Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@@H:2]([C:5]([OH:7])=[O:6])[CH2:3][OH:4].[C:8](=[O:15])([O-])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11].C(=O)([O-])O[C:18](C)([CH3:20])[CH3:19].[CH2:24](N(CC)CC)C>C(#N)C>[CH3:19][C:18]1([CH3:20])[N:1]([C:8]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:15])[C@@H:2]([C:5]([O:7][CH3:24])=[O:6])[CH2:3][O:4]1
Reactant: N[C@H](CO)C(=O)O
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)[O-]
Solvent: CC#N
Product: COC(=O)[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C

Procedure:
Under atmosphere of argon, D-serine.methylester (284 g) and di-tert-butyl di-carbonate (400 g) were dissolved in acetonitrile (2000 mL) and the mixture was added by triethylamine (255 mL) keeping the temperature inside from 6 to 1° C. under icing down and stirred for an hour and a half at room temperature. The mixture was filtrated to defecate triethylamine chloride and then the mother water was concentrated. The obtained residue was dissolved in ethyl acetate (1500 mL), washed with water (1000 mL) and saturated brine (1000 mL) and the organic layer was dried over a sodium sulfate, filtrated and concentrated. Under atmosphere of argon, the obtained residue (380 g) was added by acetone (3000 mL) and 2,2-dimethoxypropane (1800 mL), additionally added by boron trifuloride.diethylether complex (19.3 mL) and stirred for an hour and a half at room temperature. The mixture was concentrated and the residue was dissolved in ethyl acetate (1500 mL) and washed with saturated sodium hydrogen carbonate (100 mL), water (1000 mL) and saturated brine (1000 mL). The oragnic layer was dried over a sodium sulfate, filtrated and then concentrated to give the title compound (437 g) having the following physical data, which was used for the next reaction without purification.
Reaction SMILES: C1(C)C=CC=CC=1.[NH2:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]2.[C:25](Cl)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([NH:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH:14]([CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:13][CH2:12]2)(=[O:27])[CH3:26]
Reactant: CCOC(=O)CC1CCc2cc(N)ccc2O1
Reactant: CC(=O)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)CC1CCc2cc(NC(C)=O)ccc2O1
Reaction time: 0.5 h

Procedure:
The ethyl 2-(6-aminochroman-2-yl)acetate toluene solution of Example 4 (6 L) was cooled to −5° C. in a sodium chloride-ice bath, and 293 g of anhydrous pyridine added in a single portion. To the well-stirred mixture was added dropwise 246 g of acetyl chloride, maintaining the temperature between −5° C. and 5° C. The reaction was not complete by TLC after 30 min, so an additional 50 g of anhydrous pyridine and 50 g of acetyl chloride were added dropwise, and the reaction stirred for 30 min. The reaction was quenched with 4 L of water, stirred for 15 minutes, and the organic fraction was separated. The aqueous fraction was extracted with 2×500 mL of toluene, and the combined toluene fractions washed with 2 L of water. Complete removal of toluene afforded ethyl 2-(6-acetamidochroman-2-yl)acetate as a dark brown residue, which was transferred into a 12-L flask.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][CH:8]=[CH:7][C:6]=2[C:5]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:27]=[O:28])C.COC1C=CC(C2C3C=C(C=O)SC=3C=CC=2)=CC=1>C1COCC1>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:5]2[C:6]3[CH:7]=[CH:8][S:9][C:10]=3[C:2]([CH:27]=[O:28])=[CH:3][CH:4]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(-c2ccc(Br)c3sccc23)cc1
Reactant: CN(C)C=O
Agent: COc1ccc(-c2cccc3sc(C=O)cc23)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc(C=O)c3sccc23)cc1
Reaction time: 0.25 h

