Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][C@@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH3:22])=[C:12]([N+:17]([O-])=O)[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:29][CH3:30])=[C:5]([CH3:31])[O:4][N:3]=1.[Sn](Cl)Cl.[OH-].[Na+].O>CCO>[CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:20][C@@H:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=4)[CH3:22])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:29][CH3:30])=[C:5]([CH3:31])[O:4][N:3]=1
Reactant: COc1cc2c(N[C@H](C)c3ccccn3)c([N+](=O)[O-])cnc2cc1-c1c(C)noc1C
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COc1cc2c(N[C@H](C)c3ccccn3)c(N)cnc2cc1-c1c(C)noc1C
Temperature: 40 °C
Reaction time: 2.5 h
Yield: 55.5 %

Procedure:
To a suspension of 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-3-nitro-N—((R)-1-(pyridin-2-yl)ethyl)quinolin-4-amine (Intermediate 24) (1.05 g, 2.503 mmol) in EtOH (20 mL) was added tin(II) chloride (1.66 g, 8.76 mmol) and the mixture stirred at 40° C. for 2.5 h. The reaction mixture was basified to pH 12 using 2M aq. sodium hydroxide solution. Water (30 mL) was added and the aqueous suspension extracted with DCM (3×30 mL). The organic layers were combined, dried by passing through a hydrophobic frit and concentrated to dryness under a stream of nitrogen. The resulting residue was purified by chromatography (100 g column, 2M methanolic ammonia gradient) to give 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4—((R)-1-(pyridin-2-yl)ethyl)quinoline-3,4-diamine (543 mg, 1.39 mmol, 56% yield) as a dark brown gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:12]=[C:13]([NH2:16])[S:14][CH:15]=1.Cl.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([F:10])[C:3]=1[C:11]1[N:12]=[C:13]([NH:16][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)[S:14][CH:15]=1
Reactant: COc1cc(F)c(-c2csc(N)n2)c(Cl)c1
Reactant: O=C(Cl)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1cc(F)c(-c2csc(NC(=O)c3ccncc3)n2)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 43.6 %

Procedure:
To a solution of 4-(2-chloro-6-fluoro-4-methoxyphenyl)thiazol-2-ylamine (0.10 g, 0.39 mmol) in CH2Cl2 (10 mL) was added DMAP (95 mg, 0.78 mmol) followed by isonicotinoyl chloride hydrochloride (90 mg, 0.51 mmol). The reaction mixture was stirred at room temperature overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was collected and recrystallized in toluene to give N-(4-(2-chloro-6-fluoro-4-methoxyphenyl)thiazol-2-yl)isonicotinamide (13, 60 mg, 0.17 mmol) as white solids in 42% yield: 1H NMR (500 MHz, CDCl3) δ 8.76 (s, 2 H), 7.85 (d, J=4.5 Hz, 2 H), 7.12 (s, 1 H), 6.67 (s, 1 H), 6.45 (m, 1 H), 3.79 (s, 3H). ESI-MS: m/z 364.2 (M+H)+.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9](OC)[C:6]([CH:7]=O)=[C:5]([OH:13])[CH:4]=1.[CH3:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([O:23]C)=[CH:19][CH:18]=1)=[O:16].[ClH:25]>CCOCC>[CH:18]1[C:17]([C:15]2[CH:14]=[CH:7][C:6]3[C:5]([OH:13])=[CH:4][C:3]([OH:2])=[CH:10][C:9]=3[O+:16]=2)=[CH:22][CH:21]=[C:20]([OH:23])[CH:19]=1.[Cl-:25].[Cl-:25]
Reactant: Cl
Reactant: COc1cc(O)c(C=O)c(OC)c1
Reactant: COc1ccc(C(C)=O)cc1
Solvent: CCOCC
Product: Oc1ccc(-c2ccc3c(O)cc(O)cc3[o+]2)cc1
Product: [Cl-]

