Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][CH2:6][C@H:5]([C:9]([OH:11])=[O:10])[CH2:4]1.[CH2:12](O)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27]([OH:30])(=[O:29])=[O:28])=[CH:23][CH:22]=1.C(OCC)C>C1(C)C=CC=CC=1>[C:21]1([CH3:31])[CH:22]=[CH:23][C:24]([S:27]([OH:30])(=[O:28])=[O:29])=[CH:25][CH:26]=1.[CH2:12]([O:10][C:9]([C@H:5]1[CH2:6][CH2:7][CH2:8][C@@H:3]([NH2:2])[CH2:4]1)=[O:11])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCc1ccccc1
Reactant: N[C@@H]1CCC[C@H](C(=O)O)C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: O
Product: N[C@@H]1CCC[C@H](C(=O)OCc2ccccc2)C1

Procedure:
cis-3-Aminocyclohexanecarboxylic acid hydrochloride (8.78 g, 49 mmole) was refluxed for 24 hours with benzyl alcohol (26.4 g, 0.24 mole) and para-toluenesulphonic acid monohydrate (11.17 g, 0.59 mole) in toluene (150 ml) using a Dean-Stark trap. On cooling and addition of diethyl ether the required benzyl ester crystallised as a white solid (18.68 g, 94%), m.p. 148°-150° C. Found: C,62.21; H,6.75; N,3.34. C21H27NO5S requires C,62.20; H,6.71; N,3.45%.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([C:18]#[N:19])[CH2:17][CH2:16]C[CH2:14][CH2:13]2)=[CH:8][CH:7]=1.ClCCC[O:24]C1C=CC(C2(C#N)CCCCC2)=CC=1.[CH:39]([N:42](CC)[CH:43]([CH3:45])[CH3:44])([CH3:41])[CH3:40].C[C@@H]1CC[C@H](C)N1>CN1C(=O)CCC1>[CH3:45][C@@H:43]1[CH2:44][CH2:41][C@H:39]([CH3:40])[N:42]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2([C:18]#[N:19])[CH2:13][CH2:14][O:24][CH2:16][CH2:17]2)=[CH:10][CH:11]=1
Reactant: N#CC1(c2ccc(OCCCCl)cc2)CCCCC1
Reactant: CCN(C(C)C)C(C)C
Reactant: N#CC1(c2ccc(OCCCBr)cc2)CCCCC1
Agent: C[C@@H]1CC[C@H](C)N1
Solvent: CN1CCCC1=O
Product: C[C@@H]1CC[C@H](C)N1CCCOc1ccc(C2(C#N)CCOCC2)cc1
Temperature: 160 °C
Reaction time: 0.17 h
Yield: 28 %

Procedure:
A (1:3) mixture of 1-[4-(3-bromo-propoxy)-phenyl]-cyclohexanecarbonitrile and 1-[4-(3-chloro-propoxy)-phenyl]-cyclohexanecarbonitrile (150 mg, 0.54 mmol), N,N-diisopropylethylamine (187 μL, 1.07 mmol) and (2R,5S)-2,5-dimethylpyrrolidine (145 mg, 1.07 mmol) in NMP (0.5 mL) was heated at 160° C. in the microwave (Smith Personal Synthesiser) for 400 seconds then 170° C. for 600 seconds. The reaction mixture was quenched with NaHCO3 (15 mL) and extracted with ethyl acetate (2×15 mL), dried over Na2SO4, filtered and concentrated in vacuo. The compound was purified by column chromatography on Biotage® silica gel, eluting with dichloromethane:methanol:ammonia, 97:3:0.3 to 90:10:1. Yield=28% 1H NMR (400 MHz, CDCl3) δ7.36 (d, 2H), 6.92 (d, 2H), 4.10-4.04 (m, 2H), 4.00 (t, 2H), 3.88 (dt, 2H), 2.72 (t, 2H), 2.64-2.52 (m, 2H), 2.14-1.98 (m, 4H), 1.94 (pentet, 2H), 1.86-1.78 (m, 2H), 1.42-1.28 (m, 2H), 1.10 (d, 6H); HRMS (ESI+) 343.2380 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([CH:15]3[O:19]C(C)(C)C(C)(C)[O:16]3)=[CH:11][CH:10]=2)[N:7]=[C:6](C)[CH:5]=1)[CH3:2].I[C:26]1[C:34]2[C:29](=[N:30][CH:31]=[N:32][C:33]=2[NH2:35])[N:28]([C@H:36]2[CH2:41][CH2:40][C@H:39]([N:42]3[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]3)[CH2:38][CH2:37]2)[N:27]=1.O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:15]([OH:19])(=[O:16])[CH3:12].[CH2:1]([O:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:26]3[C:34]4[C:29](=[N:30][CH:31]=[N:32][C:33]=4[NH2:35])[N:28]([C@H:36]4[CH2:41][CH2:40][C@H:39]([N:42]5[CH2:47][CH2:46][N:45]([CH3:48])[CH2:44][CH2:43]5)[CH2:38][CH2:37]4)[N:27]=3)=[CH:11][CH:10]=2)[N:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCOc1cc(C)nn1-c1ccc(C2OC(C)(C)C(C)(C)O2)cc1
Reactant: CN1CCN([C@H]2CC[C@H](n3nc(I)c4c(N)ncnc43)CC2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(=O)O
Product: CCOc1ccnn1-c1ccc(-c2nn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)cc1
Temperature: 25 °C

