Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][C:3]=1[CH3:24].[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Na+].[Na+].B(O)O>C1(C)C=CC=CC=1.C(O)C.O>[CH3:24][C:3]1[CH:4]=[C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])[CH:6]=[CH:7][C:2]=1[C:28]1[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=1
Reactant: OB(O)c1ccncc1
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1Br
Agent: O=C([O-])[O-]
Agent: OBO
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1-c1ccncc1
Reaction time: 24 h
Yield: 34.4 %

Procedure:
A suspension of (4-bromo-3-methylphenyl)-[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone of Step A (1.14 g, 2.9 mmol), pyridine-4-boronic acid (0.368 mg, 2.9 mmol) and sodium carbonate (0.760 g, 7.2 mmol) in a mixture of toluene (30 mL), water (10 mL), and ethanol (5 mL) was sparged with nitrogen for 15 minutes. To this was added tetrakis(triphenylphosphine)palladium(0) (0.027 g) and the mixture was heated to reflux under a static pressure of nitrogen. After 24 hours additional boronic acid (0.128 mg, 1 mmol) and sodium carbonate (0.116 g) were added and the heating was continued for 24 hours. Additional catalyst (0.012 g) was added and heating was continued for another 24 hours. The mixture was partitioned between ethyl acetate and hexane. The water layer was washed twice with ethyl acetate and the combined organic layers were dried over anhydrous magnesium sulfate and stripped to a solid. Flash chromatography of the residue on silica gel eluting with 30% ethyl acetate in hexane provided 0.379 g of the desired product which was recrystallized from ethyl acetate/hexanes as tan plates, m.p. 208-210° C.
Reaction SMILES: [N+:1]([C:4]1[C:9]([NH:10][C:11](=[O:32])[CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])=[CH:18][C:17]=2[C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])[CH2:13][CH3:14])=[C:8]([Cl:33])[CH:7]=[C:6]([NH:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:5]=1[OH:43])([O-])=O>O1CCCC1.C(O)C.[Pd]>[NH2:1][C:4]1[C:9]([NH:10][C:11](=[O:32])[CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH2:25][CH3:26])([CH3:23])[CH3:24])=[CH:18][C:17]=2[C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])[CH2:13][CH3:14])=[C:8]([Cl:33])[CH:7]=[C:6]([NH:34][C:35](=[O:42])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:5]=1[OH:43]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1c(Cl)cc(NC(=O)c2ccccc2)c(O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1c(Cl)cc(NC(=O)c2ccccc2)c(O)c1N

