Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(C)C)C(C)C.C([Li])CCC.[N:13]1([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C1COCC1.Cl>[N:13]1([C:24]([O:26][C:27]([CH3:29])([CH3:28])[CH3:30])=[O:25])[CH2:14][CH2:15][C:16]([C:32]([O:34][CH2:35][CH3:36])=[O:33])([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CCOC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOC(=O)Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C1(C(=O)OCC)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
To a solution of iPr2NH (4.72 g, 46.6 mmol) at −20° C. in THF (70 mL) was added n-butyllithium (13.99 mL, 35.0 mml, 2.5 M in hexanes). After 15 minutes at −20° C., the solution was cooled to −78° C., and 1-tert-butyl 4-ethyl piperidine-1,4-dicarboxylate (6.00 g, 23.3 mmol) was added. After stirring at −78° C. for 1 h, ethyl chloroformate (7.59 g, 70.0 mmol) was added dropwise. The reaction was then allowed to warm to room temperature over 4 h. The solution was diluted with 1 N HCl and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried (MgSO4), and evaporated. Flash chromatography of the crude (0-25% EtOAc/hexanes) yielded the desired product as a yellow oil. 1H NMR (CDCl3, 600 MHz) δ 4.18 (q, J=7.1 Hz, 4H), 3.43-3.38 (m, 4H), 2.05-2.00 (m, 4H), 1.42 (s, 9H), 1.23 (t, J=7.0 Hz, 6H). MS: cal'd 352 (MNa+), exp 352 (MNa+).
Reaction SMILES: [F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]([CH2:13][CH2:14][CH3:15])[O:9]2)=[C:4]2[CH:16]=[C:17]([CH3:19])[O:18][C:3]=12>C1(C)C=CC=CC=1.[Pd]>[F:1][C:2]1[C:11]([F:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH:8]([CH2:13][CH2:14][CH3:15])[O:9]2)=[C:4]2[CH:16]=[C:17]([CH3:19])[O:18][C:3]=12
Reactant: CCCC1C=Cc2c(c(F)c(F)c3oc(C)cc23)O1
Agent: [Pd]
Solvent: Cc1ccccc1
Product: CCCC1CCc2c(c(F)c(F)c3oc(C)cc23)O1

Procedure:
3.5 g (13.2 mmol) of 4,5-difluoro-2-methyl-7-propyl-7H-furo[3,2-f]chromene are hydrogenated for a few minutes in toluene using elemental hydrogen in the presence of Pd/C (5% Pd). The reaction soln. is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:1-chlorobutane=2:1). The further purification is carried out by recrystallisation from ethanol and subsequent absorptive (SiO2, n-heptane:1-chlorobutane=3:1) filtration, giving 4,5-difluoro-2-methyl-7-propyl-8,9-dihydro-7H-furo[3,2-f]chromene as a colourless solid having an m.p. of 75° C. (Δ∈c=−7.8).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[O:28]CC3C=CC=CC=3)[CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC(OCC1C=CC=CC=1)=O>CCO.[Pd].C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[C:14]([C:21]3[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=3[OH:28])[CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCc2cccc(-c3cc(F)ccc3OCc3ccccc3)c2C1
Agent: [Pd]
Agent: O=C(Cl)OCc1ccccc1
Solvent: CCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCc2cccc(-c3cc(F)ccc3O)c2C1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution under N2 of 8-(2-benzyloxy-5-fluoro-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (208 mg, 0.45 mmol, 1.0 eq.) in EtOH (10 mL), palladium on activated carbon (10 wt. %, 21 mg) was added. The flask was evacuated and refilled with H2. The black suspension was stirred at r.t. under an H2-atmosphere for 6 hours. The black suspension was filtered through Celite and the filtrate was concentrated in vacuo to give a beige foam. To an-ice cooled suspension of the residue and triethylamine (93 μL, 0.67 mmol, 1.5 eq.) in DCM (10 mL), benzyl chloroformate (67 μL, 0.45 mmol, 1.0 eq.) was added dropwise. Upon completion of the addition, the mixture was stirred at 0° C. for 1 hour and further at r.t. for 4 hours. The reaction was quenched with 1M aq. citric acid soln. (10 mL). The layers were separated. The aq. phase was extracted with DCM (3×10 mL). The comb. org. phases were dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in THF (10 mL) and 1M aq. NaOH (2 mL) was added. The mixture was stirred at r.t. for 64 hours. The org. solvent was removed in vacuo and the aq. layer was acidified with 2N aq. HCl. The aq. layer was extracted with DCM (3×10 mL). The comb. org. phases were dried over MgSO4 and concentrated in vacuo. The residue was purified by CC (SiO2, Hept/AcOEt 7:3) to give the title compound as a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:9]=1[C:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)=[O:23].[BH4-].[Na+]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[C:10]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=2[Cl:21])[C:9]=1[CH:22]([C:24]1[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=1)[OH:23]
Reactant: O=C(c1cccnc1)c1c(Cc2ccc(Cl)cc2Cl)noc1-c1ccccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC(c1cccnc1)c1c(Cc2ccc(Cl)cc2Cl)noc1-c1ccccc1Cl
Reaction time: 2 h
Yield: 80 %

