Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([C@H:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][C@H:10]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]=[CH:5][N:4]=1.[O-]CC.[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([C@@H:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11][C@H:10]2[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1ccnc(OC)c1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1c1ccnc(OC)c1
Temperature: 55 °C

Procedure:
To an ethanol solution (0.1 M) of cis-1-(1,1-dimethylethyl) 3-ethyl 4-[2-(methyloxy)-4-pyridinyl]-1,3-piperidinedicarboxylate (1 eq.) from the previous step was added freshly prepared sodium ethoxide (1.1 eq.). The resulting yellow-orange solution was heated at 55° C. for 12 h. The volatiles were then removed in vacuo and the residue was partitioned between diethyl ether and sat. aq. NH4Cl. The aqueous layer was separated and back-extracted with ether. The combined organic extracts were washed further with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of column chromatography (SiO2, 90:10 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a colorless oil.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][C@@H:8]([P:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][C@H:6]1[CH2:23][O:24][Si](C(C)(C)C)(C)C)(=[O:4])=[O:3].[OH:32]O.Cl.O>CO>[CH3:1][S:2]([N:5]1[CH2:9][C@@H:8]([P:10]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:32])[CH2:7][C@H:6]1[CH2:23][OH:24])(=[O:4])=[O:3]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@H](P(c2ccccc2)c2ccccc2)CN1S(C)(=O)=O
Reactant: OO
Agent: Cl
Solvent: O
Solvent: CO
Product: CS(=O)(=O)N1C[C@@H](P(=O)(c2ccccc2)c2ccccc2)C[C@H]1CO
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In 180 ml of methanol was dissolved 8.39 g (0.0176 mol) of 2S,4S)-N-methanesulfonyl-2 -tert-butyldimethlysilyloxymethyl-4-di-phosphinopyrrolidine [VI], and 11.85 g (0.0348 mol) of 10% hydrogen peroxide was added dropwise to the solution under ice-cooling. The mixture was stirred at 0° C. for one hour and then at room temperature for one hour. To the mixture was then slowly added dropwise a liquid mixture of 8.6 g of 35% hydrochloric acid, 52.7 g of water and 38.7 g of methanol, and the mixture was stirred for 2 hours at room temperature. Any insoluble matter was removed from the mixture by filtration and the filtrate was concentrated under reduced pressure. The concentrate was dissolved in 50 ml of water and the aqueous solution was extracted three times with 100 ml of methylene chloride in each case. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried over magnesium sulfate and concentrated under reduced pressure whereby white crystals were obtained which were then recrystallized from a mixture of ethanol and isopropyl alcohol. Yield 5.3 g (80%), melting point: 138°-139° C.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([CH2:7][C:8]2[CH:24]=[CH:23][C:11]3[N:12]=[C:13]([NH:15][C@@H:16]4[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]4[OH:22])[S:14][C:10]=3[CH:9]=2)[CH:6]=1.[CH3:25][N:26]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[N:27]1.C([O-])([O-])=O.[K+].[K+]>COCCOC.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:25][N:26]1[CH:30]=[C:29]([C:2]2[N:3]=[CH:4][N:5]([CH2:7][C:8]3[CH:24]=[CH:23][C:11]4[N:12]=[C:13]([NH:15][C@@H:16]5[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]5[OH:22])[S:14][C:10]=4[CH:9]=3)[CH:6]=2)[CH:28]=[N:27]1
Reactant: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc(Br)c3)cc2s1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Cn1cc(-c2cn(Cc3ccc4nc(N[C@@H]5CCCC[C@H]5O)sc4c3)cn2)cn1
Temperature: 100 °C
Yield: 21 %