Procedure:
In 50 ml of tetrahydrofuran and 100 ml of ethanol was dissolved 21 g (13×10-3 mole) of 2-nitro-3-{2-(2,4-di-t-amylphenoxy)butanamido}-4-chloro-6-benzamidophenol and hydrogenation was effected by using 1.2 g of Pd-C as a catalyst. The color of the nitro derivative disappeared in 4 hours, and the Pd-C was removed by filtration and a solvent was evaporated therefrom under reduced pressure, followed by extraction of the residue with ethyl acetate. The ethyl acetate layer was washed with an aqueous sodium hydrogen carbonate solution and then with water, and after drying over magnesium sulfate, ethyl acetate was evaporated. Yield: 20 g.
Reaction SMILES: Cl.Cl.[NH2:3][C@@H:4]([CH2:8]/[CH:9]=[CH:10]/[CH2:11][C@H:12]([NH2:16])[C:13]([OH:15])=[O:14])[C:5]([OH:7])=[O:6].C[Si](Cl)(C)C.[C:22](Cl)([O:24][CH2:25][CH:26]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]2[C:27]1=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23]>C[Si](N[Si](C)(C)C)(C)C.ClCCl>[CH:37]1[C:38]2[CH:26]([CH2:25][O:24][C:22]([NH:3][C@@H:4]([CH2:8]/[CH:9]=[CH:10]/[CH2:11][C@H:12]([NH:16][C:22]([O:24][CH2:25][CH:26]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:32]=4[C:33]4[C:38]3=[CH:37][CH:36]=[CH:35][CH:34]=4)=[O:23])[C:13]([OH:15])=[O:14])[C:5]([OH:7])=[O:6])=[O:23])[C:27]3[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:33]=2[CH:34]=[CH:35][CH:36]=1
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: N[C@@H](C/C=C/C[C@H](N)C(=O)O)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(N[C@@H](C/C=C/C[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)C(=O)O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
(S,S)-2,7-Diamino-E-oct-4-enedioic acid dihydrochloride (1.59 g, 5.8 mmol) was suspended in HMDS (20 ml) and TMSCl and refluxed overnight. The solvents were removed, and the residue was dissolved in anhydrous dichloromethane. This solution was cooled to 0° C. and a solution of FmocCl (3.10 g, 12 mmol) in dichloromethane was added. The solution was stirred for 1 hour at this temperature and overnight at ambient temperature. The solvent was evaporated and the residue dissolved in THF. After addition of 1N aqueous HCl the solution was stirred for two hours, extracted with chloroform and dried (MgSO4). The residue was dissolved in dichloromethane and crystallized by the addition of diethylether.
Reaction SMILES: [Li+].[OH-].[C:3]1([C:12]([O:14]CC)=[O:13])[C:8]2[CH2:9][CH2:10][CH2:11][C:7]=2[CH:6]=[CH:5][N:4]=1>O.CO>[C:3]1([C:12]([OH:14])=[O:13])[C:8]2[CH2:9][CH2:10][CH2:11][C:7]=2[CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)c1nccc2c1CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1nccc2c1CCC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.2 %

Procedure:
A 2N solution of LiOH (50 mL) in water was slowly added to the title compound of step 1 (10 g, 52.4 mmol) in MeOH (250 mL) at 0° C. The mixture was allowed to warm to rt and stirred for 30 min. The MeOH was reduced under vacuum and the residual aqueous solution was washed with EtOAc. The organic phase was re-extracted with water. The combined aqueous extracts were acidified to pH=2 with 1N HCl. The water was removed and preparative HPLC gave the title compound (5.4 g, 63%) as a white solid. 1H NMR (CD3OD, 400 MHz): δ 8.45 (d, J=5.6 Hz, 1H), 7.88 (d, J=5.6 Hz, 1H), 3.39 (t, J=8.0, 7.6 Hz, 2H), 3.16 (d, t, J=8.0, 7.6 Hz, 2H), 2.16-2.20 (m, 2H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](=O)[CH:11](Br)[CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1.[CH3:15][C:16]1[N:20]=[C:19]([CH3:21])[N:18]([C:22]2[C:26]([CH3:27])=[N:25][NH:24][C:23]=2[OH:28])[N:17]=1>>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[N:24]4[N:25]=[C:26]([CH3:27])[C:22]([N:18]5[C:19]([CH3:21])=[N:20][C:16]([CH3:15])=[N:17]5)=[C:23]4[O:28][C:11]=3[CH3:12])=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: Cc1nc(C)n(-c2c(C)n[nH]c2O)n1
Reactant: CC(Br)C(=O)c1ccc2occc2c1
Product: Cc1nc(C)n(-c2c(C)nn3c(-c4ccc5occc5c4)c(C)oc23)n1

Procedure:
The title compound is prepared from 1-(benzofuran-5-yl)-2-bromopropan-1-one (step 3) and 4-(3,5-dimethyl-[1,2,4]triazol-1-yl)-5-methyl-2H-pyrazol-3-ol (Intermediate KF) analogously to Example 6.2. MS: m/z 348.1 [M+H]+.
Reaction SMILES: ClC1C=CC=C2C=1NC([B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1)=C2.[CH3:20][C:21]1[C:29]2[O:28][CH:27]=[CH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1>>[CH3:20][C:21]1[C:29]2[O:28][C:27]([B:11]3[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]3)=[CH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1
Reactant: Cc1cccc2ccoc12
Reactant: CC1(C)OB(c2cc3cccc(Cl)c3[nH]2)OC1(C)C
Product: Cc1cccc2cc(B3OC(C)(C)C(C)(C)O3)oc12

