Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8][N:9]2[CH:12]2[CH2:14][CH2:13]2)=[CH:4][C:3]=1[F:19].[NH:20]1[CH2:23][CH:22]([NH:24][CH2:25][C@H:26]2[O:30][C:29](=[O:31])[N:28]([C:32]3[CH:33]=[CH:34][C:35]4[S:40][CH2:39][C:38](=[O:41])[NH:37][C:36]=4[CH:42]=3)[CH2:27]2)[CH2:21]1>CC#N.O>[CH:12]1([N:9]2[C:10]3[C:5](=[CH:4][C:3]([F:19])=[C:2]([N:20]4[CH2:23][CH:22]([NH:24][CH2:25][C@H:26]5[O:30][C:29](=[O:31])[N:28]([C:32]6[CH:33]=[CH:34][C:35]7[S:40][CH2:39][C:38](=[O:41])[NH:37][C:36]=7[CH:42]=6)[CH2:27]5)[CH2:21]4)[N:11]=3)[C:6](=[O:18])[C:7]([C:15]([OH:17])=[O:16])=[CH:8]2)[CH2:14][CH2:13]1
Reactant: O=C(O)c1cn(C2CC2)c2nc(Cl)c(F)cc2c1=O
Reactant: O=C1CSc2ccc(N3C[C@@H](CNC4CNC4)OC3=O)cc2N1
Solvent: O
Solvent: CC#N
Product: O=C1CSc2ccc(N3C[C@@H](CNC4CN(c5nc6c(cc5F)c(=O)c(C(=O)O)cn6C5CC5)C4)OC3=O)cc2N1
Temperature: 75 °C

Procedure:
A mixture of 7-chloro-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (commercial; 141 mg), 6-[(5R)-5-[(3-azetidinylamino)methyl]-2-oxo-3-oxazolidinyl]-2H-1,4-benzothiazin-3(4H)-one (prepared according to WO 2008/126034; 167 mg) and TEA (0.15 ml) in MeCN (4 ml) was heated at 75° C. for 2 h. The reaction mixture was allowed to reach rt, diluted with water, filtered and the solid was washed with MeOH and EA, affording a beige solid.
Reaction SMILES: Br[C:2]1[C:3]2[C:7]([CH:8]=[CH:9][CH:10]=1)=[N:6][N:5]([CH3:11])[CH:4]=2.[CH2:12]([OH:15])[C:13]#[CH:14]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][N:5]1[CH:4]=[C:3]2[C:7]([CH:8]=[CH:9][CH:10]=[C:2]2[C:14]#[C:13][CH2:12][OH:15])=[N:6]1
Reactant: Cn1cc2c(Br)cccc2n1
Reactant: C#CCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: Cn1cc2c(C#CCO)cccc2n1
Temperature: 70 °C
Reaction time: 14 h
Yield: 45.7 %

Procedure:
Under argon gas atmosphere, a mixture of 4-bromo-2-methyl-2H-indazole (1.00 g, 4.74 mmol), propargyl alcohol (1.10 mL, 18.9 mmol) and bis(triphenylphosphine)palladium(II) dichloride (665 mg, 0.947 mmol) in triethylamine (47 mL) was stirred at 70° C. for 14 hr, and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and insoluble material was filtered off. The filtrate was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane=70/30→100/0) and the obtained crudely purified product was washed with ethyl acetate to give the title compound (403 mg, yield 46%).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][NH:7][C:8](=[O:26])[C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:16]=2[NH2:25])[CH:10]=1.[C:32]([O:36][C:37](=[O:51])[CH2:38][CH2:39][S:40][CH2:41][C:42]1[CH:43]=[C:44]([CH:48]=[CH:49][CH:50]=1)[C:45](O)=[O:46])([CH3:35])([CH3:34])[CH3:33].CCN=C=NCCCN(C)C.Cl>ClCCl.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[F:31][C:2]([F:30])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[CH:28][CH:29]=1)[CH2:6][NH:7][C:8]([C:9]1[CH:14]=[CH:13][N:12]=[C:11]([C:15]2[CH:20]=[C:19]([O:21][CH:22]([CH3:24])[CH3:23])[CH:18]=[CH:17][C:16]=2[NH:25][C:45]([C:44]2[CH:43]=[C:42]([CH:50]=[CH:49][CH:48]=2)[CH2:41][S:40][CH2:39][CH2:38][C:37]([O:36][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:51])=[O:46])[CH:10]=1)=[O:26]
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)O)c1
Reactant: CC(C)Oc1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)Oc1ccc(NC(=O)c2cccc(CSCCC(=O)OC(C)(C)C)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.6 %