Procedure:
To a solution of 50 mg (0.11 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorobenzyl)-4-[(3-pyridyl)carbonyl]isoxazole in 15 mL of THF was added 21 mg (0.56 mmol) of sodium borohydride at room temperature. After 2 hrs, the solution was diluted with ethyl acetate, washed with saturated sodium chloride, and dried over magnesium sulfate. The drying agent was filtered off, and solvent was removed by rotoevaporation. The crude product was purified by prep TLC to give 39 mg (0.088 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorobenzyl)-4-[(3-pyridyl)hydroxymethyl]isoxazole. 1H NMR (CDCl3): δ 3.91 (d, 1), 4.00 (d, 1), 6.97 (br s, 1), 7.64 (d, 1), 8.42 ppm (br m, 2). MS m/z: 445.0 (M+H).
Reaction SMILES: C([O:5][C:6](=[O:44])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:14]([C@H:16]1[C@H:20]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[C:22]=2[F:28])[C@:19]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=2[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17]1)=[O:15])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[Cl:27][C:23]1[C:22]([F:28])=[C:21]([C@@H:20]2[C@:19]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][C:32]=3[F:38])([C:29]#[N:30])[C@H:18]([CH2:39][C:40]([CH3:43])([CH3:42])[CH3:41])[NH:17][C@H:16]2[C:14]([NH:13][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([OH:44])=[O:5])=[O:15])[CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccccc2C(=O)OC(C)(C)C)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)Nc2ccccc2C(=O)O)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F

Procedure:
rac 2-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid t-butyl ester (50 mg, 0.031 mmol) was treated with 30% TFA/methylene chloride (10 mL) overnight. Removal of solvent and freeze drying of the residue give a white powder. 15 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:15][CH:14]([N:16]([CH3:25])[C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])[CH2:13]2)=[C:6]([CH:11]=1)[C:7]([O:9]C)=[O:8]>O1CCOCC1.O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:12]2[CH2:13][CH:14]([N:16]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=3[CH3:24])[CH3:25])[CH2:15]2)=[C:6]([CH:11]=1)[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(Cl)cnc1N1CC(N(C)c2ccc(F)cc2C)C1
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(F)ccc1N(C)C1CN(c2ncc(Cl)cc2C(=O)O)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of methyl 5-chloro-2-(3-(methyl(2-methyl-4-fluoro-phenyl)amino)azetidin-1-yl)nicotinate (D87) (170 mg, 0.467 mmol) in 1,4 dioxane (3 ml) and water (1 ml) 1M NaOH (0.7 ml) was added. The mixture was stirred at 60° C. for 2 h. Organic solvent was evaporated and remaining aqueous were acidified 2N HCl and extracted with ethylacetate (3×5 ml). The combined organic phases after solvent evaporation afforded the title compound (D120) (156 mg)
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C:16]#[N:17])[CH2:11][CH2:10]1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][NH2:17])[CH2:13][CH2:14]1
Reactant: N#CCN1CCN(c2cccc(Cl)c2Cl)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCN1CCN(c2cccc(Cl)c2Cl)CC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 102.9 %