Procedure:
Prepared according to a procedure analogous to that described for 7-chloro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-indole using 7-methyl-benzofuran.
Reaction SMILES: [OH:1][C:2]([C:15]([F:18])([F:17])[F:16])([CH2:5][C:6]([CH3:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])[CH:3]=O.[NH2:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24]([CH3:30])=[N:25]2.O>C1(C)C=CC=CC=1.[Ti]>[F:16][C:15]([F:18])([F:17])[C:2]([CH:3]=[N:19][C:20]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:21]=1[CH:22]=[CH:23][C:24]([CH3:30])=[N:25]2)([OH:1])[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)([CH3:14])[CH3:7]
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1ccccc1
Reactant: Cc1ccc2c(N)cccc2n1
Agent: [Ti]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2c(N=CC(O)(CC(C)(C)c3ccccc3)C(F)(F)F)cccc2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 65.5 %

Procedure:
120 mg of 2-hydroxy-4-methyl-4-phenyl-2-(trifluoromethyl)pentanal, 67 mg of 5-amino-2-methylquinoline and 163 μl of titanium tetraethylate are stirred in 8 ml of toluene for 2 hours at 100° C. After cooling, the batch is mixed with 2 ml of water, stirred for 15 minutes at room temperature, and concentrated by evaporation in a vacuum. Column chromatography on silica gel with cyclohexane-ethyl acetate yields 111 mg of product.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:5]2[S:10][C:9]([C:11]3[CH:12]=[C:13]([C:17]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)=[O:18])[CH:14]=[CH:15][CH:16]=3)=[CH:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:39]2[CH:47]=[CH:46][CH:45]=[C:44]3[C:40]=2[CH:41]=[N:42][NH:43]3)O1>>[NH:43]1[C:44]2[C:40](=[C:39]([C:2]3[N:3]=[C:4]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)[C:5]4[S:10][C:9]([C:11]5[CH:12]=[C:13]([C:17]([N:19]6[CH2:24][CH2:23][O:22][CH2:21][CH2:20]6)=[O:18])[CH:14]=[CH:15][CH:16]=5)=[CH:8][C:6]=4[N:7]=3)[CH:47]=[CH:46][CH:45]=2)[CH:41]=[N:42]1
Reactant: O=C(c1cccc(-c2cc3nc(Cl)nc(N4CCOCC4)c3s2)c1)N1CCOCC1
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Product: O=C(c1cccc(-c2cc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)c1)N1CCOCC1

Procedure:
3-(2-Chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)benzoic acid (49 mg) was reacted with morpholine via General Procedure B to yield 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(morpholino)methanone. Crude 3-(2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)phenyl(morpholino)methanone (58 mg) was coupled to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 via General Procedure A to yield 23.7 mg of 337. MS (Q1) 527.2 (M)+
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:15]([N:17]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([CH2:26][NH2:27])=[CH:23]2)=[N:18]1)[CH3:16]>>[CH2:15]([N:17]1[CH:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([CH2:26][NH:27][S:2]([C:5]3[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=3)(=[O:4])=[O:3])=[CH:23]2)=[N:18]1)[CH3:16]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: CCn1cc2cc(CN)ccc2n1
Product: CCn1cc2cc(CNS(=O)(=O)c3ccc(C(=O)OC)cc3)ccc2n1

