Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH:15]([C:17](O)=[O:18])[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]2=[O:26])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[N:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]2[CH2:16][CH:15]([C:17]([N:38]3[CH2:39][CH2:40][N:35]([C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=4[O:28][CH3:27])[CH2:36][CH2:37]3)=[O:18])[N:14]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:13]2=[O:26])(=[O:10])=[O:11])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1cccc(S(=O)(=O)N2CC(C(=O)O)N(c3ccccc3)C2=O)c1
Product: COc1cccc(S(=O)(=O)N2CC(C(=O)N3CCN(c4ccccc4OC)CC3)N(c3ccccc3)C2=O)c1

Procedure:
In analogy to example 1, (RS)-1-(3-methoxy-benzenesulfonyl)-2-oxo-3-phenyl-imidazolidine-4-carboxylic acid (step 4 of example 1) was reacted with 1-(2-methoxyphenyl)-piperazine to give the title compound as a colorless solid. MS: 551.3 ([M+H]+)
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][NH:3]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[C:55]1[CH:60]=[CH:59][C:58]([C:61]2[CH:66]=[CH:65][C:64]([F:67])=[CH:63][CH:62]=2)=[CH:57][CH:56]=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:67][C:64]1[CH:63]=[CH:62][C:61]([C:58]2[CH:59]=[CH:60][C:55]([N:6]3[CH2:5][CH2:4][NH:3][C@H:2]([CH3:1])[CH2:7]3)=[CH:56][CH:57]=2)=[CH:66][CH:65]=1
Reactant: Fc1ccc(-c2ccc(Br)cc2)cc1
Reactant: C[C@@H]1CNCCN1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(c2ccc(-c3ccc(F)cc3)cc2)CCN1
Temperature: 90 °C

Procedure:
A mixture of (R)-2-methylpiperazine (2.2 g, 22.1 mmol, 1.0 eq.), tris(dibenzylidene acetone)dipalladium(0) (607 mg, 0.66 mmol, 0.03 eq.) and (+/−)-BINAP (137 mg, 0.22 mmol; 0.01 eq.) in toluene was degassed 15 min under N2. 4-bromo-4′-fluorobiphenyl (4.99 g, 19.9 mmol, 0.90 eq.) was added followed by sodium tert-butoxide (2.97 g, 30.9 mmol, 1.4 eq.). The resulting mixture was heated to 90° C. for 14 h. The reaction was cooled to room temperature, filtered on a bed of cellite and washed with Et2O. The combined organic layers were then washed with H2O (3×), dried over MgSO4, filtered and evaporated to give a dark brown oil. This residue was purified by chromatography on silicagel (DCM/MeOH 20/80) to give the title product as off white solid (3.0 g, 50%) M+(ESI): 271.3. HPLC (Condition A), Rt: 2.8 min (HPLC purity: 99.8%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH2:14][OH:15])[NH:12][N:13]=2)=[CH:5][CH:4]=1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:10]=[C:11]([CH:14]=[O:15])[NH:12][N:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cc(CO)[nH]n2)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2cc(C=O)[nH]n2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
4.06 g (41.0 mmol) of manganese dioxide was added to a chloroform solution (30 ml) of 1.67 g (8.20 mmol) of the obtained [5-(4-methoxyphenyl)-2H-pyrazol-3-yl]-methanol, and stirred at 80° C. for 8 hours. The reaction liquid was filtered through Celite, and concentrated under reduced pressure to obtain 762 mg (yield: 44%) of 5-(4-methoxyphenyl)-2H-pyrazole-3-carbaldehyde as a white solid.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[N:11]1[C:19]2[C:14](=[N:15][CH:16]=[CH:17][CH:18]=2)[NH:13][C:12]=1[CH2:20][C:21]([O:23]CC)=O.[NH2:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)[C:28]=1[C:29]#[N:30]>C1COCC1>[NH2:30][C:29]1[C:28]2[C:27](=[CH:34][CH:33]=[CH:32][C:31]=2[N:35]2[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]2)[NH:26][C:21](=[O:23])[C:20]=1[C:12]1[NH:13][C:14]2=[N:15][CH:16]=[CH:17][CH:18]=[C:19]2[N:11]=1
Reactant: CCOC(=O)Cc1nc2cccnc2[nH]1
Reactant: C[C@@H]1CN(c2cccc(N)c2C#N)C[C@H](C)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1CN(c2cccc3[nH]c(=O)c(-c4nc5cccnc5[nH]4)c(N)c23)C[C@H](C)O1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
LiHMDS (3.0 eq) was added to ethyl 3H-imidazo[4,5-b]pyridin-2-ylacetate (1.0 eq) in THF at −78° C. After 20 minutes, a solution of 2-amino-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]benzonitrile (1.1 eq) in THF was added. The resulting mixture was allowed to warm to room temperature, stirred for 2 hours and then heated to 60° C. overnight. The mixture was cooled to 0° C. and quenched with an aqueous saturated NH4Cl solution. The aqueous phase was extracted with CH2Cl2 (5 times) and the organic extracts were collected, dried (Na2SO4), and concentrated. The crude product was purified by HPLC. LC/MS m/z 391.2 (MH+), Rt 2.35 minutes.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:23])=[N:8][N:9]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=3[CH3:21])=[C:12]([CH3:22])[O:11][C:10]=12)=[O:5])C.O.[OH-].[Li+]>CCO.O>[CH3:21][C:15]1[CH:16]=[C:17]([CH3:20])[CH:18]=[CH:19][C:14]=1[C:13]1[N:9]2[N:8]=[C:7]([CH3:23])[C:6]([C:4]([OH:5])=[O:3])=[C:10]2[O:11][C:12]=1[CH3:22]
Reactant: CCOC(=O)c1c(C)nn2c(-c3ccc(C)cc3C)c(C)oc12
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccc(-c2c(C)oc3c(C(=O)O)c(C)nn23)c(C)c1
Temperature: 45 °C