Procedure:
A solution of 4-(2,3-dichlorophenyl)-1-piperazine-acetonitrile (5.45 g, 0.0202 mol) in dry tetrahydrofuran (50 mL) is added dropwise to a suspension of lithium aluminum hydride (LiAIH4) (0.84 g, 0.210 mol) in dry tetrahydrofuran (50 mL) at 0° C. The suspension is stirred at 0° C. for 3 hours, followed by dropwise addition of 2N sodium hydroxide (NaOH). The mixture is filtered through Celite and concentrated in vacuo to give 5.7 g of the title compound as a yellow oil.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[C:4]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:13])[CH:3]=1.[CH3:20][NH:21][C:22]([C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1)=[O:23].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:20][NH:21][C:22]([C:24]1[CH:29]=[C:28]([C:2]2[CH:10]=[C:9]3[C:5]([CH:6]=[N:7][NH:8]3)=[C:4]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)=[O:13])[CH:3]=2)[CH:27]=[CH:26][CH:25]=1)=[O:23]
Reactant: O=C(Nc1cc(Br)cc2[nH]ncc12)c1ccccn1
Reactant: CNC(=O)c1cccc(B(O)O)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1cccc(-c2cc(NC(=O)c3ccccn3)c3cn[nH]c3c2)c1

Procedure:
N-(6-Bromo-1H-indazol-4-yl)-2-pyridinecarboxamide (100 mg, 0.31 mmol), {3-[(methylamino)carbonyl]phenyl}boronic acid (66 mg, 0.37 mmol), Pd(dppf)Cl2 (31 mg, 0.038 mmol) and 2 M sodium carbonate (aq) (0.468 ml, 0.936 mmol) in 1,4-dioxane (1.5 ml) and water (1 ml) were heated in a Biotage microwave at 150° C. for 30 mins. The reaction was purified by HPLC as follows to give title compound, 7 mg.
Reaction SMILES: [CH3:1][N:2]([S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[NH:10][C:9]([C:12]([OH:14])=O)=[CH:8]2.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH3:45][O:46][CH2:47][C:48]([NH:50][NH2:51])=[O:49]>O.CN(C)C=O>[CH3:45][O:46][CH2:47][C:48]([NH:50][NH:51][C:12]([C:9]1[NH:10][C:11]2[C:7]([CH:8]=1)=[CH:6][CH:5]=[CH:4][C:3]=2[N:2]([CH3:1])[S:15]([C:18]1[S:19][CH:20]=[CH:21][CH:22]=1)(=[O:17])=[O:16])=[O:14])=[O:49]
Reactant: COCC(=O)NN
Reactant: CN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: COCC(=O)NNC(=O)c1cc2cccc(N(C)S(=O)(=O)c3cccs3)c2[nH]1
Reaction time: 0.17 h
Yield: 57.7 %

Procedure:
To a mixture of 7-[methyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.40 g), 1H-1,2,3-benzotriazol-1-ol (0.19 g) and N,N-dimethylformamide (10 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.28 g) at room temperature. The mixture was stirred for 10 min, and methoxyacetohydrazide (0.19 g) was added. The reaction mixture was stirred at room temperature for 2 hr, water was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography and the title compound (0.29 g, yield 58%) was obtained as colorless crystals from a fraction eluted with ethyl acetate. melting point 148-149° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:11][CH3:12])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[CH3:14]NOC.C[Mg]Br>>[Br:1][C:2]1[CH:10]=[C:6]([C:7](=[O:9])[CH3:14])[CH:5]=[N:4][C:3]=1[O:11][CH3:12]
Reactant: COc1ncc(C(=O)O)cc1Br
Reactant: CNOC
Agent: C[Mg]Br
Agent: Cl
Product: COc1ncc(C(C)=O)cc1Br

