Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][N:23]=[C:22](S(C)(=O)=O)[N:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[F:34][C:35]1([F:39])[CH2:38][NH:37][CH2:36]1.C(N(C(C)C)CC)(C)C>C1COCC1>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([Br:26])=[CH:24][N:23]=[C:22]([N:37]4[CH2:38][C:35]([F:39])([F:34])[CH2:36]4)[N:21]=3)[C@H:14]2[CH3:31])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: FC1(F)CNC1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(S(C)(=O)=O)ncc1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1nc(N2CC(F)(F)C2)ncc1Br
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 85.9 %

Procedure:
To a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-bromo-2-(methylsulfonyl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (Step A, 2.5 g, 4.45 mmol), and 3,3-difluoroazetidine (1.73 g, 13.34 mmol) in THF (40 mL) was added diisopropylethylamine (3.88 mL, 22.23 mmol). It was stirred at 60° C. for 15 minutes at which time complete conversion by LCMS was noted. The solvent was evaporated, and the residue was purified on a silica gel column, eluting with 50% ethyl acetate in hexanes to get the title compound (2.2 g, 86% yield) as a white solid. LCMS (M+H)+: 577.1; 575.2. 1H NMR (CDCl3, 500 MHz): δ 8.38 (s, 1H), 7.93 (s, 1H), 7.81 (s, 2H), 5.82 (d, J=8.5 Hz, 1H), 4.84 (d, J=18.0 Hz, 1H), 4.48 (m, 4H), 4.40 (m, 1H), 4.23 (d, J=18.0 Hz, 1H), 0.83 (d, J=6.5 Hz, 3H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C@H:7]([OH:9])[CH3:8])=[CH:3][CH:2]=1.C(O)(=O)C>CO.O=[Pt]=O>[NH:1]1[CH2:6][CH2:5][CH:4]([C@H:7]([OH:9])[CH3:8])[CH2:3][CH2:2]1
Reactant: C[C@@H](O)c1ccncc1
Agent: O=[Pt]=O
Solvent: CO
Solvent: CC(=O)O
Product: C[C@@H](O)C1CCNCC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 56.8 %

Procedure:
A solution of (1R)-1-(4-pyridinyl)ethanol (37 g, 0.3 mol, 78% ee) in MeOH (2 L) was charged with PtO2 (5 g) under nitrogen atmosphere followed by acetic acid (19 mL). The mixture was evacuated and purged with hydrogen several times and then stirred under an atmosphere of hydrogen for 2 d at room temperature. The mixture was filtered to remove catalyst and the filtrate was concentrated in vacuo and triturated with EtOAc to yield a cream-colored solid which was collected by filtration. The filter cake was dissolved in MeOH (500 mL) and 50% NaOH (15.8 g) was added. The resulting solution was stirred at 25° C. for 30 min and concentrated. The resulting solid was triturated with Et2O (700 mL) and stirred at 25° C. for 30 min, the solids were removed by filtration and the filtrate was dried over MgSO4 and filtered again. The final filtrate was concentrated to yield (1R)-1-(4-piperidinyl)ethanol (22 g, 57% yield) as a light beige solid. 1H NMR (400 MHz, CDCl3): δ 3.50 (quint, 1H, J=6.3 Hz), 3.13-3.01 (m, 2H), 2.61-2.47 (m, 2H), 1.88 (br, 2H), 1.84-1.73 (m, 1H), 1.63-1.52 (m, 1H), 1.41-1.27 (m, 1H), 1.23-1.05 (m, 2H), 1.13 (d, 3H, J=6.2 Hz).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:5][C@H:4]([CH:6]([NH:8][C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[C:28]5[C:23](=[CH:24][C:25]([F:29])=[CH:26][CH:27]=5)[N:22]([CH3:30])[N:21]=4)[N:18]=3)[N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:12]=2)=[O:10])[CH3:7])[CH2:3]1.C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[F:29][C:25]1[CH:24]=[C:23]2[C:28]([C:20]([C:17]3[N:18]=[C:19]4[C:11]([C:9]([NH:8][CH:6]([C@@H:4]5[CH2:3][C@H:2]([O:1][S:47]([CH3:46])(=[O:49])=[O:48])[CH2:5]5)[CH3:7])=[O:10])=[CH:12][N:13]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:36])[CH3:38])[C:14]4=[N:15][CH:16]=3)=[N:21][N:22]2[CH3:30])=[CH:27][CH:26]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)[C@H]1C[C@@H](OS(C)(=O)=O)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a partial suspension of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [1-(cis-3-hydroxy-cyclobutyl)-ethyl]-amide (100 mg, 0.19 mmol) in CH2Cl2 (3 mL) at 0° C. was added triethylamine (39 μL, 0.28 mmol) followed by methanesulfonyl chloride (16 μL, 0.21 mmol). The reaction mixture was stirred at 0° C. for 1 h then quenched with water and extracted with CH2Cl2. The organics were dried over MgSO4 and concentrated to give methanesulfonic acid cis-3-(1-{[2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbonyl]-amino}-ethyl)-cyclobutyl ester as an off-white foam which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([Cl:10])[CH:5]=1)(=[O:3])[CH3:2].C(O[CH:14](OCC)[N:15]([CH3:17])[CH3:16])C>>[CH3:14][N:15]([CH3:17])[CH:16]=[CH:2][C:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([Cl:10])[CH:5]=1)=[O:3]
Reactant: CCOC(OCC)N(C)C
Reactant: CC(=O)c1ccnc(Cl)c1
Product: CN(C)C=CC(=O)c1ccnc(Cl)c1