Procedure:
Into a 50-mL round bottom flask, was placed a solution of N-(3-(trifluoromethyl)benzyl)-2-(2-amino-5-isopropoxyphenyl)isonicotinamide (230 mg, 0.48 mmol, 1.00 equiv, 90%) in dichloromethane (8 mL), 3-((3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid 1.1c (317 mg, 0.86 mmol, 2.00 equiv, 80%), EDC.HCl (206 mg, 1.07 mmol, 2.00 equiv), and 4-dimethylaminopyridine (131 mg, 1.07 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at 25° C. The resulting solution was diluted with 100 mL of ethyl acetate and washed with 1×20 mL of aqueous NH4Cl, 1×20 mL of 10% sodium bicarbonate, and 1×20 mL of brine. The mixture was dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2). The product was obtained as 240 mg (60%) of a brown oil.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]3[CH2:18][CH2:17][CH2:16][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][CH:15]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[I:20]I.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Br:1][C:2]1[C:7]2[C:8](=[O:19])[N:9]3[CH2:18][CH2:17][CH2:16][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[I:20])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: II
Reactant: O=C1c2c(Br)cccc2-n2cncc2[C@@H]2CCCN12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2c(Br)cccc2-n2cnc(I)c2[C@@H]2CCCN12
Reaction time: 0.5 h

Procedure:
15.90 g (50 mmol) of (S)-8-bromo-11,12,13,13a-tetrahydro-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one was stirred at 100° for 3 hours with 44 g (175 mmol) of iodine and 14 g (100 mmol) of potassium carbonate in 100 ml of N,N-dimethylformamide. The reaction mixture was poured into 1 l of water and, after stirring for 30 minutes, the precipitated product was filtered off. The filter residue was rinsed with water, dried and recrystallized from N,N-dimethylformamide. There was obtained (S)-8-bromo-11,12,13,13a-tetrahydro-1-iodo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-9-one of melting point 301°-303°.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([CH3:14])[CH:6]=1)(=[O:3])[CH3:2].B.C1COCC1>C1COCC1>[OH:10][CH2:9][C:8]1[CH:12]=[CH:13][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][C:7]=1[CH3:14]
Reactant: CC(=O)Nc1ccc(C(=O)O)c(C)c1
Agent: B
Solvent: C1CCOC1
Product: CC(=O)Nc1ccc(CO)c(C)c1
Reaction time: 8 h
Yield: 20.3 %

