Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:19])[C:5]([C:15]([O:17]C)=[O:16])=[N:6][N:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1.[ClH:20]>>[ClH:20].[CH3:1][O:2][C:3]1[C:4](=[O:19])[C:5]([C:15]([OH:17])=[O:16])=[N:6][N:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1
Reactant: COC(=O)c1nn(-c2cccnc2)cc(OC)c1=O
Agent: Cl
Product: COc1cn(-c2cccnc2)nc(C(=O)O)c1=O
Yield: 95 %

Procedure:
A solution of methyl 5-methoxy-4-oxo-1-pyridin-3-yl-1,4-dihydropyridazine-3-carboxylate (2.0 g, 7.7 mmol) in 6 M HCl aqueous solution (20 ml) was refluxed for 4 h. The mixture was concentrated under reduced pressure to give the title compound (2.1 g, 95% yield) as off-white crystals: 1H NMR (300 MHz, DMSO-d6): δ ppm 3.98 (3H, s), 7.78 (1H, dd, J=8.7, 4.5 Hz), 8.36-8.42 (1H, m), 8.79 (1H, dd, J=4.5, 1.1 Hz), 9.02 (1H, s), 9.15 (1H, d, J=2.6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:26])[C:21]([O:23]CC)=[S:22])=[CH:15][CH:14]=3)[N:8]([CH3:27])[C:7]=2[CH:28]=1.O.[OH-].[K+].[OH-].[K+].[ClH:34]>O1CCCC1.CN(C)C=O.O>[ClH:34].[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:10]=[C:9]([CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][CH:20]([CH3:26])[C:21]([OH:23])=[S:22])=[CH:15][CH:14]=3)[N:8]([CH3:27])[C:7]=2[CH:28]=1
Reactant: CCOC(=S)C(C)Cc1ccc(OCc2nc3ccc(OC)cc3n2C)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc2nc(COc3ccc(CC(C)C(O)=S)cc3)n(C)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 3-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)phenyl]-2-methylthiopropionate (2.0 g) in tetrahydrofuran (25 ml) were added successively potassium hydroxide monohydrate (0.42g), and dimethylformamide (5 ml). The mixture was stirred at room temperature for 2 hours. After addition of potassium hydroxide (0.42 g) and water (5 ml) the mixture was stirred at room temperature for 20 minutes. And then after addition of dimethylformamide (5 ml) the mixture was further stirred at room temperature for 1 hour and allowed to stand over night. To the reaction mixture was further added potassium hydroxide (0.42 g), water (5 ml) and dimethylformamide (5 ml) and the the mixture was stirred at 75° C. for 8 hours. The reaction mixture was poured into 1N hydrochloric acid (800 ml), stirred for 30 minutes and filtrated to give crystals. The crystals were washed successively with water, acetone and ethyl acetate and dried under reduced pressure to afford the title compound (1.27 g, mp 201-206° C.).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[C@H:18]([CH2:19][CH2:20][C:21](=[O:25])[CH:22]=2)[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]1.[Br-].[Li+].O.C(=O)(O)[O-].[Na+]>C(#N)C.[Cu](Br)Br.C(OCC)(=O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C@@H:7]1[CH2:24][C:23]2[CH:22]=[C:21]([OH:25])[CH:20]=[CH:19][C:18]=2[C@@H:17]2[C@@H:8]1[C@H:9]1[C@@:13]([CH2:15][CH2:16]2)([CH3:14])[C:12](=[O:26])[CH2:11][CH2:10]1
Reactant: C[C@]12CC[C@H]3[C@@H]([C@H](CCCCCCl)CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: Br[Cu]Br
Agent: O=C([O-])O
Agent: [Br-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: C[C@]12CC[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCl)[C@H]3[C@@H]1CCC2=O
Yield: 53 %

