Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][C:28](=[O:30])[CH3:29])[CH2:25][CH3:26])[C:5]1=[O:31])[CH:2]=[CH2:3].[CH3:33][Mg]Br>C1COCC1.C1(C)C=CC=CC=1>[CH2:1]([C@@:4]1([CH3:32])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@H:24]([CH2:27][C:28]([OH:30])([CH3:33])[CH3:29])[CH2:25][CH3:26])[C:5]1=[O:31])[CH:2]=[CH2:3]
Reactant: C[Mg]Br
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC(C)=O)C1=O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CC(C)(C)O)C1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-1-((S)-5-oxohexan-3-yl)piperidin-2-one (90 mg, 0.19 mmol; Example 131, Step A) in THF (1.9 mL) was added 1.4 M methylmagnesium bromide in toluene and THF (75:25) (408 μL, 0.571 mmol) at 0° C. Then the reaction was allowed to warm to rt and stirred for 4 h. The reaction was quenched (sat NH4Cl solution), extracted (2×EtOAc), and washed (sat. aq. NaCl solution). The combined organic layer was dried (Na2SO4) and concentrated under reduced pressure and purification of the residue by chromatography on silica gel (12 g SiO2, 30% and 35% EtOAc/Hex) provided the title compound as a colorless foam.
Reaction SMILES: [CH2:1](Cl)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12]/[CH:13]=[CH:14]\[CH2:15][CH3:16].[C:18]([O-:21])(=[O:20])[CH3:19].[Na+].CN(C)C(=O)C>[I-].[Na+].O>[C:18]([O:21][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]#[C:12]/[CH:13]=[CH:14]\[CH2:15][CH3:16])(=[O:20])[CH3:19]
Reactant: CC/C=C\C#CCCCCCCCCCCCl
Reactant: CC(=O)[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CC/C=C\C#CCCCCCCCCCCOC(C)=O
Temperature: 122.5 °C
Reaction time: 6 h
Yield: 94 %

Procedure:
In a reactor equipped with a stirrer, a cooling condenser, a dropping funnel and a thermometer were placed Z-13-hexadecen-11-yn-yl chloride (254.8 g: 1.0 mol), sodium acetate (98.4 g: 1.2 mol), sodium iodide (8.9 g: 0.06 mol) and N,N-dimethylacetamide (113.2 g), and stirred at from 120 to 125° C. for 6 hours. After the completion of the reaction was confirmed by gas chromatography, water (350.0 g) was added to the reaction mixture. The organic phase separated from the aqueous phase was washed with an aqueous 1.0% by weight sodium bicarbonate solution (250.0 g). The organic phase was subjected to removal of the solvent under reduced pressure, followed by dehydration. The residue was then distilled under reduced pressure to obtain Z-13-hexadecen-11-yn-yl acetate [bp: from 126 to 130° C./0.13 KPa, 261.2 g, 0.94 mol]. [Yield: 93.8%]
Reaction SMILES: [I-:1].[Na+].[Br-].[C:4]([NH2:8])(=[O:7])[CH2:5][CH3:6].C(OC([N:15]1[C@H:19](/[CH:20]=[CH:21]/[C:22]2[N:23]3[CH:29]=[N:28][CH:27]=[C:24]3[S:25][CH:26]=2)[CH2:18][C@H:17]([S:30][C:31]2[C@H:32]([CH3:48])[C@@H:33]3[C@@H:43]([C@H:44]([OH:46])[CH3:45])[C:42](=[O:47])[N:34]3[C:35]=2[C:36](OCC=C)=[O:37])[CH2:16]1)=O)C=C>CC(C)=O.CN(C=O)C>[C:4]([CH2:5][CH2:6][N:28]1[CH:27]=[C:24]2[S:25][CH:26]=[C:22](/[CH:21]=[CH:20]/[C@H:19]3[NH:15][CH2:16][C@@H:17]([S:30][C:31]4[C@H:32]([CH3:48])[C@@H:33]5[C@@H:43]([C@H:44]([OH:46])[CH3:45])[C:42](=[O:47])[N:34]5[C:35]=4[C:36]([I:1])=[O:37])[CH2:18]3)[N:23]2[CH2:29]1)(=[O:7])[NH2:8]
Reactant: CCC(N)=O
Reactant: C=CCOC(=O)C1=C(S[C@H]2C[C@@H](/C=C/c3csc4cncn34)N(C(=O)OCC=C)C2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Reactant: [I-]
Agent: [Br-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)I)=C(S[C@@H]3CN[C@H](/C=C/C4=CSC5=CN(CCC(N)=O)CN45)C3)[C@H](C)[C@H]12
Yield: 3.3 %

