Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[NH2:7][C:8]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=1[C:10]([NH:12][CH:13]([CH:15]1[CH2:17][CH2:16]1)[CH3:14])=[O:11].[Br:23][C:24]1[CH:28]=[C:27]([C:29](OCCCCC)=[O:30])[N:26]([C:37]2[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][N:38]=2)[N:25]=1.Cl>CS(C)=O>[Br:23][C:24]1[CH:28]=[C:27]([C:29]([NH:7][C:8]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:9]=2[C:10](=[O:11])[NH:12][CH:13]([CH:15]2[CH2:17][CH2:16]2)[CH3:14])=[O:30])[N:26]([C:37]2[C:42]([Cl:43])=[CH:41][CH:40]=[CH:39][N:38]=2)[N:25]=1
Reactant: CC(NC(=O)c1cc(Cl)ccc1N)C1CC1
Reactant: CCCCCOC(=O)c1cc(Br)nn1-c1ncccc1Cl
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: CC(NC(=O)c1cc(Cl)ccc1NC(=O)c1cc(Br)nn1-c1ncccc1Cl)C1CC1
Yield: 13.9 %

Procedure:
0.11 g potassium tert-butoxide was added to a mixed solution comprising 0.19 g of 2-amino-5-chloro-N-(1-cyclopropylethyl)benzamide, 0.30 g of pentyl 3-bromo-1-(3-chloropyridin-2-yl)-1H-pyrazole-5-carboxylate and 3 ml of dimethyl sulfoxide, followed by reaction at room temperature for 45 minutes. The reaction liquid was slowly added to 40 ml of diluted hydrochloric acid. The mixed liquid was subjected to extraction with ethyl acetate, and the organic layer was washed with a saturated sodium hydrogen carbonate aqueous solution and with a sodium chloride aqueous solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=8/2 to 7.5/2.5) to obtain 0.058 g of the desired product (melting point: 231 to 233° C.) in the form of white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5](Cl)=[O:6].[CH3:12][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:23])[CH3:22])[C:16]=1[NH:24][C:25](=[O:41])[CH2:26][NH:27][CH:28]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH3:14]>C(N(CC)CC)C>[CH3:14][CH:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]([CH3:22])[CH3:23])[C:16]=1[NH:24][C:25](=[O:41])[CH2:26][N:27]([CH:28]([C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:5](=[O:6])[C:4]1[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=1[O:2][CH3:1])[CH3:12]
Reactant: CC(C)c1cccc(C(C)C)c1NC(=O)CNC(c1ccccc1)c1ccccc1
Reactant: COc1ccccc1C(=O)Cl
Solvent: CCN(CC)CC
Product: COc1ccccc1C(=O)N(CC(=O)Nc1c(C(C)C)cccc1C(C)C)C(c1ccccc1)c1ccccc1
Reaction time: 48 h

Procedure:
2-Methoxy benzoyl chloride (0.65 g) was added to a mixture of 1.50 g the product of Example 4 and excess triethylamine in 100 mL EtoAc. The reaction mixture was allowed to sit 2 days at room temperature and was then concentrated to dryness, the residue dissolved in 250 mL CH2Cl2, the organic solution washed with dilute sulfuric acid, brine, potassium carbonate solution, and brine. The solution was dried over MgSO4, filtered, and concentrated to an oil which crystallized upon addition of 1/1, hexane/EtoAc to give the title compound. Total yield, 1.53 g (76%).
Reaction SMILES: Br[C:2]([C@:4]([C:28](=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)([C@@:6]([C:20](=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C@:8]([C:12](=[O:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)([CH2:10][OH:11])[OH:9])[OH:7])[OH:5])=[O:3].O>CC(C)=O.C(=O)([O-])[O-].[Ag+2]>[C:28]([C@@:4]([C@@:6]([C:20](=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)([C@:8]([C:12](=[O:19])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)([CH2:10][OH:11])[OH:9])[OH:7])([OH:5])[CH:2]=[O:3])(=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(Br)[C@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(CO)C(=O)c1ccccc1
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)=O
Product: O=C[C@](O)(C(=O)c1ccccc1)[C@@](O)(C(=O)c1ccccc1)[C@@](O)(CO)C(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 73.1 %