Procedure:
A mixture of 5-ethoxy-3-methyl-1-[4-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)phenyl]-1H-pyrazole (0.062 g, 0.00019 mol), trans-3-iodo-1-[4-(4-methylpiperazino)-cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.070 g, 0.000159 mol), tetrakis(triphenylphosphine)palladium (0.011 g, 0.0000095 mol) and sodium carbonate monohydrate (0.049 g, 0.000398 mol) was heated in a mixture of ethylene glycol dimethyl ether (5 mL) and water (3 mL) at 80° C. for 16 hours under an atmosphere of nitrogen. The mixture was allowed to cool to ambient temperature and solvents were removed under the reduced pressure. The residue was purified by preparative HPLC (Hypersil C18, 8 μm, 25 cm; 10-60% acetonitrile-0.1M ammonium acetate over 25 min, 21 mL/min) to yield trans-3-[4-(5-ethoxy-1H-1-pyrazolyl)phenyl]-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine acetate (0.037 g, 0.000064 mol) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.O.[CH:13](O)=[O:14]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][CH:13]=[O:14])[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(CCN)c1
Reactant: O=CO
Solvent: O
Product: COc1cccc(CCNC=O)c1
Yield: 73 %

Procedure:
A solution of 2-(3-methoxy-phenyl)-ethylamine (50.0 g, 0.33 mol) in formic acid (60 mL) was refluxed overnight. Water (250 mL) was added and the emulsion extracted with ethyl acetate (2×150 mL). The organic layer was separated, dried (Na2SO4) and concentrated to give N-[2-(3-methoxy-phenyl)-ethyl]-formamide (43.1 g, 73%). MS: 180.1 (M+1+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:20][C:21]([CH3:26])([CH3:25])[C:22](Cl)=[O:23]>O1CCCC1>[CH3:20][C:21]([CH3:26])([CH3:25])[C:22]([O:11][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:23]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)OC(=O)Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C

Procedure:
Combine 3,4-dichlorophenyl acetic acid (31.5 g, 154 mmol) and triethylamine (25.7 ml, 184 mmol) and tetrahydrofuran (300 ml). Cool in a dry-ice/acetone bath. Add trimethylacetyl chloride (18.5 grams, 154 mmol) and tetrahydrofuran (200 ml). Warm to ambient temperature to give the title compound in solution.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][S:18][C:17]([CH3:22])([CH3:21])[C@@H:16]2[C:23]([O:25]C)=[O:24])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH:2]=[C:3]=[CH2:4].[OH-].[Li+].O>O1CCCC1.CO>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15]2[CH2:20][CH2:19][S:18][C:17]([CH3:22])([CH3:21])[CH:16]2[C:23]([OH:25])=[O:24])(=[O:13])=[O:14])=[CH:8][CH:7]=1)[CH:2]=[C:3]=[CH2:4]
Reactant: C=C=CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)[C@@H]2C(=O)OC)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: C=C=CCOc1ccc(S(=O)(=O)N2CCSC(C)(C)C2C(=O)O)cc1
Yield: 34.3 %