Procedure:
A stirred mixture of 3-(2,4-dimethyl-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazole-7-carboxylic acid ethyl ester (224 mg, 0.72 mmol, 1 eq.) and lithium hydroxide monohydrate (150 mg, 3.59 mmol, 5 eq.) in EtOH (4 ml) and water (2 ml) is heated at 45° C. for 14 h. The reaction mixture is cooled to RT then concentrated under reduced pressure. The residue is dissolved in water and the resulting aqueous solution is neutralized using 2M HCl in water (1.8 ml). The resulting precipitate is filtered, washed with water and dried under vacuum to yield the title compound as a white solid. The crude compound is used without further purification. HPLC: AtRet=2.12; MS: m/z 285.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 2.20 (s, 3H), 2.33 (s, 3H), 2.36 (s, 3H), 2.39 (s, 3H), 7.16 (m, 1H), 7.24 (br. s., 1H), 7.31 (m, 1H), 12.30 (br. s., 1H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[NH:23][C:17]3[N:18]=[CH:19][N:20]=[C:21]([Cl:22])[C:16]=3[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[OH-].[Na+]>C(Cl)Cl.C(O)(C(F)(F)F)=O.O.O>[Cl:22][C:21]1[C:16]2[CH:15]=[C:14]([C:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=3)[NH:23][C:17]=2[N:18]=[CH:19][N:20]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: O
Product: Clc1ncnc2[nH]c(C3=CCNCC3)cc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound Intermediate 1 (2.60 g, 7.77 mmol) in 10 ml DCM, 30 ml TFA/water 95:5 were added. The resulting mixture was stirred at room temperature for 2 hours. The mixture was diluted with water and basified by addition of 2N sodium hydroxide and extracted with DCM. The organic layer was washed with brine (2×), dried over sodium sulfate and evaporated. The residue was purified by flash chromatography on silica (cyclohexane/EtOAc 1:1 to EtOAc) to afford the compound Intermediate 2 as a beige solid.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:36][CH2:37][CH2:38][CH2:39][N:40]1[C:44]2=[N:45][CH:46]=[CH:47][CH:48]=[C:43]2[C:42]([C:49]2[C:50](=[O:68])[NH:51][C:52](=[O:67])[C:53]=2[C:54]2[C:59]3[O:60][C:61]4[CH:66]=[CH:65][CH:64]=[CH:63][C:62]=4[C:58]=3[CH:57]=[CH:56][CH:55]=2)=[CH:41]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH:57]1[C:58]2[C:62]3[CH:63]=[CH:64][CH:65]=[CH:66][C:61]=3[O:60][C:59]=2[C:54]([C:53]2[C:52](=[O:67])[NH:51][C:50](=[O:68])[C:49]=2[C:42]2[C:43]3[C:44](=[N:45][CH:46]=[CH:47][CH:48]=3)[N:40]([CH2:39][CH2:38][CH2:37][OH:36])[CH:41]=2)=[CH:55][CH:56]=1
Reactant: CC(C)(C)[Si](OCCCn1cc(C2=C(c3cccc4c3oc3ccccc34)C(=O)NC2=O)c2cccnc21)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: O=C1NC(=O)C(c2cccc3c2oc2ccccc23)=C1c1cn(CCCO)c2ncccc12
Reaction time: 18 h
Yield: 71 %

