Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([C:17]1[CH:31]=[CH:30][C:20]([CH2:21][N:22]2[C:26]([CH:27]=O)=[CH:25][N:24]=[C:23]2[CH3:29])=[CH:19][CH:18]=1)#[N:16].[ClH:32].[CH2:33]([C@H:37]1[CH2:42][N:41]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[C:44]=2[CH3:50])[C:40](=[O:51])[CH2:39][NH:38]1)[CH2:34][CH2:35][CH3:36].CN1CCOCC1.C1(N)C(F)=C(F)C(F)=C(N)C=1F.Cl.Cl>ClC(Cl)C>[ClH:32].[ClH:32].[CH2:33]([C@H:37]1[CH2:42][N:41]([C:43]2[CH:48]=[CH:47][CH:46]=[C:45]([CH3:49])[C:44]=2[CH3:50])[C:40](=[O:51])[CH2:39][N:38]1[CH2:27][C:26]1[N:22]([CH2:21][C:20]2[CH:30]=[CH:31][C:17]([C:15]#[N:16])=[CH:18][CH:19]=2)[C:23]([CH3:29])=[N:24][CH:25]=1)[CH2:34][CH2:35][CH3:36]
Reactant: CCCC[C@H]1CN(c2cccc(C)c2C)C(=O)CN1
Reactant: Cc1ncc(C=O)n1Cc1ccc(C#N)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: Nc1c(F)c(N)c(F)c(F)c1F
Solvent: CC(Cl)Cl
Solvent: CN1CCOCC1
Product: CCCC[C@H]1CN(c2cccc(C)c2C)C(=O)CN1Cc1cnc(C)n1Cc1ccc(C#N)cc1

Procedure:
Sodium triacetoxyborohydride (0.265 g, 1.25 mmol) was added to a solution of 1-(4-cyanobenzyl)-2-methylimidazole-5-carboxaldehyde (0.190 g, 0.843 mmol), 5(S)-butyl-1-(2,3-dimethylphenyl)piperazin-2-one hydrochloride (0.250 g, 0.843 mmol), N-methylmorpholine (0.093 mL, 0.843 mmol) in dichloroethane (10 mL), according to the procedure described in Example 39, Step E. The title compound was purified by preparative HPLC using a gradient of 70 to 45% Solvent A. The free base was isolated and converted to dihydrochloride salt. The title compound was obtained as a white solid. FAB ms: 470 (M+1). Anal. Calc for C29H35N5O.2 HCl.1.45 H2O, C, 61.25; H, 7.07; N, 12.32. Found: C, 61.56; H, 6.99; N, 11.32.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[NH2:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([CH:17]3[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1>C(Cl)Cl.N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:12][C:13]1[C:22]([C:23]([O:25][CH3:26])=[O:24])=[C:21]2[C:16]([CH:17]3[CH2:27][CH:18]3[CH2:19][O:20]2)=[CH:15][CH:14]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(Cl)c1ccccc1Br
Reactant: COC(=O)c1c(N)ccc2c1OCC1CC21
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2Br)ccc2c1OCC1CC21
Yield: 76.5 %

Procedure:
2-Bromobenzenesulfonyl chloride (0.559 g) was added to a solution of methyl (1aRS,7bSR)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42, 0.40 g) in DCM (12 mL) and pyridine (4 mL) and the resultant mixture was stirred at room temperature for 1 hour. The mixture was evaporated to dryness and the residue was dissolved in DCM and washed with 2N HCl, dried (Na2SO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-35% to give methyl (1aRS,7bSR)-5-(2-bromo-benzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.612 g) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5]1[CH:10]=[C:9]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:8]=[N:7][CH:6]=1)[CH3:2]>CCO.Cl.O=[Pt]=O>[CH:12]1([CH2:11][CH:9]2[CH2:8][NH:7][CH2:6][CH:5]([C:4]([O:3][CH2:1][CH3:2])=[O:18])[CH2:10]2)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1cncc(Cc2ccccc2)c1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CNCC(CC2CCCCC2)C1
Yield: 72.7 %

