Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH:10]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:19][CH:18]=2)[CH2:11][C:12]([O:14]CC)=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(#N)C>Cl>[N:1]1([CH:10]([C:17]2[CH:18]=[CH:19][C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)[CH2:11][C:12]([OH:14])=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)CC(c1ccc(-c2ccccc2)cc1)n1cnc2ccccc21
Agent: Cl
Solvent: CC#N
Product: O=C(O)CC(c1ccc(-c2ccccc2)cc1)n1cnc2ccccc21
Temperature: 25 °C
Reaction time: 110 h

Procedure:
A solution of ethyl 3-(1H-benzimidazol-1-yl)-3-(1,1′-biphenyl)-4-ylpropanoate (276 mg, 746 μmol) in hydrochloric acid (50 mL of a 5N solution) was stirred at room temperature for 12 hours. Acetonitrile (I mL) was then added, and stirring continued for 110 hours. The solution was warmed to reflux for 24 hours and was then cooled to room temperature and evaporated in vacuo. The residue was taken up into aqueous sodium carbonate and the resulting solution extracted with diethyl ether. The aqueous phase was acidified with dilute hydrochloric acid (pH<4), and re-extracted with dichloromethane. The combined dichloromethane extracts were evaporated in vacuo, and the residue was recrystallized from methanol to afford the title compound, [LCMS (Method A, Mobile Phase I) RT=4.66 min, MH+ 343].
Reaction SMILES: N1(CCOC2C=CC(C#N)=CC=2)CCCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].N1(CCOC2C=CC(CN)=CC=2)CCCCC1.FC(F)(F)S(OC1C=C(OC)C=CC=1CC1CCC2C(=CC=C(OC)C=2)C1)(=O)=O.C[O:71][C:72]1[CH:73]=[CH:74][C:75]([CH2:95][CH:96]2[CH2:105][CH2:104][C:103]3[C:98](=[CH:99][CH:100]=[C:101]([O:106]C)[CH:102]=3)[CH2:97]2)=[C:76]([NH:78][CH2:79][C:80]2[CH:85]=[CH:84][C:83]([O:86][CH2:87][CH2:88][N:89]3[CH2:94][CH2:93][CH2:92][CH2:91][CH2:90]3)=[CH:82][CH:81]=2)[CH:77]=1>>[OH:71][C:72]1[CH:73]=[CH:74][C:75]([CH2:95][CH:96]2[CH2:105][CH2:104][C:103]3[CH:102]=[C:101]([OH:106])[CH:100]=[CH:99][C:98]=3[CH2:97]2)=[C:76]([NH:78][CH2:79][C:80]2[CH:81]=[CH:82][C:83]([O:86][CH2:87][CH2:88][N:89]3[CH2:90][CH2:91][CH2:92][CH2:93][CH2:94]3)=[CH:84][CH:85]=2)[CH:77]=1
Reactant: COc1ccc2c(c1)CCC(Cc1ccc(OC)cc1NCc1ccc(OCCN3CCCCC3)cc1)C2
Agent: COc1ccc2c(c1)CCC(Cc1ccc(OC)cc1OS(=O)(=O)C(F)(F)F)C2
Agent: N#Cc1ccc(OCCN2CCCCC2)cc1
Agent: NCc1ccc(OCCN2CCCCC2)cc1
Product: Oc1ccc2c(c1)CCC(Cc1ccc(O)cc1NCc1ccc(OCCN3CCCCC3)cc1)C2
Yield: 68.7 %

Procedure:
Obtained by reducing 4-(2-piperidin-1-ylethoxy)benzonitrile with lithium aluminum hydride, 4-(2-piperidin-1-ylethoxy)benzylamine (350 mg) and 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)phenyl trifluoromethanesulfonate (1.0 g) were used according to an analogous synthetic method to Example 116 to synthesize [5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-ylmethyl)phenyl][4-(2-piperidin-1-ylethoxy)benzyl]amine (400 mg), which was used according to an analogous synthetic method to Example 111 to provide the title compound (260 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]([CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([Cl:34])[CH:32]=2)[CH:27]=[CH:26][CH:25]=1)=[N+]=[N-].Cl.C([O-])(O)=O.[Na+]>C1COCC1.O>[ClH:34].[Cl:34][C:31]1[CH:32]=[C:33]2[C:28]([CH:27]=[CH:26][CH:25]=[C:24]2[CH2:23][NH2:20])=[CH:29][CH:30]=1
Reactant: [N-]=[N+]=NCc1cccc2ccc(Cl)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: NCc1cccc2ccc(Cl)cc12
Reaction time: 5 h