Procedure:
5-Bromo-6-methoxynicotinic acid and N,O-dimethylhydroxylamine hydrochloride were treated in the similar manner to Reference Example 7(5), and then the resulting compound and methylmagnesium bromide were treated in the similar manner to Reference Example 7(6) to give 1-(5-bromo-6-methoxypyridin-3-yl)ethanone [Ex(296-1)] as a colorless powder.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]([CH3:10])[CH3:9])=[C:6]([CH3:11])[N:5]=[C:4]([CH2:12][N:13]([CH3:15])[CH3:14])[N:3]=1.[CH3:16][C:17]1[NH:49][C:20]2=[N:21][CH:22]=[C:23]([C:25]3[CH:26]=[CH:27][C:28]4[O:34][CH2:33][CH2:32][N:31](C5C6C(=CC(OC)=CC=6)N=C(C)N=5)[CH2:30][C:29]=4[CH:48]=3)[CH:24]=[C:19]2[N:18]=1.ClC1C2C(=CC(OC)=CC=2)N=C(C)N=1>>[CH3:14][N:13]([CH3:15])[CH2:12][C:4]1[N:5]=[C:6]([CH3:11])[C:7]([CH:8]([CH3:10])[CH3:9])=[C:2]([N:31]2[CH2:30][C:29]3[CH:48]=[C:25]([C:23]4[CH:24]=[C:19]5[N:18]=[C:17]([CH3:16])[NH:49][C:20]5=[N:21][CH:22]=4)[CH:26]=[CH:27][C:28]=3[O:34][CH2:33][CH2:32]2)[N:3]=1
Reactant: Cc1nc(CN(C)C)nc(Cl)c1C(C)C
Reactant: COc1ccc2c(N3CCOc4ccc(-c5cnc6[nH]c(C)nc6c5)cc4C3)nc(C)nc2c1
Agent: COc1ccc2c(Cl)nc(C)nc2c1
Product: Cc1nc2cc(-c3ccc4c(c3)CN(c3nc(CN(C)C)nc(C)c3C(C)C)CCO4)cnc2[nH]1

Procedure:
Synthesized according to the method of example 6 using 1-(4-chloro-5-isopropyl-6-methylpyrimidin-2-yl)-N,N-dimethylmethanamine (reagent preparation 17) in step 3. 1H NMR (400 MHZ, CDCl3): 12.78 (br, 1H), 8.51 (s, 1H), 8.08 (br, 1H), 7.46 (d, 1H), 7.43 (s, 1H), 7.14 (d, 1H), 4.37 (s, 2H), 4.30 (tr, 2H), 3.76 (tr, 2H), 3.55 (s, 2H), 3.40 (m, 1H), 2.75 (s, 3H), 2.55 (s, 3H), 2.34 (s, 6H), 1.35 (d, 6H). MS (EI) for C28H34N7O: 472 (MH+). 7-(2-methyl-3H-imidazo[4,5-b]pyridin-6-yl)-4-[2-methyl-7-(methyloxy)quinazolin-4-yl]-2,3,4,5-tetrahydro-1,4-benzoxazepine. Synthesized according to the method of example 6 using 4-chloro-7-methoxy-2-methylquinazoline in step 3. 1H NMR (400 MHz, DMSO-d6) δ 8.53 (s, 1H), 8.06 (s, 1H), 7.90 (d, 1H), 7.74 (d, 1H), 7.56 (dd, 1H), 7.11 (d, 1H), 7.03 (m, 3H), 5.02 (s, 3H), 4.41 (t, 3H), 4.11 (d, J=36.2 Hz, 3H), 3.88 (s, 5H), 2.55 (s, 5H), 2.43 (s, 5H), 1.90 (s, 1H); MS (EI) for C26H24N6O2: 453.3 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][C:16]#[N:17])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>O.C(O)C.N.[Rh]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][CH2:16][NH2:17])([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(CC#N)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Rh]
Agent: N
Solvent: CCO
Solvent: O
Product: CC1(CCN)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.5 %

Procedure:
To 5% Rh/Al2O3 (0.600 g) suspended in water (2 mL) is added ethanol (5 mL), 4-cyanomethyl-4-methylpiperidine-1-carboxylic acid tert-butyl ester (0.258 g, 1.083 mmol) dissolved in ethanol (10 mL) and 28% NH3 (aq) (0.25 mL). The reaction mixture is subjected to 50 psi hydrogen gas and stirred at room temperature for 18 hours. The reaction mixture is filtered to remove the catalyst, then the filtrate is concentrated and chromatographed on silica gel, eluting with 0-10% (2 M NH3 in MeOH) in dichloromethane to give the title compound (130 mg, 50% yield).
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9](=O)[CH3:10])[CH:6]=[CH:5][CH:4]=1.[NH2:12][OH:13]>C(O)C>[OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9](=[N:12][OH:13])[CH3:10])[CH:6]=[CH:5][CH:4]=1
Reactant: NO
Reactant: CC(=O)c1cccc(CO)n1
Solvent: CCO
Product: CC(=NO)c1cccc(CO)n1
Reaction time: 8 h