Procedure:
A suspension of ethyl-5-benzylnicotinate (1.0 g, 4.1 mmol) and PtO2 (800 mg) in EtOH (25 mL) and HCl (conc., 5.0 mL) was mixed in a Parr shaker under 40 psi of H2 for 2 hours. The mixture was filtered through celite and concentrated to about 10% of the original volume. The resulting mixture was extracted with CH2Cl2 (3×30 mL). The organic layer was concentrated under reduced pressure to furnish the title compound (755 mg, 73% yield) as a white solid. MS m/z: 254.3 (M+1).
Reaction SMILES: FC(F)(F)C([O-])=O.[C:8]([C:11]1[C:12]([NH:25][C:26]2[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=2)=[N:13][N:14]([C:16]2([CH2:22][C:23]#[N:24])[CH2:21][CH2:20][NH2+:19][CH2:18][CH2:17]2)[CH:15]=1)(=[O:10])[NH2:9].CCN(C(C)C)C(C)C.Br[C:43]1[CH:48]=[CH:47][N:46]=[CH:45][N:44]=1>ClCCCl.C(Cl)Cl.CC(O)C>[C:23]([CH2:22][C:16]1([N:14]2[CH:15]=[C:11]([C:8]([NH2:9])=[O:10])[C:12]([NH:25][C:26]3[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=3)=[N:13]2)[CH2:21][CH2:20][N:19]([C:43]2[CH:48]=[CH:47][N:46]=[CH:45][N:44]=2)[CH2:18][CH2:17]1)#[N:24]
Reactant: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CC[NH2+]CC1
Reactant: Brc1ccncn1
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Solvent: ClCCCl
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CCN(c2ccncn2)CC1
Temperature: 130 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-{4-carbamoyl-3-[(4-fluorophenyl)amino]-1H-pyrazol-1-yl}-4-(cyanomethyl)piperidinium trifluoroacetate (Intermediate #38-5) (50 mg, 0.11 mmol) in DCE (1.0 mL) was added DIPEA (0.096 mL, 0.55 mmol) followed by 4-bromopyrimidine (32 mg, 0.16 mmol). The reaction mixture was heated under microwave irradiation to 130° C. and allowed to stir for 15 minutes. The reaction mixture was then cooled to ambient temperature and diluted with a mixture of DCM and IPA. The resulting mixture was sequentially washed with water, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The resulting residue was purified by reverse-phase preparative HPLC (MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were identified, combined, and concentrated in vacuo to afford the title compound, Example #26, as a solid.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1.Br[C:18]1[CH:19]=[CH:20][C:21]([N+:26]([O-:28])=[O:27])=[C:22]([CH:25]=1)[NH:23][CH3:24].CNCCNC.C(=O)([O-])[O-].[K+].[K+].N>[Cu](I)I.CS(C)=O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:18]3[CH:19]=[CH:20][C:21]([N+:26]([O-:28])=[O:27])=[C:22]([NH:23][CH3:24])[CH:25]=3)[C:10](=[O:14])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: CNc1cc(Br)ccc1[N+](=O)[O-]
Reactant: O=c1cc(OCc2ccc(F)cc2)cc[nH]1
Agent: I[Cu]I
Agent: CNCCNC
Agent: N
Solvent: CS(C)=O
Product: CNc1cc(-n2ccc(OCc3ccc(F)cc3)cc2=O)ccc1[N+](=O)[O-]
Temperature: 150 °C
Reaction time: 2 h
Yield: 75.8 %

Procedure:
A mixture of 4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (2.06 g), 5-bromo-N-methyl-2-nitroaniline (2.17 g), N,N′-dimethylethylenediamine (1.00 ml), copper iodide (1.79 g), potassium carbonate (3.90 g) and DMSO (30 ml) was stirred at 150° C. for 2 h. The mixture was added to 28% NH3 solution. The precipitate was collected and washed with water to give the title compound (2.63 g) as a yellow solid.
Reaction SMILES: [CH2:1]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)=[CH:11][C:6]=2[CH2:5][CH2:4][NH:3][CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>CN(C=O)C>[CH2:29]([N:3]1[CH2:4][CH2:5][C:6]2[CH:11]=[C:10]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:9]=[CH:8][C:7]=2[CH2:1][CH2:2]1)[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCCc1ccccc1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCNCC3)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCN(CCc2ccccc2)CC3)nc1