Procedure:
16.2 g (104.2 mmol) of 4-acetyl-2-chloro-pyridine are stirred for 1 h at 110° with 116 ml of dimethylformamide diethylacetal. After cooling to 0°, filtering and drying at 60° under HV, 3-dimethylamino-1-(2-chloro-4-pyridyl)-2-propen-1-one is obtained; 1H-NMR (dimethyl sulfoxide): 2.98 (3H,s), 3.2 (3H,s), 5.9 (1H,d), 7.8 (3H.m), 8.5
Reaction SMILES: [Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21]Cl)=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1.[CH3:32][NH2:33]>CO>[Cl:1][C:2]1[O:3][C:4]2[CH:10]=[CH:9][C:8]([C:11]([CH2:30][CH3:31])=[C:12]([C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][NH:33][CH3:32])=[CH:15][CH:14]=3)=[CH:7][C:5]=2[CH:6]=1
Reactant: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)c1ccc2oc(Cl)cc2c1
Reactant: CN
Solvent: CO
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCNC)cc1)c1ccc2oc(Cl)cc2c1
Temperature: 85 °C
Yield: 48 %

Procedure:
To a stirred solution of 4-(2-(2-chlorobenzofuran-5-yl)-1-(4-(2-chloroethoxy)-phenyl)but-1-enyl)phenol (220 mg, 1.0 eq) in 15 mL MeOH was added 5 mL CH3NH2 (aq) and heated at 85° C. for 48 h. The organic solvent was removed in vacuo, water was added to the residue and extracted with EtOAc. The extract was dried, concentrated, and purified by column chromatography to give the desired product (105 mg, 48%, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.23 (s, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.14 & 7.08 (d, J=8.4 Hz, 2H), 7.00 (d, J=8.4 Hz, 1H), 6.87 & 6.78 (d, J=8.8 Hz, 2H), 6.73 & 6.69 (d, J=8.8 Hz, 2H), 6.49 & 6.42 (d, J=8.6 Hz, 2H), 6.45 (s, 1H), 4.10 & 3.92 (t, J=5.0 Hz, 2H), 3.00 & 2.89 (t, J=5.0 Hz, 2H), 2.53 & 2.46 (s, 3H), 2.50 (q, J=7.6 Hz, 2H), 0.91 (t, J=7.6 Hz, 3H); m/z=448[M+1]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([OH:12])[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][OH:12]
Reactant: C#CCCO
Reactant: Brc1ccccn1
Product: OCCC#Cc1ccccn1