Procedure:
To a suspension of (1R,2R)-2-((6-((4-bromo-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (50 mg, 0.12 mmol) from Step 7 of this Example and 1-methylpyrazole-4-boronic acid pinacol ester (51 mg, 0.25 mmol) in a mixture of DME (0.7 mL) and H2O (0.3 mL) was added K2CO3 (68 mg, 0.5 mmol). Argon was bubbled into the mixture for 5 min. To the mixture was added tetrakis(triphenylphosphine)palladium (0) (14 mg, 0.01 mmol). Argon was bubbled into the mixture for 5 min. The reaction vessel was sealed and the mixture was heated at 100° C. for 16 h. Additional portions of 1-methylpyrazole-4-boronic acid pinacol ester (51 mg, 0.25 mmol) and tetrakis(triphenylphosphine)palladium (0) (14 mg, 0.01 mmol) were added to the mixture and argon was bubbled into the mixture for 5 min. The reaction vessel was sealed and the mixture was heated at 110° C. for 4 h. The mixture was cooled to rt and partitioned between EtOAc (100 mL) and aq 1 N K2CO3 (50 mL). The EtOAc layer was separated and washed with water (50 mL) and brine (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C18 column as the stationary phase to afford (1R,2R)-2-((6-((4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (10.3 mg, 20%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 7.97 (d, J=7.5 Hz, 1H), 7.80 (s, 1H), 7.71 (s, 1H), 7.54-7.62 (m, 2H), 7.32 (d, J=8.3 Hz, 1H), 7.24 (s, 1H), 7.16 (dd, J=1.3, 8.3 Hz, 1H), 5.13 (s, 2H), 4.75 (brm, 1H), 3.80 (s, 3H), 3.52 (br s, 1H), 3.34 (br s, 1H), 2.04 (d, J=10.2 Hz, 1H), 1.88 (d, J=9.4 Hz, 1H), 1.55-1.66 (m, 2H), 1.10-1.33 (m, 4H). LCMS (ESI) m/z 409 (M+H)+.
Reaction SMILES: I[C:2]1[C:6]([CH2:7][N:8](C)[CH2:9][CH2:10][NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:5][N:4]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[N:3]=1.[C:26]([O:30][C:31]([N:33]1[C:41]2[C:36](=[CH:37][C:38](B(O)O)=[CH:39][CH:40]=2)[CH:35]=[N:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(Cl)Cl.CC#N>COCCOC.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]>[C:14]([O:13][C:12]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:6]1[C:2]([C:38]2[CH:37]=[C:36]3[C:41](=[CH:40][CH:39]=2)[N:33]([C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[N:34]=[CH:35]3)=[N:3][N:4]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][O:21]2)[CH:5]=1)=[O:18])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)n1ncc2cc(B(O)O)ccc21
Reactant: CN(CCNC(=O)OC(C)(C)C)Cc1cn(C2CCCCO2)nc1I
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)NCCNCc1cn(C2CCCCO2)nc1-c1ccc2c(cnn2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 21.5 %

Procedure:
A mixture of (R/S) tert-butyl N-[2-([[3-iodo-1-(oxan-2-yl)-1H-pyrazol-4-yl]methyl](methyl)amino)ethyl]carbamate (200 mg, 0.43 mmol, 1.00 equiv), K3PO4.3H2O (439 mg, 1.65 mmol, 3.83 equiv), 1-(tert-butoxycarbonyl)-1H-indazol-5-ylboronic acid (300 mg, 1.14 mmol, 2.66 equiv) and Pd(dppf)Cl2.CH2Cl2 (135 mg) in ethylene glycol dimethyl ether (20 mL) and water (1 mL) was stirred under nitrogen at 85° C. for 3 h. The resulting mixture was cooled to room temperature and concentrated under vacuum. The residue was dissolved in 5 mL of methanol and 5 mL of DMSO and then purified by Prep-HPLC with the following conditions (1#-Pre-HPLC-005 (Waters)): Column, XBridge Shield RP18 OBD Column, 5 μm, 19×150 mm; mobile phase, water with 10 mmol NH4HCO3 and CH3CN (18% CH3CN up to 58% in 10 min, up to 95% in 1 min, down to 18% in 2 min); Detector, UV 254/220 nm to give 50 mg (21%) of (R/S) tert-butyl 5-(4-(((2-(tert-butoxycarbonylamino)ethyl)amino)methyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-3-yl)-1H-indazole-1-carboxylate as a colorless oil. LCMS (method A, ESI): RT=1.34 min, m/z=555.1 [M+H].
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[N:8]1([C@H:14]2[CH2:31][C@@:30]3([CH3:32])[C@@H:17]([CH2:18][CH2:19][C@@H:20]4[C@@H:29]3[CH2:28][CH2:27][C@@:25]3([CH3:26])[C@H:21]4[CH2:22][C@H:23]([N:34]4[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]4)[C@@H:24]3[OH:33])[CH2:16][CH2:15]2)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.C(=O)([O-])[O-].[Na+].[Na+]>N1C=CC=CC=1>[C:1]([O:33][C@H:24]1[C@@H:23]([N:34]2[CH2:35][CH2:36][CH2:37][CH2:38][CH2:39]2)[CH2:22][C@H:21]2[C@H:20]3[C@H:29]([CH2:28][CH2:27][C@:25]12[CH3:26])[C@:30]1([CH3:32])[C@H:17]([CH2:16][CH2:15][C@@H:14]([N:8]2[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:31]1)[CH2:18][CH2:19]3)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12C[C@H](N3CCCCC3)CC[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCCCC3)C[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)O[C@H]1[C@@H](N2CCCCC2)C[C@H]2[C@@H]3CC[C@H]4CC[C@@H](N5CCCCC5)C[C@]4(C)[C@H]3CC[C@@]21C
Reaction time: 19 h