Procedure:
Sodium iodide (70 mg) and 71 mg of propionamide bromide are added to a solution of 55 mg of allyl(1R,5S,6S)-2-[(3S,5S)-1-allyloxycarbonyl-5-[2(E)-(imidazo[5,1-b]thiazol-3-yl)ethenyl]pyrrolidin-3-yl]thio-6-((1R)-1-hydroxyethyl)-1-methylcarbapen-2-em-3-carboxylate, described in Example 38-a) in 1 ml of acetone and 0.5 ml of DMF, and the mixture is stirred in a light-shielded state at room temperature for 36 hr. The solvent is removed under reduced pressure, and the residue is purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1). The procedure of Example 49-a) is repeated, except that the purification product prepared just above is used. Thus, 2 mg of the title compound is prepared.
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][N:10]=2)[N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.CC1OCCC1.Cl.O1CCOCC1>CCOC(C)=O>[NH:5]1[C:6]2[C:11](=[N:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[CH2:3][CH2:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)c2ncccc21
Agent: Cl
Solvent: C1COCCO1
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Product: O=C1CCNc2cccnc21

Procedure:
To a solution of tert-butyl 4-oxo-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate (1 eq.) and 2-MeTHF (0.2 M) is added 4M HCl in dioxane (5 eq.). The reaction is monitored by TLC. The reaction is diluted with EtOAc and washed with saturated NaHCO3. The organic solution is dried over MgSO4 and concentrated in vacuo. The compound that may be thus obtained is purified by column chromatography to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[F:27][C:28]1[C:33]([F:34])=[CH:32][CH:31]=[C:30]([NH2:35])[C:29]=1[NH2:36].C(N(CC)C(C)C)(C)C>CN(C=O)C>[NH2:36][C:29]1[C:28]([F:27])=[C:33]([F:34])[CH:32]=[CH:31][C:30]=1[NH:35][C:10](=[O:12])[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: Nc1ccc(F)c(F)c1N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(F)c(F)c1N
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a 130 mL DMF solution of [(tert-butoxycarbonyl)amino]acetic acid (14.1 g, 80.4 mmol) were added EDC (18.8 g, 96.2 mmol), HOBt (13.1 g, 96.2 mmol), 3,4-difluoro-benzene-1,2-diamine (11.2 g, 77.7 mmol) and N,N-diisopropylethylamine (27.1 mL, 156 mmol). The reaction mixture was stirred at room temperature for 6 hr. The resulting suspension was filtered and the filtrate was diluted with EtOAc, washed with sat. ammonium chloride aq., sat. sodium bicarbonate aq. and brine, dried over anhydrous Na2SO4 filtered and concentrated to give the title compound as crude solid product (24 g). LC/MS: m/z 302(M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][N:6]([C:8]2[CH:9]=[C:10]([NH2:20])[C:11]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:12][CH:13]=2)[CH2:5][CH2:4][O:3]1.Cl[C:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][C:31]=2[F:33])[N:26]=[C:25]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:24]=1[CH3:40].Cl.O1CCOCC1.CN1C(=O)CCC1>>[CH3:1][C:2]1([CH3:21])[O:3][CH2:4][CH2:5][N:6]([C:8]2[CH:9]=[C:10]([NH:20][C:23]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][C:31]=4[F:33])[N:26]=[C:25]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=4)[C:24]=3[CH3:40])[C:11]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)=[N:12][CH:13]=2)[CH2:7]1
Reactant: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Cl
Reactant: CC1(C)CN(c2cnc(N3CCOCC3)c(N)c2)CCO1
Agent: Cl
Solvent: C1COCCO1
Solvent: CN1CCCC1=O
Product: Cc1c(-c2ccccn2)nc2cccc(F)c2c1Nc1cc(N2CCOC(C)(C)C2)cnc1N1CCOCC1
Temperature: 160 °C

