Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:21])[C:5]([NH2:20])=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[Cl:19].[F:22][C:23]([F:34])([F:33])[C:24]([F:32])([F:31])[C:25](F)(F)C(O)=O>>[Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:16])[F:17])=[CH:11][C:10]=2[Cl:19])=[CH:6][C:5]2[NH:20][C:25]([C:24]([F:32])([F:31])[C:23]([F:34])([F:33])[F:22])=[N:21][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Oc2ccc(C(F)(F)F)cc2Cl)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)F
Product: FC(F)(F)c1ccc(Oc2cc3[nH]c(C(F)(F)C(F)(F)F)nc3cc2Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
To a solution of 4-chloro-5-[2-chloro-4-(trifluoromethyl)phenoxy]benzene-1,2-diamine (50 mg, 0.15 mmol) was added heptafluorobutanoic acid (3 ml). The resulting solution was stirred overnight at 80° C. and quenched with the addition of water (100 ml). The pH value of the solution was adjusted to 8 with potassium carbonate, extracted with ethyl acetate (3×50 ml), organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue which was purified by Prep-HPLC to produce 5-chloro-6-[2-chloro-4-(trifluoromethyl)phenoxy]-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a light yellow solid (41.2 mg, 54%).
Reaction SMILES: [H-].[Na+].CCO.[C:6]([CH2:14][C:15]#[N:16])(=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:18]1[N:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH2:22])=[O:21]>[NH4+].[Cl-]>[C:7]1([C:6]2[NH:22][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][CH:25]=[N:26][C:18]=3[C:14]=2[C:15]#[N:16])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: N#CCC(=O)c1ccccc1
Reactant: NC(=O)c1cccnc1Cl
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CCO
Product: N#Cc1c(-c2ccccc2)[nH]c(=O)c2cccnc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
NaH (36 mg 1.5 mmol) was added in portions to anhydrous EtOH (4 mL) under N2. After 30 minutes, benzoylacetonitrile (218 mg, 1.5 mmol) was added, and the reaction mixture was allowed to stir under a nitrogen atmosphere for 30 minutes. 2-Chloronicotinamide (236 mg, 1.5 mmol) and CuOAc (36 mg, 0.3 mmol) were then added and the reaction mixture was heated to 50° C. The temperature was maintained for 10 days, after which time the reaction mixture was allowed to cool, was diluted with a 10% aqueous solution of NH4Cl (25 mL), and extracted with three portions of EtOAc (30 mL). The combined extracts were washed with brine, dried and evaporated to an oil which was triturated with CH2Cl2. The resulting solid (39 mg) was recrystallized from EtOH providing 30 mg (7.3%) of the title compound, mp 292-5° C.
Reaction SMILES: C([Li])(C)(C)C.BrC1C(C)=CC(C)=CC=1C.[Cl:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH3:24])[N:18]=1.[CH:25](=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>O.O1CCCC1.CCCCC>[Cl:16][C:17]1[N:18]=[C:19]([O:23][CH3:24])[C:20]([CH:25]([OH:32])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:21][CH:22]=1
Reactant: O=Cc1ccccc1
Reactant: COc1cccc(Cl)n1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1nc(Cl)ccc1C(O)c1ccccc1
Reaction time: 1 h

Procedure:
100 ml of a pentane solution containing 1.56 mol of tert-butyllithium was slowly added dropwise into a solution of 200 ml of tetrahydrofuran containing 11.9 ml of 2-bromomesitylene at −78° C. under cooling. After stirring at the same temperature for one hour, 7.2 ml of 2-chloro-6-methoxypyridine was slowly added dropwise thereinto. After stirring under ice-cooling for one hour and then at room temperature for one hour, 8.5 ml of benzaldehyde was added thereto under ice-cooling, followed by stirring at room temperature for further one hour. Water was added to the reaction solution, followed by extracting with ethyl acetate. The organic phase was washed with brine and the solvent was removed. The residue was subjected to silica gel column chromatography and eluted with hexane and then with hexane/ethyl acetate (7:1), to give 15.0 g of the target compound.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8](=S(=O)=O)[C:7]([O:12][CH3:13])=[N:6][C:5](C)=[N:4]1.[OH:15][CH:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:12][CH3:13])[N:6]=[C:5]([O:15][CH:16]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])[N:4]=1
Reactant: COC(=O)C(O)C(C)(C)C
Reactant: COC1=NC(C)=NC(OC)C1=S(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)C(Oc1nc(OC)cc(OC)n1)C(C)(C)C
Reaction time: 3 h