Procedure:
Acetic anhydride (1.21 ml) was added to a solution of 2β,16β-di-(1-piperidinyl)-5α-androstan-17β-ol (3.77 g) in dry pyridine (75 ml) at 0°-5° C. and the solution was set aside at room temperature for 19 h. Saturated sodium carbonate solution (40 ml) was added to precipitate the product, which was filtered off and washed well with water (200 ml). A solution of the crude product in diethyl ether (50 ml) was washed with water (2×100 ml), dried (MgSO4) and concentrated to afford 2β,16β-di-(1-piperidinyl)-5α-androstan-17β-ol acetate (3.91 g), m.p. 156°-161° C.; [α]D +28.7° (c 0.47 in CHCl3).
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.[CH3:16][O:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22](B3OC(C)(C)C(C)(C)O3)=[CH:23][N:24]2[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:20][CH:19]=1>O1CCOCC1.C([O-])(O)=O.[Na+].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]>[N:3]1[C:4]2[N:5]3[CH2:15][CH2:14][O:13][CH2:12][CH:6]3[CH2:7][NH:8][C:9]=2[CH:10]=[N:11][C:2]=1[C:22]1[C:21]2[C:25](=[CH:26][C:18]([O:17][CH3:16])=[CH:19][CH:20]=2)[N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH:23]=1
Reactant: COc1ccc2c(B3OC(C)(C)C(C)(C)O3)cn(C(=O)OC(C)(C)C)c2c1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Solvent: C1COCCO1
Product: COc1ccc2c(-c3ncc4c(n3)N3CCOCC3CN4)cn(C(=O)OC(C)(C)C)c2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 1 using 2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 50 mg, 0.221 mmol), tert-butyl 6-methoxy-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole-1-carboxylate (124 mg, 0.331 mmol) and PdCl2(dppf) (12.91 mg, 0.018 mmol) in dioxane (1.9 mL) and aqueous saturated NaHCO3 (0.4 mL).
Reaction SMILES: Br[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][C:10]([C:15]([OH:18])([CH3:17])[CH3:16])=[CH:11][CH:12]=3)[NH:7][C:6]=2[C:5]([C:19]([NH2:21])=[O:20])=[CH:4][C:3]=1[Cl:22].[Cl:23][C:24]1[C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][CH:27]=[CH:26][C:25]=1[N:39]1[C:48](=[O:49])[C:47]2[C:42](=[C:43]([F:50])[CH:44]=[CH:45][CH:46]=2)[NH:41][C:40]1=[O:51].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2].C1COCC1>[Cl:22][C:3]1[CH:4]=[C:5]([C:19]([NH2:21])=[O:20])[C:6]2[NH:7][C:8]3[C:13]([C:14]=2[C:2]=1[C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([N:39]2[C:48](=[O:49])[C:47]4[C:42](=[C:43]([F:50])[CH:44]=[CH:45][CH:46]=4)[NH:41][C:40]2=[O:51])[C:24]=1[Cl:23])=[CH:12][CH:11]=[C:10]([C:15]([OH:18])([CH3:17])[CH3:16])[CH:9]=3
Reactant: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(Br)c12
Reactant: CC1(C)OB(c2cccc(-n3c(=O)[nH]c4c(F)cccc4c3=O)c2Cl)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(Cl)c(-c3cccc(-n4c(=O)[nH]c5c(F)cccc5c4=O)c3Cl)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.9 %