Procedure:
Prepared according to Procedure K, method 2 using 5-(2,2-dimethylmorpholino)-2-morpholinopyridin-3-amine (62 mg, 0.213 mmol; described herein), 4-chloro-5-fluoro-3-methyl-2-(pyridin-2-yl)quinoline (58 mg, 0.213 mmol; described herein), 4.0M hydrochloric acid in 1,4-dioxane (50 μL, 0.21 mmol), and NMP (310 μL, 3.2 mmol), and heating in a microwave for 3 h at 160° C. Purification afforded N-(5-(2,2-dimethyl-4-morpholinyl)-2-(4-morpholinyl)-3-pyridinyl)-5-fluoro-3-methyl-2-(2-pyridinyl)-4-quinolinamine as a yellow solid. 1H NMR (400 MHz, chloroform-d) δ ppm 8.70 (1H, d, J=4.7 Hz), 7.86-8.04 (4H, m), 7.54-7.66 (2H, m), 7.38 (1H, ddd, J=6.7, 4.7, 2.0 Hz), 7.19 (1H, dd, J=13.7, 7.8 Hz), 6.45 (1H, d, J=2.3 Hz), 3.93 (4H, t, J=4.3 Hz), 3.78-3.87 (2H, m), 3.02-3.31 (6H, m), 2.88 (2H, s), 2.21 (3H, s) 1.24-1.34 (6H, m). Mass Spectrum (ESI) m/e=529.2 (M+1).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([O:24][C:25]([N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][N:36]=[N+]=[N-])[CH2:29][CH2:28]1)=[O:26])([CH3:23])([CH3:22])[CH3:21].C1COCC1.C(#N)C>O>[C:20]([O:24][C:25]([N:27]1[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][CH2:35][NH2:36])[CH2:31][CH2:32]1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)N1CCN(CCCN=[N+]=[N-])CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CCCN)CC1

Procedure:
Triphenylphosphine (2.78 g, 10.6 mmol) is added to a stirred solution of 4-(3-azido-propyl)-piperazine-1-carboxylic acid tert-butyl ester (2.05 g, 7.61 mmol) in a solution of THF (10 mL)/acetonitrile (30 mL)/water (4 mL). The resultant mixture is stirred for 16 hours. After concentration and subsequent chromatography on silica gel, eluting with 2 M NH3/CH3OH in dichloromethane 0-20%, the title compound is obtained as a clear oil (1.76 g, 95% yield).
Reaction SMILES: [CH2:1]([N:6]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:29])[N:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:11]([C:30]([N:32]([CH2:34][CH2:35][N:36](C)[C:37](OC(C)(C)C)=O)[CH3:33])=[O:31])[CH2:10]1)=[O:8])[CH2:2][CH2:3][CH2:4][CH3:5].C1(OC)C=CC=CC=1.[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61]>>[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61].[CH2:45]([N:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:7]([N:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:29])[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C@H:11]([C:30]([N:32]([CH2:34][CH2:35][NH:36][CH3:37])[CH3:33])=[O:31])[CH2:10]1)=[O:8])[CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)C(C(=O)N(C)CCN(C)C(=O)OC(C)(C)C)C1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CCCCCN(CCCCC)C(=O)N1CCN(C(=O)N(c2ccccc2)c2ccccc2)[C@H](C(=O)N(C)CCNC)C1
Yield: 98 %