Procedure:
One method consists, for example, in preparing, in a first step, trimethylapigenidin by condensation of commercially available 4,6-dimethoxy-2-hydroxybenzaldehyde with commercially available 4-methoxyacetophenone at 0° C. in anhydrous ether medium, and saturation with anhydrous HCl in order to obtain, after filtration, an orange-red precipitate of trimethylapigenidin. In a second step, in hydrolysing the trimethylapigenidin obtained in the preceding step to apigenidin chloride, the reaction being carried out in an HI and phenol and AgCl medium in solution in methanol. Such a method of synthesis is described by R. Robinson and A. Robertson in J., Chem., Soc. 1951-(1926) and 2196-(1927).
Reaction SMILES: [F:1][C:2]1[C:3]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)=[C:4]([CH:8]=[C:9]([CH3:11])[CH:10]=1)[C:5]([OH:7])=O.[CH3:17][C@@H:18]1[CH2:23][CH2:22][CH2:21][NH:20][C@@H:19]1[CH2:24][N:25]1C(=O)C2C(=CC=CC=2)C1=O.Cl[C:37]1[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=1>>[F:1][C:2]1[C:3]([N:12]2[N:16]=[CH:15][CH:14]=[N:13]2)=[C:4]([C:5]([N:20]2[CH2:21][CH2:22][CH2:23][C@@H:18]([CH3:17])[C@H:19]2[CH2:24][NH:25][C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][N:38]=2)=[O:7])[CH:8]=[C:9]([CH3:11])[CH:10]=1
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: Cc1cc(F)c(-n2nccn2)c(C(=O)O)c1
Product: Cc1cc(F)c(-n2nccn2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1

Procedure:
The title compound was prepared following the same general protocol as described in Example A318, using 3-fluoro-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoic acid, 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione and 2-chloro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 477 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[SH:9].Cl[C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:12]=1[N+]([O-])=O.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>CN(C)C=O>[F:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[NH:1][C:11]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:12]=1[S:9]2
Reactant: Nc1ccc(F)cc1S
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cccc2c1Nc1ccc(F)cc1S2
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.1 %

Procedure:
2.2 g (15 mmol) of 2-amino-5-fluorobenzenethiol was dissolved in 30 ml of dimethylformamide and 2.5 g (12 mmol) of 1-chloro-2,6-dinitrobenzene was added thereto. The resulting mixture was stirred at room temperature. After 12 hours, 2.6 ml of N,N-diisopropylethylamine was added thereto and the mixture was heated at 80° C. for 2 hours. After cooling, the reaction mixture was poured into a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. After concentrating, the residue was purified by silica gel column chromatography. Thus 1.2 g of the title compound was obtained.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([O:11][CH3:12])[N:8]=[C:7]([O:13][CH:14]2[CH2:18][CH:17]([C:19](O)=[O:20])[CH:16]([C:22](=[O:34])[NH:23][C:24]3([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:26][CH:25]3[CH:27]=[CH2:28])[CH2:15]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:44][NH:45][CH:46]=[CH:47][CH2:48][CH2:49][CH2:50][CH3:51].Cl.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH2:32]([O:31][C:29]([C:24]1([NH:23][C:22]([CH:16]2[CH2:15][CH:14]([O:13][C:7]3[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[N:10]=[C:9]([O:11][CH3:12])[N:8]=3)[CH2:18][CH:17]2[C:19](=[O:20])[N:45]([CH2:46][CH2:47][CH2:48][CH2:49][CH:50]=[CH2:51])[CH3:44])=[O:34])[CH2:26][CH:25]1[CH:27]=[CH2:28])=[O:30])[CH3:33]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2cc(C(C)(C)C)nc(OC)n2)CC1C(=O)O)C(=O)OCC
Reactant: CCCCC=CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCCCN(C)C(=O)C1CC(Oc2cc(C(C)(C)C)nc(OC)n2)CC1C(=O)NC1(C(=O)OCC)CC1C=C
Temperature: 25 °C
Yield: 78 %