Procedure:
4-(Acetylamino)-2-methylbenzoic acid (2 g, 10.4 mmol) was suspended in THF (50 mL) and borane-THF complex (1M in THF, 26 mL, 26 mmol) added drop-wise over 15 minutes. The reaction mixture was stirred under argon overnight. The reaction mixture was quenched with water (51 mL) and extracted with EtOAc (×3). The combined organics were dried and concentrated. The crude product was purified by chromatography. Elution with 0-100% EtOAc/petroleum ether yielded the title compound as a cream solid (0.379 g). δH (MeOD, 400 MHz) 7.36 (2H, d), 7.25 (1H, d), 4.57 (2H, s), 2.31 (3H, s), 2.10 (3H, s). MS (ES+): MH+ 180.2.
Reaction SMILES: [I-:1].[Na+].CS(O[CH2:8][CH2:9][CH2:10][C@H:11]([CH3:21])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])(=O)=O.O>CC(C)=O.[Cl-].[Na+].O>[I:1][CH2:8][CH2:9][CH2:10][C@H:11]([CH3:21])[CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: C[C@@H](CCCOS(C)(=O)=O)CO[Si](C)(C)C(C)(C)C
Reactant: [I-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: C[C@@H](CCCI)CO[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
Anhydrous sodium iodide (600 mg, 4.0 mmol, 2 equiv) is added to a solution of (S)-1-methanesulfonyloxy-5-(tert-butyldimethylsilyloxy)-4-methyl-pentane 7 (622 mg, 2.0 mmol) in 3.0 ml of absolute acetone. The mixture is stirred for 2 h at 50° C. 10 ml of a mixture of brine and water (1:1) are added, and the mixture is extracted with diethyl ether (3×20 ml). The combined organic extracts are dried over magnesium sulfate and concentrated in vacuo. Purification of the residue by flash column chromatography (pentane/diethyl ether 20:1) affords (S)-1-iodo-5-(tert-butyidimethylsilyloxy)-4-methyl-pentane 8 (647 mg, 94%) as a colourless oil. FG 342.34; 13C-NMR (100 MHz, CDCl3): δ=68.1, 35.1, 34.3, 31.3, 26.0, 16.7, 7.4, −5.3
Reaction SMILES: [NH3:1].[F:2][C:3]1[C:8]([N+:9]([O-:11])=[O:10])=[C:7](F)[C:6]([F:13])=[C:5]([F:14])[C:4]=1[F:15]>C(OCC)C>[N+:9]([C:8]1[C:3]([F:2])=[C:4]([F:15])[C:5]([F:14])=[C:6]([F:13])[C:7]=1[NH2:1])([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1c(F)c(F)c(F)c(F)c1F
Reactant: N
Solvent: CCOCC
Product: Nc1c(F)c(F)c(F)c(F)c1[N+](=O)[O-]

Procedure:
2-Nitro-3,4,5,6-tetrafluoroaniline was prepared using an adaptation of the method of Brooke et al., J. Chem. Soc. 802 (1961). Ammonia gas was bubbled through a solution of pentafluoronitrobenzene (3.00 g, 114.1 mmol) in 200 mL anhydrous diethyl ether for 4 h. During this time the color changed from clear white to a deep yellow and a white precipitate formed. The precipitate (ammonium fluoride) was separated by vacuum filtration and washed with ether (30 mL). The filtrate was rotary evaporated and the resulting orange crystals gave 3 spots on TLC (alumina, benzene). Purification of this sample was achieved by column chromatography (basic alumina, benzene). Purification of this sample was achieved by column chromatography (basic alumina, activity II) on a 1.5"×20" column. The first band was collected and concentrated to yield a yellow solid 1.88 g (63.0%), mp 44.5-45 (lit. 42.5°-43.5° C.). 19F NMR (C6F6 external standard, δ -162.9) δ -149.9(m), -1.56.6(m), -162.0 (m), -178.3(m).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]1[CH:16]=[CH:15][C:14]([C:17](=[O:19])[CH3:18])=[CH:13][C:12]=1[OH:20].[OH-].[Na+].[CH3:23][C:24]([CH3:49])([CH2:37]C1C=C(C)C=CC=1S([O-])(=O)=O)[CH2:25]C1C=C(C)C=CC=1S([O-])(=O)=O>CN(C=O)C>[CH3:23][C:24]1([CH3:49])[CH2:37][O:20][C:12]2[CH:13]=[C:14]([C:17](=[O:19])[CH3:18])[CH:15]=[CH:16][C:11]=2[C:3]2[CH:4]=[CH:5][C:6]([C:8](=[O:10])[CH3:9])=[CH:7][C:2]=2[O:1][CH2:25]1
Reactant: CC(=O)c1ccc(-c2ccc(C(C)=O)cc2O)c(O)c1
Reactant: Cc1ccc(S(=O)(=O)[O-])c(CC(C)(C)Cc2cc(C)ccc2S(=O)(=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1)OCC(C)(C)COc1cc(C(C)=O)ccc1-2
Temperature: 150 °C
Reaction time: 20 h
Yield: 31.9 %