Procedure:
Take up 6-(2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy)nicotinamide (0.0500 g, 0.176 mmol) and K2CO3 (0.0488 g, 0.353 mmol) in DMF (1.0 mL). Add 2-bromoethylbenzene (0.0265 mL, 0.194 mmol) and heat to 70° C. overnight. Remove DMF as an azeotrope with xylenes. Purify by 5 g SCX column by washing with methanol and eluting with 2.0 M NH3 in methanol. Then purify by flash chromatography, eluting with 0-10% ethyl acetate and 5% (2.0 M NH3 in methanol) in dichloromethane to give the title compound: MS ES+ 388.1 (M+H)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 30-99% over 19 min], tR=1.7 min, 100% purity.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7](Cl)=[O:8])([O-:3])=[O:2].[C:16]1(=[O:23])[NH:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C1C=CC=CC=1>N1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([N+:13]([O-:15])=[O:14])[CH:12]=1)[C:7]([CH:17]1[CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:16]1=[O:23])=[O:8])([O-:3])=[O:2]
Reactant: O=C1CCCCCN1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C1NCCCCC1C(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reaction time: 1 h
Yield: 66.6 %

Procedure:
A solution of 3,5-dinitrobenzoyl chloride (50.00 g, 0.22 mol), freshly distilled ε-caprolactam (24.54 g, 0.22 mol) and 500 ml of benzene is added to a 1L, three-necked, round-bottom flask equipped with an overhead stirrer, condenser and a nitrogen inlet tube. The solution is heated to 90°-100° C. After all the solids are dissolved, 165 ml of pyridine is added. White pyridine salts form immediately, and the reaction solution is kept at 90°-100° C. for 1 hour before removing the pyridine salts by filtration. The solvent is removed from the filtrate under reduced pressure and the residue is washed by a 5 percent NaHCO3 aqueous solution and distilled water several times before being dried. The product is recrystallized from a mixture of ethyl acetate and hexane to obtain 45 g (68 percent) of white crystals: mp 126°-126.5° .
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].[CH3:21][NH:22][C:23]1[CH:28]=[CH:27][C:26](C2OC(C)(C)C(C)(C)O2)=[CH:25][N:24]=1>>[CH3:21][NH:22][C:23]1[N:24]=[CH:25][C:26]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:27][CH:28]=1
Reactant: CNc1ccc(C2OC(C)(C)C(C)(C)O2)cn1
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: CNc1ccc(-c2ccn3c(=O)c(C(=O)OC)cc(C4CC4)c3c2C)cn1
Yield: 106.5 %

Procedure:
Methyl 8-(6-(methylamino)pyridin-3-yl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (100 mg, 0.34 mmol) and N-methyl-5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)pyridin-2-amine (96.2 mg, 0.41 mmol). Purification by flash silica column chromatography (DCM:MeOH) (1:0 to 9:1) afforded the title compound as a yellow solid (131.6 mg, 96%).
Reaction SMILES: [Cl:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]2[NH:6][C:7]([C:9]3[C:13]([N+:14]([O-])=O)=[CH:12][NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1.[Sn](Cl)(Cl)(Cl)Cl.C(=O)([O-])O.[Na+]>C(O)C>[Cl:1][C:2]1[C:18]([CH3:19])=[CH:17][C:5]2[NH:6][C:7]([C:9]3[C:13]([NH2:14])=[CH:12][NH:11][N:10]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: Cc1cc2[nH]c(-c3n[nH]cc3[N+](=O)[O-])nc2cc1Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc2[nH]c(-c3n[nH]cc3N)nc2cc1Cl