Procedure:
The titled compound was prepared according to the procedure described in step-1 of Example 1 from methyl 4-(chlorosulfonyl)benzoate and (2-ethyl-2H-indazol-5-yl)methanamine (step-4 of Example 13).
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:34]=[CH:33][NH:32][CH:31]=3)[C@H:14]2[CH3:35])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[K+].I[CH:41]([CH3:43])[CH3:42].O>CS(C)=O>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:34]=[CH:33][N:32]([CH:41]([CH3:43])[CH3:42])[CH:31]=3)[C@H:14]2[CH3:35])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1cc[nH]c1
Reactant: CC(C)I
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)n1ccc(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Reaction time: 0.25 h

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-3-[2-(1H-pyrrol-3-yl)-5-(trifluoromethyl)benzyl]-1,3-oxazolidin-2-one (6.8 mg, 0.0127 mmol) (Example 120) in DMSO (300 μL) was added powdered KOH (3.6 mg, 0.0643 mmol). After stirring for 15 minutes, 2-iodopropane (3.2 μL, 0.032 mmol) was added. After 1.5 hours of stirring at room temperature, water (5 mL) was added, and the mixture was extracted, first with CH2Cl2 (2×15 mL) and then with EtOAc (2×15 mL). The combined organics were dried over Na2SO4, filtered, and concentrated. Purification of the residue by PTLC (25% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-(1-isopropyl-1H-pyrrol-3-yl)-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.33 (25% EtOAc/hexanes). LCMS=579.2 (M+i)+. 1H NMR (CDCl3, 500 MHz) δ 7.85 (s, 1H), 7.71 (s, 2H), 7.61 (s, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.50 (d, J=8.0 Hz, 1H), 6.83 (t, J=2.1 Hz, 1H), 6.79 (t, J=2.5 Hz, 1H), 6.24 (t, J=2.3 Hz, 1H), 5.49 (d, J=8.0 Hz, 1H), 5.04 (d, J=15.5 Hz, 1H), 4.48 (d, J=15.6 Hz, 1H), 4.27 (m, 1H), 3.76 (m, 1H), 1.48 (d, J=6.6 Hz, 6H), 0.49 (d, J=6.6 Hz, 3H).
Reaction SMILES: [C:1]([Mg]Br)#[C:2][CH3:3].C1COCC1.[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[CH:13]([NH:19][C:20]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]3[O:30][C:29]([C:31]4[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=4)=[N:28][C:27]=13)=[O:21])[CH2:12]2>CN(C=O)C.[Cl-].[Zn+2].[Cl-].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>[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[CH:13]([NH:19][C:20]([C:22]1[CH:23]=[CH:24][CH:25]=[C:26]3[O:30][C:29]([C:31]4[CH:36]=[CH:35][C:34]([C:1]#[C:2][CH3:3])=[CH:33][CH:32]=4)=[N:28][C:27]=13)=[O:21])[CH2:12]2
Reactant: CC#C[Mg]Br
Reactant: O=C(NC1CN2CCC1CC2)c1cccc2oc(-c3ccc(I)cc3)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC#Cc1ccc(-c2nc3c(C(=O)NC4CN5CCC4CC5)cccc3o2)cc1
Reaction time: 0.17 h
Yield: 88 %