Procedure:
To a solution of 1,1′-(2,2′-dihydroxy-[1,1′-biphenyl]-4,4′-diyl)-diethanone (0.2 g, 0.74 mmol) (synthesized according to WO 2010/111673) in anhydrous DMF (10 mL), NaOH (0.08 g, 1.85 mmol) and 2,2-dimethylpropane-1,3-diyl-bis-(4-methylbenzenesulfonate) (0.37 g, 0.89 mmol) (synthesized according to US 2005/0113374) were added successively and the suspension was stirred at 150° C. for 20 h under nitrogen atmosphere. The reaction mixture was brought to room temperature, crushed ice was added and stirred vigorously for 15 min. The contents were extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate and purified by flash column chromatography (20% Ethyl acetate-Hexane) to yield a white solid (0.08 g, 32%). m/z 339.3 (M+H)+.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1)C.[NH2:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18]>C(#N)C>[N:7]1([CH2:6][CH2:5][CH2:4][NH:15][C:16]([CH3:20])([CH3:19])[CH2:17][OH:18])[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: CC(C)(N)CO
Reactant: CCOC(CCn1ccnc1)OCC
Solvent: CC#N
Product: CC(C)(CO)NCCCn1ccnc1

Procedure:
3-(Imidazol-1-yl)propionaldehyde diethyl acetal (8.1 g) was converted into the free aldehyde, as described in Example 24, and then added to a mixture of 2-amino-2-methylpropanol (1.83 g) in acetonitrile (40 ml) and 4A molecular sieves (6.0 g). The mixture was reacted following the procedure of Example 24 to give 2-[3-(imidazol-1-yl)propylamino]-2-methyl-1-propanol, m.p. 81°-85° C.
Reaction SMILES: [CH2:1]([OH:6])[CH2:2][CH2:3][C:4]#[CH:5].N1C=CN=C1.Cl[Si:13]([CH3:16])([CH3:15])[CH3:14]>C(Cl)Cl.O>[CH3:14][Si:13]([CH3:16])([CH3:15])[O:6][CH2:1][CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCCO
Reactant: C[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: ClCCl
Product: C#CCCCO[Si](C)(C)C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of 4-pentyn-1-ol (25.0 g, 0.30 mole) in dry CH2Cl2 (250 ml) at 0° C., was added imidazole (40.46 g, 0.60 mole) and chlorotrimethylsilane (56.6 ml, 0.45 moles) and stirred for 2 h. The reaction mixture was diluted with water and extracted with CH2Cl2 (3×100 ml). Combined organic extracts were washed with water, brine, dried (Na2SO4) and the solvent was evaporated. Purification of the crude product by vacuum distillation afforded the pure ether 13 (44.1 g, 95%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][CH2:3]1.[CH:8]1([N:11]2[C:20]3[C:15](=[CH:16][C:17]([F:23])=[C:18](F)[C:19]=3[F:21])[C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12]2)[CH2:10][CH2:9]1.C(N(CC)CC)C>C(#N)C>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:18]2[C:19]([F:21])=[C:20]3[C:15]([C:14](=[O:24])[C:13]([C:25]([OH:27])=[O:26])=[CH:12][N:11]3[CH:8]3[CH2:10][CH2:9]3)=[CH:16][C:17]=2[F:23])[CH2:3]1
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: N[C@H]1CCCNC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N[C@H]1CCCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Yield: 79.9 %

Procedure:
A suspension of (S)-3-aminopiperidine (4.0 g) obtained as described in the step (c) above 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid(11.4 g) and triethylamine (8.4 g) in acetonitrile (250 ml) was refluxed for 3 hours with stirring. Then the mixture was cooled down and filtrationof the precipitated powder followed by treatment with a mixture of ethanol (550 ml) and water (250 ml) gave (S)-7-(3-aminopiperidin-1-yl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (11.6 g) as colorless needles. m.p. 247.8° C. (decomposition).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([O:10][C:11]([F:14])([F:13])[F:12])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[Br:15]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:15][CH2:1][C:2]1[CH:9]=[C:8]([O:10][C:11]([F:12])([F:13])[F:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(OC(F)(F)F)ccc1C#N
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccc(OC(F)(F)F)cc1CBr
Yield: 70 %