Procedure:
Crude 1-bromo-2,3,4-tri-benzoyl-L-xylose 17 (14.1 g, 26.8 mmol) was dissolved in acetone (150 mL) and water (5 ml, 277 mmol) at 0° C. Silver carbonate (6.61 g, 24.0 mmol) was added over 5 min and the reaction was brought to room temperature after 15 min and stirred an additional 30 min. The solids were removed by filtration and washed with acetone (100 mL), the filtrate was concentrated in vacuo, water was removed via azeotropic distillation with ethanol and toluene and the residue was purified by silica gel flash chromatography (4:1 Hexanes:EtOAc to EtOAc) to yield 18 as white solid (9.1 g, 19.6 mmol, 74%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[OH:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=O.Cl.O>CO>[OH:12][C:13]1[CH:14]=[C:15]([CH:16]=[C:7]2[C:6](=[O:9])[C:5]3[CH:10]=[CH:11][C:2]([OH:1])=[CH:3][C:4]=3[O:8]2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=Cc1cccc(O)c1
Reactant: O=C1COc2cc(O)ccc21
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1C(=Cc2cccc(O)c2)Oc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
After 6-hydroxy-2H-benzofuran-3-one 1 g and 3-hydroxybenzaldehyde 0.813 g were dissolved in methanol 75 ml, concentrated hydrochloric acid 50 ml was added, and the mixture was refluxed for two hours. The solution was cooled to room temperature, water 400 ml was added and allowed to stand for one hour. Precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide at a temperature of 60° C. for five hours under reduced pressure to obtain the desired compound 1.20 g.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([OH:16])=O)[CH3:12])=[O:9])=[CH:4][CH:3]=1.[NH2:19][C@H:20]([C:33]([N:35]([C@@H:47]([CH3:55])[CH:48]([O:52][CH2:53][CH3:54])[O:49][CH2:50][CH3:51])[CH2:36][C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:40]=[CH:39][CH:38]=1)=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([NH:10][N:11]([CH2:13][C:14]([NH:19][C@H:20]([C:33]([N:35]([C@@H:47]([CH3:55])[CH:48]([O:49][CH2:50][CH3:51])[O:52][CH2:53][CH3:54])[CH2:36][C:37]2[C:46]3[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH:40]=[CH:39][CH:38]=2)=[O:34])[CH2:21][CH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:16])[CH3:12])=[O:9])=[CH:17][CH:18]=1
Reactant: CN(CC(=O)O)NC(=O)NCc1ccc(Cl)cc1
Reactant: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@@H](N)CCCCNC(=O)OC(C)(C)C
Product: CCOC(OCC)[C@H](C)N(Cc1cccc2ccccc12)C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)CN(C)NC(=O)NCc1ccc(Cl)cc1

Procedure:
According to the procedure described in the synthesis method of Compound II-15, 2-(2-(4-chlorobenzylcarbamoyl)-1-methylhydrazinyl)acetic acid (Compound VI-7) 79 mg (0.29 mmol) was coupled with tert-butyl (S)-5-amino-6-(((S)-1,1-diethoxypropan-2-yl)-(naphthalen-1-ylmethyl)amino)-6-oxohexylcarbamate (Compound IV-13) 100 mg (0.19 mmol) to obtain the title compound.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[CH:15]=[CH:14][N:13]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12]1=[S:23].[Cl-].CC=[N+]=CC.[CH3:30][N:31]([CH:33]=O)[CH3:32]>>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH:2]1[N:11]1[C:15]([CH2:30][N:31]([CH3:33])[CH3:32])=[CH:14][N:13]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12]1=[S:23]
Reactant: CN(C)C=O
Reactant: CCOC(=O)CCn1ccn(C2CCc3ccccc3C2)c1=S
Agent: CC=[N+]=CC
Agent: [Cl-]
Product: CCOC(=O)CCn1cc(CN(C)C)n(C2CCc3ccccc3C2)c1=S
Temperature: 80 °C