Procedure:
18.96 g of 7α-(5-chloropentyl)-estr-4-ene-3,17-dione is dissolved in 350 ml of anhydrous acetonitrile and mixed under inert gas at 80° C. with a solution of 4.36 g of lithium bromide and 22.5 g of copper(II) bromide in 390 ml of anhydrous acetonitrile. It is stirred for 5 more minutes, the mixture is cooled in an ice bath and mixed with water and ethyl acetate. The organic phase is shaken out with saturated sodium bicarbonate solution, the aqueous phase with ethyl acetate, the combined organic phases with saturated common salt solution, dried with sodium sulfate and concentrated by evaporation in a vacuum. The raw yield of 19.1 g is chromatographed on silica gel in hexane and ethyl acetate, whereby 10.0 g of oily 7α-(5-chloropentyl)-3-hydroxy-estra-1,3,5(10)-trien-17-one is obtained, which can be crystallized from hexane/dichloromethane.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:4][N:3]=1.[C:20]1([C:26]2[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][N:27]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:8]([C:5]1[CH:4]=[N:3][C:2]([C:29]2[CH:30]=[CH:31][C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:27][CH:28]=2)=[N:7][CH:6]=1)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCc1cnc(Br)nc1
Reactant: OB(O)c1ccc(-c2ccccc2)nc1
Product: CCCCCCCCCCCCc1cnc(-c2ccc(-c3ccccc3)nc2)nc1

Procedure:
The synthesis was carried out analogously to Example 27 from 2-bromo-5-dodecylpyrimidine and 2-phenylpyridine-5-boronic acid.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[C:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Product: CC(C)(C)OC(=O)N1CCC(=O)C1

Procedure:
Prepared from (R)-(+)-1-Boc-3-pyrrolidinol using the Dess-Martin oxidation (Dess, D. B.; Martin, J. C.; J. Am. Chem. Soc., 1991, 113, 7277) (85%).
Reaction SMILES: C(C1C=C(C(C)C)C=C(C(C)C)C=1S(NN=[C:21]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:22][CH2:23][N:24]1[CH2:28]CC[CH2:25]1)(=O)=O)(C)C.[CH:35](=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH:36]1([CH:35]([OH:42])[C:21]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)=[CH:22][CH2:23][N:24]([CH3:25])[CH3:28])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: CC(C)c1cc(C(C)C)c(S(=O)(=O)NN=C(CCN2CCCC2)c2ccccc2)c(C(C)C)c1
Reactant: O=Cc1ccccc1
Product: CN(C)CC=C(c1ccccc1)C(O)C1CCCCC1

Procedure:
By using a method similar to that described in Example 22, but starting from β-(1-pyrrolidinyl)propiophenone 2,4,6-triisopropylbenzenesulphonylhydrazone (20 g), and benzaldehyde (4.6 cc), 1,2-diphenyl-4-(1-pyrrolidinyl)-2-buten-1-ol (Z) hydrochloride (9.9 g) is obtained, after recrystallisation from a mixture of 2-propanol and isopropyl ether (40/60 by volume), in the form of white crystals melting at 106° C.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:6])[CH3:5])[CH3:2].C([Li])CCC.[CH3:12][C:13]1[N:14]=[C:15](S(C)(=O)=O)[O:16][C:17]=1[CH3:18]>C(OCCCC)CCCCC.CCCCCC>[CH2:1]([N:3]([C:15]1[O:16][C:17]([CH3:18])=[C:13]([CH3:12])[N:14]=1)[C:4](=[O:6])[CH3:5])[CH3:2]
Reactant: CCNC(C)=O
Reactant: Cc1nc(S(C)(=O)=O)oc1C
Agent: CCCCCCOCCCC
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CCN(C(C)=O)c1nc(C)c(C)o1
Reaction time: 0.25 h