Procedure:
The procedure of Example 12 was followed using the product from Example 24 (150 mg, 0.38 mmol), lithium hydroxide (18 mg, 0.76 mmol) in tetrahydrofuran (2 ml), methanol (2 ml), and water (1 ml) to give 50 mg of product (53%, based on unreacted starting material).
Reaction SMILES: [I-:1].F[C:3]1[CH:12]=[CH:11][C:10]2[N+:9]3[CH:13]=[C:14]4[CH:23]=[CH:22][C:21]5[CH:20]=[C:19]([CH2:24][CH2:25][CH3:26])[CH:18]=[CH:17][C:16]=5[N:15]4[C:8]=3[CH:7]=[CH:6][C:5]=2[CH:4]=1.[NH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>CN(C)C=O>[I-:1].[N:27]1([C:3]2[CH:12]=[CH:11][C:10]3[N+:9]4[CH:13]=[C:14]5[CH:23]=[CH:22][C:21]6[CH:20]=[C:19]([CH2:24][CH2:25][CH3:26])[CH:18]=[CH:17][C:16]=6[N:15]5[C:8]=4[CH:7]=[CH:6][C:5]=3[CH:4]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CCCc1ccc2c(ccc3c[n+]4c5ccc(F)cc5ccc4n32)c1
Reactant: C1CCNCC1
Agent: [I-]
Solvent: CN(C)C=O
Product: CCCc1ccc2c(ccc3c[n+]4c5ccc(N6CCCCC6)cc5ccc4n32)c1

Procedure:
A stirred mixture of 3.62 g. of 3-fluoro-10-propylimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide, 20 ml. of dimethylformamide and 2.0 ml. of piperidine is heated at 72° C. for 94 hours, then evaporated at reduced pressure. The residue is dissolved in methanol along with 2.0 g. of triethylamine hydroiodide. The solution is diluted with water and the resulting precipitate is collected by filtration and suspended in 125 ml. of 0.5% triethylamine hydroiodide. The solid 3-(1-piperidinyl)-10-propylimidazo[1,2-a:3,4-a']diquinolin-15-ium iodide is collected by filtration, triturated with 2-propanol and dried; m.p. 148°-153° C.
Reaction SMILES: O(P(O[C:18]1[C@H:19]([CH3:42])[C@H:20]2[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]2[C:22]=1[C:23]([O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:24])(OC1C=CC=CC=1)=O)C1C=CC=CC=1.C(N(CC)C(C)C)(C)C.Cl.Cl.[CH2:54]([N:56]1[CH2:60][CH2:59][CH:58]([C@@H:61]2[CH2:65][C@H:64]([SH:66])[CH2:63][NH:62]2)[CH2:57]1)[CH3:55]>C(#N)C.CN(C)C=O>[CH2:54]([N:56]1[CH2:60][CH2:59][CH:58]([C@@H:61]2[CH2:65][C@H:64]([S:66][C:18]3[C@H:19]([CH3:42])[C@@H:20]4[C@@H:37]([C@H:38]([OH:40])[CH3:39])[C:36](=[O:41])[N:21]4[C:22]=3[C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=3)=[O:24])[CH2:63][NH:62]2)[CH2:57]1)[CH3:55]
Reactant: CCN1CCC([C@@H]2C[C@H](S)CN2)C1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(OP(=O)(Oc3ccccc3)Oc3ccccc3)[C@H](C)[C@@H]12
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCN1CCC([C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2)C1
Temperature: -20 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
Under a nitrogen atmosphere at -20 ° C., to a solution of p-nitrobenzyl (1R,5S,6S)-2-diphenoxyphosphoryloxy-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (13.76 g, 23.1 mmol) in acetonitrile (150 ml) was added N,N-diisopropylethylamine (13.44 ml, 77.1 mmol), followed by a suspension of (2S,4S)-2-(N-ethylpyrrolidin-3-yl)-4-mercaptopyrrolidine dihydrochloride (7.0 g, 25.7 mmol, compound of Reference Example 40 in N,N-dimethylformamide (40 ml). After stirring overnight at -20° C., the reaction mixture was concentrated in vacuo. The resulting precipitate was collected by filtration, and washed with acetonitrile (30 ml) followed by isopropyl ether (30 ml) to obtain p-nitrobenzyl (1R,5S,6S)-2-[(2S, 4S)-2-(N-ethylpyrrolidin-3-yl)pyrrolidin-4-ylthio]-6-[(R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate (10.1 g, yield: 72%) as a crude crystal.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[CH2:14][CH2:13][C:12](=[O:15])[CH2:11][CH2:10]1)C1C=CC=CC=1.[CH3:23]S(C)=O.C(Cl)(=O)C(Cl)=O.C(N(CC1C=CC=CC=1)[C@H]1CC[C@H](O)CC1)C1C=CC=CC=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:23][C:12]1([OH:15])[CH2:11][CH2:10][CH:9]([NH2:8])[CH2:14][CH2:13]1
Reactant: CS(C)=O
Reactant: O=C1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(O)CCC(N)CC1
Temperature: -78 °C
Yield: 82 %