Procedure:
A mixture of ethyl 3-[3-(1,2,3,4-tetrahydronaphthalen-2-yl)-2-thioxo-2,3-dihydro-1H-imidazol-1-yl]propionate (0.5 g, 1.5 mmol), prepared as in Example 34, and N,N-dimethylmethyleneammonium chloride (0.17 g, 1.8 mmol) in 7 mL of DMF was heated at 80° C. under nitrogen for 16 hours. The mixture then was partitioned between saturated sodium bicarbonate solution and ethyl acetate. The organic layer was separated, washed with brine, dried (NaSO4), filtered and concentrated. The residue was purified by column chromatography on silica gel eluting with ethyl acetate/hexane to give ethyl 3-[3-(1,2,3,4-tetrahydronaphthalen-2-yl)-4-dimethylaminomethyl-2-thioxo-2,3-dihydro-1H-imidazol-1-yl]propionate (277 mg, 0.7 mmol), m.p. 128°-130° C.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[S:12][CH:13]=[CH:14][N:15]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.FC(F)(F)C(O)=O.[NH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[CH:30][C:31]([C:34]([NH:36][CH3:37])=[O:35])=[N:32][CH:33]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C>[CH3:37][NH:36][C:34]([C:31]1[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][CH2:24][NH:23][C:2]2[C:3]3[C:10]([C:11]4[S:12][CH:13]=[CH:14][N:15]=4)=[CH:9][S:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:33][N:32]=1)=[O:35]
Reactant: CNC(=O)c1ccc(OCCCN)cn1
Reactant: Clc1ncnc2scc(-c3nccs3)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1ccc(OCCCNc2ncnc3scc(-c4nccs4)c23)cn1
Temperature: 120 °C
Yield: 82.1 %

Procedure:
A mixture of 4-chloro-5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidine (0.050 g, 0.20 mmol), 5-(3-aminopropoxy)-N-methylpyridine-2-carboxamide trifluoroacetate (0.070 g, 0.22 mmol), potassium carbonate (0.272 g, 1.97 mmol) and N,N-dimethylacetamide (2.4 mL) was heated at 120° C. for 13 h. The solvent was evaporated in vacuo, and the residue was treated with 5% sodium bicarbonate (20 mL) and ethyl acetate (20 mL). The precipitate was filtered and washed with water and ethyl ether. The resulting white solid was purified by column chromatography over silica gel to give 70 mg (81%) N-methyl-5-(3-[5-(1,3-thiazol-2-yl)thieno[2,3-d]pyrimidin-4-yl]aminopropoxy)pyridine-2-carboxamide. MS [M+H]=427, LC/MS (EI) tR 3.54 min (Method D), 1H NMR (10% MeOD/CDCl3) δ (ppm) 10.85 (s, 1H), 8.30 (s, 1H), 8.12 (d, J=2.4 Hz, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.94 (b, 1H), 7.71 (s, 1H), 7.50 (d, J=3.6 Hz, 1H), 7.28 (s, 1H), 7.21 (dd, J=8.7, 3.0 Hz, 1H), 4.15 (t, J=0.6 Hz, 2H), 3.80-3.74 (m, 2H), 2.94 (d, J=0.6 Hz, 3H), 2.24-2.18 (m, 2H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][CH2:7][N:8]=[C:9]=[O:10])=[C:2]=[O:3].[NH2:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[C:39]3[C:34](=[C:35]([Cl:41])[CH:36]=[C:37]([Cl:40])[CH:38]=3)[CH2:33][N:32]([CH3:42])[CH2:31]2)=[CH:26][CH:25]=1)(=[O:23])=[O:22]>>[O:3]=[C:2]([NH:1][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:10])[NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[C:39]3[C:34](=[C:35]([Cl:41])[CH:36]=[C:37]([Cl:40])[CH:38]=3)[CH2:33][N:32]([CH3:42])[CH2:31]2)=[CH:28][CH:29]=1)(=[O:23])=[O:22])[NH:11][CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][NH:20][S:21]([C:24]1[CH:25]=[CH:26][C:27]([CH:30]2[C:39]3[C:34](=[C:35]([Cl:41])[CH:36]=[C:37]([Cl:40])[CH:38]=3)[CH2:33][N:32]([CH3:42])[CH2:31]2)=[CH:28][CH:29]=1)(=[O:23])=[O:22]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCN)cc2)C1
Reactant: O=C=NCCCCN=C=O
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCOCCOCCNC(=O)NCCCCNC(=O)NCCOCCOCCNS(=O)(=O)c3ccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)cc3)cc2)C1
Yield: 3 %