Procedure:
To a 25 ml round bottom flask was added 7-bromo-4-(4-methoxyphenyl)-1-benzothiophene (300 mg, 0.94 mmol) to anhydrous THF (10 ml) and the solution was cooled to −78° C. n-BuLi (0.38 ml of 2.5 M in hexanes, 0.94 mmol) was added dropwise and the solution was stirred for 10 min after which anhydrous DMF (0.15 ml, 1.9 mmol) was added all at once at −78° C. The reaction was stirred for 15 min then quenched with water (10 ml) and extracted with ether. The organic layers were combined, dried over anhydrous Na2SO4, and concentrated to 180 mg (71.4%) of aldehyde products as a yellow oil. Reverse phase HPLC (CH3CN 0.1% TFA, water 0.1% TFA) produced 160 mg of a 8:3 mixture of desired product and 4-(4-methoxyphenyl)-1-benzothiophene-2-carbaldehyde as a single peak. Another side product (7-bromo-4-(4-methoxyphenyl)-1-benzothiophene-2-carbaldehyde, 20 mg) was collected: 1H NMR (8:3 ratio of desired+7-bromo-4-(4-methoxyphenyl)-1-benzothiophene-2-carbaldehyde) (300 MHz, DMSO-d6): δ 3.86 (3H, s, desired+minor), 7.14 (2H, d, J=8.9 Hz, minor), 7.14 (2H, d, J=8.6 Hz, desired), 7.47 (1H, d, J=7.3 Hz, minor), 7.54–7.67 (4H, m, desired+minor), 7.99 (1H, d, J=5.6 Hz, desired), 8.09 (1H, d, J=8.1 Hz, minor), 8.19 (1H, d, J=7.5 Hz), 8.41 (1H, s, minor), 10.14 (1H, s, minor), 10.27 (1H, s, desired). Anal. for C16H12O2S:
Reaction SMILES: Br[C:2]1[C:3]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:4]([CH3:16])[C:5]([C:14]#[N:15])=[C:6]2[C:10]=1[O:9][C:8]([CH:11]1[CH2:13][CH2:12]1)=[N:7]2.[C:23]([O:27][C:28]([NH:30][CH:31]1[CH2:35][CH2:34][C:33]([Sn](CCCC)(CCCC)CCCC)=[CH:32]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)(C)(C)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.O1CCOCC1>[C:14]([C:5]1[C:6]2[N:7]=[C:8]([CH:11]3[CH2:12][CH2:13]3)[O:9][C:10]=2[C:2]([C:33]2[CH2:34][CH2:35][CH:31]([NH:30][C:28](=[O:29])[O:27][C:23]([CH3:25])([CH3:24])[CH3:26])[CH:32]=2)=[C:3]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:4]=1[CH3:16])#[N:15]
Reactant: CCCC[Sn](CCCC)(CCCC)C1=CC(NC(=O)OC(C)(C)C)CC1
Reactant: Cc1c(-c2ccccc2)c(Br)c2oc(C3CC3)nc2c1C#N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: C1COCCO1
Product: Cc1c(-c2ccccc2)c(C2=CC(NC(=O)OC(C)(C)C)CC2)c2oc(C3CC3)nc2c1C#N
Yield: 75.8 %

Procedure:
A 1,4-dioxane (6 ml) solution of 7-bromo-2-cyclopropyl-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-46) (89 mg, 0.252 mmol), 1-(N-tert-butoxycarbonylamino)-3-tri-n-butylstannyl-2-cyclopentene (143 mg, 0.302 mmol), bis(triphenylphosphine)palladium(II) chloride (8.8 mg, 0.0126 mmol), 2,6-di-tert-butyl-p-cresol (5.6 mg, 0.0252 mmol) was refluxed overnight. After cooling, the reaction liquid was concentrated under reduced pressure, the residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1→8:1→5:1) to obtain the entitled compound (87 mg, 75%) as a pale brown solid.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)COC4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1.BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C=CC(CP(=O)(O)OCC)=C([Cl:95])C=3OC)N=2)=CC=1.CC1(C)C(C)(C)OB(C2C=NN(CCCO)C=2)O1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][CH2:35][CH2:39][N:40]4[CH:44]=[C:43]([B:45]5[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]5)[CH:42]=[N:41]4)[O:30][CH2:31][CH3:32])=[C:26]([Cl:95])[C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1
Reactant: CCOP(=O)(O)Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1Cl
Agent: CC1(C)OB(c2cnn(CCCO)c2)OC1(C)C
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1Cl)OCCCn1cc(B2OC(C)(C)C(C)(C)O2)cn1