Procedure:
A stirred solution of 5-chloro-6-methyl-2-(4-nitro-1H-pyrazol-3-yl)-1H-benzoimidazole [0.320 g, Example 249(g)] and tin chloride (1.10 g) in ethanol (5 ml) was heated in a Smith Creator microwave at 140° C. for 10 minutes. The reaction mixture was basified using saturated sodium hydrogen carbonate solution to pH 8 and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated to give 3-(5-chloro-6-methyl-1H-benzoimidazol-2-yl)-1H-pyrazol-4-ylamine as a pale brown solid. LC-MS (METHOD B): RT=2.28 minutes, 248.13 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[C:24]([F:25])=[C:23]([CH2:26][O:27][C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[C:22]([F:34])=[C:21]([NH:35][C:36](=[O:39])[CH2:37]Cl)[C:17]=3[C:18](=[O:20])[CH:19]=2)=[CH:10][C:9]=1[F:40])=[O:6])[CH:2]=[CH2:3].Cl.[CH3:42][NH:43][CH3:44].C(N(C(C)C)CC)(C)C.O>CN(C)C=O>[CH2:1]([O:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[O:15][C:16]3[C:24]([F:25])=[C:23]([CH2:26][O:27][C:28]([O:30][CH2:31][CH:32]=[CH2:33])=[O:29])[C:22]([F:34])=[C:21]([NH:35][C:36](=[O:39])[CH2:37][N:43]([CH3:44])[CH3:42])[C:17]=3[C:18](=[O:20])[CH:19]=2)=[CH:10][C:9]=1[F:40])=[O:6])[CH:2]=[CH2:3]
Reactant: CNC
Reactant: C=CCOC(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)CCl)c(F)c(COC(=O)OCC=C)c(F)c3o2)cc1F
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: C=CCOC(=O)Nc1ccc(-c2cc(=O)c3c(NC(=O)CN(C)C)c(F)c(COC(=O)OCC=C)c(F)c3o2)cc1F
Temperature: 50 °C
Reaction time: 2 h
Yield: 98.5 %

Procedure:
To a solution of 2-[4-(allyloxycarbonyl)amino-3-fluorophenyl]-7-[(allyloxycarbonyl)oxy]methyl-5-(chloroacetamido)-6,8-difluoro-4H-1-benzopyran-4-one (2.12 g, 3.65 mmol) in dimethylformamide (40 mL) were added dimethylamine hydrochloride (1.49 g, 18.3 mmol) and diisopropylethylamine (3.2 mL, 18 mmol), and the mixture was stirred at 50° C. for 2 hours. Water was added thereto, and the mixture was extracted with ethyl acetate to afford 2-[4-(allyloxycarbonyl)amino-3-fluorophenyl]-7-[(allyloxycarbonyl)oxy]methyl-5-(dimethylamino)acetamido-6,8-difluoro-4H-1-benzopyran-4-one (2.12 g, 99%)
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:18]([O-:20])=[O:19])[C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:21])[C:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[CH2:28]1COCC1>C[Mg]Cl>[CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([N+:18]([O-:20])=[O:19])[C:10]([F:17])=[C:11]([F:16])[C:12]=3[O:14][CH3:15])[C:7](=[O:21])[CH:6]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:5]2[CH3:28])[CH2:2][CH2:3]1
Reactant: C1CCOC1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(OC)c(F)c(F)c([N+](=O)[O-])c2c1=O
Agent: C[Mg]Cl
Agent: Cl
Product: CCOC(=O)C1C(=O)c2c(c(OC)c(F)c(F)c2[N+](=O)[O-])N(C2CC2)C1C
Temperature: -78 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a stirred solution of ethyl 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-5-nitro-4-oxoquinoline-3-carboxylate (2.50 g, 6.79 mmol) and cuprous iodide (389 mg, 2.04 mmol) in THF (70 mL), 3 M methylmagnesium chloride in THF (3.40 mL, 10.2 mmol) was added under argon atmosphere at −78° C. After stirred at −78° C. for 1 h and at room temperature for 1 h, the reaction mixture was poured into ice-water (300 mL) and concentrated HCl (30 mL) was added to stirred for 30 min. The crude product was extracted with EtOAc, washed with brine, dried over MgSO4 and the solvent was removed in vacuo. The crude product was purified by column chromatography (Hexane:EtOAc 20:1→5:1) to yield ethyl 1-cyclopropyl-6,7-difluoro-1,2,3,4-tetrahydro-8-methoxy-2-methyl-5-nitro-4-oxoquinoline-3-carboxylate (1.44 g, 55%) as a yellow solid.
Reaction SMILES: Cl.[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1.Cl.O[C@H:29](COC1C=CC(C(C)(C)C)=CC=1)[CH2:30]NC(C)(C)CC1C=CC(OC)=CC=1.Cl.OC(COC1C=CC(C(C)(C)C)=CC=1)CNC(C)(C)CC1C=CC(OC)=CC=1>>[ClH:26].[OH:2][CH:3]([CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:29][CH3:30])[CH:21]=1)[CH2:4][NH:5][C:6]([CH3:17])([CH3:16])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1
Reactant: COc1ccc(CC(C)(C)NC[C@H](O)COc2ccc(C(C)(C)C)cc2)cc1
Reactant: COc1ccc(CC(C)(C)NCC(O)COc2ccc(Cl)cc2)cc1
Agent: COc1ccc(CC(C)(C)NCC(O)COc2ccc(C(C)(C)C)cc2)cc1
Agent: Cl
Product: CCc1cccc(OCC(O)CNC(C)(C)Cc2ccc(OC)cc2)c1