Procedure:
N-Ethyl-acetamide (10.0 g, 0.115 m) in dry butyl hexyl ether (50 ml) was stirred at room temperature under nitrogen during the dropwise addition of a 1.445 M solution of n-butyl lithium in hexane (79.6 ml, 0.115 m). After the addition, the mixture was stirred for 15 minutes and then a solution of 4,5-dimethyl-2-methylsulphonyloxazole (20.0 g, 0.114 m) in dry butyl hexyl ether (50 ml) was added dropwise. The mixture was stirred for 2 hours at room temperature. Isolation of the product and distillation gave a colourless oil, b.p. 61°-62° C/0.3 mm.
Reaction SMILES: [CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH:11]=[CH:12][C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]([CH2:21][CH3:22])[CH3:20])[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:23])=[N:4][CH:3]=1.C(Cl)Cl.CO>[Pd].CO>[CH3:1][C:2]1[N:7]2[N:8]=[C:9]([CH2:11][CH2:12][C:13]3[N:17]([CH3:18])[N:16]=[C:15]([N:19]([CH2:21][CH3:22])[CH3:20])[N:14]=3)[N:10]=[C:6]2[C:5]([CH3:23])=[N:4][CH:3]=1
Reactant: CCN(C)c1nc(C=Cc2nc3c(C)ncc(C)n3n2)n(C)n1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CCN(C)c1nc(CCc2nc3c(C)ncc(C)n3n2)n(C)n1
Temperature: 25 °C
Reaction time: 14 h
Yield: 49.7 %

Procedure:
A mixture of 5-(2-(5,8-dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)vinyl)-N-ethyl-N,1-dimethyl-1H-1,2,4-triazol-3-amine (7 mg, 22.4 μmol, Eq: 1.00) and palladium on carbon 10% (4.77 mg, 4.48 μmol, Eq: 0.2) in methanol (1 ml) was stirred for 14 hours at 25° C. under hydrogen atmosphere. TLC (CH2Cl2/MeOH 19:1/UV 254 nm) showed complete reaction (spot to spot). palladium was filtered off and the filtrate was evaporated and applied on silica gel. Purification by column chromatography over 10 g SiO2 using ethyl acetate/methanol (0-10% MeOH) as eluent to give {5-[2-(5,8-Dimethyl-[1,2,4]triazolo[1,5-a]pyrazin-2-yl)-ethyl]-1-methyl-1H-[1,2,4]triazol-3-yl}-ethyl-methyl-amine (3.5 mg, 49.7%) as off-white solid
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5](F)=[N:6][CH:7]=1.[OH:10][C:11]1[CH:23]=[CH:22][C:14]([O:15][CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C1OCCOCCOCCOCCOCCOC1>[Cl:1][C:2]1[CH:3]=[C:4]([F:9])[C:5]([O:10][C:11]2[CH:12]=[CH:13][C:14]([O:15][CH:16]([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:22][CH:23]=2)=[N:6][CH:7]=1
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Reactant: Fc1cc(Cl)cnc1F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)Oc1ccc(Oc2ncc(Cl)cc2F)cc1
Temperature: 0 °C
Yield: 62.6 %

Procedure:
A solution of 14.95 g (0.10 mol) of 5-chloro-2,3-difluoropyridine in 30 ml of acetonitrile is added dropwise to a mixture of 21.6 g (0.11 mol) of methyl 2-(4-hydroxyphenoxy)propionate, 15.2 g (0.11 mol) of potassium carbonate, 1.45 g (0.0055 mol) of 18-crown-6 and 100 ml of acetonitrile and the reaction mixture is then heated for 40 hours to a temperature in the range from 50° to 60° C. The mixture is taken up in ice water, the organic phase is separated, the aqueous phase is extracted three times with ethyl acetate and the combined organic phases are dried and concentrated by evaporation, affording an oily residue which for purification is dissolved in a mixture of hexane and ethyl acetate and filtered through silica gel. The solvent is evaporated off, affording from the filtrate 20.4 g (63% of theory) of methyl 2-[4-(5-chloro-3-fluoropyridin-2-yloxy)phenoxy]propionate, m.p. 58° -59° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([CH2:16][C:17]([OH:19])=O)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:15][CH:14]([CH2:16][C:17](=[O:19])[NH:27][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: NCc1ccccc1
Reactant: O=C(O)CC1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Product: O=C(CC1Cc2cc(Br)cc3[nH]c(=O)c(=O)n1c23)NCc1ccccc1
Yield: 49.5 %