Procedure:
Prepared analogously to Compound 44A using ethyl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-chloro-3-methoxybenzyl)phosphonate (Compound 54B, 200 mg, 0.306 mmol) and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]propan-1-ol (Compound 3E, 81 mg, 0.321 mmol) to afford 203 mg of the title compound as a racemic mixture (75%). MS (ESI): m/z=887.65/889.64 [M+H]+. UPLC: tR=1.68 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][C:22]=1[F:23])[C:5]([N:7]1[CH:16](C(O)=O)[CH2:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8]1)=O.[C:24]([C:30]([O:32][CH3:33])=[O:31])#[C:25][C:26]([O:28][CH3:29])=[O:27]>C(OC(=O)C)(=O)C>[CH3:29][O:28][C:26]([C:25]1[C:24]([C:30]([O:32][CH3:33])=[O:31])=[C:5]([C:4]2[CH:20]=[CH:21][C:22]([F:23])=[C:2]([F:1])[CH:3]=2)[N:7]2[C:16]=1[CH2:15][C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:8]2)=[O:27]
Reactant: O=C(O)C1Cc2ccccc2CN1C(=O)c1ccc(F)c(F)c1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CC(=O)OC(C)=O
Product: COC(=O)c1c(C(=O)OC)c(-c2ccc(F)c(F)c2)n2c1Cc1ccccc1C2
Temperature: 65 °C
Yield: 78.9 %

Procedure:
A mixture of 2-(3,4-difluorobenzoyl)-1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid (11.10 g, 35 mmol) and dimethyl acetylenedicarboxylate (7.39 g, 52 mmol) in acetic anhydride (70 mL) was heated at 60-70° C. for 15 min. The reaction mixture was then cooled and evaporated in vacuo to dryness. The solid residue was recrystallized from ethanol to give 3-(3,4-difluorophenyl)-5,10-dihydropyrrolo[1,2-b]isoquinoline-1,2-dicarboxylic acid dimethyl ester 10.97 g, (78.6%); mp 142-144° C.; 1H NMR (DMSO-d6) δ 3.61 (3H, s, Me), 3.77 (3H, s, Me), 4.31 (2H, s, CH2), 5.00 (2H, s, CH2), 7.21-7.27 (1H, m, ArH), 7.29-7.35 (3H, m, 3×ArH), 7.37-7.43 (1H, m, ArH), 7.50-7.65 (2H, m, 2×ArH); m/z 397.00 (M+H)+ Anal. Calcld. for C22H17F2NO4: C, 66.50; H, 4.31; N, 3.52. Found: C, 66.65; H, 4.51; N, 3.47.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[OH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1.Cl[C:16]1[CH:21]=[CH:20][C:19]([CH:22]=[O:23])=[CH:18][N:17]=1>O>[N:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][C:16]2[N:17]=[CH:18][C:19]([CH:22]=[O:23])=[CH:20][CH:21]=2)[CH:10]=1
Reactant: Oc1cccnc1
Reactant: O=Cc1ccc(Cl)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(Oc2cccnc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 35.7 %

Procedure:
To a suspension of sodium hydride (407 mg, 8.48 mmol, 50% in oil) and N,N-dimethylformamide (45 mL) was added an N,N-dimethylformamide (5 mL) solution of 3-hydroxypyridine (806 mg, 8.48 mmol) at 0° C., which was stirred for 30 minutes. An N,N-dimethylformamide (5 mL) solution of 2-chloro-5-formylpyridine (1.0 g, 7.06 mmol) was added to this reaction mixture at the same temperature, which was stirred for 5 hours at 100° C. The reaction mixture was cooled to room temperature, and water was added thereto, which was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH silica gel column chromatography (ethyl acetate) to obtain the title compound (505.1 mg, 36%).
Reaction SMILES: [O:1]1[CH:11]2[CH:2]1[CH2:3][C:4]1[C:9]([CH2:10]2)=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:12]1([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(C)C.C(OC(C)C)(C)C>C1(C)C(C)=CC=CC=1>[C:12]1([N:18]2[CH2:23][CH2:22][N:21]([C@@H:2]3[CH2:3][C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[CH2:10][C@H:11]3[OH:1])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: c1ccc2c(c1)CC1OC1C2
Solvent: CC(C)O
Solvent: CC(C)OC(C)C
Solvent: Cc1ccccc1C
Product: O[C@@H]1Cc2ccccc2C[C@H]1N1CCN(c2ccccc2)CC1
Yield: 64.3 %