Procedure:
Zinc chloride (1.0 M in ether, 0.33 mL, 0.33 mmol) was added dropwise to a solution of 1-propynylmagnesium bromide in THF (0.5 M in THF, 0.66 mL, 0.33 mmol) at room temperature and the mixture was stirred under nitrogen for 10 min. N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-(4-iodophenyl)benzoxazole-4-carboxamide (50 mg, 0.11 mmol) in DMF (2 mL) was added followed by bis(triphenylphosphine)dichloropalladium(II) (7.7 mg, 0.011 mmol). The resulting mixture was stirred under nitrogen at room temperature for 2 h, and then was quenched with saturated ammonium chloride, extracted with methylene chloride. The combined organic layers were washed with water and brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by column chromatography (silica gel, 90:10:1 ethyl acetate/methanol/concentrated ammonium hydroxide) to afford N-(1-azabicyclo[2.2.2]oct-3-yl)-2-(4-propyn-1-ylphenyl)benzoxazole-4-carboxamide (36 mg, 88%) as a light yellow solid: 1H NMR (300 MHz, CDCl3) δ 9.56 (d, J=7.0 Hz, 1H), 8.23 (dd, J=8.0, 1.0 Hz, 1H), 8.17 (d, J=8.4 Hz, 2H), 7.73 (dd, J=8.0, 1.0 Hz, 1H), 7.58 (d, J=8.4 Hz, 2H), 7.49 (t, J=8.0 Hz, 1H), 4.35-4.29 (m, 1H), 3.54 (ddd, J=14.0, 9.5, 2.0 Hz, 1H), 3.16-2.82 (m, 5H), 2.20-2.03 (m, 2H), 2.14 (s, 3H), 1.80-1.60 (m, 3H); MS (ESI+) m/z 386 (M+H); HPLC>99% (AUC), tR=13.24 min.
Reaction SMILES: ClC1C=CC([C:8]2C3C(NC)=NC=CC=3C3C(C)=NOC=3C[N:14]=2)=CC=1.Cl[C:26]1[N:47]=[CH:46][C:29]2[C:30]3[C:44]([CH3:45])=[N:43][O:42][C:31]=3[CH2:32][N:33]=[C:34]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[C:28]=2[CH:27]=1.ClC1C=CC(C2C3C(F)=NC=CC=3C3C(C)=NOC=3CN=2)=CC=1>>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([C:34]2[C:28]3[CH:27]=[C:26]([NH:14][CH3:8])[N:47]=[CH:46][C:29]=3[C:30]3[C:44]([CH3:45])=[N:43][O:42][C:31]=3[CH2:32][N:33]=2)=[CH:36][CH:37]=1
Reactant: Cc1noc2c1-c1cnc(Cl)cc1C(c1ccc(Cl)cc1)=NC2
Reactant: CNc1nccc2c1C(c1ccc(Cl)cc1)=NCc1onc(C)c1-2
Agent: Cc1noc2c1-c1ccnc(F)c1C(c1ccc(Cl)cc1)=NC2
Product: CNc1cc2c(cn1)-c1c(C)noc1CN=C2c1ccc(Cl)cc1

Procedure:
A procedure similar to 6-(4-chlorophenyl)-N,1-dimethyl-4H-isoxazolo[5,4-c]pyrido[4,3-e]azepin-7-amine was followed, except that 8-chloro-6-(4-chlorophenyl)-1-methyl-4H-isoxazolo[5,4-c]pyrido[3,4-e]azepine was used as starting material instead of 6-(4-chlorophenyl)-7-fluoro-1-methyl-4H-isoxazolo[4,5-e]pyrido[3,4-c]azepine. LC/MS m/z 339 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.49-7.41 (m, 4H), 6.84 (q, J=5.00 Hz, 1H), 6.33 (s, 1H), 4.67 (br. s, 2H), 2.79 (d, J=4.78 Hz, 3H), 2.48 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[CH:3]=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1.CCCCCCC.CCOC(C)=O>C(Cl)Cl.CC1C=CC(S(O)(=O)=O)=CC=1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]([C:16]([F:19])([F:17])[F:18])=[CH:14][CH:15]=2)[CH:5]=[C:6]([CH2:8][O:9][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][O:20]2)[N:7]=1
Reactant: OCc1cc(-c2ccc(C(F)(F)F)cc2)cc(Br)n1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(Br)nc(COC3CCCCO3)c2)cc1
Temperature: 23 °C
Reaction time: 18 h
Yield: 87.2 %

