Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]1([NH:13][C:14]2[N:19]=[C:18]([NH2:20])[N:17]=[C:16]([C:21]3[N:25]=[C:24](C(Cl)(Cl)Cl)[O:23][N:22]=3)[N:15]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCOCC1>[C:7]1([NH:13][C:14]2[N:19]=[C:18]([NH2:20])[N:17]=[C:16]([C:21]3[N:25]=[C:24]([N:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[O:23][N:22]=3)[N:15]=2)[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C1CCNCC1
Reactant: Nc1nc(Nc2ccccc2)nc(-c2noc(C(Cl)(Cl)Cl)n2)n1
Solvent: C1COCCO1
Product: Nc1nc(Nc2ccccc2)nc(-c2noc(N3CCCCC3)n2)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 26 %

Procedure:
Piperidine (0.483 mL, 4.902 mmol) was added to a solution of 2-N-phenyl-6-[5-(trichloromethyl)-1,2,4-oxadiazol-3-yl]-1,3,5-triazine-2,4-diamine (prepared in an analogous manner to Intermediate 134, 0.913 g, 2.451 mmol) in dioxane (4 mL) at room temperature. The reaction mixture was stirred at room temperature for two days before being concentrated. The resulting residue was dissolved in EtOAc and water, and washed successively with 1M aq. HCl and brine. The organic phase was dried over sodium sulfate, filtered and concentrated. The crude compound was purified by flash chromatography (heptane:EtOAc 3:2) to afford the title compound (100 mg, 26%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[O:6][CH:7]=1.[F:15][C:16]1[C:24]([OH:25])=[CH:23][CH:22]=[C:21]([F:26])[C:17]=1[C:18]([NH2:20])=[O:19].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[O:6][CH:7]=[C:3]([CH2:2][O:25][C:24]3[C:16]([F:15])=[C:17]([C:21]([F:26])=[CH:22][CH:23]=3)[C:18]([NH2:20])=[O:19])[N:4]=2)=[CH:9][CH:10]=1
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Reactant: NC(=O)c1c(F)ccc(O)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)ccc(OCc2coc(-c3ccc(Cl)cc3)n2)c1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 35.2 %

Procedure:
To a solution of 4-Chloromethyl-2-(4-chloro-phenyl)-oxazole (0.20 g, 0.87 mmol) in 2 ml of anhydrous DMF was added 2,6-Difluoro-3-hydroxy-benzamide (0.15 g, 0.78 mmol) and potassium carbonate (0.363 g, 2.60 mmol). The reaction mixture was stirred at 25° C. for 24 h under nitrogen atmosphere. The reaction mixture was evaporated to dryness under reduced pressure and the residue was purified by column chromatography on silica (60-120 M) using ethyl acetate/hexane (50:50) as the eluent to provide the title compound as white solid (0.10 g, 31%). 1H NMR (DMSO-d6, 400 MHz): δ 5.14 9s, 2H), 7.12 (t, J=9.20 Hz, 1H), 7.40 (m, 1H), 7.63 (d, J=8.40, 2H), 7.85 (br s, 1H), 8.0 (d, J=8.40 Hz, 2H), 8.13 (br s, 1H) and 8.36 (s, 1H). MS ES+ (365.13), HPLC (method I) Rt=16.36 min.
Reaction SMILES: C([O:4][C@@H:5]1[C@@:9]([C:15]#[CH:16])([CH2:10][O:11]C(=O)C)[O:8][C@@H:7]([N:17]2[C:26]3[N:25]=[C:24]([F:27])[N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[CH:18]2)[CH2:6]1)(=O)C.N>CO>[C:15]([C@:9]1([CH2:10][OH:11])[O:8][C@@H:7]([N:17]2[C:26]3[N:25]=[C:24]([F:27])[N:23]=[C:21]([NH2:22])[C:20]=3[N:19]=[CH:18]2)[CH2:6][C@@H:5]1[OH:4])#[CH:16]
Reactant: C#C[C@]1(COC(C)=O)O[C@@H](n2cnc3c(N)nc(F)nc32)C[C@@H]1OC(C)=O
Agent: N
Solvent: CO
Product: C#C[C@]1(CO)O[C@@H](n2cnc3c(N)nc(F)nc32)C[C@@H]1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound 3 (200 mg, 0.53 mmol) was dissolved in methanol (7.00 ml), and 28% aqueous ammonia (5.00 ml) was added to the resultant solution, followed by stirring at room temperature for four hours. The resultant reaction mixture was concentrated under reduced pressure, and a mixture of chloroform and methanol (20:1) was added to the resultant residue. The thus-precipitated crystals were filtered, and then the resultant crystals were recrystallized from water, to thereby yield compound 4 (113 mg, 0.39 mmol, 73.6%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[N:6][CH:7]=1.[OH:11][CH:12](O)[C:13]([C:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][CH:16]=1)=[O:14]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH:12]([OH:11])[C:13]([C:15]2[C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=[CH:17][CH:16]=2)=[O:14])=[O:9])=[N:6][CH:7]=1
Reactant: NC(=O)c1ccc(Br)cn1
Reactant: O=C(c1cccc2ccccc12)C(O)O
Solvent: C1COCCO1
Product: O=C(NC(O)C(=O)c1cccc2ccccc12)c1ccc(Br)cn1
Temperature: 100 °C
Yield: 65.8 %