Procedure:
A solution of 7.30 g of 2,3-epoxy-1,2,3,4-tetrahydronaphthalene, 8.91 g of N-phenylpiperazine, and 19 ml of isopropanol in 50 ml of xylene is refluxed for five days. The xylene is removed in vacuo leaving a solid residue, which yields 9.9 g of crude material on trituration with isopropyl ether. Two recrystallizations from ethyl acetate yield 6.5 g of the title compound, melting point 152°-154° C.
Reaction SMILES: [C-:1]#[N:2].[Na+].S(=O)(=O)(O)O.C#N.[C:11]([C:14]1[CH:15]=[C:16]([Cl:31])[C:17]([CH2:29]Br)=[C:18]([C:27]#[N:28])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)(=[O:13])[CH3:12]>O.C(#N)C>[C:11]([C:14]1[CH:15]=[C:16]([Cl:31])[C:17]([CH2:29][C:1]#[N:2])=[C:18]([C:27]#[N:28])[C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)(=[O:13])[CH3:12]
Reactant: CC(=O)c1cc(Cl)c(CBr)c(C#N)c1-c1cccc(F)c1
Reactant: [C-]#N
Agent: C#N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: CC(=O)c1cc(Cl)c(CC#N)c(C#N)c1-c1cccc(F)c1

Procedure:
To a mixture of sodium cyanide (100 mg, 2.0 mmol) in water (0.5 mL) was added sulfuric acid (0.95 g, 0.97 mmol) at 0° C. (the reaction generates hydrogen cyanide and must be run in a fume hood with good ventilation), followed by a solution of 6-acetyl-3-(bromomethyl)-4-chloro-3′-fluorobiphenyl-2-carbonitrile (70 mg, 0.2 mmol) in acetonitrile (2 mL). The reaction was heated at 80° C. for 1 hour with pH adjustment to 9 by addition of solid sodium cyanide. The reaction mixture was cooled and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated to dryness under reduced pressure. The residue was purified on silica gel, eluting with 0 to 40% ethyl acetate in hexane. LCMS calculated for C17H11ClFN2O (M+H)+: m/z=313.1. found: 313.1.
Reaction SMILES: N[C@H:2]([CH2:6][C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)[C:3]([OH:5])=[O:4].C(OC(N[C@H]([CH2:24][C:25]1[CH:29]=CO[CH:26]=1)C(O)=O)=O)(C)(C)C.CN1CC[O:34][CH2:33]C1.C(OC(Cl)=O)C(C)C>C(COC)OC>[O:9]1[CH:10]=[CH:11][C:7]([CH2:6][C@@H:2]([C:3]([O:5][C:25]([CH3:29])([CH3:26])[CH3:24])=[O:4])[CH2:33][OH:34])=[CH:8]1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccoc1)C(=O)O
Reactant: N[C@H](Cc1ccoc1)C(=O)O
Reactant: CN1CCOCC1
Agent: CC(C)COC(=O)Cl
Solvent: COCCOC
Product: CC(C)(C)OC(=O)[C@@H](CO)Cc1ccoc1
Temperature: -30 °C
Reaction time: 1 h

Procedure:
Starting from (R)-2-amino-3-furan-3-yl-propionic acid (DE3829451), (R)-2-tert-butoxycarbonylamino-3-furan-3-yl-propionic acid is prepared. Under argon 420 mg (R)-2-tert-butoxycarbonylamino-3-furan-3-yl-propionic acid are suspended in 2.5 ml dimethoxyethane suspended. The reaction mixture is cooled to −30° C. 220 μl N-methylmorpholine are added and then 240 μl isobutylchloroformate in 1.5 ml dimethoxyethane is added dropwise. The reaction mixture is allowed to come up to −5° C. and the precipitate is quickly filtered. The filtrate is cooled to −15° C. 100 mg sodium borohydride and a few drops of water are added. The reaction mixture is stirred for 1 hour at ambient temperature and evaporated to dryness. The residue is suspended in ethyl acetate. The reaction mixture is dried and evaporated to dryness. 370 mg of the product are obtained as a solid. Analytical HPLC-MS (method D): RT=1.21 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[C:9]([CH:10]=1)=[N:8][NH:7][C:6]=2[CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH2:19])[CH2:13][CH2:12]1.[F:20][C:21]1[CH:22]=[C:23]2[C:28](=O)[O:27][C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1.C(Cl)Cl.CO>CN(C=O)C>[F:20][C:21]1[CH:22]=[C:23]2[C:28](=[O:27])[N:19]([CH2:18][CH2:17][N:14]3[CH2:13][CH2:12][CH:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[CH2:16][CH2:15]3)[C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1
Reactant: NCCN1CCC(c2[nH]nc3cc(F)ccc23)CC1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: O=C1c2ccc(F)cc2C(=O)N1CCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 37.8 %