Procedure:
TBAF (0.7 mL, 0.06 mmol; 1 M solution in THF) was added dropwise to a solution of 3-{1-[3-(tert-butyldiphenylsilanyloxy)-propyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}-4-dibenzofuran-4-yl-pyrrole-2,5-dione Compound 20a (0.03 g, 0.04 mmol) in THF (1 mL) under nitrogen. After 18 hours, the mixture was concentrated and purified by column chromatography (SiO2) to give Compound 29 (0.013 g, 71%) as a yellow solid. 1H NMR (300 MHz, Acetone-d6) δ 8.28 (s, 1H), 8.18 (dd, J=7.7, 1.3 Hz 1H), 8.02 (ddd, J=8.3, 4.5, 1.5 Hz, 2H), 7.74 (dd, J=7.5, 1.1 Hz, 1H), 7.51 (m, 1H), 7.32 (m, 2H), 7.17 (m, 1H), 6.64 (dd, J=7.9, 1.5 Hz, 1H), 6.53 (dd, J=8.1, 4.7 Hz, 1H), 4.50 (t, J=6.6 Hz, 2H), 3.49 (m, 2H), 2.04 (m, 2H); MS (ES) m/z: 438 (M+H+).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[CH3:6][NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Br)C#C>CCCCCCC.CCOCC.C1(C)C=CC=CC=1>[CH3:6][N:7]([CH2:3][C:2]#[CH:1])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CNc1ccccc1
Reactant: [Li]CCCC
Agent: C#CCBr
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCCCCCC
Product: C#CCN(C)c1ccccc1
Temperature: -10 °C
Reaction time: 8 h

Procedure:
34 ml of a 2.7M solution of n-butyllithium in n-heptane are added dropwise at room temperature under nitrogen in the course of 1 hour to a solution of 10 g (93 mmol) of N-methylaniline in 100 ml of absolute ether. The temperature increases to reflux of the reaction mass. After 1 hour's reflux, the yellow solution is cooled to −10° C. and then in the course of 30 minutes a solution of 11.3 g (102 mmol) of propargyl bromide in toluene is added dropwise. The mixture is then stirred at room temperature for 8 hours. After customary aqueous working-up, the product of formula (101a) is purified by distillation. A yellow oil is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16](Br)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:21]1([CH2:26][CH2:27][NH2:28])[CH2:25][CH2:24][CH2:23][CH2:22]1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC([O-])(C)C.[Na+]>O1CCOCC1.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]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([NH:28][CH2:27][CH2:26][N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)c2)CC1
Reactant: NCCN1CCCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(NCCN3CCCC3)c2)CC1
Temperature: 120 °C
Yield: 61.6 %

Procedure:
A mixture of 4-(3-bromo-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (300 mg, 0.88 mmol), 2-pyrrolidin-1-yl-ethylamine (0.165 mL, 1.32 mmol), Pd2(dba)3 (40 mg, 0.044 mmol), xantphos (50 mg, 0.088 mmol) and NaOt-Bu (124 mg, 1.32 mmol) in dioxane (15 mL) was bubbled with nitrogen in a sealed tube for 10 min. The mixture was heated at 120° C. for 2 h. After this time the mixture was cooled and filtered through celite and concentrated. Chromatography on silica (ethyl acetate/MeOH) provided the title compound (203 mg, 62%). m/z (M+1) 375.53
Reaction SMILES: Cl.[F:2][CH:3]([F:32])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH:15]3[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]3)=[CH:11][CH:12]=2)[CH:7]=[C:6]1[C:24]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:25].[CH3:33][N:34]([CH3:38])[C:35](Cl)=[O:36]>>[CH3:33][N:34]([CH3:38])[C:35]([N:29]1[CH2:28][CH2:27][N:26]([C:24]([C:6]2[N:5]([CH2:4][CH:3]([F:2])[F:32])[C:13]3[C:8]([CH:7]=2)=[CH:9][C:10]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([CH:21]([CH3:23])[CH3:22])[CH2:17][CH2:16]2)=[CH:11][CH:12]=3)=[O:25])[CH2:31][CH2:30]1)=[O:36]
Reactant: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCNCC2)n3CC(F)F)CC1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(C(=O)N(C)C)CC2)n3CC(F)F)CC1