Procedure:
To a solution of 1643 mg of 1-[6-(hydroxymethyl)pyridin-2-yl]ethanone in 25 ml of ethanol was added 0.72 ml of a 50% aqueous hydroxylamine solution, followed by stirring overnight. The reaction solution was concentrated under reduced pressure to obtain 1806 mg of 1-[6-(hydroxymethyl)pyridin-2-yl]ethanone oxime as an amorphous substance.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:13]2[C:21]([CH3:22])=[CH:20][CH:19]=[C:18]3[C:14]=2[CH:15]=[CH:16][CH2:17]3)[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=1)([CH3:3])[CH3:2].[Br:23]N1C(=O)CCC1=O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CS(C)=O.O.C1(C)C=CC=CC=1>[Br:23][C:16]1[CH2:17][C:18]2[C:14]([CH:15]=1)=[C:13]([C:6]1[CH:7]=[C:8]([CH:10]([CH3:12])[CH3:11])[CH:9]=[C:4]([CH:1]([CH3:2])[CH3:3])[CH:5]=1)[C:21]([CH3:22])=[CH:20][CH:19]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc2c(c1-c1cc(C(C)C)cc(C(C)C)c1)C=CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: Cc1ccc2c(c1-c1cc(C(C)C)cc(C(C)C)c1)C=C(Br)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.8 %

Procedure:
The obtained 4-(3,5-diisopropylphenyl)-5-methylindene (4.69 g, 15.9 mmol) was dissolved in dimethylsulfoxide (40 mL), and water (1.1 g) was added. N-Bromosuccinimide (NBS)(3.1 g, 17.5 mmol) was added at 5 to 10° C., and after elevating the temperature naturally, reaction solution was stirred for 1 hour at room temperature. Reaction solution was slowly added to mixed solution of toluene and water at room temperature, then, aqueous phase was separated. Organic layer was washed with diluted hydrochloric acid, and after aqueous phase was removed, p-toluene sulfonic acid mono hydrate (0.43 g, 2.3 mmol) was added. After reacting for 1.5 hours while heating under reflux, reaction solution was washed with aqueous solution of sodium hydroxide (1N) and water, and organic layer was extracted. Organic layer was dried over magnesium sulfate, then, solvent was distilled off under reduced pressure to obtain the crude product (5.98 g).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH:8][N:9]=[C:10]2[CH2:17][CH:16]3[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11]2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH3:28]I.O>CN(C=O)C>[Br:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[N:9]=[C:10]2[CH2:17][CH:16]3[N:18]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:12]([CH2:13][CH2:14][CH2:15]3)[CH2:11]2)[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C2CCCC1CC(=NNc1cccc(Br)n1)C2
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(N=C1CC2CCCC(C1)N2C(=O)OC(C)(C)C)c1cccc(Br)n1
Reaction time: 0.5 h
Yield: 103.8 %

Procedure:
tert-Butyl 3-(2-(6-bromopyridin-2-yl)hydrazono)-9-azabicyclo[3.3.1]nonane-9-carboxylate (609 mg, 1.49 mmol) was dissolved in DMF, and NaH (60%, 65 mg, 1.63 mmol) was added. After 30 min, MeI (232 mg, 1.63 mmol, 102 μL) was added, and stirring continued for 30 min. The mixture was poured into water and extracted with ethyl acetate. The ethyl acetate was concentrated to provide the crude product (655 mg, >100%) as a red oil: ESI MS m/z 423 [M+H]+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[N:21]([CH3:28])[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[C:18]=3[C:17]3[C:29](=[O:33])[NH:30][C:31](=[O:32])[C:16]=3[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N+]=[N-]>O1CCCC1.C(O)C.[Pd]>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[N:21]([CH3:28])[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:27]=4[C:18]=3[C:17]3[C:29](=[O:33])[NH:30][C:31](=[O:32])[C:16]=3[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2
Reactant: Cn1c2ccccc2c2c3c(c4c5ccccc5n(CCCCN=[N+]=[N-])c4c21)C(=O)NC3=O
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: Cn1c2ccccc2c2c3c(c4c5ccccc5n(CCCCN)c4c21)C(=O)NC3=O
Reaction time: 48 h