Procedure:
A mixture of 4-bromo-3-chloro-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide [Intermediate 3] (103 mg, 0.269 mmol), 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-8-fluoroquinazoline-2,4(1H,3H)-dione [Intermediate 42] (140 mg, 0.336 mmol), THF (5 mL), 2 M aqueous K3PO4 (0.504 mL, 1.01 mmol) was bubbled with nitrogen for 15 min. The mixture was treated with 1,1′-bis(di-tert-butylphosphino)ferrocene palladium(II) chloride (17.5 mg, 0.027 mmol) and was stirred at room temperature overnight. The mixture was concentrated, and the residue was partitioned between EtOAc and water. The organic phase was dried and concentrated. The residue was purified by preparative HPLC. The appropriate fractions were treated with saturated aqueous NaHCO3 and concentrated. The aqueous residue was extracted with EtOAc. The organic phase was washed sequentially with water and brine, and dried and concentrated to give 3-chloro-4-(2-chloro-3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide (mixture of four atropisomers) (30 mg, 15% yield). This material was separated by chiral super-critical fluid chromatography as follows: column: CHIRALCEL® OJ-H (3×25 cm, 5 nm); Mobile Phase: CO2-MeOH-MeCN (65:17.5:17.5) at 85 mL/min; sample preparation: 6.8 mg/mL in MeOH—CHCl3 (1:1); injection: 3.0 mL. The first peak eluting from the column provided a single atropisomer of 3-chloro-4-(R)-(2-chloro-3-(8-fluoro-2,4-dioxo-1,2-dihydroquinazolin-3(4H)-yl)phenyl)-7-(2-hydroxypropan-2-yl)-9H-carbazole-1-carboxamide. Mass spectrum m/z 573 (M+H—H2O)+. 1H NMR (500 MHz, DMSO-d6) δ 11.63-11.48 (m, 1H), 8.39-8.25 (m, 1H), 8.17-8.12 (m, 1H), 7.99-7.92 (m, 1H), 7.88-7.85 (m, 1H), 7.85-7.81 (m, 1H), 7.81-7.76 (m, 1H), 7.76-7.70 (m, 1H), 7.70-7.62 (m, 2H), 7.57-7.46 (m, 1H), 7.32-7.20 (m, 1H), 7.13-6.99 (m, 1H), 6.77-6.63 (m, 1H), 5.10-4.98 (m, 1H), 1.47-1.45 (m, 6H). 19F NMR (400 MHz, chloroform-d) δ −129.63.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:17][S:18][CH2:19][C:20]([O:22]CC)=[O:21])[O:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[CH:5][CH:4]=1.[Li+].[OH-]>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:17][S:18][CH2:19][C:20]([OH:22])=[O:21])[O:14][CH2:13][C:12]([CH3:16])([CH3:15])[CH2:11][O:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)CSCC1(c2ccc(OC)cc2)OCC(C)(C)CO1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(C2(CSCC(=O)O)OCC(C)(C)CO2)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 98.5 %

Procedure:
Ethyl ({[2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxan-2-yl]methyl}thio)acetate (5.95 g, 16.8 mmol) was dissolved in THP (75 ml) and cooled to 0° C. LiOH (2.11 g, 50.4 mmol) in water (40 ml) was added and the mixture was stirred for 90 minutes. Water was added and the mixture was extracted twice with diethyl ether. The aqueous layer was acidified using 2M HCl until pH=4 and extracted twice with CH2Cl2. The combined CH2Cl2 layers were dried (Na2SO4) and concentrated under reduced pressure to afford 5.4 g (>98%) of the title compound as a white solid. 1H-NMR (CDCl3, 200 MHz): δ 0.6 (s, 3H), 1.4 (s, 3H), 3.0 (s, 2H), 3.4 (s, 2H), 3.5 (s, 4H), 3.9 (s, 3H), 6.9 (d, 2H), 7.4 (d, 2H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C([O:9][C:10](=O)[CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[OH:9][CH2:10][CH2:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)CC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCO)CC1
Reaction time: 1 h
Yield: 92 %