Yield: 63.6 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromopyridine (10.3 g, 65.1 mmol) and but-3-yn-1-ol (5.08 mL, 67.1 mmol). Reaction time: 14 hours. The crude residue was purified by flash chromatography (DCM/AcOEt 3:7 to 1:9) to yield 6.10 g (41.4 mmol, 64%) of 4-(pyridin-2-yl)but-3-yn-1-ol as a brown oil.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][C:12]([C:14]1[CH:31]=[CH:30][C:17]2[CH2:18][CH:19]([CH2:25][C:26]([O:28]C)=[O:27])[C:20](=[O:24])[N:21]([CH3:23])[CH2:22][C:16]=2[CH:15]=1)=[O:13].O[Li].O.C1COCC1>O>[N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][NH:11][C:12]([C:14]1[CH:31]=[CH:30][C:17]2[CH2:18][CH:19]([CH2:25][C:26]([OH:28])=[O:27])[C:20](=[O:24])[N:21]([CH3:23])[CH2:22][C:16]=2[CH:15]=1)=[O:13]
Reactant: COC(=O)CC1Cc2ccc(C(=O)NCc3nc4ccccc4[nH]3)cc2CN(C)C1=O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CN1Cc2cc(C(=O)NCc3nc4ccccc4[nH]3)ccc2CC(CC(=O)O)C1=O
Yield: 35.9 %

Procedure:
A solution of methyl (±)-8-[[[(2-benzimidazolyl)methyl]amino]carbonyl]-2-methyl-3-oxo-2,3,4,5-tetrahydro-1H-2-benzazepine-4-acetate (0.10 g, 0.24 mmol), LiOH.H2O (0.013 g, 0.31 mmol), THF (2 mL), and H2O (2 mL) was stirred at RT for 18 h, then was concentrated to dryness. The residue was dissolved in H2O, and the solution was brought to pH 4-5 with 3N HCl. The resulting precipitate was collected by filtration and dried. Recrystallization from boiling isopropanol gave the title compound (0.035 g, 36%) as a colorless solid: 1H NMR (DMSO-d6) δ 9.13 (t, J=5.7 Hz, 1H), 7.79 (m, 1H), 7.48 (m, 2H), 7.23 (d, J=7.9 Hz, 1H), 7.14 (m, 2H), 5.32 (d, J=16.9 Hz, 1H), 4.69 (d, J=5.7 Hz, 2H), 4.03 (d, J=16.7 Hz, 1H), 3.79 (m, 1H), 3.14 (dd, J=18, 2 Hz, 1H), 2.90 (s, 3H), 2.70 (m, 2H), 2.38 (dd, J=11.4, 3 Hz, 1H); MS (ES) m/e 407 (M+H)+. Anal. Calcd for C22H22N4O4.1.5 H2O.0.5 C3H8O: C, 60.90; H, 6.31; N, 12.09. Found: C, 60.68; H, 6.05; N, 12.05.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31](=[O:34])[NH:32][CH3:33])=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C1C(=O)N([Cl:47])C(=O)C1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[C:11]([Cl:47])=[CH:10][C:9]([N:12]([C:17]2[C:36]([CH:37]3[CH2:39][CH2:38]3)=[CH:35][C:20]3[C:21]([C:31](=[O:34])[NH:32][CH3:33])=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[O:23][C:19]=3[CH:18]=2)[S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3cc(Cl)c(N)c(C(=O)OC)c3)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 60 °C
Yield: 99 %