Procedure:
To a solution of the above described [6-bromo-4-(4-trifluoromethyl-phenyl)-pyridin-2-yl]-methanol (4.2 g, 95%, purity 81%) and 3,4-dihydro-2H-pyran (1.4 ml, 15.4 mmol) in DCM (20 ml) at 23° C. was added a catalytic amount of p-TsOH.H2O (10 mg) and the mixture was stirred at 23° C. for 18 h. Then again 3,4-dihydro-2H-pyran (0.7 ml, 7.68 mmol) was added and stirring was continued at 23° C. for another 2 h. The entire reaction mixture was directly subjected to silica gel column chromatography with n-heptane/AcOEt to give the title compound (4.59 g, 100%, 93% purity) as a light yellow oil. MS (ISP) 418.2 [(M+H)+].
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][N:4]=[C:3]1[S:7]([CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)(=[O:9])=[O:8].[Cl:16][C:17]1[N:18]=[C:19]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[C:20]2[S:25][C:24]([CH:26]=O)=[CH:23][C:21]=2[N:22]=1>>[Cl:16][C:17]1[N:18]=[C:19]([N:28]2[CH2:29][CH2:30][O:31][CH2:32][CH2:33]2)[C:20]2[S:25][C:24]([CH2:26][N:13]3[CH2:14][CH2:15][CH:10]([S:7]([C:3]4[S:2][CH:6]=[CH:5][N:4]=4)(=[O:9])=[O:8])[CH2:11][CH2:12]3)=[CH:23][C:21]=2[N:22]=1
Reactant: O=S(=O)(c1nccs1)C1CCNCC1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: Cl
Product: O=S(=O)(c1nccs1)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Yield: 31.9 %

Procedure:
4-(Thiazole-2-sulfonyl)-piperidine HCl salt (124 mg) was reacted with 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (130 mg) using standard reductive amination conditions. Aqueous work-up, purification on silica and trituration with hot ethyl acetate yielded 2-chloro-4-morpholin-4-yl-6-[4(thiazole-2-sulfonyl)-piperidin-1-ylmethyl]-thieno[3,2-d]pyrimidine (73 mg), which was reacted with 2-aminopyrimidine-5-boronic acid in General Procedure A. Purification on silica yielded 415. NMR (CDCl3): 2.03-2.18 (4H, m), 2.18-2.22 (2H, m), 3.12-3.16 (2H, m), 3.39-3.46 (1H, m), 3.84 (2H, s), 3.90-3.93 (4H, m), 4.03-4.06 (4H, m), 5.20 (2H, br), 7.26 (1H, s), 7.79 (1H, d, J=3.0), 8.11 (1H, d, J=3.0), 9.29 (2H, s) MS (ESI+): MH+ 559.13 (100%)
Reaction SMILES: [N:1]1([C:14]([O:16][CH2:17][CH:18]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:13][C@H:7]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:6][C@H:2]1[C:3]([OH:5])=[O:4].[CH2:31](O)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C)C1C=CN=CC=1.ClCCl>[N:1]1([C:14]([O:16][CH2:17][CH:18]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[O:15])[CH2:13][C@H:7]([O:8][C:9]([CH3:11])([CH3:12])[CH3:10])[CH2:6][C@H:2]1[C:3]([O:5][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:4]
Reactant: CC(C)(C)O[C@@H]1C[C@@H](C(=O)O)N(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Reactant: OCc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)O[C@@H]1C[C@@H](C(=O)OCc2ccccc2)N(C(=O)OCC2c3ccccc3-c3ccccc32)C1
Reaction time: 1 h