Procedure:
4-(Dibenzylamino)cyclohexanone. A solution of dimethyl sulfoxide (5.77 mL, 81 mmol) in methylene chloride (20 mL) was added dropwise, to a solution of oxalyl chloride (3.26 mL, 37.2 mmol) in methylene chloride (150 mL) stirring at −78° C. After stirring for 15 min at −78° C., a solution of trans-4-(dibenzylamino)cyclohexanol (10.0 g, 33.9 mmol) in methylene chloride (100 mL) was added dropwise. After stirring at −78° C. for another 15 min, triethylamine (23.59 mL, 169 mmol) was added dropwise and the reaction was allowed to warm to room temperature and stirred for 16 h. The reaction mixture appeared as a suspension and was washed with brine (100 mL). The organic layer was separated, dried over magnesium sulfate and concentrated to give a colorless oil that was purified using silica gel flash column chromatography (5-100% ethyl acetate in hexanes) to give the title compound as a colorless oil (8.11 g, 82% yield). 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.35-7.39 (m, 4H), 7.28-7.33 (m, 4H), 7.18-7.24 (m, 2H), 3.61 (s, 4H), 2.89-2.99 (m, 1H), 2.26-2.38 (m, 2H), 2.14-2.24 (m, 2H), 2.06 (td, J=2.81, 6.43 Hz, 2H), 1.81 (qd, J=4.27, 12.49 Hz, 2H). Rf=0.36 (TLC, 20% ethyl acetate in hexane); MS (ESI) m/z 294.4 [M+1]+.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH:19]1[CH2:31][OH:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:11]([N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:28])([CH3:29])[CH3:30])=[O:25])[CH2:20][CH:19]1[CH:31]=[O:32])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(CO)C1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)C(C=O)C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 93.6 %

Procedure:
Dimethyl sulfoxide (0.252 mL, 3.55 mmol) was added to a to −78° C. solution of oxalyl chloride (0.200 mL, 2.37 mmol) in methylene chloride (5.4 mL). After 10 min, a solution of tert-butyl 4-benzyl-3-(hydroxymethyl)piperazine-1-carboxylate (0.63 g, 2.0 mmol from Step 1) in methylene chloride (2.8 mL) was slowly introduced over 15 min. After stirring at −78° C. for 1 h, triethylamine (1.38 mL, 9.87 mmol) was added. The mixture was warmed to RT over 30 min and then stirred for another 30 min at that temperature. The reaction mixture was diluted with DCM, washed with water (twice) and brine (once), dried over sodium sulfate, decanted and concentrated to give product as a light yellow oil (570 mg, 95%). 1H NMR (300 MHz, CDCl3): δ 9.67 (d, 1H), 7.36-7.24 (m, 5H), 3.89 (d, 1H), 3.65 (dd, 1H), 3.57 (d, 1H), 3.57-3.45 (br m, 2H), 3.36-3.22 (br m, 1H), 3.10-2.98 (br m, 1H), 2.93 (ddd, 1H), 2.30 (ddd, 1H), 1.45 (s, 9H); LCMS (M+H)+: 305.0.
Reaction SMILES: [C:1]1([OH:9])[C:2]([CH3:8])=[CH:3][CH:4]=[C:5]([CH3:7])[CH:6]=1.[OH-:10].[Na+].[CH2:12]=O.N>C(O)(=O)C.O>[OH:10][CH2:12][C:4]1[C:5]([CH3:7])=[CH:6][C:1]([OH:9])=[C:2]([CH3:8])[CH:3]=1
Reactant: C=O
Reactant: Cc1ccc(C)c(O)c1
Reactant: [OH-]
Agent: N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(CO)c(C)cc1O
Temperature: 12 °C
Reaction time: 1 h