Procedure:
Compound 3g (583 mg, 1.227 mmol) was dissolved in 15 ml dry DMF. DIEA (0.96 ml, 5.522 mmol), N-methylhexeneamine×HCl (270 mg, 1.779 mmol) and HATU (676 mg, 1.779 mmol) were added at 0° C., and the reaction mixture was stirred at RT over night. The DMF was evaporated and the residue was dissolved in EtOAc and washed with saturated NaHCO3(aq), H2O and brine. The organic layer was dried (MgSO4), filtered and evaporated. Purification by column chromatography (heptane/EtOAc) gave the pure title compound (550 mg, 78%), MS (M+H)+573.
Reaction SMILES: [O-2:1].[Mg+2:2].[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][OH:11])=[O:9])=[CH:6][CH:5]=1.[C:14]([OH:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(OCC)(=O)C.O>[OH2:9].[OH2:21].[OH2:1].[OH2:9].[Cl:3][C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][O-:11])=[O:9])=[CH:6][CH:5]=1.[C:14]([O-:22])(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Mg+2:2]
Reactant: [O-2]
Reactant: O=C(O)c1ccccc1
Reactant: O=C(OO)c1ccc(Cl)cc1
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(O[O-])c1ccc(Cl)cc1
Product: O=C([O-])c1ccccc1
Reaction time: 1.5 h

Procedure:
Magnesium oxide (0.443 g, 11.0 mmol) was added to a solution of 4-chloroperoxybenzoic acid (94.6%, 2.00 g, 11.0 mmol) and benzoic acid (1.26 g, 10.3 mmol) in 65 mL of ethyl acetate and 0.80 mL of water. After 90 min of vigorous stirring, the precipitate was collected via filtration, washed with ethyl acetate (ca. 50 mL), and vacuum dried to give 3.50 g (82% based on Mg2+) of a white powder: Anal. Calcd for C14H17ClMgO9 : C, 43.22; H, 4.40; Cl, 9.11; Mg, 6.25; O(active), 4.11. Found: C, 43.88; H, 4.07; Cl, 9.79; Mg, 6.80; O(active), 3.95.
Reaction SMILES: [NH3:1].[C:2]12([C:12]3[CH:13]=[C:14]([C:25]#[C:26][C:27]4[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=4)[CH:15]=[CH:16][C:17]=3[O:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.O>C1COCC1>[C:2]12([C:12]3[CH:13]=[C:14]([C:25]#[C:26][C:27]4[CH:35]=[CH:34][C:30]([C:31]([NH2:1])=[O:32])=[CH:29][CH:28]=4)[CH:15]=[CH:16][C:17]=3[O:18][CH2:19][O:20][CH2:21][CH2:22][O:23][CH3:24])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: N
Reactant: COCCOCOc1ccc(C#Cc2ccc(C(=O)Cl)cc2)cc1C12CC3CC(CC(C3)C1)C2
Solvent: O
Solvent: C1CCOC1
Product: COCCOCOc1ccc(C#Cc2ccc(C(N)=O)cc2)cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 3 h

Procedure:
500 μl (9.1 mmol) of an aqueous ammonia solution (32%) and 20 ml of THF were introduced into a round-bottomed flask. A solution of 1.1 g (2.3 mmol) of 4-[3-(1-adamantyl)-4-methoxyethoxymethoxyphenylethynyl]benzoyl chloride dissolved in 30 ml of THF was added dropwise and stirring was carried out at room temperature for three hours. The reaction mixture was poured into water and extracted with ethyl acetate and the organic phase was separated by settling, dried over magnesium sulfate and evaporated.
Reaction SMILES: [CH3:1][C@@:2]([OH:30])([C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:3]1[C@@:8]2([O:24][CH3:25])[C@@H:9]3[O:23][C:18]4=[C:19]([OH:22])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][NH:13][C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1.C(=O)(O)[O-].[Na+].[CH:36]1([CH2:39]Br)[CH2:38][CH2:37]1.CN(C=O)C>CO.O>[CH3:1][C@@:2]([OH:30])([C:26]([CH3:29])([CH3:28])[CH3:27])[C@@H:3]1[C@:8]2([O:24][CH3:25])[C@@H:9]3[O:23][C:18]4=[C:19]([OH:22])[CH:20]=[CH:21][C:16]5=[C:17]4[C@:10]43[CH2:11][CH2:12][N:13]([CH2:39][CH:36]3[CH2:38][CH2:37]3)[C@H:14]([CH2:15]5)[C@@:5]4([CH2:6][CH2:7]2)[CH2:4]1
Reactant: BrCC1CC1
Reactant: CO[C@]12CC[C@@]3(C[C@@H]1[C@](C)(O)C(C)(C)C)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1)[C@H]2O5
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: CO[C@@]12CC[C@@]3(C[C@@H]1[C@](C)(O)C(C)(C)C)[C@H]1Cc4ccc(O)c5c4[C@@]3(CCN1CC1CC1)[C@H]2O5
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
A mixture of 11.5 g of norbuprenorphine, 4.6 g of sodium bicarbonate, 4.85 g of cyclopropylmethyl bromide (1% butenyl bromide in it by GC) and 46 ml of dry DMF is heated in an oilbath at 80-100° C. for 4 hours until the reaction is substantially complete. The reaction mixture is transferred to a dropping funnel, with minimal DMF as a wash. The reaction mixture is added over 5 minutes to 160 ml of water, with mechanical stirring. (Adding water to the reaction yields a gum). The mixture is stirred for about 10 minutes and filtered. The filter cake is washed with 20 ml water. The HPLC will show about 90% by area of desired product, and 0.2-0.5% of an N-butenyl substituted impurity. The resulting product is dried, yielding about 12 g. The resulting product is boiled in 30 ml of methanol for about 30 minutes, cooled, and filtered to yield about 7.3 g buprenorphine.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)=[N:4][C:3]=1[CH2:17][N:18]1[CH:22]=[C:21]([C:23]([O:25]CC)=[O:24])[CH:20]=[N:19]1.[OH-].[Na+].O>C(O)C.O1CCCC1>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:14])([F:16])[F:15])[CH:8]=2)=[N:4][C:3]=1[CH2:17][N:18]1[CH:22]=[C:21]([C:23]([OH:25])=[O:24])[CH:20]=[N:19]1
Reactant: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(F)(F)F)c3)sc2C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1sc(-c2cccc(C(F)(F)F)c2)nc1Cn1cc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.3 %