Procedure:
To a mixture of 130 mg (0.19 mmole) of 4-(N,N-di-n-pentylcarbamoyl)-1-(N,N-diphenylcarbamoyl)-2-(2-(N-methyl-N-(t-butoxycarbonyl)amino)-N-(methyl)ethylaminocarbonyl)piperazine and 0.4 mL of anisole at 0° C. was added 2 mL of trifluoroacetic acid precooled to 0° C. After 45 min the solution was concentrated in vacuo and the residue purified by flash chromatography on 16 g of silica gel eluting with 100:9 CH2Cl2 :MeOH to give 130 mg (98%) of an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2O.C(Cl)Cl.N1C(C)=CC=CC=1C.[F:27][C:28]([F:34])([F:33])[S:29](Cl)(=[O:31])=[O:30].[OH2:35]>CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([O:30][S:29]([C:28]([F:34])([F:33])[F:27])(=[O:35])=[O:31])[CH:7]=[CH:6]2
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: O
Reactant: COc1cc2nccc(O)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: COc1cc2ccc(OS(=O)(=O)C(F)(F)F)nc2cc1OC
Temperature: 25 °C
Yield: 80 %

Procedure:
To a dry 1 L RBF containing 6,7-dimethoxyquinolin-4-ol (20.9 g, 102 mmol), which can be prepared according to the procedure of Riegel, B. (J. Amer. Chem. Soc. 1946, 68, 1264), was added DCM (500 mL), 4-dimethylaminopyridine. (1.24 g, 10 mmol) and 2,6-lutidine (24 mL, 204 mmol). The mixture was vigorously stirred at RT. Trifluoromethanesulfonyl chloride (14 mL, 132 mmol) was added dropwise to the solution. After addition was complete, the mixture was stirred ice bath for 2 to 3 hrs. On LC/MS indicating the reaction completion, the reaction mixture was concentrated in vacuo and placed under high vacuum to remove residual 2,6-lutidine. To the resulting brown solids was added methanol (250 mL). The resulting slurry was stirred for 30 min before adding water (1 L). The solids were isolated by filtration, followed by a water wash. The resulting solid was dried under high vacuum overnight yielding trifluoromethanesulfonic acid 6,7-dimethoxy-quinolinyl ester as a light brown solid (27 g, 80%). 1H NMR (400 MHz, DMSO, d6): δ 8.82 (d, 1H), 7.59 (m, 2H), 7.20 (s, 1H), 3.97 (d, 6H). LC/MS: M+H=338.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][NH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[NH:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(N(CC)C(C)C)(C)C.[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]1[CH:38]=[CH:37][C:33]([C:34](Cl)=[O:35])=[CH:32][CH:31]=1>ClCCl.C(Cl)(Cl)Cl>[S:25]1[CH:29]=[CH:28][CH:27]=[C:26]1[C:30]1[CH:38]=[CH:37][C:33]([C:34]([N:9]2[CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[NH:6][C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]2=3)=[O:35])=[CH:32][CH:31]=1
Reactant: c1ccc2c(c1)CNc1ccccc1N2
Reactant: O=C(Cl)c1ccc(-c2cccs2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1ccc(-c2cccs2)cc1)N1Cc2ccccc2Nc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.2 %