Procedure:
To a solution consisting of 2-[4-(6-fluoro-2H-indazol-3-yl)-1-piperidinyl]ethylamine (6.1 g, 23.2 mmol) in DMF (230 ml) was added 4-fluorophthalic anhydride (4.2 g, 25.5 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to 80 C. for 2.5 hours at which time it was allowed to cool to room temperature. The DMF was removed under reduced pressure (<0.5 mmHg, 55 C.) to give a brown oil which was dissolved into DCM/MeOH. Purification via flash column chromatography (silica gel, 2% MeOH/DCM) afforded 3.6 g of 4-fluoro-N-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]phthalimide. To a solution of the latter compound (3.6 g 8.8 mmol) in anhydrous THF (100 ml) was added LAH (18.4 ml of a 1.0M solution in THF, 18.4 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to reflux for 4 hours. Upon cooling to room temperature, the reaction was quenched with water (1.5 ml, dropwise). The precipitated salts were removed via filtration and washed with DCM. The combined filtrates were concentrated to give a solid which was purified via flash column chromatography (silica gel, 0-8% MeOH/DCM). The product containing fractions were concentrated to give 2.4 g product as an off-white solid. The dimaleate salt was prepared in methanol using 2.4 eq. of maleic acid. The white precipitate was collected via filtration and washed with methanol, m.p. 186°-188° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:39]=[CH:38][C:18]([C:19]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([O:30][C:31]3[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=3)=[O:29])=[CH:24][CH:23]=2)=[O:20])=[CH:17][CH:16]=1.[CH2:40]([O:52][C:53]1[CH:70]=[CH:69][C:56]([C:57]([O:59][C:60]2[CH:68]=[CH:67][C:63]([C:64](O)=[O:65])=[CH:62][CH:61]=2)=[O:58])=[CH:55][CH:54]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.CC(=O)OCC>[CH2:40]([O:52][C:53]1[CH:54]=[CH:55][C:56]([C:57]([O:59][C:60]2[CH:68]=[CH:67][C:63]([C:64]([O:37][C:33]3[CH:34]=[CH:35][CH:36]=[C:31]([O:30][C:28](=[O:29])[C:25]4[CH:24]=[CH:23][C:22]([O:21][C:19](=[O:20])[C:18]5[CH:38]=[CH:39][C:15]([O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[CH:16][CH:17]=5)=[CH:27][CH:26]=4)[CH:32]=3)=[O:65])=[CH:62][CH:61]=2)=[O:58])=[CH:69][CH:70]=1)[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51]
Reactant: O=C(Oc1ccc(C(=O)Oc2cccc(O)c2)cc1)c1ccc(OCCCCCCCCCCCCBr)cc1
Reactant: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCOc1ccc(C(=O)Oc2ccc(C(=O)Oc3cccc(OC(=O)c4ccc(OC(=O)c5ccc(OCCCCCCCCCCCCBr)cc5)cc4)c3)cc2)cc1

Procedure:
Synthesized as described for the preparation of compound BC1. Quantities: 25 (0.15 g, 0.25 mmol), 17 (0.11 g, 0.25 mmol), DMAP (0.03 g, 0.25 mmol), DCC (0.10 g, 0.5 mmol). Yield 0.18 g (72%). EA: Found: C, 69.39; H, 7.13. C58H69BrO10 requires C, 69.24; H, 6.91%. 1H NMR: δH (CDCl3; 300 MHz): 0.91 (3 H, t, 3J=6.8 Hz, CH3), 1.19-1.56 (34 H, m, CH2), 1.85 (6 H, m, O—CH2—CH2/Br—CH2—CH2), 3.43 (2 H, t, 3J=6.8 Hz, CH2Br), 4.08 (4 H, t, 3J=6.5 Hz, OCH2), 7.01 (2 H, d, 3J=8.8 Hz, Ar—H), 7.21 (3 H, m, Ar—H), 7.40 (4 H, d, 3J=8.6 Hz, Ar—H), 7.52 (1 H, t, 3J=8.1 Hz, Ar—H), 8.18 (4 H, d, 3J=8.8 Hz, Ar—H), 8.30 (4 H, d, 3J=8.6 Hz, Ar—H). 13C NMR: δC (CDCl3; 75 MHz): 14.5, 23.1, 26.4, 28.6, 29.2, 29.5, 29.75, 29.8, 29.85, 29.9, 29.95, 30.0, 32.3, 33.2, 34.4, 68.8, 114.7, 114.8, 116.2, 119.7, 121.4, 122.5, 127.0, 130.2, 132.2, 132.25, 132.3, 132.8, 151.8, 151.85, 155.9, 164.2, 164.5, 164.7. m/z (MALDI) 1028.00 (100%) and 1030.03 (97%) [M+Na]+, C58H69BrNaO10 requires 1027.40 (100%) and 1029.40 (97%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[H-].[Na+].[Cl:25][C:26]1[N:31]=[C:30](Cl)[CH:29]=[CH:28][N:27]=1>CN(C)C=O>[Cl:25][C:26]1[N:31]=[C:30]([O:18][CH2:17][C:14]2[CH:15]=[CH:16][C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:19]([F:20])([F:21])[F:22])[CH:4]=3)=[C:10]([CH:13]=2)[C:11]#[N:12])[CH:29]=[CH:28][N:27]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: N#Cc1cc(CO)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(COc2ccnc(Cl)n2)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68.8 %