Procedure:
A mixture of 5-bromopicolinamide 111 (0.588 g, 2.92 mmol) and 2,2-dihydroxy-1-(naphthalen-1-yl)ethanone 112 (1.20 g, 5.67 mmol) in dioxane (20 mL) were heated at 100° C. for 18 hours. The dioxane was removed under vacuum and the residue was dissolved in chloroform and methanol and concentrated onto silica gel. The material was purified by auto flash system (CH2Cl2 to 1% MeOH: CH2Cl2) to give 5-bromo-N-(1-hydroxy-2-(naphthalen-1-yl)-2-oxoethyl)picolinamide 113 as a tan solid (0.74 g, 66%).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]=O.[CH3:12][N:13]1[CH2:17][CH2:16][CH2:15][CH:14]1[CH2:18][CH2:19][NH2:20].[Na]>ClCCl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH2:10][NH:20][CH2:19][CH2:18][CH:14]1[CH2:15][CH2:16][CH2:17][N:13]1[CH3:12]
Reactant: O=Cc1cc2ccccc2o1
Reactant: CN1CCCC1CCN
Agent: [Na]
Solvent: ClCCl
Product: CN1CCCC1CCNCc1cc2ccccc2o1
Yield: 32.1 %

Procedure:
Experimental condition analogous to Example 5, from 2-benzofurancarboxaldehyde 0.14 g (1.1 mmol), 2-(1-methyl-pyrrolidin-2-yl)-ethylamine 0.14 g (1 mmol), and sodium triacethoxyborohydride 0.31 g (1.5 mmol), in 10 mL Dichloromethane. Purification using silica chromatography, elution with dichloromethane-methanol-ammonium hydroxide, 9-1-0.25, gave 83 mg of compound.
Reaction SMILES: C([O:8][C:9]1[C:14]2[N:15]([CH2:19][CH2:20][O:21][CH3:22])[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[C:11]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:10]=1)C1C=CC=CC=1>C(O)C.[C].[Pd]>[OH:8][C:9]1[C:14]2[N:15]([CH2:19][CH2:20][O:21][CH3:22])[C:16]([CH3:18])=[N:17][C:13]=2[CH:12]=[C:11]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[CH:10]=1
Reactant: COCCn1c(C)nc2cc(C(=O)N(C)C)cc(OCc3ccccc3)c21
Agent: [Pd]
Solvent: CCO
Product: COCCn1c(C)nc2cc(C(=O)N(C)C)cc(O)c21
Reaction time: 19 h
Yield: 95.5 %

Procedure:
A mixture of 7-(benzyloxy)-1-(2-methoxyethyl)-N,N,2-trimethyl-1H-benzimidazole-5-carboxamide (483 mg, 1.31 mmol, Step 1) and 10% palladium-carbon (50 mg) in ethanol (30 mL) was stirred under hydrogen gas for 19 hours. The resulting mixture was filtered through a pad of Celite, and the filtrate was concentrated in vacuo to afford the title compound as a white solid (347 mg, 95%).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]([C:20]([O:22]C)=[O:21])[S:18][CH:19]=2)[O:4][N:3]=1.[OH-].[K+]>C(O)C.O>[CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]([C:20]([OH:22])=[O:21])[S:18][CH:19]=2)[O:4][N:3]=1
Reactant: COC(=O)c1cc(OCCCCCCCc2cc(C)no2)cs1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1cc(CCCCCCCOc2csc(C(=O)O)c2)on1