Procedure:
2.18 g (10.0 mmol) of 4,6-dimethoxy-2-methyl-sulfonylpyrimidine and 1.62 g (11.0 mmol) of methyl (+/-)-2-hydroxy-3,3-dimethylbutanoate were heated in the presence of 2.07 g (15.0 mmol) of potassium carbonate in 20 ml of N,N-dimethylformamide to 60° with stirring. After 3 hours, the solvent was removed in a rotary evaporator at 60° C./20 mbar. The residue was taken up in 40 ml of water and 40 ml of ethyl acetate. After the organic phase had been separated off, the aqueous phase was again extracted with 40 ml of ethyl acetate. The combined organic phases was washed with water, dried over magnesium sulfate and evaporated. The title product was obtained in a yield of 2.76 g (93.8 percent of theory) in the form of pale yellowish crystals (GC content 96.6 percent).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](Br)=[CH:5][CH:4]=1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:15]2[CH:16]=[CH:17][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(-c2ccc(OC)cc2)cc1
Yield: 87 %

Procedure:
From 4-methoxy-bromobenzene and 4-methoxyphenyl boronic acid, yield 87%; mp 178-180° C. (lit.,1 179-180° C.); IR: 1599, 1493, 1466 and 1290; 1H NMR (400 MHz; CDCl3): 7.47 (4H, d, J 8.7), 6.96 (4H, d, J 8) and 3.84 (6H, s); 13C NMR (CDCl3): 159.1, 133.9, 128.1, 114.5 and 55.7; m/z (EI) 214 (100%, M+), 171 (70), 128 (50) and 69 (40)(Found: M+, 214.099. C14H14O2 requires M, 214.099).
Reaction SMILES: [CH3:1][C:2]([CH:4]=[C:5]([CH3:7])[CH3:6])=[CH-:3].[K+].[CH3:9][Si:10](Cl)([CH3:12])[CH3:11]>C1COCC1>[CH3:9][Si:10]([CH3:12])([CH3:11])[CH2:3][C:2]([CH3:1])=[CH:4][C:5]([CH3:7])=[CH2:6]
Reactant: C[Si](C)(C)Cl
Reactant: [CH-]=C(C)C=C(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=C(C)C=C(C)C[Si](C)(C)C
Reaction time: 8 h

Procedure:
A solution of 15.1 g (112 mmol) of potassium 2,4-dimethylpentadienide in 250 mL of THF was added to a -35° C. solution of 36.0 g (33.1 mmol) of trimethylsilyl chloride in 200 mL of THF. The yellow-orange color of the pentadienyl anion faded instantly upon addition. The reaction mixture was stirred overnight. The solvent was removed under reduced pressure, the residue was extracted with pentane, the resulting solution was filtered from insolubles and concentrated under reduced pressure to give the product as a pale yellow liquid. The yield was 11.65g, 61.5%. 1H NMR(C6D6) δ 5.63 (s, 1H), 4.95 (s, 1H), 4.92 (s, 1H), 1.83 (s, 3H), 1.81 (s, 2H), 1.68 (s, 3H), 0.03 (s, 9H). 13C NMR (C6D6) δ 142.5, 136.0 125.2, 113.1, 27.8, 24.5, -0.2.
Reaction SMILES: [CH3:1][CH2:2][C:3]1[CH2:14][N:12]2[CH2:13][C@@H:5]([CH2:6][C@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:27]=[C:26]4[C@@:28]56[C@@H:39]([N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:53][CH3:54])[C@@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@H:37]([O:47][C:48]([CH3:50])=[O:49])[C@:33]3([CH2:51][CH3:52])[CH:34]=[CH:35][CH2:36][N:31]([C@H:32]53)[CH2:30][CH2:29]6)[C:8]3[NH:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:9]=3[CH2:10][CH2:11]2)[CH:4]=1.CN(C)C=[O:62]>>[CH3:1][CH2:2][C@@:3]12[O:62][C@@H:4]1[C@H:5]1[CH2:13][N:12]([CH2:11][CH2:10][C:9]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[NH:21][C:8]=3[C@@:7]([C:55]([O:57][CH3:58])=[O:56])([C:22]3[CH:27]=[C:26]4[C@:28]56[C@@H:32]7[C@:33]([CH2:51][CH3:52])([C@@H:37]([O:47][C:48]([CH3:50])=[O:49])[C@:38]([OH:46])([C:42]([O:44][CH3:45])=[O:43])[C@@H:39]5[N:40]([CH3:41])[C:25]4=[CH:24][C:23]=3[O:53][CH3:54])[CH:34]=[CH:35][CH2:36][N:31]7[CH2:30][CH2:29]6)[CH2:6]1)[CH2:14]2
Reactant: CCC1=C[C@H]2CN(CCc3c([nH]c4ccccc34)[C@@](C(=O)OC)(c3cc4c(cc3OC)N(C)[C@H]3[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]5(CC)C=CCN6CC[C@]43[C@@H]65)C2)C1
Reactant: CN(C)C=O
Product: CC[C@]12CN3CCc4c([nH]c5ccccc45)[C@@](C(=O)OC)(c4cc5c(cc4OC)N(C)[C@H]4[C@@](O)(C(=O)OC)[C@H](OC(C)=O)[C@]6(CC)C=CCN7CC[C@]54[C@@H]76)C[C@H](C3)[C@H]1O2
Reaction time: 18 h
Yield: 61 %