Procedure:
GC/EI-MS, m/z (rel. int.) 342 (M-15,.6), 237(16), 236 (100), 163 (5), 121 (21), 114 (6), 105 (5), 90 (6).
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH2:26][C:27]([O:29]C)=O)=[N:4][CH:5]=[C:6]([NH:8][C:9]2[N:25]=[C:12]3[CH:13]=[CH:14][CH:15]=[C:16]([NH:17][C@H:18]4[CH2:23][CH2:22][C@@H:21]([OH:24])[CH2:20][CH2:19]4)[N:11]3[N:10]=2)[CH:7]=1>ClCCl.CO.[Ni]>[OH:24][C@@H:21]1[CH2:22][CH2:23][C@H:18]([NH:17][C:16]2[N:11]3[N:10]=[C:9]([NH:8][C:6]4[CH:7]=[C:2]5[NH:1][C:27](=[O:29])[CH2:26][C:3]5=[N:4][CH:5]=4)[N:25]=[C:12]3[CH:13]=[CH:14][CH:15]=2)[CH2:19][CH2:20]1
Reactant: COC(=O)Cc1ncc(Nc2nc3cccc(N[C@H]4CC[C@@H](O)CC4)n3n2)cc1N
Agent: [Ni]
Solvent: CO
Solvent: ClCCl
Product: O=C1Cc2ncc(Nc3nc4cccc(N[C@H]5CC[C@@H](O)CC5)n4n3)cc2N1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Methyl cis-2-(3-amino-5-(5-(4-hydroxycyclohexylamino)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino)pyridin-2-yl)acetate. To a mixture of diethyl cis-2-(3-amino-5-(5-(4-hydroxycyclohexylamino)-[1,2,4]triazolo[1,5-c]pyridin-2-ylamino)pyridin-2-yl)malonate (120.0 mg, 0.23 mmol) in a mixture of dichloromethane (10 mL) and methanol (50 mL) was added Raney nickel (100 mg), and the mixture was stirred under hydrogen at room temperature for 24 hours. LCMS analysis showed that the major product was the desired product (if the reaction was not completed, just kept the hydrogenation until the reaction was completed). The mixture was filtered, concentrated under reduced pressure, and purified on silica gel column (eluting with 1-2% dichloromethane in methanol) to give methyl cis-2-(3-amino-5-(5-(4-hydroxycyclohexylamino)-[1,2,4]triazolo[1,5-c]pyridin-2-ylamino)pyridin-2-yl)acetate.
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:5][N:4]=1.[NH2:21][CH2:22][C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:6]2[C:7]3[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:3]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)=[N:4][N:5]=2)=[CH:15][CH:16]=1
Reactant: NCc1ccncc1
Reactant: Clc1ccc(Nc2nnc(Cl)c3ccccc23)cc1
Agent: Cl
Product: Clc1ccc(Nc2nnc(NCc3ccncc3)c3ccccc23)cc1
Temperature: 90 °C
Reaction time: 36 h

Procedure:
A mixture of 0.5 g (1.5436 mmol) 1-chloro-4-(4-chloroanilino)phthalazine hydrochloride (for preparation see J. Chem. Soc. 1948, 777-782) and 2 g (18.50 mmol) 4-aminomethylpyridine is stirred for 36 h at 90° C. and then purified by means of flash chromatography on silica gel with a particle size of 0.04-0.06 mm using acetate and acetate/methanol (20:1). Evaporation of product-containing fractions, recrystallization of the residue from methanol, and drying of the crystallizate under HV yield the title compound; m.p. 233-236° C.; ESI-MS: (M+H)+=362.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH2:5]([O:7][C:8]([N:10]1[CH2:16][C:15](=O)[C:14]2[CH:18]=[CH:19][S:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])[CH3:6]>C(Cl)Cl>[CH2:5]([O:7][C:8]([N:10]1[CH2:16][CH2:15][C:14]2[CH:18]=[CH:19][S:20][C:13]=2[CH2:12][CH2:11]1)=[O:9])[CH3:6]
Reactant: CCOC(=O)N1CCc2sccc2C(=O)C1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)N1CCc2ccsc2CC1
Reaction time: 0.17 h
Yield: 65 %