Procedure:
65 mmol of N,N-dicyclohexylcarbodiimide are added to a mixture containing 61 mmol of Fmoc-Hyp(tBu)-OH, 65 mmol of benzyl alcohol and 27 mmol of 4-dimethylaminopyridine in 150 ml of dichloromethane cooled on an ice bath. After one hour at 0° C., the mixture is adjusted to room temperature and left stirring for 18 hours. The dicyclohexylurea precipitate is filtered and the filtrate is evaporated. The residual oil is taken up in ethyl acetate. The solution is washed with 5% sodium bicarbonate, with 5% citric acid and then with a saturated sodium chloride solution. After drying and evaporation, the expected product is obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])=[CH:4][CH:3]=1.C([Li])(CC)C.C1CCCCC1.[C:32](=[O:34])=[O:33]>CCOCC.O.C1COCC1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[Si:11]([CH:15]([CH3:17])[CH3:16])([CH:18]([CH3:20])[CH3:19])[CH:12]([CH3:13])[CH3:14])=[CH:4][C:3]=1[C:32]([OH:34])=[O:33]
Reactant: O=C=O
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2ccc(F)cc21
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(C(=O)O)c(F)cc21
Temperature: -75 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
In a 250 mL round bottomed flask, 6-fluoro-1-(triisopropylsilyl)-1H-indole (5.12 g, 17.57 mmol) was treated with THF (35 mL), cooled to −75° C. and treated with sec-butyllithium, 1.4 M in cyclohexane (12.55 mL, 17.57 mmol) and stirred at −75° C. for 2 h. The reaction mixture was treated with crushed dry ice and was warmed to RT over 30 min. The reaction mixture was treated with 10 mL water and the organic layer was washed with 1 M citric acid (2×20 mL) in an extraction funnel. The organic layer was then concentrated under reduced pressure (rotary evaporator) and recrystallized from a 9:1 mixture of hexanes:Et2O (100 mL) overnight in the freezer affording 6-fluoro-1-(triisopropylsilyl)-1H-indole-5-carboxylic acid (4.36 g, 13.00 mmol, 74.0% yield) as a white crystalline solid. MS (ESI, pos. ion) m/z: 336.0 (M+H)+. 1H NMR (400 MHz, CDCl3) δ ppm 8.25 (1H, d, J=7.4 Hz), 7.26 (1H, d, J=3.1 Hz), 7.20 (1H, d, J=12.9 Hz), 6.65 (1H, d, J=2.9 Hz), 1.68 (3H, quin, J=7.5 Hz), 1.14 (18H, d, J=7.6 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([OH:8])=[O:7].Cl.[CH3:14]O>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:6]([O:8][CH3:14])=[O:7]
Reactant: CO
Reactant: COc1cc(C(=O)O)ccc1C
Agent: Cl
Product: COC(=O)c1ccc(C)c(OC)c1

Procedure:
A solution of 3-methoxy-4-methylbenzoic acid (10 grams) in 200 mL of methanol was saturated with hydrochloric acid gas. The resulting solution was warmed on a steam bath for 4 hours. The reaction was allowed to cool and the methanol was evaporated. The residue was dissolved in ethyl acetate and the ethyl acetate layer was washed with water, dried over sodium sulfate and evaporated to give the title compound. NMR (CDCl3) δ:2.15 (s, 3H), 3.80 (s, 3H), 7.48-7.18 (m, 3H).
Reaction SMILES: CS([O:5][CH2:6][C:7]1([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8]1)(=O)=O.[Br:16][C:17]1[CH:22]=[CH:21][C:20](O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:16][C:17]1[CH:22]=[CH:21][C:20]([O:5][CH2:6][C:7]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:10][CH2:9][CH2:8]2)=[CH:19][CH:18]=1
Reactant: Oc1ccc(Br)cc1
Reactant: CCOC(=O)C1(COS(C)(=O)=O)CCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(COc2ccc(Br)cc2)CCC1
Temperature: 135 °C
Reaction time: 6 h
Yield: 46.6 %

Procedure:
The mixture of ethyl 1-{[(methylsulfonyl)oxy]methyl}cyclobutanecarboxylate (1.50 g, 6.3 mmol), 4-bromophenol (1.2 g, 7.0 mmol), and caesium carbonate (4.13 g, 7.0 mmol) in DMF (15 ml) was stirred for 6 hours at 135° C. After dilution with EtOAc and H2O, the organic layer was washed with H2O, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel chromatography (hexane:EtOAc=100:0-70:30) to give ethyl 1-[(4-bromophenoxy)methyl]cyclobutanecarboxylate (919 mg).