Procedure:
A procedure similar to that described in Example 5 was carried out with 8-bromo-5-carboxymethyl-5,6-dihydro-1H-pyrrolo[1,2,3-de]quinoxaline-2,3-dione (130 mg, 0.40 mmol) and benzylamine (48 μL, 0.44 mmol) to give 82 mg of the title compound (51%): mp 252° C. (dec); 1H NMR (270 MHz, DMSO-d6) δ12.13 (s, 1H), 8.69 (t, 1H, J=6 Hz), 7.18~7.34 (m, 5H), 7.20 (s, 2H), 5.16~5.22 (m, 1H), 4.27 (d, 2H, J=6 Hz), 2.80 (dm, 1H, J=18 Hz), 2.55 (dm, 1H, J=14 Hz), 2.46 (m, 1H, J=14 Hz), 1.87~2.03 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:15]=[N:14][C:5]2[NH:6][C:7](=[O:13])[C:8]([CH3:12])([CH3:11])[CH2:9][O:10][C:4]=2[CH:3]=1.[CH3:16][O:17][C:18]1[C:19]([O:31][CH2:32][CH2:33][CH3:34])=[C:20]([CH:28]=[CH:29][CH:30]=1)[CH2:21][N:22]([CH3:27])[C:23](=[O:26])[CH:24]=[CH2:25].C(N(C(C)C)C(C)C)C.CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)CC.CN(C=O)C.O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:11][C:8]1([CH3:12])[C:7](=[O:13])[NH:6][C:5]2[N:14]=[CH:15][C:2](/[CH:25]=[CH:24]/[C:23]([N:22]([CH2:21][C:20]3[CH:28]=[CH:29][CH:30]=[C:18]([O:17][CH3:16])[C:19]=3[O:31][CH2:32][CH2:33][CH3:34])[CH3:27])=[O:26])=[CH:3][C:4]=2[O:10][CH2:9]1
Reactant: C=CC(=O)N(C)Cc1cccc(OC)c1OCCC
Reactant: CC1(C)COc2cc(Br)cnc2NC1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)OCC(C)(C)C(=O)N3)cccc1OC
Reaction time: 0.25 h
Yield: 44.8 %

Procedure:
To a solution of 3-bromo-7,7-dimethyl-6,7-dihydro-9H-5-oxa-1,9-diaza-benzocyclohepten-8-one (200 mg, 0.738 mmol) in propionitrile (24 mL) and DMF (6 mL) were added N-(3-methoxy-2-propoxy-benzyl)-N-methylacrylamide (253 mg, 0.959 mmol), (i-Pr)2EtN (0.26 mL, 1.5 mmol), Pd(OAc)2 (17 mg, 0.074 mmol) and P(o-tol)3 (45 mg, 0.15 mmol), and the mixture was de-oxygenated with argon for 15 min. The mixture was heated to reflux overnight, allowed to cool and then diluted with water (60 mL). The mixture was extracted with CH2Cl2 (3×50 mL). The combined extracts were washed with water and brine, dried (Na2SO4) and the solvent was removed in vacuo. Purification by column chromatography (silica gel, CH2Cl2/MeOH, 97:3) then by slow precipitation from CH2Cl2/hexanes gave the title compound (150 mg, 45%) as a pale-yellow solid and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.12-10.10 (m, 1H), 8.28-8.22 (m, 1H), 7.95-7.85 (m, 1H), 7.54-7.47 (m, 1H), 7.33-7.27 (m, 1H), 7.07-6.93 (m, 2H), 6.68-6.61 (m, 1H), 4.80-4.63 (m, 2H), 4.08-4.04 (m, 2H), 3.91-3.84 (m, 2H), 3.79 (s, 3H), 3.10-2.73 (m, 3H), 1.74-1.67 (m, 2H), 1.20-1.17 (m, 6H), 1.01-0.93 (m, 3H); MS (ESI) m/e 454 (M+H)+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(Cl)(Cl)Cl.Cl[C:17]1[CH:18]=[C:19]([CH:28]=[CH:29][C:30]=1Cl)[CH2:20]N=C([O-])C(Cl)(Cl)Cl.FC(F)(F)S(O)(=O)=O>CCCCCC>[CH2:20]([O:1][C@H:2]1[CH2:6][CH2:5][CH2:4][C@H:3]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:19]1[CH:28]=[CH:29][CH:30]=[CH:17][CH:18]=1
Reactant: CCOC(=O)[C@@H]1CCC[C@@H]1O
Reactant: [O-]C(=NCc1ccc(Cl)c(Cl)c1)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1CCC[C@@H]1OCc1ccccc1
Reaction time: 3 h