Procedure:
A mixture of 3 g of 4-(2-thienyl)benzoic acid and 30 ml of sulfonyl chloride is refluxed for 45 minutes and the solvent removed. The residue is dissolved in carbon tetrachloride and the solvent removed under vacuum (2-times) to give 4-(2-thienyl) benzoyl chloride. To a cooled (0° C.) solution of 2.0 g of 5,11-dihydro-10H-dibenz[b,e][1,4]diazepine and 7 ml of N,N-diisopropylethylamine in 30 ml of dichloromethane is added dropwise a solution of 3.15 g of 4-(2-thienyl)benzoyl chloride in 30 ml of dichloromethane. The mixture is stirred at room temperature for 16 hours and diluted with 50 ml of chloroform. The solution is washed with 30 ml each of water, 2N HCl, saturated NaHCO3, water and dried (Na2 SO4). The solvent is removed under vacuum and the residue (3.1 g) chromatographed on silica gel (column) with hexane-ethyl acetate (2:1) as eluent to give 1.8 g of solid, m.p. 114° C.-116° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:30]COCC[Si](C)(C)C)=[CH:5][C:6]2[NH:12][C:11]3[CH:13]=[C:14]([C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH3:27])[CH:18]=4)[CH:15]=[CH:16][C:10]=3[C:9](=[O:28])[NH:8][C:7]=2[CH:29]=1.Cl.O1CCOCC1>C(Cl)Cl.CO>[OH:30][C:4]1[C:3]([O:2][CH3:1])=[CH:29][C:7]2[NH:8][C:9](=[O:28])[C:10]3[CH:16]=[CH:15][C:14]([C:17]4[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[C:19]([O:26][CH3:27])[CH:18]=4)=[CH:13][C:11]=3[NH:12][C:6]=2[CH:5]=1
Reactant: COc1cc2c(cc1OCOCC[Si](C)(C)C)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Agent: Cl
Solvent: CO
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1cc2c(cc1O)Nc1cc(-c3ccc([N+](=O)[O-])c(OC)c3)ccc1C(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of Example 476H (429 mg, 0.8 mmol) in methylene chloride (20 mL) and methanol (10 mL) was treated with 4N HCl/dioxane (1 mL, 4.0 mmol) and stirred one hour at room temperature. The mixture was concentrated under vacuum to provide 325 mg (quantitative) of desired product. MS (ESI) m/e 408 (M+H)+; 1H NMR (300 MHz, DMSO-d6) □ 9.57 (s, 1H), 8.89 (s, 1H), 8.01 (d, J=8.1 Hz, 1H), 7.76 (d, J=8.1 Hz, 1H), 7.65 (s, 1H), 7.51 (d, J=1.7 Hz, 1H), 7.26-7.35 (m, 3H), 6.59 (s, 1H), 6.52 (s, 1H), 4.03 (s, 3H), 3.67 (s, 3H).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9]N)=[CH:5][CH:4]=1.[CH3:11][CH:12]1[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]1>C(O)C>[CH3:2][CH:3]1[CH2:8][C:7]2[C:16]3[C:15](=[CH:14][CH:13]=[C:12]([CH3:11])[CH:17]=3)[NH:9][C:6]=2[CH2:5][CH2:4]1
Reactant: CC1CCC(=O)CC1
Reactant: Cc1ccc(NN)cc1
Agent: Cl
Solvent: CCO
Product: Cc1ccc2[nH]c3c(c2c1)CC(C)CC3
Temperature: 0 °C
Yield: 66.2 %

Procedure:
Bis-1,3(N-3',6'-dimethylcarbazolyl)propane. A mixture of 25.0 g (157 mmol) of p-methylphenylhydrazine hydrochloride and 17.6 g (157 mmol) of 4-methylcyclohexanone was stirred overnight in 75 ml of 95% ethanol. The mixture was cooled to 0° C, filtered, and the product recrystallized from ethanol/water to give 20.7 g (66%) of 3,6-dimethyl-1,2,3,4-tetrahydrocarbazole, mp 118.5°-20° C (lit. mp 112° C).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([NH:8]C(=O)C)[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[O:23][N:22]=[C:21]([CH3:24])[CH:20]=2)[CH:14]=1.Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>C1COCC1.O>[CH3:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[O:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]([C:19]2[O:23][N:22]=[C:21]([CH3:24])[CH:20]=2)[CH:14]=1
Reactant: CC(=O)Nc1ccc(Oc2ccnc(-c3cc(C)no3)c2)c(C)n1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2cc(Oc3ccc(N)nc3C)ccn2)on1
Temperature: 60 °C
Yield: 94 %