Procedure:
A suspension of 55.0 g (100 mmol) of methyl 2-amino-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate in 320 mL of DMF was heated to 60° C. The resulting yellow solution was treated with 14.0 g (105 mmol) of NCS in one portion. The solution quickly darkened. After 5 minutes LCMS indicated complete conversion to the desired chloro compound. The solution was cooled to RT and diluted with 1 L of EtOAc. The resulting solution was washed with 5% aqueous NaCl (1×1 L), 5% aqueous sodium bisulfite (2×200 mL), saturated aqueous sodium bicarbonate (3×200 mL), and saturated aqueous brine (1×200 mL). The solution was dried over sodium sulfate and concentrated to dryness at reduced pressure to give 58.0 g (99%) of methyl 2-amino-3-chloro-5-(N-(5-cyclopropyl-2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-6-yl)methylsulfonamido)benzoate as a brown solid. This material was taken forward to the next step without purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.46 (q, J=4.42 Hz, 1H) 8.25 (s, 1H) 7.94-8.04 (m, 3H) 7.90 (d, J=2.63 Hz, 1H) 7.34-7.46 (m, 2H) 7.18 (s, 1H) 6.93 (br. s., 2H) 3.83 (s, 3H) 3.33 (s, 3H) 2.84 (d, J=4.59 Hz, 3H) 2.26-2.36 (m, 1H) 0.84-1.11 (m, 3H) 0.40 (br. s., 1H). LCMS (ESI): 586 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:4]([C:5](O)=O)[C:3]=1[OH:11].[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[SH:19]>>[OH:11][C:3]1[C:2]([NH2:1])=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]1[S:19][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]=1
Reactant: Nc1cccc(C(=O)O)c1O
Reactant: Nc1ccccc1S
Product: Nc1cccc(-c2nc3ccccc3s2)c1O

Procedure:
2(2'-hydroxy-3'-aminophenyl)benzothiazole was prepared by reacting 3-aminosalicylic acid with o-aminobenzenethiol according to the process of Example I. At the end of 6 hours the desired product precipitated and said product was filtered and air-dried.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:4][CH:3]=1.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:38][CH2:39][CH2:40][C:41]1[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=1>C(Cl)(Cl)Cl.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH:38][CH2:39][CH2:40][C:41]3[CH:46]=[CH:45][N:44]=[CH:43][CH:42]=3)=[O:14])=[CH:10][C:9]=2[CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:21][CH:22]=1
Reactant: CC(C)Cc1cc(C(=O)O)ccc1OCc1ccc(F)cc1
Reactant: NCCc1ccncc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)Cc1cc(C(=O)NCCc2ccncc2)ccc1OCc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 85.7 %

Procedure:
4-(4-fluorobenzyloxy)-3-isobutylbenzoic acid(1.51 g) was dissolved in chloroform(50 ml) and triethylamine(1.38 ml), and then diphenylphosphinic chloride(0.95 ml) was added thereto while being cooled with ice. After being stirred for 30 minutes, the mixture, with 4-(2-aminoethyl)pyridine(0.61 g) added thereto, was stirred for 2 hours at room temperature. The reaction mixture was washed with saturated sodium hydrogencarbonate aqueous solution and saturated brine successively, dried over sodium sulfate anhydride, and then concentrated under a vacuum. The residue was purified by silica gel column chromatography (chloroform:methanol=20:1). The resulting solid was recrystallized from n-hexane/ethyl acetate, thereby yielding 1.74 g of the aimed compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17](F)=[C:16]([CH3:21])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:32]([SH:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:22]([F:25])([F:24])[F:23])[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([S:39][CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[C:16]([CH3:21])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: SCc1ccccc1
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1SCc1ccccc1
Temperature: 90 °C
Yield: 80 %