Procedure:
11.34 g (33.61 mmol) of methyl 4-(7-(3-methyl-5-isoxazolyl)-heptyloxy)-2-thiophenecarboxylate are heated under reflux in 95 ml of ethanol and 45 ml of water, and 2.18 g (38.9 mmol) of KOH, dissolved in 70 ml of water and 46 ml of ethanol, are added dropwise to this solution. After the mixture has been heated under reflux for 3 hours, it is cooled and concentrated, the residue is partitioned between water and ether and the aqueous phase, after acidification to pH 1 with 2N HCl, is extracted several times with ether. The combined organic phases are dried over sodium sulfate/active charcoal and evaporated.
Reaction SMILES: [N:1]1([C:11]2[C:12]([CH2:17][NH:18][CH2:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][N:21]=3)=[N:13][CH:14]=[CH:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[O:28]=[C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:31](=[O:38])[N:30]1[CH2:39][CH2:40][CH2:41][CH:42]=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[N:1]1([C:11]2[C:12]([CH2:17][N:18]([CH2:19][C:20]3[C:25]([CH3:26])=[CH:24][C:23]([CH3:27])=[CH:22][N:21]=3)[CH2:42][CH2:41][CH2:40][CH2:39][N:30]3[C:31](=[O:38])[C:32]4[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:29]3=[O:28])=[N:13][CH:14]=[CH:15][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: O=CCCCN1C(=O)c2ccccc2C1=O
Reactant: Cc1cnc(CNCc2ncccc2N2CCCc3ccccc32)c(C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cnc(CN(CCCCN2C(=O)c3ccccc3C2=O)Cc2ncccc2N2CCCc3ccccc32)c(C)c1

Procedure:
Using General Procedure B: Reaction of [3-(3,4-Dihydro-2H-quinolin-1-yl)-pyridin-2-ylmethyl]-(3,5-dimethyl-pyridin-2-ylmethyl)-amine in CH2Cl2 and 4-(1,3-Dioxo-1,3-dihydro-isoindol-2-yl)-butyraldehyde (1.36 g, 6.28 mmol) with NaBH(OAc)3 gave 2-{4-[[3-(3,4-Dihydro-2H-quinolin-1-yl)-pyridin-2-ylmethyl]-(3,5-dimethyl-pyridin-2-ylmethyl)-amino]-butyl}-isoindole-1,3-dione as a yellow fluffy solid. 1H NMR (CDCl3) δ 1.35-1.50 (m, 4H), 1.95-1.80 (m, 2H), 2.03 (s, 3H), 2.22 (s, 3H), 2.50-2.65 (m, 2H), 2.65-2.95 (m, 2H), 3.27-3.40 (m, 2H), 3.45-3.55 (m, 2H), 3.65-3.80 (m, 4H), 5.99 (d, 1H, J=7.7 Hz), 6.59 (t, 1H, J=7.7 Hz), 6.81 (t, 1H, J=1.3, 7.7 Hz), 6.95 (d, 1H, J=7.7 Hz), 7.07 (s, 1H), 7.21 (dd, 1H, J=4.6, 7.9 Hz), 7.50 (dd, 1H, J=1.0, 7.9 Hz), 7.65-7.75 (m, 2H), 7.75-7.85 (m, 2H), 8.9 (s, 1H), 8.53 (dd, 1H, J=1.0, 4.6 Hz). Deprotection with H2NNH2.H2O following General Procedure E gave N1-[3-(3,4-Dihydro-2H-quinolin-1-yl)-pyridin-2-ylmethyl]-N1-(3,5-dimethyl-pyridin-2-ylmethyl)-butane-1,4-diamine as a free base.
Reaction SMILES: [NH2:1][C:2]([CH3:23])([CH3:22])[CH2:3][C:4]1[N:5]([CH2:18][CH2:19][O:20][CH3:21])[N:6]=[C:7]2[C:16]=1[C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N:9]=[C:8]2[NH2:17].[F:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>>[NH2:17][C:8]1[C:7]2=[N:6][N:5]([CH2:18][CH2:19][O:20][CH3:21])[C:4]([CH2:3][C:2]([NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][C:25]([F:24])=[CH:26][CH:27]=3)([CH3:23])[CH3:22])=[C:16]2[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:9]=1
Reactant: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)N
Reactant: O=C(Cl)c1ccc(F)cc1
Product: COCCn1nc2c(N)nc3ccccc3c2c1CC(C)(C)NC(=O)c1ccc(F)cc1
Yield: 79.1 %