Procedure:
To a mixed solution of the compound (31 mg, 0.078 mmol) obtained in Example 71c in ethanol/tetrahydrofuran (v/v=1/1, 4 mL) was added 2N aqueous sodium hydroxide solution (0.31 mL, 0.62 mmol), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the aqueous layer was washed with diethyl ether, neutralized with 1N aqueous hydrochloric acid solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The resulting crude title compound was recrystallized (ethyl acetate-hexane) to give the title compound (21 mg, 72%) as colorless crystals.
Reaction SMILES: [C:1]([O:9][C:10]1[C:11]([C:29]([O:31][CH3:32])=[O:30])=[N:12][C:13]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[N:14][C:15]=1[OH:16])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33]I>C1COCC1.C([O-])([O-])=O.[Cs+].[Cs+]>[C:1]([O:9][C:10]1[C:15](=[O:16])[N:14]([CH3:33])[C:13]([CH:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])=[N:12][C:11]=1[C:29]([O:31][CH3:32])=[O:30])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1nc(C2CCCN2C(=O)OC(C)(C)C)nc(O)c1OC(=O)c1ccccc1
Reactant: CI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Product: COC(=O)c1nc(C2CCCN2C(=O)OC(C)(C)C)n(C)c(=O)c1OC(=O)c1ccccc1
Temperature: 40 °C