Procedure:
Compound 238 was prepared following the procedure outlined in Example 208 using 1,4-diisocyanatobutane (5.64 mg, 0.402 mmol) and N-(2-(2-(2-aminoethoxy)ethoxy)ethyl)-4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (Compound 175.1, 58.8 mg, 0.805 mmol). Purification by preparative HPLC gave the title compound (13.8 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ 7.86 (d, J=8 Hz, 2H), 7.72 (s, 2H), 7.61 (t, 2H), 7.52 (s, 2H), 7.47 (d, J=7 Hz, 2H), 7.18 (s, 5H), 7.78 (s, 2H), 4.77-4.68 (m, 5H), 4.48-4.40 (m, 2H), 3.35-3.28 (m, 2H), 3.56-3.51 (m, 16H), 3.45 (t, J=5 Hz, 5H), 3.35-3.32 (m, 10H), 3.09 (s, 6H), 3.03 (t, J=5 Hz, 3H). MS (m/z): 1145.01 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[C@H:19](/[CH:20]=[CH:21]/[C@@H:22]([OH:28])[CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C@H:5]2[CH2:6][C:7]3[C:12]([CH2:13][C@H:4]2[CH2:3]1)=[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[CH:9][CH:8]=3.[OH-].[K+]>CO.[Pd]>[CH3:27][CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]([OH:28])[CH2:21][CH2:20][C@H:19]1[C@H:2]([OH:1])[CH2:3][C@H:4]2[C@@H:5]1[CH2:6][C:7]1[C:12]([CH2:13]2)=[C:11]([O:14][CH2:15][C:16]([OH:18])=[O:17])[CH:10]=[CH:9][CH:8]=1
Reactant: CCCCC[C@H](O)/C=C/[C@@H]1[C@H]2Cc3cccc(OCC(=O)O)c3C[C@H]2C[C@H]1O
Agent: [Pd]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCCCC[C@H](O)CC[C@@H]1[C@H]2Cc3cccc(OCC(=O)O)c3C[C@H]2C[C@H]1O
Yield: 88 %

Procedure:
2-((1R,2R,3aS,9aS)-2,3,3a,4,9,9a-hexahydro-2-hydroxy-1-((S,E)-3-hydroxyoct-1-enyl)-1H-cyclopenta[b]naphthalen-5-yloxy)acetic acid (2.5 g, 0.008 mol) in dry methanol (25 ml) was treated with potassium hydroxide (0.5 g, 0.008 mol), then with 5% Pd/C (0.5 g, 20% wt) under hydrogen overnight at room temperature. Then, the reaction mixture was filtered with celite pad. The solvent was evaporated off under vacuum. The residues was diluted with 50 nm ethyl, acetate and 50 ml saturated sodium bicarbonate aqueous. The mixture was phase separated and the organic layers was extracted with 50 ml saturated sodium bicarbonate aqueous. The aqueous layers were combined and then 3N HCl was added slowly until pH=˜2. The aqueous layer was extracted with 100 ml ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solid was filtered off. The solvent was evaporated off under vacuum. The crude product was purified by crystallization. The titled compound was obtained in a crystalline form. Yield: 88%
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:17][C:18]1[CH:30]=[C:29]([CH2:31][N:32](C2C(C)=C(C3C=CC(C(F)(F)F)=CC=3)N=CN=2)[CH2:33][CH2:34][CH3:35])[CH:28]=[CH:27][C:19]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH3:17][C:18]1[CH:30]=[C:29]([CH2:31][N:32]([C:2]2[C:7]([CH3:8])=[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH2:33][CH2:34][CH3:35])[CH:28]=[CH:27][C:19]=1[O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: COc1ccc(-c2ncnc(Cl)c2C)cc1
Reactant: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(C(F)(F)F)cc2)c1C
Product: CCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(OC)cc2)c1C