Procedure:
Into a 5 liter four-necked flask were charged 610.9 g of 2,5-xylenol, 200 gof sodium hydroxide and 2500 g of water. While stirring at 12° C., 565 g of 37% formaldehyde was added dropwise thereto over 1 hour and 30 minutes, and the reaction was conducted for 4 more hours. After completionof the reaction, 89 g of 28% aqueous ammonia solution was added and the mixture was stirred for 30 minutes. Thereafter, 400 g of acetic acid was added thereto, and the resulting mixture was filtered and washed with water. The filtered product thus obtained was dried to obtain 609 g of 4-hydroxymethyl-2,5-dimethylphenol. Purity measured by liquid chromatography (LC): 99%
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][N:9]2[C:13](=[O:14])[C:12]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:11]3[C:10]2=[O:19])=[CH:4][CH:3]=1.C[CH2:23][CH2:24][C:25]([CH2:27][C:28]([O-])=[O:29])=O.O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:24]([C:25]1[CH2:27][C:28](=[O:29])[C:3]2[C:2](=[CH:21][CH:20]=[C:5]([O:6][CH2:7][CH2:8][N:9]3[C:10](=[O:19])[C:11]4=[CH:18][CH:17]=[CH:16][CH:15]=[C:12]4[C:13]3=[O:14])[CH:4]=2)[N:1]=1)[CH3:23]
Reactant: Nc1ccc(OCCN2C(=O)c3ccccc3C2=O)cc1
Reactant: CCCC(=O)CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CCC1=Nc2ccc(OCCN3C(=O)c4ccccc4C3=O)cc2C(=O)C1
Temperature: 25 °C
Yield: 46.4 %

Procedure:
A mixture of N-(2-(4-aminophenoxy)ethyl)phthalimide (4.2 g), methylpropionylacetate (1.94 g) and p-toluenesulphonic acid (100 mg) in benzene (95 ml) was stirred and heated at reflux for 3 hours with azeotropic removal of water. Volatile material was then removed by evaporation and the residue was added to a refluxing eutectic mixture of 26.5% v/v diphenyl and 73.5% v/v diphenyl oxide (25 ml). The mixture was heated at reflux for 15 minutes and then cooled to ambient temperature. Hexane (80 ml) was added to the mixture which was triturated to give a solid. The solid was collected by filtration and washed with hexane. Ethyl acetate (70 ml) was added to the solid and the mixture was heated at reflux for 5 minutes and then cooled in an ice-bath. The undissolved solid was collected by filtration and washed with ethyl acetate to give 2-ethyl-6-(2-phthalimidoethoxy)-4-quinolone (2.5 g) as an off white solid, m.p. 168°-171° C.; NMR (d6 -DMSO): 1.24(t, 3H), 2.59(q, 2H), 4.0(t, 2H), 4.28(t, 2H), 5.87(s, 1H), 7.18(dd, 1H), 7.45(m, 2H), 7.84(m, 4H), 11.4(br s, 1H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:11]=[C:10]([O:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:9]=[C:8]2[C:4]=1[N:5]=[C:6](OC)[N:7]2[CH2:17][CH:18]1[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1>O1CCOCC1.CO>[ClH:1].[CH2:13]([O:12][C:10]1[N:9]=[C:8]2[C:4]([N:5]=[CH:6][N:7]2[CH2:17][CH:18]2[CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)=[C:3]([NH2:2])[N:11]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCN(C(=O)OC(C)(C)C)CC3)c2n1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCCCOc1nc(N)c2ncn(CC3CCNCC3)c2n1
Reaction time: 4.5 h

