33]([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)=[O:31])[CH2:28][CH2:29]2)/[C:15]([NH:17][C@@H:18]2[C:21](=[O:22])[NH:20][C@@H:19]2[CH2:23][O:24][S:47]([CH3:46])(=[O:49])=[O:48])=[O:16])[N:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2CO)cs1
Reactant: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1nc(/C(=N/OC2(C(=O)OC(c3ccccc3)c3ccccc3)CC2)C(=O)N[C@@H]2C(=O)N[C@@H]2COS(C)(=O)=O)cs1
Reaction time: 2 h

Procedure:
To a solution of benzhydryl 1-(((Z)-(1-(2-((tert-butoxycarbonyl)amino)thiazol-4-yl)-2-(((2S,3S)-2-(hydroxymethyl)-4-oxoazetidin-3-yl)amino)-2-oxoethylidene)amino)oxy)cyclopropanecarboxylate (1 g, 1.57 mmol) at 0° C. in THF (15.7 ml) was added TEA (0.66 ml, 4.7 mmol) and MsCl (25 μl, 0.32 mmol). After 2 h, the reaction mixture was diluted with EtOAc, washed with brine, dried over Na2SO4, filtered and concentrated in vacuo, affording the title compound (assumed quantitative). LCMS: R=0.99 min, m/z=714.1 (M+1), Method 2m_acidic.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[N+:15]([O-])=O.S(S([O-])=O)([O-])=O.[Na+].[Na+].C(=O)(O)[O-].[Na+].[Na+].[Cl-]>O.CCOC(C)=O.CO>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:4]=1[CH2:5][NH:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][C:8]=1[NH2:15]
Reactant: COc1ccc(CNc2ccc(C#N)cc2[N+](=O)[O-])c(OC)c1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: COc1ccc(CNc2ccc(C#N)cc2N)c(OC)c1
Reaction time: 0.25 h
Yield: 105.5 %

Procedure:
A solution of 4-(2,4-dimethoxybenzylamino)-3-nitrobenzonitrile (4.54 g) in THE (400 mL) was treated with a solution of sodium hydrosulfite (20 g) and sodium bicarbonate (10 g) in distilled water (350 mL). Enough methanol was immediately added (50 mL) to maintain a homogeneous solution. After 15 minutes, EtOAc (500 mL) and saturated aqueous NaCl (500 mL) were added and the organic layer was separated. The aqueous layer was extracted again with 400 mL EtOAc. The combined organic layers were washed with saturated aqueous NaCl (500 mL) and separated. The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo to provide 4.33 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C@@:6]2([CH2:20][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:8]=3[CH2:7]2)[N:15]=[C:14]([CH:18]=[O:19])[CH:13]=[CH:12]4)[C:5](=[O:21])[NH:4][C:3]1=[O:22].CN1C2(CC3C(=CC=C([N+]([O-])=O)C=3)C2)C(=O)NC1=O>>[CH3:1][N:2]1[C:6]2([CH2:20][C:9]3[CH:10]=[C:11]4[C:16](=[CH:17][C:8]=3[CH2:7]2)[N:15]=[C:14]([CH:18]=[O:19])[CH:13]=[CH:12]4)[C:5](=[O:21])[NH:4][C:3]1=[O:22]
Reactant: CN1C(=O)NC(=O)[C@]12Cc1cc3ccc(C=O)nc3cc1C2
Agent: CN1C(=O)NC(=O)C12Cc1ccc([N+](=O)[O-])cc1C2
Product: CN1C(=O)NC(=O)C12Cc1cc3ccc(C=O)nc3cc1C2

Procedure:
Essentially following the procedures described for Intermediate 13, but using (±)-5′-amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (described in Intermediate 7) in place of (R)-5′-amino-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione, the title compound is prepared.
Reaction SMILES: [Mg].BrCCBr.Br[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]1[CH2:15][CH2:14]1.[C:16](=[O:18])=[O:17]>O1CCCC1>[CH:13]1([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:16]([OH:18])=[O:17])[CH2:15][CH2:14]1
Reactant: O=C=O
Reactant: BrCCCCCCC1CC1
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: O=C(O)CCCCCCC1CC1

Procedure:
0.684 g. Magnesium metal is covered with 2 ml. anhydrous tetrahydrofuran and 0.2 ml. 1,2-dibromoethane is added with stirring and heating. 1-Bromo-6-cyclopropylhexane (4.8 g.) and tetrahydrofuran (25 ml.) are added portionwise. An additional 0.207 ml. of 1,2-dibromoethane is added and the reaction mixture refluxed for 3 hours. The solution is then maintained at 24°-28° while anhydrous carbon dioxide is bubbled through it for 11/2 hours. After stirring overnight under carbon dioxide, dry ether, water and 2N sulfuric acid are added until the pH is less than 7. The solution is extracted with ether and washed with water and brine, dried over calcium sulfate, filtered and the solvent removed to yield 7-cyclopropylheptanoic acid.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[O:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH2:20][NH2:21])[CH2:14][CH2:13]1.Cl>CCOCC>[ClH:1].[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([NH:21][CH2:20][CH2:19][CH2:18][N:15]3[CH2:16][CH2:17][O:12][CH2:13][CH2:14]3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: NCCCN1CCOCC1
Reactant: Clc1ccc2ncc(Cl)n2n1
Agent: Cl
Solvent: CCOCC
Product: Clc1cnc2ccc(NCCCN3CCOCC3)nn12
Yield: 57 %

Procedure:
Prepared from 3,6-dichloroimidazo[1,2-b]pyridazine and 3-morpholinopropylamine according to general procedure 3. The free base was converted to the HCl salt with 2N HCl in Et2O to provide the title compound (153 mg, 57%) as a white solid; 1H NMR (500 MHz, CD3OD) δ 7.60 (d, J=9.7 Hz, 1H), 7.39 (s, 1H), 6.70 (d, J=9.7 Hz, 1H), 3.90 (br, 4H), 3.53 (t, J=6.7 Hz, 2H), 3.35-3.27 (m, 6H), 2.20-2.14 (m, 2H): 13C NMR (75 MHz, CD3OD) δ 155.8, 137.2, 127.9, 126.1, 115.6, 114.7, 65.2, 56.8, 53.4, 39.6, 24.5; HPLC tR=8.9 min (Synergi), >99%; ES-MS: (M+H)=332 m/z.