Procedure:
0.6 g. of 3',4'-anhydro-vinblastine are dissolved in 75 ml. of dimethyl formamide. Oxygen is bubbled through the solution slowly for 10 minutes, whereupon the reaction mixture is allowed to stand at room temperature for 16 to 20 hours. The pH is adjusted to 8.5 with a concentrated aqueous ammonium hydroxide solution. The alkaline mixture obtained is extracted with three 100-ml. portions of benzene. The combined extracts are dried with sodium sulphate, filtered and the filtrate is evaporated. The residue is dissolved in 3 ml. of ethanol and allowed to stand at 5° C. for 16 hours. The precipitated crystals are filtered off, washed with a small portion of cool methanol and dried. 0.366 mg. (61.0%) of the named compound is obtained.
Reaction SMILES: [CH2:1]([O:3][CH:4]=[CH:5][CH2:6][CH2:7][CH:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH:10]=[CH:11]2)[CH3:2].C(O)C[OH:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH:9]12[CH2:14][CH:12]([CH:11]=[CH:10]1)[CH2:13][CH:8]2[CH2:7][CH2:6][CH2:5][CH:4]1[O:17][CH2:2][CH2:1][O:3]1
Reactant: OCCO
Reactant: CCOC=CCCC1CC2C=CC1C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C1=CC2CC1CC2CCCC1OCCO1
Yield: 85 %

Procedure:
Next, the thus obtained 5-(4-ethoxy-3-buten-1-yl)-2-norbornene was mixed with 90 g of ethylene glycol, 1.0 g of p-toluenesulfonic acid and 300 ml of toluene and heated under reflux for one hour. The reaction mixture was allowed to cool down and poured into 100 ml of saturated sodium bicarbonate water. The resulting mixture separated into two layers. The organic layer was washed with water and saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated in vacuum. It was further purified by vacuum distillation, obtaining 177 g of 2-{3-(5-norbornen-2-yl)-1-propyl}-1,3-dioxolane (boiling point 92° C./27 Pa, yield 85%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][C:24](=[O:30])[CH2:25][C:26]([O:28][CH3:29])=[O:27])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Na+].[CH3:33]C(C)=O>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@H:14]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][C@H:12]1[CH2:21][O:22][CH2:23][CH:24]([OH:30])[CH2:25][C:26]([O:28][CH2:29][CH3:33])=[O:27])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CC(=O)COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Reactant: CC(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)CC(O)COC[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccccc1
Reaction time: 6 h