Procedure:
A mixture of N-(6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)acetamide (0.11 g, 0.339 mmol) and 2M HCl (1.696 mL, 3.39 mmol) in THF (3 mL) was heated at 60° C. for 4 h. The mixture was cooled to RT, treated with EtOAc and H2O, neutralized with NaHCO3, the layers separated and the aqueous layer extracted with EtOAc (1×). The combined organics were washed with brine, dried over Na2SO4 and concentrated to dryness to afford 6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-amine (90 mg, 94%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 8.51 (d, J=5.7 Hz, 1H); 7.26 (d, J=2.5 Hz, 1H); 7.22 (d, J=8.7 Hz, 1H); 6.95 (s, 1H); 6.89 (dd, J=5.7, 2.5 Hz, 1H); 6.36 (d, J=8.7 Hz, 1H); 6.00 (s, 2H); 2.28 (s, 3H); 2.06 (s, 3H); MS (ESI) m/z: 283.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([CH2:20][CH3:21])(=[O:19])=[O:18])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1.[CH3:29]C(S(Cl)(=O)=O)C.C(S(Cl)(=O)=O)C>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:22])[C:10]2[CH:15]=[CH:14][C:13]([CH2:16][S:17]([CH:20]([CH3:29])[CH3:21])(=[O:19])=[O:18])=[CH:12][CH:11]=2)=[CH:4][C:3]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: CCS(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1
Agent: CCS(=O)(=O)Cl
Product: CC(C)S(=O)(=O)Cc1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)cc1

Procedure:
N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(isopropylsulfonylmethyl)benzamide was prepared using the same procedure as N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(ethylsulfonylmethyl)benzamide except propane-2-sulfonyl chloride was substituted for ethanesulfonyl chloride. The product was purified on reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(isopropylsulfonylmethyl)benzamide. MS (Q1) 429 (M)+.
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[C:4](=[O:6])[CH3:5])[CH3:2].C([N-]C(C)C)(C)C.[Li+].[C:17]([CH2:19][C@@H:20]([OH:27])[CH2:21][C:22](OCC)=[O:23])#[N:18].Cl>O1CCCC1.O1CCCC1.CCCCCCC>[C:17]([CH2:19][C@@H:20]([OH:27])[CH2:21][C:22](=[O:23])[CH2:5][C:4]([N:3]([CH2:7][CH3:8])[CH2:1][CH3:2])=[O:6])#[N:18]
Reactant: CCOC(=O)C[C@H](O)CC#N
Reactant: CCN(CC)C(C)=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)CC(=O)C[C@H](O)CC#N
Reaction time: 0.5 h

Procedure:
To a stirred -10° C. solution of N,N-diethyl-acetamide (prepared from N,N-diethylamine and acetyl chloride by refluxing for 2 hours in toluene) (28.75 g, 0.25 mol) in tetrahydrofuran (0.25 L) is slowly added a solution of lithium diisopropylamide in tetrahydrofuran-heptane (0.125 L of 2M) while maintaining the temperature between -10° C. to -5° C., and the mixture is stirred at -20° C. to 0° C. for 30minutes. (R)-4-cyano-3-hydroxybutyric acid, ethyl ester (Brower, supra) (10 g, 0.06 mol) as a solution in 200 mL of tetrahydrofuran is added to the previously prepared mixture. The reaction mixture is stirred for 30 minutes at -5° C. to -20° C., and transferred to a 2.2N aqueous hydrochloric acid solution (0.25 L). The aqueous layer is extracted with 300 mL of ethyl acetate, the aqueous layer is separated and reextracted with 50 mL of ethyl acetate, the extracts are combined and concentrated in vacuo to afford crude (R)-6-cyano-N,N-diethyl-5-hydroxy-3-oxohexanamide as an oil;
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[C:12](=[CH:17]\[O:18][CH3:19])/[C:13]([O:15][CH3:16])=[O:14].[ClH:23].N([O-])=O.[Na+].[S:28](=[O:30])=[O:29]>C(O)(=O)C.O>[Cl:23][S:28]([C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[C:12](=[CH:17]\[O:18][CH3:19])/[C:13]([O:15][CH3:16])=[O:14])(=[O:30])=[O:29]
Reactant: O=S=O
Reactant: Cl
Reactant: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(N)c1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CO/C=C(/C(=O)OC)c1ccccc1Oc1cccc(S(=O)(=O)Cl)c1
Reaction time: 0.5 h