Procedure:
Using the general method of Example 599, 1-(2-amino-2-methylpropyl)-2-(2-methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-4-amine (500 mg, 1.60 mmol, prepared as described in Example 590) was reacted with 4-fluorobenzoyl chloride (634 mg, 4.00 mmol). The crude product was purified by IFC (silica gel eluting with a gradient of 5 to 20% CMA in chloroform) followed by recrystallization from ethyl acetate/hexanes to provide 551 mg of N-{2-[4-amino-2-(methoxyethyl)-2H-pyrazolo[3,4-c]quinolin-1-yl]-1,1-dimethylethyl}-4-fluorobenzamide as a white solid, mp 187-189° C. MS (ESI) m/z 436 (M+H)+; Anal. Calcd for C24H26FN5O2: C, 66.19; H, 6.02; N, 16.08. Found: C, 65.92; H, 5.93; N, 15.87.
Reaction SMILES: [CH3:1][N:2]1[C:10]([CH:11]=O)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[N:29]1([CH2:34][CH2:35][NH2:36])[CH:33]=[CH:32][CH:31]=[N:30]1>>[CH3:1][N:2]1[C:10]([CH2:11][NH:36][CH2:35][CH2:34][N:29]2[CH:33]=[CH:32][CH:31]=[N:30]2)=[N:9][C:8]2[C:3]1=[N:4][C:5]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH3:28])=[N:6][C:7]=2[N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1
Reactant: NCCn1cccn1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCCn3cccn3)n(C)c2n1

Procedure:
Following General Procedure L for reductive amination, 9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-6-morpholino-9H-purine-8-carbaldehyde and 2-(1H-pyrazol-1-yl)ethanamine were reacted to give 431. [M+H]+ 473.3
Reaction SMILES: CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[Cl:14][CH2:15][C:16](=[O:31])[C@@H:17]([NH:26][C:27](=[O:30])[O:28][CH3:29])[CH2:18][S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>C(O)(C)C>[Cl:14][CH2:15][C@@H:16]([OH:31])[C@@H:17]([NH:26][C:27](=[O:30])[O:28][CH3:29])[CH2:18][S:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)N[C@@H](CSc1ccccc1)C(=O)CCl
Agent: CC(C)[O-]
Agent: Cl
Agent: [Al+3]
Solvent: CC(C)O
Product: COC(=O)N[C@@H](CSc1ccccc1)[C@H](O)CCl
Temperature: 70 °C
Reaction time: 4 h

Procedure:
To a suspension of 2.15 g aluminium isopropoxide in 35 ml of isopropanol were added 2.88 g of methyl [3-chloro-2-oxo-(R)-1-(phenylthiomethyl)-propyl]-carbamate and the suspension was stirred at 70° C./400mbar for 4 hours. The mixture was cooled to 0° C., the pH was adjusted to 1 by adding hydrochloric acid and the isopropanol was evaporated. The suspension was filtered and the residue was recrystallized from toluene to give 2.18 g (75%) isomerically pure methyl (1R, 2S)-[3-chloro-2-hydroxy-1-(phenylthiomethyl)-propyl]-carbamate, m.p. 113-114° C. IR (KBr): 3389 m and 3327 m (NH,OH), 1695 s (C═O), 1537 s (amide II). MS (EI): 289/35 (M+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13](/[C:16](/[CH3:36])=[CH:17]/[CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C@H:27]([O:33][CH2:34][CH3:35])[C:28]([O:30]CC)=[O:29])=[CH:22][CH:21]=3)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[OH-].[Na+]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13](/[C:16](/[CH3:36])=[CH:17]/[CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C@H:27]([O:33][CH2:34][CH3:35])[C:28]([OH:30])=[O:29])=[CH:24][CH:25]=3)=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(C(C)=O)cc3)cc2)cc1)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCO[C@@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(C(C)=O)cc3)cc2)cc1)C(=O)O
Yield: 37.1 %