Procedure:
To a solution of (2S,4R)-1-benzyloxycarbonyl-2-[{3-(methoxycarbonyl)-2-oxopropyl}oxymethyl]-4-methanesulfonyloxypyrrolidine (7 g) in ethanol (80 ml) was added by portions sodium borohydride (1.2 g) at 0° C. After 6 hours, to the reaction mixture was carefully added dropwise acetone (30 ml) at 0° C. and then the solvent was evaporated in vacuo. To the resultant residue were added ethyl acetate (100 ml) and water (50 ml). The organic layer was separated, washed with brine (50 ml) and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (500 ml) eluting with a mixture of dichloromethane and methanol (18:1 V/V) to give (2S,4R)-1-benzyloxycarbonyl-2-[{3-(ethoxycarbonyl)-2-hydroxypropyl}oxymethyl]-4-methanesulfonyloxypyrrolidine (5.1 g).
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]5[CH2:30][CH2:29][N:28](C(OC(C)(C)C)=O)[CH2:27][CH:26]=5)[CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([O:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([C:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH:26]=5)[CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1noc(N2CCC(Oc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1noc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)n1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
To a solution of tert-butyl 4-(2-(1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (238 mg, 0.453 mmol) in CH2Cl2 (3.5 mL) was added TFA (0.5 mL, 6.7 mmol). The reaction mixture was stirred at rt for 4 h. The reaction mixture was diluted with CH2Cl2 (3 mL) and washed with aq. NaOH (1 N, 10 mL), then brine. The organic layer was dried (Na2SO4), filtered, and concentrated to afford 3-isopropyl-5-(4-(6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazol-2-yloxy)piperidin-1-yl)-1,2,4-oxadiazole (190 mg, 0.446 mmol, 99% yield) as a yellow foam. LCMS (m/z)=426 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)=[C:23]([C:33]([F:36])([F:35])[F:34])[CH:22]=2)=[O:19])[CH2:13][CH2:12]3)[CH:3]=1.[C:37]([NH2:40])(=[O:39])[CH3:38].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[N:27]1([C:24]2[CH:25]=[CH:26][C:21]([NH:20][C:18]([N:14]3[C:15]4[C:11](=[CH:10][C:9]([O:8][C:4]5[N:5]=[CH:6][N:7]=[C:2]([CH2:38][C:37]([NH2:40])=[O:39])[CH:3]=5)=[CH:17][CH:16]=4)[CH:12]=[CH:13]3)=[O:19])=[CH:22][C:23]=2[C:33]([F:35])([F:36])[F:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: CC(N)=O
Reactant: O=C(Nc1ccc(N2CCOCC2)c(C(F)(F)F)c1)N1CCc2cc(Oc3cc(Cl)ncn3)ccc21
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: NC(=O)Cc1cc(Oc2ccc3c(ccn3C(=O)Nc3ccc(N4CCOCC4)c(C(F)(F)F)c3)c2)ncn1
Temperature: 70 °C

Procedure:
A mixture of 2,3-dihydro-5-(6-chloro-4-pyrimidinyloxy)-N-[4-(4-morpholinyl)-3-(trifluoromethyl)phenyl]-1H-indole-1-carboxamide (Intermediate IIa; 1.30 g, 2.5 mmol), acetamide (0.22 g, 3.75 mmol), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis[diphenylphosphine] (90 mg, 0.15 mmol), tris(dibenzylideneacetone)dipalladium (45 mg, 0.05 mmol), caesium carbonate (1.14 g, 3.5 mmol) in dry dioxan (10 mL) is heated under an argon atmosphere at 70° C. for 15 h. The cooled suspension is filtered and the residue is dissolved in DMF (50 mL). The resulting solution is filtered (hyflo) and the solvent is evaporated off under reduced pressure to afford the crude product which is purified by preparative HPLC (VP Reprosil 100 Å-5 μm; eluent 0.1% TFA/H2O→0.09% TFA/CH3CN) and neutralised with saturated aqueous NaHCO3 to give the title compound as a colourless crystalline solid, m.p. 272-275° C.
Reaction SMILES: [F:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][O:27][CH2:28][C:29]4[N:30]=[N:31][N:32](CCF)[CH:33]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[C:10](=[O:11])[C:8]2=[O:9])=[CH:4][CH:3]=1.[F:39][CH2:40]N=[N+]=[N-]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21]4[CH2:25][CH2:24][CH2:23][C@H:22]4[CH2:26][O:27][CH2:28][C:29]4[N:30]=[N:31][N:32]([CH2:40][F:39])[CH:33]=4)(=[O:19])=[O:20])=[CH:15][CH:16]=3)[C:10](=[O:11])[C:8]2=[O:9])=[CH:37][CH:38]=1
Reactant: O=C1C(=O)N(Cc2ccc(F)cc2)c2ccc(S(=O)(=O)N3CCC[C@H]3COCc3cn(CCF)nn3)cc21
Reactant: [N-]=[N+]=NCF
Product: O=C1C(=O)N(Cc2ccc(F)cc2)c2ccc(S(=O)(=O)N3CCC[C@H]3COCc3cn(CF)nn3)cc21