Procedure:
To a solution of 5-(3,5-dichlorophenyl)-3-(4-fluoro-3-methylphenyl)-4,5-dihydro-5-(trifluoromethyl)isoxazole (i.e. the product from Step B of Example 2) (2.6 g, 6.65 mmol) and potassium carbonate (2.3 g, 16.6 mmol) in N,N-dimethylformamide (25 mL) was added benzyl mercaptan (0.782 mL, 6.65 mmol). The reaction mixture was heated at 90° C. for 4 h. The reaction mixture was then cooled and excess-water was added, and the mixture was extracted with ethyl acetate (2×100 mL). The organic extracts were dried (MgSO4) and concentrated under reduced pressure to provide a solid residue. The crude product was partially purified by silica gel column chromatography eluted with mixtures of hexane and ethyl acetate to afford a product containing the title compound (about 80% purity, 2.8 g).
Reaction SMILES: Cl.[F:2][C:3]1[CH:13]=[CH:12][C:11]2=[C:14]3[C:4]=1[O:5][CH2:6][C@@H:7]([CH3:33])[N:8]3[C:9]([C@@H:15]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]3[C:19]=1[N:20]=[CH:21][N:22]3C1CCCCO1)[CH3:16])=[N:10]2>O1CCOCC1.CO>[F:2][C:3]1[CH:13]=[CH:12][C:11]2=[C:14]3[C:4]=1[O:5][CH2:6][C@@H:7]([CH3:33])[N:8]3[C:9]([C@@H:15]([NH:17][C:18]1[N:26]=[CH:25][N:24]=[C:23]3[C:19]=1[N:20]=[CH:21][NH:22]3)[CH3:16])=[N:10]2
Reactant: C[C@H](Nc1ncnc2c1ncn2C1CCCCO1)c1nc2ccc(F)c3c2n1[C@H](C)CO3
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)c3c2n1[C@H](C)CO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
HCl (260 μL of a 4M solution in dioxane) was added to a solution of [(S)-1-((R)-6-fluoro-3-methyl-3,4-dihydro-5-oxa-1,2a-diazaacenaphthylen-2-yl)ethyl][9-(tetrahydropyran-2-yl)-9H-purin-6-yl]amine (93 mg, 0.21 mmol) in MeOH (1 mL) and the reaction was stirred at RT for 30 min. The crude reaction mixture was passed through a 2 g Isolute® SCX-2 cartridge, eluting with 2M NH3/MeOH. The basic fraction was concentrated in vacuo to give 439 (71 mg, 96%) as a white solid. LCMS (Method K): RT 2.50 min [M+H]+ 354.0. 1H NMR (CD3OD, 400 MHz): δ 8.21 (1H, s), 8.07 (1H, s), 7.07 (1H, dd, J=8.8, 3.1 Hz), 6.93 (1H, dd, J=11.9, 8.8 Hz), 5.89 (1H, br s), 4.88 (1H, qdd, J=6.6, 2.3, 1.6 Hz), 4.45 (1H, dd, J=11.8, 1.6 Hz), 4.22 (1H, dd, J=11.8, 2.3 Hz), 1.76 (3H, d, J=7.0 Hz), 1.44 (3H, d, J=6.6 Hz)
Reaction SMILES: [CH3:1][N:2]([CH:25]([CH3:27])[CH3:26])[C:3]1[C:4]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([CH3:24])=[CH:18]3)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([C:13]#[N:14])=[CH:8][CH:7]=2.[N-:28]=[N+:29]=[N-:30].[Na+]>CS(C)=O.O.[Zn+2].[Br-].[Br-]>[CH:25]([N:2]([CH3:1])[C:3]1[C:4]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][C:19]([CH3:24])=[CH:18]3)=[N:5][C:6]2[C:11](=[CH:10][C:9]([C:13]3[NH:30][N:29]=[N:28][N:14]=3)=[CH:8][CH:7]=2)[N:12]=1)([CH3:27])[CH3:26]
Reactant: Cc1cc2cc(-c3nc4ccc(C#N)cc4nc3N(C)C(C)C)ccc2[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: [Br-]
Agent: [Na+]
Agent: [Zn+2]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc2cc(-c3nc4ccc(-c5nnn[nH]5)cc4nc3N(C)C(C)C)ccc2[nH]1
Temperature: 130 °C
Reaction time: 8 h
Yield: 21.2 %