Procedure:
To a stirred solution of the product of Step 2 (1.0 eq.) in THF, Cs2CO3 was added (1.2 eq.) followed by the addition of CH3I (2.0 eq.). The reaction was stirred at 40° C. until the starting material was consumed as determined by MS analysis. The reaction was concentrated and the residue taken up with EtOAc, washed with 1 N HCl, saturated solution of NaHCO3 and brine. The organic phase was dried over anhydrous Na2SO4, filtered and concentrated. Reaction crude showed 3.4:1 ratio N (desired product) versus O methylation. The title product was purified by flash column chromatography (EtOAc: Petroleum Ether=1:1) and obtained as a 1:1 mixture of rotamers by NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](O)([C:33]2[N:34]([CH3:38])[CH:35]=[N:36][CH:37]=2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH:13]=[C:12]3[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[C:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:22]=2)=[CH:4][CH:3]=1.N#N.C(=O)([O-])[O-].[K+].[K+].[NH:48]1[CH:52]=[N:51][CH:50]=[N:49]1>S(Cl)(Cl)=O.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([C:33]2[N:34]([CH3:38])[CH:35]=[N:36][CH:37]=2)([N:48]2[CH:52]=[N:51][CH:50]=[N:49]2)[C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[N:15]([CH3:19])[C:14](=[O:20])[CH:13]=[C:12]3[C:21]2[CH:26]=[CH:25][CH:24]=[C:23]([C:27]#[C:28][C:29]([CH3:31])([CH3:32])[CH3:30])[CH:22]=2)=[CH:6][CH:7]=1
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(C#CC(C)(C)C)c1)cc(=O)n2C
Reactant: c1nc[nH]n1
Agent: N#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: Cn1cncc1C(c1ccc(Cl)cc1)(c1ccc2c(c1)c(-c1cccc(C#CC(C)(C)C)c1)cc(=O)n2C)n1cncn1
Temperature: 80 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
6[(4chloro-phenyl)-hydroxy-(3-methyl-3H-imidazol-4-yl)-methyl]-4-[3-(3,3-dimethyl-but-1-ynyl)-phenyl]-1-methyl-1H-quinolin-2-one (330 mg, 0.633 mMol) was dissolved in 4 mL of thionyl chloride and stirred at ambient temperature under a stream of dry N2 for 2 hours. The reaction mixture was then concentrated under vacuum and toluene (5 mL) was added to the reaction mixture which was subsequently concentrated under vacuum to give a yellow solid. 210 mg of the yellow solid was dissolved in 5.0 mL of anhydrous DMF under an atmosphere of dry N2. To this solution was added 800 mg of potassium carbonate and 300 mg of 1,2,4-triazole and the reaction mixture was subsequently heated to 80° C. and stirred overnight at this temperature. The reaction mixture was then concentrated under vacuum and partitioned between EtOAc and water. The EtOAc layer was washed 3 more times with water and then with brine. The EtOAc layer was then dried over Na2SO4, filtered and concentrated under vacuum to give a yellow solid. The solid was chromatographed on flash silica gel eluting with a gradient of MeOH/DCM/NH4OH (2/9810.1) to MeOH/DCM/NH4OH (7/93/0.1) to give 150 mg of the titled product as a white solid.
Reaction SMILES: C([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]([F:42])[C:18]3[N:19](C(OC(C)(C)C)=O)[C:20]4[C:25]([S:26][C:27]=3[CH:28]=2)=[CH:24][C:23]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)=[CH:22][CH:21]=4)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[Cl:43]CCl>>[Cl-:43].[N:11]1([C:15]2[CH:16]=[C:17]([F:42])[C:18]3[C:27]([CH:28]=2)=[S+:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([N:29]4[CH2:30][CH2:31][O:32][CH2:33][CH2:34]4)[CH:24]=2)[N:19]=3)[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCCN(c2cc(F)c3c(c2)Sc2cc(N4CCOCC4)ccc2N3C(=O)OC(C)(C)C)CC1
Product: Fc1cc(N2CCCNCC2)cc2[s+]c3cc(N4CCOCC4)ccc3nc12
Product: [Cl-]
Temperature: 40 °C
Reaction time: 3 h

Procedure:
To a solution 3-(4-Boc-1,4-diazepan-1-yl)-7-morpholino-1-fluoro-10-Boc-phenothiazine (0.8 g) in dichloromethane (10 mL) HCl (2 mL, 4 M solution in 1,4-dioxane)) was added. The reaction mixture was stirred at 40° C. for 3 h. Solvent was removed under vacuum. Product was purified by flash chromatography.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:24]2[C:19](=[C:20]([Br:26])[CH:21]=[C:22]([I:25])[CH:23]=2)[C:17](=[O:18])[C:15]1=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:30]=[CH:29][C:28]=1[Mg]Br>>[Si:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:24]2[C:19](=[C:20]([Br:26])[CH:21]=[C:22]([I:25])[CH:23]=2)[C:17]([OH:18])([C:29]2[CH:28]=[CH:27][C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[CH:30]=2)[C:15]1=[O:16])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCCCCCN1C(=O)C(=O)c2c(Br)cc(I)cc21
Reactant: Br[Mg]c1ccc2ccccc2c1
Product: CC(C)(C)[Si](C)(C)OCCCCCN1C(=O)C(O)(c2ccc3ccccc3c2)c2c(Br)cc(I)cc21
Yield: 75 %