Procedure:
Using 4-chloro-6-(4-methoxyphenyl)-5-methylpyrimidine (164 mg, 0.7 mmol) and the synthetic procedure described for Intermediate 80. Purification by Biotage™ chromatography (Si, 40 g) eluting 4:1 cyclohexane:EtOAc afforded the title compound as a pale yellow oil (60 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:39]#[C:40][C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[C:43]([F:49])[CH:42]=1>C1(C)C=CC=CC=1.S([O-])([O-])(=O)=O.[Cu+2]>[F:49][C:43]1[CH:42]=[C:41]([C:40]#[C:39][N:6]2[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]3[CH2:3][N:2]([CH3:1])[CH2:15][CH2:14][C:5]2=3)[CH:46]=[CH:45][C:44]=1[O:47][CH3:48]
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Reactant: COc1ccc(C#CBr)cc1F
Agent: [Cu+2]
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: Cc1ccccc1
Product: COc1ccc(C#Cn2c3c(c4cc(C)ccc42)CN(C)CC3)cc1F
Temperature: 80 °C
Yield: 7.6 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.49 mmol) was dissolved in toluene (5 mL), and copper sulfate (24 mg, 0.099 mmol) was added, followed by 1,10-phenanthroline (35 mg, 0.19 mmol), potassium phosphate (0.211 mg, 0.99 mmol) and 4-(bromoethynyl)-2-fluoro-1-methoxybenzene (125 mg, 0.54 mmol), and the mixture flushed with nitrogen. The reaction mixture was heated at 80° C. overnight (16 h). Product was detected by LCMS. The reaction mixture was filtered through Celite, and washed with DCM. The combined organic layer was concentrated under vacuum to obtain product which was purified by column chromatography (60-80% EtOAc in hexane as eluent), and repurified by preparative TLC to obtain product as a brown solid (13 mg). 1H NMR (CDCl3, freebase) δ (ppm): 7.42 (d, 1H), 7.25 (m, 2H), 7.18 (s, 1H), 7.10 (d, 1H), 6.92 (t, 1H), 3.95 (s, 3H), 3.62 (s, 2H), 2.95 (m, 2H), 2.85 (m, 2H), 2.60 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[C:18]([F:19])=[CH:17][CH:16]=[CH:15][C:14]=2[OH:20])[N:3]=1.[OH:21][C@H:22]([CH2:31][CH:32]([CH3:34])[CH3:33])[C:23]([N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)=[O:24].C(N(CC)CC)C>C(Cl)Cl>[F:19][C:18]1[CH:17]=[CH:16][CH:15]=[C:14]([OH:20])[C:13]=1[C:4]1[N:3]=[C:2]([N:28]2[CH2:27][CH2:26][N:25]([C:23](=[O:24])[C@H:22]([OH:21])[CH2:31][CH:32]([CH3:33])[CH3:34])[CH2:30][CH2:29]2)[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=1
Reactant: CC(C)C[C@@H](O)C(=O)N1CCNCC1
Reactant: Cc1ccc2c(Cl)nc(-c3c(O)cccc3F)nc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc2c(N3CCN(C(=O)[C@H](O)CC(C)C)CC3)nc(-c3c(O)cccc3F)nc2c1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
2-(4-Chloro-7-methylquinazolin-2-yl)-3-fluorophenol (300 mg, 1.04 mmol) in CH2Cl2 (5 mL) was cooled using an ice water batch. To this stirring solution was added (R)-2-hydroxy-4-methyl-1-(piperazin-1-yl)pentan-1-one (312 mg, 1.56 mmol), followed by triethylamine (210 mg, 291 μL, 2.08 mmol). After letting the reaction warn to room temperature, it was stirred overnight. The mixture was partitioned between water and CH2Cl2 and separated, and the aqueous layer was extracted with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated to a viscous yellow oil. Purification via silica gel chromatography using 0-30% EtOAc in CH2Cl2/hexanes (2:1) gave (R)-1-(4-(2-(2-fluoro-6-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)-2-hydroxy-4-methylpentan-1-one as a bright yellow foam/solid. (413 mg, 88%). LC/MS: m/z 453.1 (M+H)+ at 2.44 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)). 1H NMR (400 MHz, DMSO-d6) d 8.01 (d, J=8.5 Hz, 1H), 7.68 (s, 1H), 7.42 (d, J=8.5 Hz, 1H), 7.37-7.32 (m, 1H), 6.80 (d, J=8.3 Hz, 1H), 6.76-6.71 (m, 1H), 4.91 (d, J=7.2 Hz, 1H), 4.40-4.35 (m, 1H), 4.02-3.65 (m, 8H), 2.52 (s, 3H), 1.82-1.73 (m, 1H), 1.47-1.34 (m, 2H), 0.91 (dd, J=6.5, 4.1 Hz, 6H) ppm.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[CH:10]([CH3:23])[CH2:11][CH:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na].[CH2:26](I)[CH2:27][CH2:28][CH3:29]>C(O)C>[CH2:1]([O:8][C:9](=[O:24])[CH:10]([CH3:23])[CH2:11][C:12]([C:18]([O:20][CH2:21][CH3:22])=[O:19])([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:26][CH2:27][CH2:28][CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCI
Reactant: CCOC(=O)C(CC(C)C(=O)OCc1ccccc1)C(=O)OCC
Agent: [Na]
Solvent: CCO
Product: CCCCC(CC(C)C(=O)OCc1ccccc1)(C(=O)OCC)C(=O)OCC
Temperature: 10 °C