Procedure:
To a mixture of 1.00 g of ethyl cis-2-hydroxy-1-cyclopentane carboxylate, 8.00 mL of chloroform, 16.0 mL of normal hexane, and 1.77 mL of 3,4-dichlorobenzyl-2,2,2-trichloroacetimidate was added 0.335 mL of trifluoromethane sulfonic acid at room temperature under a nitrogen atmosphere, followed by stirring for 3 hours. The insoluble materials were removed by filtration, and to the filtrate was added a saturated aqueous sodium hydrogen carbonate solution under ice-cooling to adjust the pH to about 7, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate, and then the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (normal hexane/ethyl acetate) to obtain 1.27 g of ethyl cis-2-benzyloxy-1-cyclopentane carboxylate as a colorless oily substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:12]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:11]=3[N:10]=2)=[C:6]([OH:8])[CH:7]=1.[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37]Br)=[CH:33][CH:32]=1>>[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([CH2:37][O:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[C:9]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=3)[C:12]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:11]=3[N:10]=2)=[CH:33][CH:32]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: Oc1cc(Cl)ccc1-c1nc2cc(F)c(F)cc2n1Cc1cccc(Cl)c1
Product: COC(=O)c1ccc(COc2cc(Cl)ccc2-c2nc3cc(F)c(F)cc3n2Cc2cccc(Cl)c2)cc1

Procedure:
The title compound was prepared in analogy to Example 5, intermediate a, from 5-chloro-2-[1-(3-chloro-benzyl)-5,6-difluoro-1H-benzoimidazol-2-yl]-phenol (Example 53, intermediate a) and 4-bromomethyl-benzoic acid methyl ester (CAS Reg. No. 2417-72-3). Colorless sticky solid (56%). MS (Turbo Spray): m/z=553.1 (M+H).
Reaction SMILES: [F:1][C:2]1([F:12])[CH2:5][C:4]([C:9]([NH2:11])=O)([C:6]([NH2:8])=O)[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[F:1][C:2]1([F:12])[CH2:5][C:4]([CH2:9][NH2:11])([CH2:6][NH2:8])[CH2:3]1
Reactant: NC(=O)C1(C(N)=O)CC(F)(F)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCC1(CN)CC(F)(F)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 72.8 %