Procedure:
4N hydrogen chloride in dioxane (5.3 mL) was added to a solution of 1,1-dimethylethyl 4-{[6-amino-2-(butyloxy)-8-(methyloxy)-9H-purin-9-yl]methyl}-1-piperidinecarboxylate (630 mg) in methanol (16 mL). After 4.5 hours at room temperature, the reaction mixture was concentrated and dried under high vacuum. Purification by chromatography on silica gel eluting with a gradient of chloroform/methanol/water 90:10:1 to 75:25:1 afforded the title compound as a white solid (404 mg).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[CH3:8][O:9][C:10]([C:12]1([NH2:20])[CH2:17][CH2:16][N:15]([O:18][CH3:19])[CH2:14][CH2:13]1)=[O:11].[CH:21]1([C:24]2[C:25]([CH3:35])=[CH:26][C:27]([CH3:34])=[C:28]([CH2:30][C:31](Cl)=[O:32])[CH:29]=2)[CH2:23][CH2:22]1>C(#N)C>[CH3:8][O:9][C:10]([C:12]1([NH:20][C:31](=[O:32])[CH2:30][C:28]2[CH:29]=[C:24]([CH:21]3[CH2:22][CH2:23]3)[C:25]([CH3:35])=[CH:26][C:27]=2[CH3:34])[CH2:17][CH2:16][N:15]([O:18][CH3:19])[CH2:14][CH2:13]1)=[O:11]
Reactant: Cc1cc(C)c(C2CC2)cc1CC(=O)Cl
Reactant: COC(=O)C1(N)CCN(OC)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1(NC(=O)Cc2cc(C3CC3)c(C)cc2C)CCN(OC)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To 4 g of potassium carbonate and 2.5 g of 4-amino-1-methoxy-piperidine-4-carboxylic acid methyl ester hydrochloride (preparation example P1, step P1.3) in 10 ml of acetonitrile is added at 0-5° C. a solution of 2.1 g of crude (5-cyclopropyl-2,4-dimethyl-phenyl)-acetyl chloride in 5 ml of acetonitrile. After stirring for 18 hours at room temperature, the solvent is removed in vacuo and the crude residue of 4-[2-(5-cyclopropyl-2,4-dimethyl-phenyl)-acetylamino]-1-methoxy-piperidine-4-carboxylic acid methyl ester (3.2 g) is used without further purification in the next step.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])=[CH:16][CH:15]=1)=[C:8]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:7]([CH3:32])=[CH:6]2.B(Br)(Br)Br.CCOC(C)=O>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][S:21]([CH2:24][CH3:25])(=[O:23])=[O:22])=[CH:16][CH:15]=1)=[C:8]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:7]([CH3:32])=[CH:6]2
Reactant: CCS(=O)(=O)Nc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(OC)ccc23)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)Nc1ccc(Oc2c(-c3ccccc3)c(C)cc3cc(O)ccc23)cc1
Temperature: 0 °C
Reaction time: 0.02 h