Procedure:
4,4-Diethoxycarbonyl-2-methylbutyric acid benzyl ester [prepared by Michael condensation of benzylmethacrylate and malonic ester as per J. Am. Chem. Soc., 52, 4598 (1930)] (3.36 g, 10 mmole) is added to a solution of 0.23 g of sodium in ethanol (3 ml) chilled to 10° C. Butyl iodide (1.85 g, 10 mmoles) is added and the mixture is refluxed for four hours. The solvent is removed in vacuo and the mixture is distilled in vacuo to yield 4,4-diethoxycarbonyl-2-methyloctanoic acid benzyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:13][C:14]1[CH:15]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:17]=[CH:18][CH:19]=1>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[S:9]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]2[NH:24][N:23]=[N:22][N:21]=2)[CH:15]=1)(=[O:11])=[O:10]
Reactant: Nc1cccc(-c2nnn[nH]2)c1
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1Cl
Product: O=S(=O)(Nc1cccc(-c2nnn[nH]2)c1)c1cccc(Cl)c1Cl
Yield: 74 %

Procedure:
The product was prepared according to General Procedure 6, described in Example 65, with 2,3-dichlorobenzenesulfonyl chloride (13.5 mg, 0.055 mmol) and 5-(3-aminophenyl)tetrazole (8.0 mg, 0.050 mmol). The title compound was obtained in 74% yield (13.7 mg). MS (ESI+) calcd mass for C13H9Cl2N5O2S 368.985401, found 368.984901.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[NH2:18][C:19](=[N:25]O)[C:20]([O:22][CH2:23][CH3:24])=[O:21].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]1[O:11][N:25]=[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[N:18]=1
Reactant: CCOC(=O)C(N)=NO
Reactant: O=C(O)Cc1ccccc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)c1noc(Cc2ccccc2Cl)n1
Yield: 38.4 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-(2-chlorophenyl)acetic acid (0.646 g; 3.78 mmol) and oxalyl chloride (0.352 mL; 4.16 mmol) in dichloromethane (12 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (6 mL) and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.387 g (38%) of ethyl 5-(2-chlorobenzyl)-1,2,4-oxadiazole-3-carboxylate as a white solid.
Reaction SMILES: Cl[C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][C:6]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:5][CH:4]=2.[CH2:20]([NH2:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[OH-].[Na+]>C1(O)C=CC=CC=1>[CH2:20]([NH:27][C:2]1[C:3]2[C:8]([N:9]=[C:10]3[C:15]=1[CH2:14][CH2:13][CH2:12][CH2:11]3)=[CH:7][C:6]([C:16]([CH3:19])([CH3:18])[CH3:17])=[CH:5][CH:4]=2)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)c1ccc2c(Cl)c3c(nc2c1)CCCC3
Reactant: NCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Product: CC(C)(C)c1ccc2c(NCc3ccccc3)c3c(nc2c1)CCCC3
Yield: 55.4 %

Procedure:
9-Chloro-6-(1,1-dimethylethyl)-1,2,3,4-tetrahydroacridine (3.0 g) was dissolved in 60 ml of phenol and heated at 150° C. with 3.54 g of benzylamine. After 2 hours the reaction mixture was poured into 10% NaOH and extracted with Et2O. The organic phase was separated, washed with H2O, and then treated with 5% HCl. The insoluble hydrochloride was filtered off and recrystallized from isopropanol/ether and then from methanol/ether to give 2.09 g of product, m.p. 247° (d).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[N:20]=[CH:19][CH:18]=[CH:17]3)(=[O:10])=[O:9])=[C:4]([N+:22]([O-])=O)[CH:3]=1.O.O.[Sn](Cl)Cl>>[NH2:22][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[S:8]([NH:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:9])=[O:10]
Reactant: O=[N+]([O-])c1cc(F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Agent: Cl[Sn]Cl
Solvent: O
Product: Nc1cc(F)ccc1S(=O)(=O)Nc1cccc2cccnc12
Yield: 89.5 %

Procedure:
In a similar fashion using route 15 general procedure 29, 4-fluoro-2-nitro-N-quinolin-8-yl-benzenesulfonamide (Example Compound 30) (1.1 g, 3.17 mmol) and tin (II) chloride dihydrate (4.29 g, 19 mmol) gave the title compound (900 mg, 90%).