Procedure:
To a solution of 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-(hydroxymethyl)benzonitrile (2.50 g, 7.63 mmol) in N,N-dimethylformamide (20 mL) was added sodium hydride (1.22 g, 30.5 mmol) at 0° C., then 2,4-dichloropyrimidine (1.25 g, 8.39 mmol) was added at 0° C. after 10 min. The reaction mixture was stirred for 30 min, and poured into ice-water (100 mL), extracted with ethyl acetate (50 mL) twice. Combined organic parts were washed with water and brine, dried over sodium sulfate, filtered and concentrated. Purification via ISCO system afforded the title product (2.31 g). LC-MS (ESI): m/z 440 [M+H]+; 3.95 min (ret time).
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([CH3:17])[CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]4=[CH:7][C:6]=3[CH:5]=[C:4]([CH3:17])[CH:3]=2)=[CH:22][CH:21]=1
Reactant: Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Reactant: COc1ccc(B(O)O)cc1
Product: COc1ccc(-c2cc(C)cc3cc4n(c23)CCCNC4=O)cc1

Procedure:
The title compound, off-white solid (33 mg, 60%), MS (ISP) m/z=321.5 [(M+H)+], mp 208° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-methyl-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 11) (50 mg, 0.17 mmol) and commercially available 4-methoxy-phenylboronic acid (33.7 mg, 0.22 mmol).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1.[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH:11]1[CH:16]=O.C([O:20][C:21](=O)[C:22](=[O:33])[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)C>C(O)C>[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH:11]1[CH:16]1[N:9]([CH2:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[C:21](=[O:20])[C:22]([OH:33])=[C:23]1[C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1
Reactant: CCOC(=O)C(=O)Cc1c[nH]c2ccccc12
Reactant: NCCCn1ccnc1
Reactant: O=CC1CCC=CO1
Solvent: CCO
Product: O=C1C(O)=C(c2c[nH]c3ccccc23)C(C2CCC=CO2)N1CCCn1ccnc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
3-Imidazol-1-yl-propylamine (1 mmol) and 3,4-Dihydro-2H-pyran-2-carbaldehyde (1 mmol) were added to ethanol (5 ml). After 30 min 3-(1H-Indol-3-yl)-2-oxo-propionic acid ethyl ester (1 mmol) was added. The reaction was heated to 50° C. and stirred for 24 h. After evaporation of the solvent the residue was purified with chromatographic methods.
Reaction SMILES: C(O[C:4]1[CH:16]=[C:15]2[C:7]([C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[NH:14]2)=[CH:6][C:5]=1[C:17]([OH:19])=[O:18])C.C1(Cl)C(=O)C(Cl)=C(Cl)[C:22](=[O:23])[C:21]=1Cl.[C:32]1(C)C=CC=C[CH:33]=1>>[CH2:32]([N:14]1[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[C:7]2[C:15]1=[CH:16][CH:4]=[C:5]([C:17]([OH:19])=[O:18])[C:6]=2[O:23][CH2:22][CH3:21])[CH3:33]
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Reactant: CCOc1cc2[nH]c3c(c2cc1C(=O)O)CCCC3
Reactant: Cc1ccccc1
Product: CCOc1c(C(=O)O)ccc2c1c1ccccc1n2CC

Procedure:
The 7-ethoxytetrahydrocarbazole-6-carboxylic acid obtained in Example 37 was dissolved in 8 mL of toluene, and the solution was added with 2.14 g of chloranil and refluxed for 2 hours and 30 minutes. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (ethyl acetate) to obtain 336 mg of 9-ethyl-5-ethoxycarbazole-6-carboxylic acid. Compound 1-38 was obtained in the same manner as in Example 36 except that the 9-ethyl-5-ethoxycarbazole-6-carboxylic acid obtained was used.