Procedure:
To a solution of 3-[methyl(propan-2-yl)amino]-2-(2-methyl-1H-indol-5-yl)quinoxaline-6-carbonitrile (200 mg, 0.56 mmol) in DMSO (20 ml) was added NaN3 (110 mg, 1.69 mmol) in water (2 ml), and ZnBr2 (64 mg, 0.28 mmol). The resulting solution was stirred overnight at 130° C. and then quenched with water (200 ml). The pH was adjusted to 3 with HCl (2N). Then the solution was extracted with ethyl acetate (4×50 ml) and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography (10%-15% dichloromethane in methanol) to afford N-isopropyl-N-methyl-3-(2-methyl-1H-indol-5-yl)-7-(1H-tetrazol-5-yl)quinoxalin-2-amine as an orange solid (47.4 mg, 21%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([N:14]([CH2:16][CH3:17])[CH3:15])=[N:8][C:9](Cl)=[CH:10][C:11]=1[CH3:12])=[O:5])[CH3:2].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1>[OH-].[Na+].CCOC(C)=O>[CH2:1]([O:3][C:4]([C:6]1[C:7]([N:14]([CH2:16][CH3:17])[CH3:15])=[N:8][C:9]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[CH:10][C:11]=1[CH3:12])=[O:5])[CH3:2]
Reactant: C1COCCN1
Reactant: CCOC(=O)c1c(C)cc(Cl)nc1N(C)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(C)cc(N2CCOCC2)nc1N(C)CC
Temperature: 135 °C
Yield: 41 %

Procedure:
A mixture of 4.0 g (15.6 mmol) 6-chloro-2-(ethyl(methyl)amino)-4-methyl-pyridine-3-carboxylic acid ethylester and 13.6 ml (155.8 mmol) morpholine was heated in the MW to 135° C. for 2 h. Then the mixture was diluted with a 1M aq. NaOH sol. and EtOAc. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 9:1) provided 2.0 g (6.4 mmol, 41%) 2-(ethyl(methyl)amino)-4-methyl-6-morpholino-pyridine-3-carboxylic acid ethylester.
Reaction SMILES: [C:1]([O:8]C([O-])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=O.O1CCCC1.[NH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][CH2:29][NH:28][CH2:27]2)=[O:25])=[CH:20][CH:19]=1>C(OCC)(=O)C>[NH2:17][C:18]1[CH:19]=[CH:20][C:21]([C:24]([CH:26]2[CH2:31][CH2:30][CH2:29][N:28]([C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:8])[CH2:27]2)=[O:25])=[CH:22][CH:23]=1
Reactant: Nc1ccc(C(=O)C2CCCNC2)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)c2ccc(N)cc2)C1
Reaction time: 1.5 h
Yield: 111.4 %

Procedure:
t-Butyl dicarbonate (0.562 ml, 2.45 mmol) was added to a tetrahydrofuran solution (12 ml) of (4-aminophenyl)(3-piperidinyl)methanone (500 mg, 2.45 mmol) obtained in 1) under ice-cooling, which was stirred for 1.5 hours. Ethyl acetate was added to the reaction mixture, which was washed with saturated sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting oily substance was purified by silica gel column chromatography (development solvent; hexane:ethyl acetate=1:1), to give the titled compound (831 mg).
Reaction SMILES: [CH3:1][C:2]1[C:29]([CH3:30])=[CH:28][C:5]2[N:6]([C:9]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[Li]CCCC.[Si:36]([O:43][C:44]1[C:45]([F:54])=[C:46]([CH:49]=[C:50]([CH2:52][CH3:53])[CH:51]=1)[CH:47]=[O:48])([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:38])[CH3:37]>C1COCC1>[Si:36]([O:43][C:44]1[C:45]([F:54])=[C:46]([CH:47]([C:7]2[N:6]([C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]3[CH:28]=[C:29]([CH3:30])[C:2]([CH3:1])=[CH:3][C:4]=3[N:8]=2)[OH:48])[CH:49]=[C:50]([CH2:52][CH3:53])[CH:51]=1)([C:39]([CH3:40])([CH3:42])[CH3:41])([CH3:38])[CH3:37]
Reactant: Cc1cc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c2cc1C
Reactant: CCc1cc(C=O)c(F)c(O[Si](C)(C)C(C)(C)C)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1cc(O[Si](C)(C)C(C)(C)C)c(F)c(C(O)c2nc3cc(C)c(C)cc3n2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 66.7 %