Procedure:
LAH (819 mg, 21.58 mmol, 1.3 eq) was placed in THF (50 ml) at 0° C.; a solution of tert-butyl 4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (4.5 g, 16.60 mmol, 1 eq) in THF (50 ml) was added dropwise and then stirring was carried out for 1 h at RT. After monitoring by thin-layer chromatography, the reaction mixture was hydrolyzed with sat. sodium sulfate solution (2 ml), filtered over Celite and washed with THF (300 ml). The filtrate was concentrated under reduced pressure and a colourless oil was obtained, which was used in the next stage without being purified and analyzed further. Yield: 92% (3.5 g, 15.28 mmol).
Reaction SMILES: [CH3:1][C:2]1([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]3[CH:15]=[N:16][O:17][C:18]=3[CH3:19])=[O:13])=[CH:7][CH:6]=2)[CH2:4][CH2:3]1.NC1C=CC(C2(C)CC2)=CC=1.CC1(C2C=CC([N+]([O-])=O)=CC=2)CC1>>[CH3:4][C:2]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]([C:14]2[CH:15]=[N:16][O:17][C:18]=2[CH3:19])=[O:13])=[CH:9][CH:10]=1)([CH3:1])[CH3:3]
Reactant: Cc1oncc1C(=O)Nc1ccc(C2(C)CC2)cc1
Agent: CC1(c2ccc(N)cc2)CC1
Agent: CC1(c2ccc([N+](=O)[O-])cc2)CC1
Product: Cc1oncc1C(=O)Nc1ccc(C(C)(C)C)cc1

Procedure:
N-[4-(1-methylcyclopropyl)phenyl]-5-methylisoxazol-4-yl-carboxamide, viscous oil (from 1-amino-4-(1-methylcyclopropyl)benzene, b.p. 65°-70° C./0.25 mm Hg, prepared by reduction of 1-(1-methylcyclopropyl)-4-nitrobenzene, Chem.Ber. 106 525-548 (1973)).
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[O:9]1CCC[CH2:10]1>>[O:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[NH:1][C:10]1=[O:9]
Reactant: C1CCOC1
Reactant: Nc1ncccc1O
Product: O=c1[nH]c2ncccc2o1

Procedure:
5.5 g (0.05 mol) of 2-amino-3-hydroxypyridine are introduced into a three-necked flask and the system is placed under argon. 100 ml of anhydrous tetrahydrofuran (THF) are added. 12.15 g (0.075 mol) of 1,1-carbonyldiimidazole are then introduced. The mixture is heated to reflux for 5 hours (under argon). The THF is then evaporated off. The residue is taken up with dichloromethane. Washes of the organic phase are performed with NaOH solution (5%) (6×150 ml); the cyclized product passes into the aqueous phase and is precipitated at a pH in the region of 5 (by adding 2N hydrochloric acid solution). The product is filtered off and stored in a desiccator.
Reaction SMILES: [CH:1]1([CH:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([O:20]C)=[CH:15][C:14]=3[Cl:22])[C:8]2=[O:23])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>ClC(Cl)C>[CH:1]1([CH:7]2[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][C:16]([OH:20])=[CH:15][C:14]=3[Cl:22])[C:8]2=[O:23])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1cc(Cl)c(CN2CCC(C3CCCCC3)C2=O)c(Cl)c1
Agent: BrB(Br)Br
Solvent: CC(Cl)Cl
Product: O=C1C(C2CCCCC2)CCN1Cc1c(Cl)cc(O)cc1Cl
Reaction time: 12 h
Yield: 95.8 %