Procedure:
The title compound was prepared from (E)-(S)-ethyl 3-{4-[3-(4′-acetyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionate (Example 107) (200 mg, 0.411 mmol) and sodium hydroxide (1M, 1.64 ml, 1.64 mmol) by a procedure analogous to that described in example 51, yielding (E)-(S)-3-{4-[3-(4′-acetyl-biphenyl-4-yl)-but-2-enyloxy]-phenyl}-2-ethoxy-propionic acid (70 mg, 37%) as a yellow coloured solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13](=[O:22])[C:14]2[CH:19]=[C:18](Br)[CH:17]=[CH:16][C:15]=2[F:21])[CH:7]=1)[CH3:2].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]([C:14]2[CH:19]=[C:18]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([F:24])[CH:30]=3)[CH:17]=[CH:16][C:15]=2[F:21])=[O:22])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(NC(=O)c2cc(Br)ccc2F)c1
Reactant: OB(O)c1cccc(F)c1
Product: CCOC(=O)Cc1cccc(NC(=O)c2cc(-c3cccc(F)c3)ccc2F)c1

Procedure:
The phenyl bromide (78) (106 mg, 0.28 mmol) was coupled to 3-fluoro-phenylboronic acid (42 mg, 0.30 mmol) using Method E. The crude product was purified by column chromatography eluting with 20% EtOAc in heptane to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:15]3[C@@H:14]4[CH2:16][C@@H:13]4[CH2:12][C:11]=3[C:10]([C:17]([OH:19])=O)=[N:9]2)[CH:3]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:51][C@@H:52]([C:55]([CH3:58])([CH3:57])[CH3:56])[CH2:53][OH:54]>CN(C=O)C>[OH:54][CH2:53][C@@H:52]([NH:51][C:17]([C:10]1[C:11]2[CH2:12][C@H:13]3[CH2:16][C@H:14]3[C:15]=2[N:8]([C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][N:5]=2)[N:9]=1)=[O:19])[C:55]([CH3:58])([CH3:57])[CH3:56]
Reactant: O=C(O)c1nn(-c2cc(Br)ccn2)c2c1C[C@H]1C[C@@H]21
Reactant: CC(C)(C)[C@H](N)CO
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)[C@@H](CO)NC(=O)c1nn(-c2cc(Br)ccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 23 °C
Reaction time: 0.08 h
Yield: 94.6 %