Procedure:
To a solution of intermediate 415.1 (100 mg, 0.257 mmol) in 2 mL THF at 0° C., was added BuLi (1.6 M in hexanes, 193 μL, 0.309 mmol). The mixture was stirred at 0° C. for 20 min, then a solution of 3-(tert-butyldimethylsilyloxy)-5-ethyl-2-fluorobenzaldehyde (188.3) (72.6 mg, 0.257 mmol) in 0.6 mL THF was added. The mixture was removed from the ice bath and stirred 70 min, then was quenched with sat. NH4Cl. The mixture was diluted with EtOAc, washed with H2O and brine, dried (Na2SO4) and concentrated. The crude residue was purified by flash chromatography (0 to 40% EtOAc/hexanes gradient) to afford 115 mg of intermediate 415.2. LCMS (2 min gradient) RT=2.24 min, 671.13 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21]C)=[CH:17][CH:16]=2)[N:8]([CH2:23][CH2:24][CH3:25])[C:7]1=[O:26].B(Br)(Br)Br>C(Cl)Cl.CCOCC>[CH3:1][C:2]1[CH:3]=[C:4]([CH:27]=[CH:28][C:29]=1[CH3:30])[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([OH:21])=[CH:19][CH:20]=2)[N:8]([CH2:23][CH2:24][CH3:25])[C:7]1=[O:26]
Reactant: CCCn1c(CCCc2ccc(OC)cc2)c(C)n(Cc2ccc(C)c(C)c2)c1=O
Agent: BrB(Br)Br
Solvent: CCOCC
Solvent: ClCCl
Product: CCCn1c(CCCc2ccc(O)cc2)c(C)n(Cc2ccc(C)c(C)c2)c1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 120.6 %

Procedure:
A 0° C. solution of 1-(3,4-dimethyl-benzyl)-4-[3-(4-methoxy-phenyl)-propyl]-5-methyl-3-propyl-1,3-dihydro-imidazol-2-one (0.145 g, 0.357 mmol) in CH2Cl2 (6 mL) was treated dropwise with BBr3 (0.10 mL, 1.06 mmol) and then stirred at 0° C. under N2 for 30 minutes. The reaction was diluted with Et2O and then quenched with ice and then water. The organic layer was dried (MgSO4), and the solvent removed in vacuo to afford 0.169 g (100%) 1-(3,4-dimethyl-benzyl)-4-[3-(4-hydroxy-phenyl)-propyl]-5-methyl-3-propyl-1,3-dihydro-imidazol-2-one that was utilized without purification.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:8]#[N:9].C([N-]C(C)C)(C)C.[Li+].Br[CH2:19][CH:20]1[O:24][CH2:23][CH2:22][O:21]1>C(OCC)(=O)C.C1CCCCC1>[C:8]([C:2]1([CH2:19][CH:20]2[O:24][CH2:23][CH2:22][O:21]2)[CH2:3][CH:4]2[CH2:7][CH:1]1[CH2:6][CH2:5]2)#[N:9]
Reactant: BrCC1OCCO1
Reactant: N#CC1CC2CCC1C2
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: N#CC1(CC2OCCO2)CC2CCC1C2
Yield: 92.1 %

Procedure:
7.2 g of norbornane-2-carbonitrile are reacted with 60 mmoles of lithium diisopropylamide (prepared from 8.2 ml of diisopropylamine and 40 ml of n-butyllithium) and with 7 g of 2-bromomethyl-1,3-dioxolane in analogy to Example 1a. After chromatography on silica gel with ethyl acetate/cyclohexane (1:6) as the mobile phase, 8.0 g of the title compound are obtained as an oil.