Procedure:
A solution of (E)-methyl 2-[2-(3-aminophenoxy)phenyl]-3-methoxypropenoate (0.4 g) in glacial acetic acid (2 ml) was treated with 5.8M hydrochloric acid (1 ml), at -10° C. The stirred solution was then treated with sodium nitrite (0.1 g in 2 ml of water) still at -10° C. After 30 minutes, the resulting solution (containing the diazonium salt) was added to a stirred mixture of glacial acetic acid (0.5 ml) saturated with sulphur dioxide, containing 0.1 g of cuprous chloride (effervescence). After 30 minutes, the reaction mixture was poured into water and extracted with ether. The ether extracts were neutralized with a saturated aqueous solution of sodium bicarbonate, dried and concentrated to give (E)-methyl 2-[2-(3-chlorosulphonylphenoxy)phenyl]-3-methoxypropenoate (0.14 g) as a yellow oil.
Reaction SMILES: [CH3:1][C@:2]12[CH2:10][CH2:9][C:8]3[C:11]4[CH:12]=[CH:13][C:14]([OH:19])=[CH:15][C:16]=4[CH2:17][CH2:18][C:7]=3[C:6]1=[CH:5][CH2:4][C:3]2=[O:20].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[CH3:1][C@:2]12[CH2:10][CH2:9][C:8]3[C:11]4[CH:12]=[CH:13][C:14]([O:19][C:21](=[O:23])[CH3:22])=[CH:15][C:16]=4[CH2:17][CH2:18][C:7]=3[C:6]1=[CH:5][CH2:4][C:3]2=[O:20]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@]12CCC3=C(CCc4cc(O)ccc43)C1=CCC2=O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc2c(c1)CCC1=C2CC[C@]2(C)C(=O)CC=C12
Reaction time: 4 h

Procedure:
Mix 13β-methyl-3-hydroxygona-1,3,5(10),8,14-pentaen-17-one with pyridine (3 cc) and acetic anhydride (1 cc) and keep at room temperature for 4 hours. Add ethanol (1 cc) and remove low-boiling material under reduced pressure (0.1 mm) to leave a red gum which crystallizes from a mixture of ethyl acetate and light petroleum. Recrystallize from methanol to obtain crystals of 13β-methyl-3-acetoxygona-1,3,5(10),8,14-pentaen-17-one, melting partially at 161°-166° with resolidification at about 220° and finally melting at 260°-265° (decomp.); infrared absorption peaks at 5.75 μ and 8.27 μ, with absence of an absorption band due to a hydroxy group; ultraviolet absorption peak at 307.5 mμ (ε24,000).
Reaction SMILES: [NH:1]1[C:8]2[N:4]([N:5]=[CH:6][CH:7]=2)[CH:3]=[CH:2]1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>O1CCCC1>[C:9]([N:1]1[C:8]2[N:4]([N:5]=[CH:6][CH:7]=2)[CH:3]=[CH:2]1)(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: c1cc2[nH]ccn2n1
Solvent: C1CCOC1
Product: CC(=O)n1ccn2nccc12
Temperature: 35 °C

Procedure:
To a solution of 1H-imidazo[1,2-b]pyrazole (2.5 g) in tetrahydrofuran (10 ml) was added acetic anhydride (3.1 ml) under stirring at 35° C. and the mixture was stirred for 2 hours at the same temperature. The reaction mixture was evaporated in vacuo to give 1-acetyl-1H-imidazo[1,2-b]-pyrazole (2.7 g).