Procedure:
To a stirring solution of 271 (0.14 g, 0.31 mmol) in 6 mL CH2Cl2 (6 mL), chilled to −20° C. under N2, was added BBr3 (0.24 g, 0.94 mmol) dropwise, via syringe, over 1 minute. After 90 min at −20° C. the r×n was poured over 50 g ice followed by EtOAc (50 mL). The EtOAC layer was washed with brine (50 mL), dried (Na2SO4) and concentrated to a viscous yellow oil that was purified by column chromatography using a gradient of 100% DCM to 1% MeOH: CH2Cl2 to yield a foam. The foam is crystallized from EtOAc/hexanes to yield the title compound 272, as a light yellow solid (72 mg, 55%). 1H NMR (400 MHz, DMSO-d6): δ 1.13 (t, J=7.3 Hz, 3H), 2.13 (s, 3H), 4.01 (q, J=7.3 Hz, 2H), 6.53 (d, J=8.9 Hz, 2H), 6.94 (d, J=8.9 Hz, 2H), 6.97 (dd, J1=2.3 Hz, J2=9.1 Hz, 1H), 7.11-7.30 (m, 5H), 7.54 (s, 1H), 7.55 (d, J=8.8 Hz, 1H), 9.40 (s, 1H), 9.81 (s, 1H).
Reaction SMILES: [CH3:1][NH:2]N.Cl.C[N:6](C)[CH:7]=[CH:8][C:9]([C:11]1[CH:16]=[C:15]([NH:17][C:18](=[O:20])[CH3:19])[CH:14]=[CH:13][C:12]=1[O:21][CH3:22])=O.N.CN1C=CC=N1>CO>[CH3:22][O:21][C:12]1[CH:13]=[CH:14][C:15]([NH:17][C:18](=[O:20])[CH3:19])=[CH:16][C:11]=1[C:9]1[N:2]([CH3:1])[N:6]=[CH:7][CH:8]=1
Reactant: CNN
Reactant: COc1ccc(NC(C)=O)cc1C(=O)C=CN(C)C
Agent: Cl
Agent: Cn1cccn1
Agent: N
Solvent: CO
Product: COc1ccc(NC(C)=O)cc1-c1ccnn1C
Temperature: -15 °C
Yield: 80 %

Procedure:
Methylhydrazine (319.3 g) was added to methanol (13.931 L) stirred and chilled to −15° C. under nitrogen. Aqueous HCl (37 wt %, 1859.6 g) was then added at a rate sufficiently slow to enable the stirred solution to be maintained at −12 to −7° C. with reactor jacket cooling. As stirring under nitrogen was continued at −10° C., 3-dimethylamino-1-(2′-methoxy-5′-acetamidophenyl)prop-2-en-1-one (4, 1546.9 g) was added as a solid over ten minutes. The resulting homogenous dark brown solution was stirred under nitrogen first at 0° C. for 3 hours and then at 10° C. for 5.5 hours before 33% aqueous ammonia (1090 mL) was added at a rate sufficiently slow (25 minutes) to enable the stirred solution to be maintained at 8.6-15.2° C. with reactor jacket cooling. LC/MS analyses of the reaction mixture before aqueous ammonia treatment revealed 97.3% conversion of 4 to 5 and its other N-methylpyrazole isomer (in 83.3:13.2 ratio) and, after aqueous ammonia treatment, 100% conversion of 4 to 5 and its other N-methylpyrazole isomer (in 87.8:12.2 ratio). The aqueous ammonia addition raised the reaction mixture pH to 8. Methanol (ca. 12 L) was then distilled off the stirred reaction mixture at atmospheric pressure and internal temperatures rising to 74.4° C. Product crystallization, which started at the end of the distillation, was completed by cooling the reaction mixture to −2° C. and holding that temperature with stirring for 44 hours. LC/MS analysis of the crystallization mixture's liquid phase revealed 5 and its other N-methylpyrazole isomer in about 1:3 ratio. (Higher ratios of 5:other isomer in the liquid phase jeopardize product yield, and lower ratios jeopardize product purity. In either case, the crystallization can be repeated by heating the stirred mixture back to reflux at atmospheric pressure and, prior to recrystallization, either distilling off more methanol (if the ratio is high) or adding additional methanol (if the ratio is low).) The reaction mixture was filtered by suction, and the filtered solids were washed with 0° C. water (3 L, then 2×500 mL) and dried at 40° C., <1 mm HgA to provide 5 (1157.7 g, 80.0% yield).
Reaction SMILES: [CH:1]1([CH:7]([O:9][C:10](=[O:25])[NH:11][C:12]2[C:13]([CH3:24])=[N:14][O:15][C:16]=2[C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][CH:18]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:20]3[CH:21]=[CH:22][C:17]([C:16]4[O:15][N:14]=[C:13]([CH3:24])[C:12]=4[NH:11][C:10]([O:9][CH:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH3:8])=[O:25])=[CH:18][CH:19]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OC(C)C1CCCCC1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)C4CCCCC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 6 using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 1-cyclohexyl-ethyl ester and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.