Procedure:
300 mg (0.1 mmol) 12-(4-Azidobutyl)-6,7,12,13-tetrahydro-13-methyl-5,7-dioxo-5H-indolo[2,3-a]-pyrrolo[3,4-c]carbazole (see Example 1w) in 40 ml tetrahydrofuran/ethanol (1:1 v/v) are hydrogenated in the presence of 300 mg 5% palladium on active carbon at 25° C. and 50 bar pressure for 48 hours in an autoclave. After filtration of the solution, the solvent is distilled off and the residue is crystallised from ethanol. 12-(4-Aminobutyl)-6,7,12,13-tetrahydro-13-methyl-5,7-dioxo-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole is obtained in the form of yellow crystals; m.p.10 220-223° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]([S:11]([CH3:13])=[O:12])=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH:18]12[CH2:25][CH:22]([CH2:23][CH2:24]1)[C:21](=[O:26])[CH2:20][C:19]2=O.Cl.CN(C)CCCN=C=NCC.Cl>ClCCl>[CH3:1][C:2]1[C:10]([S:11]([CH3:13])=[O:12])=[C:9]([C:14]([F:15])([F:17])[F:16])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][C:19]1[CH:18]2[CH2:25][CH:22]([C:21](=[O:26])[CH:20]=1)[CH2:23][CH2:24]2)=[O:5]
Reactant: Cc1c(C(=O)O)ccc(C(F)(F)F)c1S(C)=O
Reactant: O=C1CC(=O)C2CCC1C2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: Cc1c(C(=O)OC2=CC(=O)C3CCC2C3)ccc(C(F)(F)F)c1S(C)=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
250 mg (0.94 mmol) of 2-methyl-3-(methylsulfinyl)-4-(trifluoromethyl)benzoic acid were introduced into 25 ml of dry dichloromethane. Thereafter 143 mg (1.03 mmol) of bicyclo[3.2.1]octane-2,4-dione and subsequently, in portions, 216 mg (1.13 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added. The mixture was stirred at room temperature for 16 hours and then admixed with 5 ml of 1M hydrochloric acid. Following phase separation, the organic phase was freed from the solvent on a rotary evaporator. The residue was purified by chromatography, with 170 mg of clean product being isolated.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1.[F:23]C1C=CC(C(Cl)=O)=CC=1>>[NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:23])=[CH:15][CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:22])[C:8](=[O:21])[N:9]([CH3:20])[C:10]2=[O:19])=[CH:5]1
Reactant: Cn1c(=O)c2c(-c3ccccc3)n(CCN)cc2n(C)c1=O
Reactant: O=C(Cl)c1ccc(F)cc1
Product: Cn1c(=O)c2c(-c3ccc(F)cc3)n(CCN)cc2n(C)c1=O

Procedure:
This compound was prepared analogously to Intermediate A by replacing benzoyl chloride (step 2) with 4-fluorobenzoyl chloride.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9]([CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])=[CH:8][C:7]([CH3:17])=[N:6][N:5]2[CH:18]=1.C1C(=O)N([I:26])C(=O)C1>C(#N)C>[I:26][C:18]1[N:5]2[N:6]=[C:7]([CH3:17])[CH:8]=[C:9]([CH:10]([CH2:14][CH2:15][CH3:16])[CH2:11][CH2:12][CH3:13])[C:4]2=[N:3][C:2]=1[CH3:1]
Reactant: CCCC(CCC)c1cc(C)nn2cc(C)nc12
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Product: CCCC(CCC)c1cc(C)nn2c(I)c(C)nc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A 50 mL round bottom flask is charged with 2,6-dimethyl-8-(1-propyl-butyl)-imidazo[1,2-b]pyridazine (0.51 g, 0.0021 moles) and acetonitrile (3 mL). The reaction mixture is placed on an ice bath and NIS (0.468 g, 0.00208 moles) is added neat. The reaction is stirred overnight and the ice bath melts. The next day, the reaction mixture is partitioned between dichloromethane and a saturated aqueous solution of NaHCO3. The organic layer is collected and the aqueous layer is extracted two more times with dichloromethane. The organic extracts are combined, washed with brine, and dried over Na2SO4. The solvent is evaporated and the crude material is purified via silica gel chromatography eluting with hexanes and then a 25:75 mixture of ethyl acetate and hexanes. Yield=0.435 g (56%). MS (APCI): 372 (M+1).