Procedure:
The title compound was prepared in analogy to example 51, from [1-(2,2-difluoro-ethyl)-5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-piperazin-1-yl-methanone hydrochloride and N,N-dimethylcarbamoyl chloride. Off-white solid. MS (m/z): 506.4 (M+H)+.
Reaction SMILES: CN1C2C=CC=CC=2C2C1=CC=CC=2.[S:15]([O:19][C@H:20]1[C@@H:24]([CH2:25][O:26][C:27]([O:29][CH3:30])=[O:28])[O:23][C@@H:22]([N:31]2[CH:39]=[C:37]([CH3:38])[C:35](=[O:36])[NH:34][C:32]2=[O:33])[C@@H:21]1OC(=O)C1C=CC=C(C(F)(F)F)C=1)([CH3:18])(=[O:17])=[O:16]>C(O)(C)C>[S:15]([O:19][C@H:20]1[C@@H:24]([CH2:25][O:26][C:27]([O:29][CH3:30])=[O:28])[O:23][C@@H:22]([N:31]2[CH:39]=[C:37]([CH3:38])[C:35](=[O:36])[NH:34][C:32]2=[O:33])[CH2:21]1)([CH3:18])(=[O:16])=[O:17]
Reactant: COC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@H](OC(=O)c2cccc(C(F)(F)F)c2)[C@H]1OS(C)(=O)=O
Agent: Cn1c2ccccc2c2ccccc21
Solvent: CC(C)O
Product: COC(=O)OC[C@H]1O[C@@H](n2cc(C)c(=O)[nH]c2=O)C[C@H]1OS(C)(=O)=O
Reaction time: 20 h
Yield: 68.9 %

Procedure:
A 500 mL pyrex photochemical reaction vessel equipped with a nitrogen inlet, magnetic stirrer, reflux condenser, quartz immersion well and a 450 watt medium pressure mercury-vapor immersion lamp surrounded by a uranium absorption sleeve was charged with 90% aqueous isopropyl alcohol (500 mL), N-methyl carbazole (1.46 g, 8.05 mmoles) and 1-(3-O-mesyl-5-O-(methoxycarbonyl)-2-O-(m-trifluoromethyl-benzoyl)-β-D-xylofuranosyl)thymine (3.80 g, 6.71 mmoles) from Example A3. After bubbling nitrogen through the solution for 45 minutes the solution was photolyzed for 20 hours. The solvent was concentrated to a 50 mL volume by rotary evaporation and the remaining liquid was diluted with chloroform (300 mL). The organic solution was washed with 10% aqueous NaHCO3 (2×200 ml) and the solvent was removed by rotary evaporation. The residual oil was purified by flash chromatography (3-inch diameter column containing 15 inches of flash silica gel). The column was eluted with 95:5/CHCl3 :CH3OH while collecting 125 mL fractions. Fractions 15-19 contained pure product and these fractions were concentrated in vacuo affording 1.75 g (68.9%) of 1-[2-deoxy-3-O-mesyl-5-O-methoxycarbonyl-β-D-threo-pentofuranosyl]thymine as a white crystalline solid. mp: 70°-72° C.; TLC Rf =0.51. Silica gel, CHCl3 : CH3OH/90/10
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.[Cl:13][C:14]1[CH:15]=[C:16]([C:24]2[O:28][N:27]=[C:26]([C:29]3[CH:30]=[CH:31][CH:32]=[C:33]4[C:37]=3[N:36]([CH3:38])[CH:35]=[C:34]4[CH:39]=O)[N:25]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH:21]([CH3:23])[CH3:22].[OH-].[Na+]>C(O)C>[Cl:13][C:14]1[CH:15]=[C:16]([C:24]2[O:28][N:27]=[C:26]([C:29]3[CH:30]=[CH:31][CH:32]=[C:33]4[C:37]=3[N:36]([CH3:38])[CH:35]=[C:34]4[CH2:39][N:2]3[CH2:7][CH2:6][CH:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]3)[N:25]=2)[CH:17]=[CH:18][C:19]=1[O:20][CH:21]([CH3:22])[CH3:23]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)cn(C)c34)no2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)C1CCN(Cc2cn(C)c3c(-c4noc(-c5ccc(OC(C)C)c(Cl)c5)n4)cccc23)CC1
Reaction time: 0.5 h
Yield: 57.3 %