Procedure:
AlCl3 (3.95 g, 29.7 mmol) was added to 50 mL DCM at 0° C. Borane-t-butyl amine complex (5.2 g, 59.5 mmol) was added followed by the product of step (c) (2.37 g, 9.9 mmol) dissolved in DCM (50 mL). The reaction was stirred for 2 hours at room temperature after which time another 3.95 g (29.7 mmol) of AlCl3 was added. After stirring for 10 minutes, the reaction was quenched carefully with 0.1 M HCl (˜50 mL). After concentration of the organic solvent, the crude reaction mixture was partitioned between 1M HCl and EtOAc (70 mL each). The aqueous layer was back extracted 1×EtOAc. The combined organic layers were dried over MgSO4 and concentrated. The sub-title product (1.45 g) was obtained after purification by silica gel chromatography (0 to 35% EtOAc in Hexanes). MS: ESI (positive): 226 (M+H).
Reaction SMILES: CO[C:3](=[O:22])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][C:12]2[C:13]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.COC(=O)C1C=CC(OC[C:34]2[C:35]([CH2:40]CCC)=[N:36]OC=2C)=NC=1>>[CH2:18]([C:13]1[C:12]([CH2:11][NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([NH:36][CH:35]([CH3:40])[CH3:34])=[O:22])=[CH:5][N:6]=2)=[C:16]([CH3:17])[O:15][N:14]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCc1noc(C)c1CNc1ccc(C(=O)OC)cn1
Reactant: CCCCc1noc(C)c1COc1ccc(C(=O)OC)cn1
Product: CCCCc1noc(C)c1CNc1ccc(C(=O)NC(C)C)cn1
Yield: 70 %

Procedure:
As described for example 5d, 6-[(3-butyl-5-methyl-isoxazol-4-ylmethyl)-amino]-nicotinic acid methyl ester (90 mg, 0.3 mmol) was converted, instead of 6-(3-butyl-5-methyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, to the title compound (69 mg, 70%) which was obtained as a white foam after purification by chromatography (silica, 0 to 7% methanol in dichloromethane). MS: m/e=331.4 [M+H]+.
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:38]([CH3:39])[C:37]4[CH:40]=[CH:41][C:42]([F:44])=[CH:43][C:36]=4[N:35]=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:38]([CH3:39])[C:37]4[CH:40]=[CH:41][C:42]([F:44])=[CH:43][C:36]=4[N:35]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3nc4cc(F)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(C)cc(-c3nc4cc(F)ccc4n3C)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.butyl 4'-[(2-n-propyl-4-methyl-6-(1-methyl-5-fluoro-benzimidazol-2-yl)-benzimidazol-1-y)-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [Si:1]([O:8][CH:9]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([C:31]#[N:32])[CH:29]=2)[O:24][C:11]2([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CCN(CC)CC.Cl.[OH:41][NH2:42]>CCO>[NH2:32][C:31](=[N:42][OH:41])[C:28]1[CH:29]=[C:30]2[C:25](=[CH:26][CH:27]=1)[O:24][C:11]1([CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]1)[CH2:10][CH:9]2[O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: NO
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O[Si](C)(C)C(C)(C)C)c1cc(C#N)ccc1O2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(O[Si](C)(C)C(C)(C)C)c1cc(C(N)=NO)ccc1O2

Procedure:
To a suspension of 18.2 g of tert-butyl 4-{[tert-butyl(dimethyl)silyl]oxy}-6-cyano-spiro[chroman-2,4′-piperidine]-1′-carboxylate in EtOH was added 16.3 mL of Et3N and 8.12 g of hydroxyamine hydrochloride at rt, and the reaction mixture was stirred at 85° C. for 1d. The resultant solution was cooled to rt, and concentrated in reduced pressure. To the residue was added H2O, the resultant white solid was filtered, washed with H2O, and dried in vacuo to give a crude product, which was used in the next step without further purification.