Procedure:
is prepared according to the procedure for compound 12, with the exception that fluoromethylazide is used in place of the 2-fluoroethylazide.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]([CH3:35])[C@@H:6]1[CH2:13][N:12]2[C:14]3[CH:15]=[C:16]([C:27]([O:29][CH3:30])=[O:28])[CH:17]=[CH:18][C:19]=3[C:20]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[C:11]2[C:10]2[CH:31]=[CH:32][CH:33]=[CH:34][C:9]=2[O:8][CH2:7]1.[CH:36](OCC(F)(F)F)=O>C1COCC1>[CH:21]1([C:20]2[C:19]3[CH:18]=[CH:17][C:16]([C:27]([O:29][CH3:30])=[O:28])=[CH:15][C:14]=3[N:12]3[C:11]=2[C:10]2[CH:31]=[CH:32][CH:33]=[CH:34][C:9]=2[O:8][CH2:7][C@H:6]([N:5]([CH3:35])[CH2:4][CH2:3][CH2:2][NH:1][CH3:36])[CH2:13]3)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)C[C@@H](N(C)CCCN)COc1ccccc1-3
Reactant: O=COCC(F)(F)F
Solvent: C1CCOC1
Product: CNCCCN(C)[C@H]1COc2ccccc2-c2c(C3CCCCC3)c3ccc(C(=O)OC)cc3n2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
A solution of methyl(7R)-7-[(3-aminopropyl)(methyl)amino]-14-cyclohexyl-7,8-dihydro-6H-indolo[1,2-e][1,5]benzoxazocine-11-carboxylate (0.16 M) in THF was treated dropwise with 2,2,2-trifluoroethyl formate (1.3 eq.) and stirred overnight at RT. The volatiles were removed in vacuo and the residue dissolved (0.08 M) in THF and treated dropwise with BH3-DMS complex (2 M in THF; 10 eq.). The resulting solution was stirred at RT for 3 h. The reaction was quenched by the careful addition of HCl/MeOH (1.25 M) and the resulting solution refluxed for 2 h. The volatiles were then removed in vacuo and the residue partitioned between sat. aq. NaHCO3 and EtOAc. The combined organics were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by FC (EtOAc/MeOH/Et3N 90:8:2) affording the product as a pale orange solid (80% overall for steps 2, 3, 4, 5). (ES) m/z 490 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[C:10]([CH3:12])[CH:11]=1)[N:8]([CH3:13])[CH:7]=[C:6]2[CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1.Cl.N1C=CC=CC=1>>[CH3:13][N:8]1[C:9]2[C:5](=[CH:4][C:3]([OH:2])=[CH:11][C:10]=2[CH3:12])[C:6]([CH:14]2[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)=[CH:7]1
Reactant: COc1cc(C)c2c(c1)c(C1CCN(C)CC1)cn2C
Agent: Cl
Solvent: c1ccncc1
Product: Cc1cc(O)cc2c(C3CCN(C)CC3)cn(C)c12
Yield: 91.6 %

Procedure:
By a method similar to Preparation 8, using 5-methoxy-1,7 dimethyl-3-(1-methylpiperdin-4-yl)-1H-indole (1.53 g) and pyridine hydrochloride (25 g) to afford 1.33 g (92%) of the title compound: mass spectrum (ion spray): m/z=259 (M+1); 1H NMR (DMSOd6): 8.47 (s, 1H), 6.81 (s, 1H), 6.62 (d, J=2.20 Hz, 1H), 6.33 (d, J=1.46 Hz, 1H), 3.88 (s, 3H), 2.82 (m, 2H), 2.53-2.46 (m, 4H), 2.19 (s, 3H), 1.99 (m, 2H), 1.84 (m, 2H), 1.64 (m, 1H), 1.56 (m, 1H); Calculated for C16H22N2O-0.6 H2O: C, 71.39; H, 8.69; N, 10.41. Found: C, 71.39; H, 8.31; N, 10.33.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:7]=1.Cl.[O:27]1[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[N:3]=[C:4]([NH:33][CH:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:7]=1
Reactant: NC1CCOCC1
Reactant: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c2c(Cl)nc(Cl)nc21
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1cc(-c2ccncc2)c2c(NC3CCOCC3)nc(Cl)nc21
Temperature: 120 °C
Yield: 34 %