Procedure:
To a solution of (1aR,5aR)-2-(4-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2.00 g, 6.25 mmol) and triethylamine (1.741 mL, 12.49 mmol) in DMF (15 mL) was added HATU (2.423 g, 6.37 mmol). The reaction was stirred at 23° C. for 5 min, then was added (S)-2-amino-3,3-dimethylbutan-1-ol (0.805 g, 6.87 mmol). The reaction was stirred at 23° C. for 1 h then concentrated. The residue was purified by silica gel column chromatography to give the title compound as a white solid (2.48 g). LCMS m/z=419.2 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.44 (td, J=4.6, 3.4 Hz, 1H), 1.05 (s, 9H), 1.24 (td, J=7.8, 4.9 Hz, 1H), 2.23-2.29 (m, 1H), 2.46 (t, J=5.5 Hz, 1H), 2.78-2.83 (m, 1H), 2.91 (d, J=16.7 Hz, 1H), 3.01 (dd, J=16.6, 6.3 Hz, 1H), 3.66-3.72 (m, 1H), 3.93-4.01 (m, 2H), 7.01 (d, J=8.8 Hz, 1H), 7.37 (dd, J=5.3, 1.6 Hz, 1H), 8.09 (d, J=1.6 Hz, 1H) 8.28 (d, J=5.3 Hz, 1H).
Reaction SMILES: [O-:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[Na+].[Na+].Cl[CH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1>>[N:25]1[CH:26]=[CH:27][C:22]([CH2:21][CH2:20][CH2:19][O:1][C:2]2[CH:11]=[C:10]3[C:5]([CH:6]=[CH:7][C:8]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:9]3)=[CH:4][CH:3]=2)=[CH:23][CH:24]=1
Reactant: ClCCCc1ccncc1
Reactant: O=S(=O)([O-])c1ccc2ccc([O-])cc2c1
Agent: [Na+]
Product: O=S(=O)(O)c1ccc2ccc(OCCCc3ccncc3)cc2c1
Yield: 42.3 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 26B, sodium 7-oxidonaphthalene-2-sulfonate (Pfaltz and Bauer, 200 mg, 0.75 mmol) and 4-(3-chloropropyl)pyridine (116 mg, 0.75 mmol) were converted to the title compound (109 mg, 43%). 1H NMR (DMSO-d6) δ 8.65, (s, 1H), 8.58 (s, 1H), 8.12 (s, 1H), 7.92 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.62 (d, J=5.7 Hz, 1H), 7.57 (dd, J=8.5, 1.9 Hz, 2H), 7.44 (s, 1H), 7.27 (d, J=8.7, 1H), 4.20 (t, J=6.5 Hz, 2H), 3.10 (t, J=7.7 Hz, 2H), 2.30-2.21 (m, 2H); MS(ESI+) m/z 344.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH:9]3[CH2:12][C:11](=[O:13])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[Li+]>C1COCC1>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([C@@H:9]3[CH2:10][C@H:11]([OH:13])[CH2:12]3)[S:8][C:4]=2[CH:3]=1
Reactant: O=C1CC(c2nc3ccc(Br)cc3s2)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: C1CCOC1
Product: O[C@H]1C[C@@H](c2nc3ccc(Br)cc3s2)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The product of Example 1C (710 mg, 2.52 mmole) was dissolved in 50 ml anhydrous THF and cooled to 0° C. L-selectride (1.0M in THF, 3.02 ml, 3.02 mmole) was added slowly. The mixture was stirred at 0° C. for 10 minutes, then warmed to room temperature for 30 minutes. It was then quenched with 1N sodium hydroxide (20 ml) and extracted three times with ethyl acetate. The organics were combined, dried over sodium sulfate and concentrated to give the crude product, which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18]3[N:22]([CH2:23][C:24]4[N:25]=[CH:26][S:27][CH:28]=4)[C:21]4[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=4[N:19]=3)[CH2:13][CH2:12]2)=[CH:5][CH:4]=1.[BrH:33]>O>[BrH:33].[BrH:33].[S:27]1[CH:28]=[C:24]([CH2:23][N:22]2[C:21]3[CH:29]=[CH:30][CH:31]=[CH:32][C:20]=3[N:19]=[C:18]2[NH:17][CH:14]2[CH2:13][CH2:12][N:11]([CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=3)[CH2:16][CH2:15]2)[N:25]=[CH:26]1
Reactant: COc1ccc(CCN2CCC(Nc3nc4ccccc4n3Cc3cscn3)CC2)cc1
Agent: Br
Solvent: O
Product: Oc1ccc(CCN2CCC(Nc3nc4ccccc4n3Cc3cscn3)CC2)cc1

Procedure:
A mixture of 5 parts of N-[1-[2-(4-methoxyphenyl)ethyl]-4-piperidinyl]-1-(4-thiazolylmethyl)-1H-benzimidazol-2-amine and 150 parts of a hydrobromic acid solution 48% in water was stirred and refluxed overnight. The reaction mixture was evaporated and the solid residue was crystallized from ethanol 80%, yielding 4 parts of 4-[2-[4-[[1-(4-thiazolylmethyl)-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]phenol dihydrobromide; mp. 291.0° C. (compound 59).
Reaction SMILES: [Br:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([OH:11])=O)=[CH:5][CH:4]=1.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>>[Br:1][CH2:2][C:3]1[N:8]=[CH:7][C:6]([C:9]([NH:17][C:16]2[CH:18]=[CH:19][C:13]([Cl:12])=[C:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[CH:15]=2)=[O:11])=[CH:5][CH:4]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(CBr)nc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(CBr)nc1