Procedure:
To a solution of 2-methyl-4-trifluoromethoxy-benzonitrile 15 (1.3 g, 6.5 mmol) in carbon tetrachloride (25 mL) was added N-bromosuccinimide (1.7 g, 9.7 mmol) and 2,2′-azobisisobutyronitrile (cat.). The reaction mixture was refluxed 6 hrs, filtered, concentrated, and partitioned between ether and water. The ether layer was dried, concentrated, and purified by silica gel chromatography (10% ether/hexanes) to yield a clear oil (70%). 1H NMR (400 MHz,CDCl3) δ7.73 (d, J=8.4 Hz, 1 H, Ar), 7.41 (s, 1 H, Ar), 7.27 (d, J=8.4 Hz, 19 H, Ar), 4.61 (s, 2 H, CH2).
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1C(OC(C)(C)C)=O)[C@@H:4]([CH3:16])[C:5](=[O:15])[NH:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[ClH:29]>O1CCOCC1.CO>[ClH:29].[CH3:1][O:2][C@@H:3]([C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1)[C@@H:4]([CH3:16])[C:5]([NH:6][CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:15]
Reactant: CO[C@H]([C@@H](C)C(=O)NCCc1ccccc1)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CO[C@@H]([C@@H]1CCCN1)[C@@H](C)C(=O)NCCc1ccccc1
Reaction time: 18 h

Procedure:
To #20 (7.00 g, 17.9 mmol, 1 eq.) in dioxane (50 mL, 0.36 M) and methanol (2 mL) was added a 4 M solution of hydrochloric acid in dioxane (20 mL, 80 mmol, 4.4 eq.). After stirring for 18 hours, the mixture was concentrated to afford #24 (5.86 g, quantitative) as a gum, which was used without further purification; LC-MS: 292.2 [M+H+], retention time=0.47 minutes.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[C:12]=3[O:19][CH3:20])[O:10][C:3]=12.[CH3:21][C:22]1[C:30]([NH2:31])=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>>[CH3:20][O:19][C:12]1[C:13]([O:17][CH3:18])=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[O:10][C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[NH:31][C:30]2[C:22]([CH3:21])=[C:23]3[C:27](=[CH:28][CH:29]=2)[NH:26][CH:25]=[CH:24]3)[CH:8]=1
Reactant: Cc1c(N)ccc2[nH]ccc12
Reactant: COc1cccc(-c2cc3nccc(Cl)c3o2)c1OC
Product: COc1cccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4C)c3o2)c1OC

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-(2,3-dimethoxyphenyl)furo[3,2-b]pyridine (30.00 mg; 0.10 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (15.89 mg; 0.11 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (15 mg, 37%). (HPLC (method F): 99%, RT: 4.00 min); 1H NMR (500 MHz, DMSO-d6) δ [ppm] 11.16 (s, 1H), 8.59 (s, 1H), 7.97 (d, J=5.5, 1H), 7.60 (d, J=7.6, 1H), 7.43-7.36 (m, 1H), 7.36-7.27 (m, 2H), 7.20-7.11 (m, 2H), 7.00 (d, J=8.5, 1H), 6.52 (s, 1H), 6.10 (d, J=5.5, 1H), 3.88 (s, 3H), 3.87 (s, 3H), 2.36 (s, 3H); MS (m/z) 400 [M+H]+, RT: 3.3 min.
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][N:5]=[C:4]1[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1)[CH3:2].Cl>C(O)C.O.[Pt]=O>[CH2:1]([N:3]1[CH2:7][CH2:6][N:5]=[C:4]1[CH2:8][CH2:9][CH:10]1[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]1)[CH3:2]
Reactant: CCN1CCN=C1CCc1ccncc1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCN1CCN=C1CCC1CCNCC1
Reaction time: 4 h
Yield: 70.6 %