Procedure:
Ethyl 4-piperidinecarboxylate hydrochloride (969 mg) and 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole-3-carbaldehyde (D61) (396 mg) was added to a solution of NaOH (200 mg) in ethanol (10 mL). After stirring for 0.5 hour, ethanol was evaporated off and then dichloromethane (40 mL) containing AcOH (0.5 mL) was added to the residue. NaBH(OAc)3 (1.06 g) was added to the above mixture. The reaction mixture was stirred at room temperature overnight and then terminated by saturated NaHCO3 solution. The organic layer was separated and washed with water and brine. After the solvent was evaporated off the residue was purified by Mass Directed AutoPrep to afford ethyl 1-{[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indol-3-yl]methyl}-4-piperidinecarboxylate (D79) (308 mg) as a yellow solid. MS (ES): C29H33ClN4O4 requires 536; found 537.3 (M+H+).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:14])[C:7]2[C:12]([CH:13]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:14][N:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[C:5]1[CH2:3][NH:2][CH3:1]
Reactant: CNC(=O)c1cc2ccccc2n1C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CNCc1cc2ccccc2n1C
Reaction time: 23 h
Yield: 92.9 %

Procedure:
A 3-liter 3-necked roundbottom flask equipped with overhead stirring was charged with N,1-dimethyl-1H-indole-2-carboxamide (23.45 g, 124.58 mmole) and anhydrous THF (170 mL). The solution was stirred while a solution of LiAlH4 in THF (1.0 M, 250 mL, 250 mmole) was added via syringe. Gas was evolved during the addition of the first 50 mL of LiAlH4 solution. When the addition was complete, the resulting light yellow solution was heated at gentle reflux. After 23 hr, the reaction was cooled in ice and quenched by the sequential dropwise addition of H2O (9.5 mL), 15% NaOH (9.5 mL), and H2O (28.5 mL). The mixture was stirred for 15 min, then was filtered through Celite®, and the filter pad was washed thoroughly with THF. The filtrate was concentrated and the residue was flash chromatographed on silica gel (10% MeOH/CHCl3 containing 0.5% conc. NH4OH). The title compound (20.17 g, 93%) was obtained as a light yellow oil: 1H NMR (300 MHz, CDCl3) δ 7.56 (d, J=7.8 Hz, 1H), 7.02-7.35 (m, 3H), 6.38 (s, 1H), 3.88 (s, 2H), 3.75 (s, 3H), 2.49 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:16]=[C:17]([Cl:19])[CH:18]=1)[C:5]([CH:7]1[CH2:14][C:10]2[S:11][CH:12]=[CH:13][C:9]=2[C:8]1=O)=O.O.[NH2:21][NH2:22].C(O)(=O)C>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:7]3[CH2:14][C:10]4[S:11][CH:12]=[CH:13][C:9]=4[C:8]=3[NH:22][N:21]=2)[CH:16]=[C:17]([Cl:19])[CH:18]=1
Reactant: NN
Reactant: O=C(c1cc(Cl)cc(Cl)c1)C1Cc2sccc2C1=O
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: Clc1cc(Cl)cc(-c2n[nH]c3c2Cc2sccc2-3)c1
Temperature: 25 °C
Yield: 89.6 %

Procedure:
5-(3,5-Dichloro-benzoyl)-5,6-dihydro-cyclopenta[b]thiophen-4-one (1.5 g, 4.8 mmol), hydrazine monohydrate (0.35 mL, 7.2 mmol), glacial acetic acid (0.8 mL) and ethanol (15 mL) were heated at 100° C. under nitrogen for 4 hr. The mixture was cooled to 25° C. and concentrated under reduced pressure to give a solid which was recrystallized from ethanol to provide the corresponding 6-(3,5-Dichloro-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (1.33 g, 4.3 mmol) as yellow solid in 90% yield.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.[Br:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.C(OCC)(=O)C>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([O:5][CH:3]2[CH2:4][O:1][CH2:2]2)=[CH:9][CH:8]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OC1COC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Brc1ccc(OC2COC2)cc1
Temperature: 110 °C
Reaction time: 17 h
Yield: 52.7 %