Procedure:
To a solution of 2,4-dichloro-5-(pyridin-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv) in 1,4-dioxane (0.4 M) in a sealable vessel was added tetrahydro-2H-pyran-4-amine hydrochloride (1.5 equiv) and triethylamine (3 equiv). The resulting mixture was heated at 120° C. for 2 h under nitrogen atmosphere. After the reaction was complete, the reaction mixture was cooled to room temperature and concentrated. The residue was purified by silica gel chromatography (0-30% ethyl acetate in petroleum ether) to afford the desired product (34% yield) as a yellow solid. MS (ESI) m/z 460.2 [M+1]+.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([O:25]C)=[O:24].[OH-].[Na+]>CO.C(O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH:22]([CH2:27][CH2:28][CH3:29])[C:23]([OH:25])=[O:24]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3ccccc3c2c1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3ccccc3c2c1-c1ccc(C)cc1
Temperature: 25 °C
Yield: 26.4 %

Procedure:
To a solution of methyl [2-methyl-4-p-tolylbenzo[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate (0.122 g; 0.302 mmol) in methanol (6.2 mL) and ethanol (3.1 mL) was added a 5% sodium hydroxide solution (8 mL; 10.00 mmol). The reaction mixture was heated under reflux for 3 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was suspended in water, acidified with 1N HCl (pH˜2) and extracted with ethyl acetate. The organic layer was washed with water and brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.031 g (26%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH2:23][CH2:24][OH:25])=[C:17]3[C:13]=2[C:14]2[CH:29]=[C:28]([CH3:30])[CH:27]=[N:26][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C(S(C1C=C(C2[C:47]3C4C=C(C)C=NC=4[NH:50][C:46]=3[C:45]([O:56]C[C@H](OC(=O)[C@H](C)N)C)=NC=2)C=CC=1)(=O)=O)C>>[NH2:50][C@@H:46]([CH3:47])[C:45]([O:25][CH2:24][CH2:23][CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:7]=2)=[C:13]2[C:17]=1[NH:16][C:15]1[N:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:14]2=1)=[O:56]
Reactant: CCS(=O)(=O)c1cccc(-c2cnc(OC[C@@H](C)OC(=O)[C@H](C)N)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCCO)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCCOC(=O)[C@H](C)N)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was prepared from Compound 216 by using an analogous procedure to that outlined in the preparation of Compound 64. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.17 (t, J=7.33 Hz, 3H) 1.39 (d, J=7.07 Hz, 3H) 2.20-2.24 (m, 2H) 2.26 (s, 3H) 4.14 (m, 1H) 4.32 (t, J=5.68 Hz, 2H) 4.56 (m., 2H) 7.08-7.11 (m, 1H) 7.12-7.16 (m, 1H) 7.55 (s, 1H) 7.85 (t, J=7.83 Hz, 1H) 7.98 (dd, J=10.23, 8.46 Hz, 2H) 8.06 (s, 1H) 8.28 (br. s., 3H) 12.07 (s, 1H); [M+H] calc'd for C26H30N3O5S, 496.2; found, 496.4.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[O:10][C:11]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][C:12]=2[CH:13]=1.Cl.[NH2:21][OH:22].C(=O)([O-])[O-].[K+].[K+]>CCO>[OH:22][N:21]=[C:18]([C:15]1[CH:16]=[CH:17][C:11]2[O:10][C:9]([CH2:8][CH2:7][N:3]3[CH2:4][CH2:5][CH2:6][C@H:2]3[CH3:1])=[CH:13][C:12]=2[CH:14]=1)[NH2:19]
Reactant: NO
Reactant: C[C@@H]1CCCN1CCc1cc2cc(C#N)ccc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: C[C@@H]1CCCN1CCc1cc2cc(C(N)=NO)ccc2o1
Temperature: 95 °C
Yield: 50.6 %

Procedure:
The product from Example 87B (2.5 g, 9.83 mmol) in EtOH (200 mL) was stirred at 25° C. for 10 minutes. The mixture was treated with hydroxylamine hydrochloride (1.71 g, 24.6 mmol) and potassium carbonate (4.49 g, 32.48 mmol) and the resulting mixture was heated at 95° C. for 16 h with stirring. The reaction mixture was subsequently cooled, filtered through celite, and concentrated under reduced pressure. The crude product was purified with flash chromatography to provide the title compound (1.43 g, 51% yield). MS (ESI) m/e 288 (M+H)+.