Procedure:
The solution of 4-[2-(1-ethyl-4,5-dihydro-imidazol-2-yl)ethyl]-pyridine (1.1 g, 0.0054M) in ethanol (15 ml) and water (15 ml) was added con.HCl (3 ml) and platinum oxide (0.2 g). The mixture was hydrogenated at 45 psig for 4 hrs. The catalyst was removed by filtration and the filtrate was stripped to dryness in vacuo. The residue was dissolved in methanol (25 ml) and sodium methoxide (0.011M) was added and filtered. The filtrate was stripped to dryness and distilled at about 150° to about 175° C./0.2 mm Hg to yield 4-[2-(1-ethyl-4,5-dihydro-imdazol-2-yl)ethyl]piperidine as an oil (0.8 g, 70% yield).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].Br[CH2:24][CH:25]1[CH2:27][C:26]1([F:29])[F:28].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:28][C:26]1([F:29])[CH2:27][CH:25]1[CH2:24][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: FC1(F)CC1CBr
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1N(CC2CC2(F)F)c2ccccc2C12COc1cc3c(cc12)OCCO3
Temperature: 40 °C
Yield: 72.7 %

Procedure:
A mixture of 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.29 g, 1.00 mmol), 2-(bromomethyl)-1,1-difluorocyclopropane (0.21 g, 1.20 mmol), cesium carbonate (0.65 g, 2.00 mmol) and N,N′-dimethylformamide (2.5 mL) was heated at 40° C. for 2 h and filtered while hot. The filtrate was allowed to cool to ambient temperature and water was added, causing a precipitate to be deposited. The solid was collected by filtration, washed with water and dried under vacuum. The residue was recrystallized from ethanol/diethyl ether to afford 1′-[(2,2-difluorocyclopropyl)methyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one (0.28 g, 73%) as a colourless solid: mp 162-164° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.35 (ddd, J=7.8, 7.8, 0.9 Hz, 1H), 7.23 (dd, J=7.9 Hz, 1H), 7.17 (d, J=6.9 Hz, 1H), 7.06 (dd, J=7.4, 7.4 Hz, 1H), 6.51 (d, J=1.9 Hz, 1H), 6.13 (d, J=6.2 Hz, 1H), 4.71 (dd, J=9.3 Hz, 1H), 4.69 (dd, J=9.3 Hz, 1H), 4.17 (dd, J=3.7 Hz, 2H), 4.10 (dd, J=3.4 Hz, 2H), 3.87 (d, J=6.9 Hz, 2H), 2.33-2.14 (m, 1H), 1.74-1.60 (m, 1H), 1.48-1.29 (m, 1H); 13C NMR (75 MHz, DMSO-d6) δ 176.5 (d, 4JC-F=15.9 Hz), 154.5 (d, 6JC-F=1.4 Hz), 144.1 (d, 6JC-F=1.9 Hz), 141.9, 137.7 (d, 5JC-F=3.9 Hz), 131.7 (d, 6JC-F=2.3 Hz), 128.8, 123.5, 122.9 (d, 6JC-F=1.6 Hz), 121.2 (d, 5JC-F=4.1 Hz), 114.3 (q, 1JC-F=283.4 Hz), 110.9 (d, 2JC-F=18.1 Hz), 109.1, 98.7 (d, 5JC-F=3.6 Hz), 79.2 (d, 5JC-F=3.7 Hz), 64.1, 63.5, 57.1 (d, 6JC-F=2.4 Hz), 36.6 (t, 3JC-F=5.9 Hz), 20.1 (t, 2JC-F=17.4 Hz), 14.7 (t, 2JC-F=10.7 Hz); MS (ES+) m/z 386.2 (M+1).
Reaction SMILES: S([NH:11][C@H](C(O)=O)CC1N=CNC=1)(C1C=CC(C)=CC=1)(=O)=O.N[C@H:23]([C@@H:31]([OH:36])[CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:24][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[NH2:11][CH:24]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[CH2:23][CH:31]([OH:36])[CH2:32][CH:33]([CH3:35])[CH3:34]
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]cn2)C(=O)O)cc1
Reactant: CC(C)C[C@H](O)[C@@H](N)CC1CCCCC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CC(C)CC(O)CC(N)C1CCCCC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 202.4 %