Procedure:
To oxetan-3-ol (112 mg, 1.5 mmol) in THF (5 mL) was added 4-bromophenol (200 mg, 1.16 mmol), polymeric triphenylphosphine (0.5 g, 1.5 mmol) and DIAD (305 mg, 1.5 mmol). The reaction mixture was degassed with nitrogen for 2 min and stirred at 110° C. for 17 hours. The cooled reaction mixture was filtered and the filtrate was concentrated in vacuo to give a residue, which was dissolved in ethyl acetate (50 mL) and washed with 2 M NaOH (3×15 mL) and brine (2×20 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give a residue, which was purified by flash chromatography on silica gel eluting with EtOAc/petroleum ether (1:10) to give 3-(4-bromophenoxy)oxetane (140 mg, 53%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.37 (d, 2H), δ 6.55 (d, 2H), 5.19-5.13 (m, 1H), 4.97-4.94 (m, 2H), 4.76-4.73 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH2:16]([O:18][C:19](=[O:29])[CH:20]([NH2:28])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[CH3:17]>>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:28][CH:20]([C:19]([O:18][CH2:16][CH3:17])=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1)[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: CCOC(=O)C(N)Cc1ccccn1
Product: CCOC(=O)C(Cc1ccccn1)Nc1nc2ccc(Cl)cc2cc1C(=O)O

Procedure:
In close analogy to the procedure described in Example 43, 2,6-dichloro-quinoline-3-carboxylic acid is reacted with 2-amino-3-pyridin-2-yl-propionic acid ethyl ester to provide after chromatographical separation the title compound in moderate yield.
Reaction SMILES: Cl[C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=2[F:16])[S:4][N:3]=1.[O:17]([CH3:19])[Na]>CO>[F:16][C:10]1[CH:11]=[C:12]([CH3:15])[CH:13]=[CH:14][C:9]=1[C:5]1[S:4][N:3]=[C:2]([O:17][CH3:19])[C:6]=1[C:7]#[N:8]
Reactant: CO[Na]
Reactant: Cc1ccc(-c2snc(Cl)c2C#N)c(F)c1
Solvent: CO
Product: COc1nsc(-c2ccc(C)cc2F)c1C#N
Temperature: 75 °C
Reaction time: 3 h

Procedure:
Into a 250-mL round-bottom flask, was placed 3-chloro-5-(2-fluoro-4-methylphenyl)-1,2-thiazole-4-carbonitrile (2.0 g, 7.91 mmol, 1.00 equiv), methanol (100 mL), NaOCH3 (2.1 g, 38.87 mmol, 4.91 equiv). The resulting solution was stirred for 3 h at 75° C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 1.5 g (76%) of 5-(2-fluoro-4-methylphenyl)-3-methoxy-1,2-thiazole-4-carbonitrile as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:28]3[CH:29]=[CH:30][C:31]4[C:35]([CH:36]=3)=[N:34][N:33]([CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH:32]=4)[CH:9]=[C:10]([CH:11]3[O:16][CH2:15][CH:14]4[CH2:17][N:18](C(OC(C)(C)C)=O)[CH2:19][CH2:20][N:13]4[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1>ClCCl.FC(F)(F)C(O)=O>[CH2:37]([N:33]1[CH:32]=[C:31]2[C:35]([CH:36]=[C:28]([C:8]3[CH:9]=[C:10]([CH:11]4[O:16][CH2:15][CH:14]5[CH2:17][NH:18][CH2:19][CH2:20][N:13]5[CH2:12]4)[N:6]4[C:7]=3[C:2]([NH2:1])=[N:3][CH:4]=[N:5]4)[CH:29]=[CH:30]2)=[N:34]1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CC(C)(C)OC(=O)N1CCN2CC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)OCC2C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncnn2c(C3CN4CCNCC4CO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reaction time: 0.5 h
Yield: 80 %

Procedure:
To a stirred solution of tert-butyl 3-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]hexahydropyrazino[2,1-c][1,4]oxazine-8(1H)-carboxylate (75 mg, 0.13 mmol) in dichloromethane (5 mL), trifluoroacetic acid (1 mL) was added. The reaction was allowed to stir for 30 minutes and concentrated. The mixture was partitioned between ethyl acetate (30 mL) and pH 14 saturated aqueous NaCl (10 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was triturated with Et2O to obtain 50 mg (80%) of the desired product. 1H-NMR (DMSO-d6) 8.53 (s, 1H), 7.90 (s, 1H), 7.78 (d, 1H), 7.57 (s, 1H), 7.35-7.28 (m, 5H), 7.11 (d, 1H), 6.70 (s, 1H), 5.64 (s, 2H), 5.11 (d, 1 H), 3.71 (dd, 1 H), 3.33-3.26 (m, 1H), 2.91 (d, 1H), 2.74-2.58 (m, 4H), 2.39 (t, 1H), 2.21-2.00 (m, 4H); LC-MS [M+H]+=481, RT=2.00 min.