Procedure:
To a cooled solution of 3,3-difluorocyclobutane-1,1-dicarboxamide (1.858 g, 10.4 mmol) in tetrahydrofuran (25 mL) at −10° C., was added slowly lithium aluminium hydride (2.375 g, 62.58 mmol). The reaction was stirred at 0° C. for 4 hours and then heated under reflux for 30 hours. The mixture was cooled and quenched at 0° C. by addition of water (2.5 mL), 15% aqueous solution of sodium hydroxide (7.5 mL) and water (2.5 mL) successively. The resulting mixture was stirred at room temperature for 0.5 hour. The mixture was filtered and the filtrate was concentrated in vacuo to afford 1.137 g of the crude product of (3,3-difluorocyclobutane-1,1-diyl)dimethanamine as a colorless oil (yield was 72.8%).
Reaction SMILES: [Si]([O:8][CH:9]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:10][O:11][CH:12]1[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:14][CH:13]1[F:26])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[F:26][CH:13]1[CH:12]([O:11][CH2:10][CH:9]([OH:8])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:17][CH2:16][CH:15]([NH:18][C:19](=[O:25])[O:20][C:21]([CH3:23])([CH3:22])[CH3:24])[CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCC(OCC(O[Si](C)(C)C(C)(C)C)c2ccccc2)C(F)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(OCC(O)c2ccccc2)C(F)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a solution of tert-butyl 4-(2-{[tert-butyl(dimethyl)silyl]oxy}-2-phenylethoxy)-3-fluorocyclohexylcarbamate (5.83 g, 12.5 mmol) in THF (100 mL) was added tetrabutylammonium fluoride (25 mL, 25 mmol, 1M in THF) and the reaction mixture was stirred at room temperature for 8 h. The mixture was extracted with ethyl acetate (4×), and the combined organics washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated. Purification by flash column chromatography (hexane: ethyl acetate 80:20 then 60:40) gave tert-Butyl 3-fluoro-4-(2-hydroxy-2-phenylethoxy)cyclohexylcarbamate (4.33 g) as a white solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([N+:20]([O-])=O)[C:8]([O:18][CH3:19])=[C:9]([CH:11]([NH:16][CH3:17])[C:12]([F:15])([F:14])[F:13])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([C:5]1[CH:10]=[C:9]([CH:11]([NH:16][CH3:17])[C:12]([F:15])([F:14])[F:13])[C:8]([O:18][CH3:19])=[C:7]([CH:6]=1)[NH2:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CNC(c1cc(C(C)(C)C)cc([N+](=O)[O-])c1OC)C(F)(F)F
Agent: [Pd]
Solvent: CO
Product: CNC(c1cc(C(C)(C)C)cc(N)c1OC)C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.4 %

Procedure:
To a solution of 1-(5-tert-butyl-2-methoxy-3-nitrophenyl)-2,2,2-trifluoro-N-methylethaneamine (0.413 g, 1.29 mmol) in methanol (12.0 mL), 10% palladium/activated charcoal (0.041 g) was added and the resulting mixture was stirred at room temperature under hydrogen atmosphere for 3 hours. After completion of the reaction, the insoluble materials were filtered through a Celite pad, and the solvent was evaporated under reduced pressure. The obtained residue was purified by column chromatography (amine coated silica gel, hexane/ethyl acetate=90/10-0/100) to obtain 0.215 g of the captioned compound (57% yield).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:16]([O-])([OH:18])=[O:17]>C(O)(=O)C>[N+:16]([C:11]1[CH:10]=[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:14]=[CH:13][C:12]=1[OH:15])([O-:18])=[O:17]
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1cc(OCc2ccccc2)ccc1O