Procedure:
To a solution of Nα -t-butoxycarbonyl-Nα -methyl-Nim -tosyl-L-histidine (195 mg) and (2S,3S)-2-amino-1-cyclohexyl-3-hydroxy-5-methylhexane (82 mg) in dry methylene chloride (10 ml) which was cooled at 0° C., was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (72 mg). The mixture was stirred at 0° C. for 3 hours. After evaporation of the solvent, the residue was dissolved in ethyl acetate (20 ml) and the solution was washed with 10% citric acid solution, saturated sodium bicarbonate solution, and water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:n-hexane, 2:3, V/V, as eluent) to give (2S,3S)-2-(Nα -t-butoxycarbonyl-Nα -methyl-Nim -tosyl-L-histidyl)amino-1-cyclohexyl-3-hydroxy-5-methylhexane (166 mg) as an amorphous powder. Rf: 0.29 (ethyl acetate:n-hexane, 3:2, V/V)
Reaction SMILES: [C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16](=[O:23])[CH2:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][C:25](=[O:27])[CH3:26])[CH:6]=1)(=[O:3])[CH3:2].[C:28](OC(C)=C)(=[O:30])[CH3:29].C1(C)C=CC(S(O)(=O)=O)=CC=1>>[C:1]([O:4][C:5]1[C:22]2[C@@H:21]3[C@@H:12]([C@H:13]4[C@@:17]([CH2:19][CH2:20]3)([CH3:18])[C:16]([O:23][C:28](=[O:30])[CH3:29])=[CH:15][CH2:14]4)[CH2:11][CH2:10][C:9]=2[CH:8]=[C:7]([O:24][C:25](=[O:27])[CH3:26])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc2c(c(OC(C)=O)c1)[C@H]1CC[C@]3(C)C(=O)CC[C@H]3[C@H]1CC2
Reactant: C=C(C)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)OC1=CC[C@H]2[C@H]3CCc4cc(OC(C)=O)cc(OC(C)=O)c4[C@H]3CC[C@]12C
Temperature: 125 °C

Procedure:
A mixture of 5 g. of rac.-1,3-diacetoxy-8α-estra-1,3,5(10)-trien-17-one, 100 ml. of isopropenyl acetate, and 14.4 g. of p-toluenesulfonic acid is heated for 21 hours under a slight N2 stream to 105° C. After the mixture has been heated to 125° C., 50 ml. of isopropenyl acetate are gradually distilled off. After cooling, 10 ml. of pyridine is added, the mixture is diluted with methylene chloride, washed with saturated sodium bicarbonate solution and water, and dried over sodium sulfate. The solvent is evaporated under vacuum. After chromatography on 260 g. of SiO2, 3 g. of oily rac.-1,3,17-triacetoxy-8α-estra-1,3,5(10),16-tetraene is obtained, which is further processed as the crude product.
Reaction SMILES: [NH2:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:36][CH3:37])[CH:3]=1.[CH:38](=O)[CH3:39].C([BH3-])#N.[Na+]>>[NH2:1][C:2]1[C:34]([Cl:35])=[CH:33][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][N:21]([CH2:38][CH3:39])[CH2:22][C:23]3[CH:32]=[CH:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[CH:24]=3)[CH2:12][CH2:11]2)=[O:7])=[C:4]([O:36][CH3:37])[CH:3]=1
Reactant: CC=O
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCCNCc2ccc3ccccc3c2)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Product: CCN(CCCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)CC1)Cc1ccc2ccccc2c1

Procedure:
4-Amino-5-chloro-2-methoxy-N-((1-(5-(2-naphthylmethylamino)pentyl)-piperidin-4-yl)methyl)benzamide (1.50 g) as starting compound, acetaldehyde (0.18 ml) and sodium cyanoborohydride (0.40 g) were reacted and treated in the same manner as in Example 136 to give 1.1 g of 4-amino-5-chloro-N-((1-(5-(N-ethyl-N-(2-naphthylmethyl)amino)pentyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.