Procedure:
6-(bromomethyl)pyridine-3-carboxylic acid was coupled to 4-chloro-3-(pyridin-2-yl)aniline as described in general procedure E to yield 6-(bromomethyl)-N-(4-chloro-3-(pyridin-2-yl)phenyl)pyridine-3-carboxamide.
Reaction SMILES: B(Br)(Br)Br.C([O:12][C:13]1[CH:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][C:22]([C:25]34[CH2:32][CH2:31][C:28]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH2:29][CH2:30]3)[CH2:27][CH2:26]4)=[CH:21][CH:20]=2)=[N:17][CH:18]=1)C1C=CC=CC=1>ClCCl>[OH:12][C:13]1[CH:18]=[N:17][C:16]([C:19]2[CH:20]=[CH:21][C:22]([C:25]34[CH2:32][CH2:31][C:28]([CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])([CH2:29][CH2:30]3)[CH2:27][CH2:26]4)=[CH:23][CH:24]=2)=[N:15][CH:14]=1
Reactant: CCCCCC12CCC(c3ccc(-c4ncc(OCc5ccccc5)cn4)cc3)(CC1)CC2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCC12CCC(c3ccc(-c4ncc(O)cn4)cc3)(CC1)CC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
A one molar solution of boron tribromide (120 cm3) is added dropwise to a solution 1-[4-(5-benzyloxypyrimidin-2-yl) phenyl]-4-pentylbicyclo[2.2.2]octane (38.5 g, 100 mmol) in dichloromethane (200 cm3) and cooled using an ice bath. The reaction is stirred overnight at room temperature and then poured onto an ice/water mixture (500 g). The organic layer is separated off and the aqueous layer extracted with dichloromethane (3×100 cm3). The combined organic layers are washed with water (500 cm3), dilute potassium carbonate (200 cm3) and once again with water (500 cm3) then dried (MgSO4), filtered and evaporated. The residue is purified by column chromatography (flash) on silica gel using a 97:3 dichloromethane/methanol mixture as eluent followed by recrystallisation from ethyl acetate to give the 1-[4-(5-hydroxypyrimidin-2-yl)phenyl]-4-pentylbicyclo[2.2.2]octane (14.7 g, 50%).
Reaction SMILES: [CH3:1][Mg]Br.CON(C)[C:7]([C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][CH:13]=[CH:12]2)=[O:8]>C1(C)C=CC=CC=1.C1COCC1.C1COCC1>[N:15]1[C:16]2[C:11](=[CH:10][C:9]([C:7](=[O:8])[CH3:1])=[CH:18][CH:17]=2)[CH:12]=[CH:13][CH:14]=1
Reactant: CON(C)C(=O)c1ccc2ncccc2c1
Reactant: C[Mg]Br
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc2ncccc2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium bromide (190 mL of a 1.4 M solution in toluene/THF 3:1, 270 mmol) was added over 35 min to a solution of quinoline-6-carboxylic acid methoxy-methyl-amide (Stage 1.5, 26 g, 120 mmol) in THF at 0° C. under nitrogen. The RM was stirred for 30 min at 0° C. and then allowed to warm up to rt. The RM was quenched with 1 M HCl and the THF removed under reduced pressure. The residue was taken up in EtOAc and the organic layer separated, dried and concentrated to give the title compound as a yellow solid (tR 1.0 min (conditions 1), MH+=172).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[N+:15]([O-:17])=[O:16].[H][H]>CO>[Cl:1][C:2]1[C:3]([N+:15]([O-:17])=[O:16])=[CH:4][C:5]([C:11]([CH3:13])([CH3:12])[CH3:14])=[CH:6][C:7]=1[NH2:8]
Reactant: [H][H]
Reactant: CC(C)(C)c1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Solvent: CO
Product: CC(C)(C)c1cc(N)c(Cl)c([N+](=O)[O-])c1
Yield: 78 %

Procedure:
A mixture of 100 parts of 2-chloro-5-(1,1-dimethylethyl)-1,3-dinitrobenzene and 800 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of ruthenium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions are collected and the eluent is evaporated, yielding 69 parts (78%) of 2-chloro-5-(1,1-dimethylethyl)-3-nitrobenzenamine as a residue.