Procedure:
4-Phenylmethoxy-phenol in acetic acid is nitrated by contact with a slight molar excess of nitric acid at room temperature, giving 2-nitro-4-phenylmethoxy-phenol.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15](C(C3C=CC=CN=3)C)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([NH2:8])=[N:6][CH:7]=1.[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[C:34]([CH2:35]N3CCN(C(OC(C)(C)C)=O)CC3)[C:29]=2[O:28][CH2:27]1.C(O)(C(F)(F)F)=O.BrC1C(Cl)=C([N+]([O-])=O)C(N)=NC=1>CC(O)C.CCN(C(C)C)C(C)C.C(Cl)Cl>[O:26]1[C:30]2[CH:31]=[CH:32][CH:33]=[C:34]([CH2:35][N:15]3[CH2:16][CH2:17][N:12]([C:3]4[C:2]([Br:1])=[CH:7][N:6]=[C:5]([NH2:8])[C:4]=4[N+:9]([O-:11])=[O:10])[CH2:13][CH2:14]3)[C:29]=2[O:28][CH2:27]1
Reactant: CC(c1ccccn1)N1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cccc3c2OCO3)CC1
Agent: Nc1ncc(Br)c(Cl)c1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ncc(Br)c(N2CCN(Cc3cccc4c3OCO4)CC2)c1[N+](=O)[O-]

Procedure:
This was prepared using the same procedure as for 5-bromo-3-nitro-4-(4-(1-(pyridin-2-yl)ethyl)piperazin-1-yl)pyridin-2-amine, but here using tert-butyl 4-(benzo[d][1,3]dioxol-4-ylmethyl)piperazine-1-carboxylate (1.1 eq, 0.37 mmol, 120 mg), TFA (1.5 mL) and CH2Cl2 (3 mL), then 5-bromo-4-chloro-3-nitropyridin-2-amine (86 mg, 0.34 mmol) in iPrOH (3.5 mL) and DIPEA (1 mL). Filtration and washing as previously described gave the product (131 mg, 80% for two steps) as a yellow solid; δH (500 MHz, DMSO-d6) 2.54 (s, br, 4H, piperazine N(CH2)2), 3.06 (s, br, 4H, piperazine N(CH2)2), 3.51 (s, 2H, NCH2), 6.00 (s, 2H, OCH2), 6.83-6.85 (m, 3H, phenyl H-4, H-5, H-6), 6.98 (s, br, 2H, NH2), 8.16 (s, 1H, bromopyridine H-6);
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:12]2[NH:11][C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[CH:7]=[C:6]([Cl:25])[CH:5]=1.Br[CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[Cl:3][C:4]1[C:12]2[N:11]([CH2:27][CH2:28][O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:10]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:16][CH2:17][C:9]=3[C:8]=2[CH:7]=[C:6]([Cl:25])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3c(Cl)cc(Cl)cc3c2CC1
Reactant: BrCCOc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccccc3)c3c(Cl)cc(Cl)cc23)CC1
Reaction time: 0.5 h
Yield: 77 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 51 mg, 1.3 mmol) was added to a solution of tert-butyl 7,9-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.30 g, 0.84 mmol) in DMF (5 mL). After 30 min, β-bromophenetole was added (0.23 mL). The reaction was quenched with saturated aqueous NH4Cl after 18 h and extracted with EtOAc (1×50 mL, 2×20 mL). The combined organic extracts were washed with brine, dried over Na2SO4, decanted, and concentrated. The crude product was purified by column chromatography (Biotage, 40S) with heptane/EtOAc (17:3) and crystallized from EtOAc/heptane to give 0.31 g (77%) of a white solid: mp 154.0-155.0° C.; 1H NMR (300 MHz, DMSO) δ 7.54 (d, J=1.9 Hz, 1H), 7.20 (m, 3H), 6.85 (m, 3H), 4.86 (m, 2H), 4.24 (m, 2H), 3.69 (m, 2H), 3.54 (m, 2H), 3.12 (m, 2H), 2.91 (m, 2H), 1.42 (s, 9H); IR (diffuse reflectance) 1683, 1463, 1410, 1366, 1345, 1293, 1242, 1232, 1227, 1174, 1167, 1113, 857, 756, 693 cm−1; MS (EI) m/z 474 (M+), 474, 420, 419, 418, 334, 332, 311, 238, 84, 57; Anal. Calcd for C25H28Cl2N2O3: C, 63.16; H, 5.94; N, 5.89; found: C, 63.19; H, 5.97; N, 5.86.