Procedure:
Treat a solution of 3-cyclohexyl-1-(2,6-dichloro-4-methoxy-benzyl)-pyrrolidin-2-one (1.3 g, 3.66 mmol) in dichloroethane (30 mL) at −20° C. with boron tribromide (1.0 M in DCM, 18.3 mL) for 2 hours. Warm the reaction up to room temperature and stir for 12 hours. Quench the reaction with methanol and remove the solvent under vacuum. Partition the residue with ethyl acetate and HCl (1 N). Wash the organic with water. After drying the organic layer, filtrate and concentrate to afford 1.2 g (99%) of the title compound. MS (m/z): 342 (M+).
Reaction SMILES: [N:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][NH:12][C:13](=[O:17])[NH:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:18]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CS(C)=O.C(OCC)(=O)C>[C:18]1([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:19]=[CH:20][C:21]([CH2:24][N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:16]=[C:15]4[C:10]([CH2:11][NH:12][C:13](=[O:17])[NH:14]4)=[CH:9][CH:8]=3)[CH2:2][CH2:3]2)=[CH:22][CH:23]=1
Reactant: O=C1NCc2ccc(N3CCNCC3)cc2N1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=C1NCc2ccc(N3CCN(Cc4ccc(-c5ccccc5)cc4)CC3)cc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
Representative procedure: To a solution of compound 5 (0.15 g, 0.43 mmol) and biphenyl-4-carbaldehyde (a) (0.1 g, 0.55 mmol) in DMSO (2 mL) at 0° C. was added Et3N (0.13 mL, 0.97 mmol). After being stirred for 0.5 h at room temperature, NaBH(OAc)3 (0.11 g, 0.53 mmol) was added, and the mixture was stirred for 6 h. Sat. NaHCO3 solution (5 mL) was added and stirred for 15 min, followed by the addition of ethyl acetate (20 mL). The organic layer was separated and washed with sat. NaHCO3, brine, and dried over Na2SO4 and evaporated. Column chromatography on silica gel, eluting with methanol:dichloromethane (5:95) and then changing to 10:90 afforded 0.099 g (58%) of compound 5a as an off-white solid, m.p. 134-135° C.; IR (KBr) νmax. cm−1: 3431 (NH), 3062 (Ar—H), 2963 (Alph-H), 1703 (C═O), 1620, 1512, 1430 (C═C), 1221 (C—N), 1168 (C—O). 1H NMR (500 MHz, DMSO-d6) δ=2.71 (m, 4H, 2CH2); 3.14 (m, 4H, 2CH2); 3.68 (s, 2H, CH2); 4.47 (s, 2H, CH2); 6.64 (d, 1H, J=2.3 Hz, aromatic H); 6.68 (d, 1H, J=8.3 Hz, aromatic H); 6.78 (dd, 1H, J=2.2, 8.4 Hz, aromatic H); 7.43-7.48 (m, 5H, aromatic H); 7.58-7.61 (m, 4H, aromatic H); 13C NMR (125.7 MHz, DMSO-d6) δ=43.78 (CH2), 50.11 (CH2), 53.02 (CH2), 62.69 (CH2), 98.21 (aromatic-C), 114.64 (aromatic-C), 115.15 (aromatic-C), 117.28 (aromatic-C), 118.25 (aromatic-C), 127.18 (aromatic-C), 127.28 (aromatic-C), 127.53 (aromatic-C), 127.91 (aromatic-C), 128.97 (aromatic-C), 129.21 (aromatic-C), 130.29 (aromatic-C), 130.57 (aromatic-C), 140.92 (aromatic-C), 147.12 (aromatic-C), 156.34 (C═O). Calculated (%) for C25H26N4O (398.21); C: 75.35, H: 6.58, N: 14.06. found (%); C: 75.28, H: 6.64, N: 13.97.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13](Br)=[CH:14][CH:15]=2)[C:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:37][O:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1.ClCCl>O1CCOCC1.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]>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:42]3[CH:43]=[CH:44][C:39]([O:38][CH3:37])=[CH:40][CH:41]=3)=[CH:14][CH:15]=2)[C:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[C:9]1[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Brc1ccc2c(c1)c(Cc1ccccc1)c(-c1ccccc1)n2Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccc(-c2ccc3c(c2)c(Cc2ccccc2)c(-c2ccccc2)n3Cc2ccccc2)cc1

Procedure:
The desired product was prepared using a procedure similar to step 3 of example 3. Thus, 1,3-dibenzyl-5-bromo-2-phenyl-1H-indole (1.932 g, 4.271 mmol) was reacted with aqueous 2M K2CO3 (4.3 ml), 4-methoxyphenylboronic acid (0.909 g, 5.979 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (II) complex with dichloromethane (1:1) (0.105 g, 0.128 mmol) in dioxane (43 ml) to give the product (1.163 g, 2.425 mmol, 57%) as a brown, viscous oil. 1H NMR (DMSO-d6) δ 3.76 (s, 3H), 4.06 (s, 2H), 5.34 (s, 2H), 6.87 (d, J=7.6 Hz, 2H), 6.97 (d, J=8.8 Hz, 2H), 7.09-7.23 (m, 8H), 7.34 (dd, J=1.7, 8.6 Hz, 1H), 7.39-7.49 (m, 8H), 7.56 (s, 1H); [ESI(+)], m/z 480 (M+H)+.