Procedure:
The title compound (463 mg, 75%) was prepared from 1-(5-t-butyldimethylsilyloxypentyl)-4-bromo-6-iodoisatin (500 mg, 0.923 mmol) and 2-naphthylmagnesium bromide by the procedure similar to that described in Example 1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12](OC)=[O:13])=[CH:10][CH:9]=2)[CH:2]=1.[NH2:18][NH2:19]>CCO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[CH:17]=[CH:16][C:11]([C:12]([NH:18][NH2:19])=[O:13])=[CH:10][CH:9]=2)[CH:2]=1
Reactant: COC(=O)c1ccc(Oc2cccnc2)cc1
Reactant: NN
Solvent: CCO
Product: NNC(=O)c1ccc(Oc2cccnc2)cc1
Yield: 100 %

Procedure:
Methyl 4-(pyridine-3-yloxy)benzoate (4.8 g, 20.94 mmol) was dissolved in ca. 150 mL of EtOH and anhydrous hydrazine (4.08 g, 4.0 mL) was added via a syringe. The resulting yellow solution was refluxed for 24 hrs. Then solvent was removed in vacuo to give the title product (4.8 g, 100% yield) as yellow viscous oil, which upon standing slowly solidified.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O)([O-])=O>C(O)C.C(OCC)(=O)C.[Pd]>[CH:14]1[N:10]2[C:5]3[C:4]([NH:1][CH2:15][C:11]2=[CH:12][CH:13]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: O=Cc1cccn1-c1ccccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: c1ccc2c(c1)NCc1cccn1-2
Reaction time: 2 h
Yield: 44.5 %

Procedure:
To a solution of 1.0 g of 1-(2-nitrophenyl)-1H-pyrrole-2-carboxaldehyde in 40 ml of ethyl alcohol and 40 ml of ethyl acetate, under argon, is added 40 mg of 10% Pd/C. The mixture is hydrogenated at 40 psi for 2 hours and filtered through diatomaceous earth. The filtrate is concentrated in vacuo to a residue which is dissolved in ether and treated with hexanes to give 0.35 g of the desired product as a beige solid, m.p. 108°-110° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([N:7]([CH3:23])[C:8]2[N:13]=[C:12]([N:14]3[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=4[N:16]=[CH:15]3)[CH:11]=[CH:10][N:9]=2)[CH2:2]1.C(N(C(C)C)CC)(C)C.[C:33]1([S:39](Cl)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[C:33]1([S:39]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([N:7]([CH3:23])[C:8]3[N:13]=[C:12]([N:14]4[C:18]5[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=5[N:16]=[CH:15]4)[CH:11]=[CH:10][N:9]=3)[CH2:2]2)(=[O:41])=[O:40])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCCNC1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(c1nccc(-n2cnc3ccccc32)n1)C1CCCN(S(=O)(=O)c2ccccc2)C1
Reaction time: 1 h
Yield: 48 %

Procedure:
To a stirred solution of 2-[(piperidin-3-yl)-methylamino]-4-[benzimidazol-1-yl]pyrimidine (20 mg, 0.065 mmol, 1 eq) in THF (1 mL) at 0° C. was added diisopropylethylamine (0.023 mL, 0.13 mmol, 2 eq) followed by addition of benzenesulfonylchloride (0.009 mL, 0.071 mmol, 1.1 eq) via syringe. Removed the cooling bath and let stir for 1 h. Quenched the reaction with saturated aqueous NaHCO3 and extracted 3× with CH2Cl2. Combined the organic extracts, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative thin layer chromatography (eluted with 2:1 hexanes/acetone) to give 14 mg of the title compound. 1H NMR (500 MHz, CDCl3): δ 1.1-1.2 (1H, m), 1.6-1.9 (4H, m), 2.12 (1H, m), 2.42 (1H, t, J=10 Hz), 2.57 (1H, t, J=10 Hz), 3.4-3.6 (2H, m), 3.63 (1H, d, J=8.5 Hz), 5.6 (1H, br s), 6.84 (1H, d, J=5.5 Hz), 7.3-7.8 (7H, m), 7.88 (1H, d, J=7 Hz), 8.18 (1H, d, J=7 Hz), 8.41 (1H, d, J=5.5 Hz), 8.62 (1H, s). Mass spectrum (CI) 449.1 (M+1).