Procedure:
1.24 g of Triphenylphosphine and 410 μl of H2O are added to 998 mg of 1-azidomethyl-7-chloro-naphthalene in 20 ml of THF. The mixture obtained is stirred at 50° for 5 hours and solvent is evaporated. The residue obtained is acidified with aq. 1N HCl solution and extracted with EtOAc. The aq. phase obtained is basified with aq. 10% NaHCO3 solution and extracted with EtOAc. The organic phase obtained is dried and solvent is evaporated. The title compound is obtained as the free amine compound and converted to the hydrochloride salt by addition of 4M HCl solution in dioxane. Solvent is evaporated and the residue obtained is stirred with ether, the mixture obtained is filtered and the filtrate obtained is dried to yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[CH2:18][C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:20]([C:22]1[NH:23][C:24]([CH:32]([CH3:34])[CH3:33])=[CH:25][C:26]=1[CH2:27][CH2:28][C:29]([OH:31])=[O:30])=O>N1CCCCC1.C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:11]3[C:18](=[CH:20][C:22]4[NH:23][C:24]([CH:32]([CH3:34])[CH3:33])=[CH:25][C:26]=4[CH2:27][CH2:28][C:29]([OH:31])=[O:30])[C:17](=[O:19])[NH:16][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1Cc2c(ncnc2Nc2ccc(F)c(Cl)c2)N1
Reactant: CC(C)c1cc(CCC(=O)O)c(C=O)[nH]1
Solvent: CCO
Solvent: C1CCNCC1
Product: CC(C)c1cc(CCC(=O)O)c(C=C2C(=O)Nc3ncnc(Nc4ccc(F)c(Cl)c4)c32)[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 70.7 %

Procedure:
A mixture of 4-(3-chloro-4-fluoro-phenylamino)-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (70 mg, 0.25 mmol), 3-(2-formyl-5-isopropyl-1H-pyrrol-3-yl)-propionic acid (54.4 mg, 0.26 mmol) and piperidine (3 drops) in ethanol (2 mL) was stirred at room temperature for 2 days. The precipitate was collected by vacuum filtration, washed with water, 1N HCl, water and finally ethanol, dried in vacuum oven to give 83 mg (71%) of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 13.44 (br s, 1H, NH), 12.15 (br s, 1H, COOH), 11.69 (br s, 1H, NH), 9.02 (br s, 1H), 8.29 (s, 1H), 7.77 (dd, J=2.5 & 6.4 Hz, 1H), 7.47 (s, 1H), 7.43 (m, 1H), 7.33 (t, J=8.9 Hz, 1H), 6.14 (d, J=2 Hz, 1H), 3.01 (m, 1H, CH(CH3)2), 2.83 (t, J=7.2 Hz, 2H, CH2), 2.48 (m, 2H, CH2), 1.21.27 (d, J=6.8 Hz, 6H, CH(CH3)2). MS 469 [M++1].
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[CH:9][NH:8][CH:7]=1)([OH:3])=[O:2].CO.[CH3:14][C:15]1C=CC(S(N(N=O)C)(=O)=O)=CC=1.[OH-].[K+]>C(OCC)C.C(O)C.O>[CH2:14]([O:2][C:1]([CH2:4][CH2:5][C:6]1[C:10]([CH3:11])=[CH:9][NH:8][CH:7]=1)=[O:3])[CH3:15]
Reactant: Cc1c[nH]cc1CCC(=O)O
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CO
Solvent: O
Product: CCOC(=O)CCc1c[nH]cc1C
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 74.2 %

Procedure:
3-(2-Carboxyethyl)-4-methylpyrrole (123 g) was mixed with 1500 mL of ethyl ether and 250 mL of methanol in a magnetically stirred receiver flask. A separate 3 L, 3 neck round bottom flask was equipped with magnetic stirring, a distillation head and condenser leading to the inlet of the receiver flask, and heated in a water bath. Into the 3 L flask was placed 240 g of Diazald dissolved in 1800 mL of ethyl ether and a solution of 73 g of potassium hydroxide dissolved in 360 mL of 95% ethanol and 112 mL of water. The 3L flask was stirred and heated to 65-75° C. in a water bath and the diazomethane-ether mixture was distilled into the stirred receiver flask over about 2.5 hours. Ethyl ether (200 mL) was added to the 3 L flask and the distillation continued until complete. The receiver flask was stirred for another 30 minutes and then 10 mL of acetic acid was added. The mixture was extracted twice with 500 mL of water, then twice with 200 mL of saturated sodium bicarbonate. The ether layer was dried over anhydrous sodium sulfate and distilled to leave a dark fluid residue. The residue was distilled twice through a 4 inch Vigreux column and once through a 10 inch vacuum-jacketed Vigreux column to give 108 g (80.6% yield) of 3-(2-ethoxycarbonylethyl)-4-methylpyrrole. BP 108-113° C. at 0.5 mm.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:9]=[C:10](I)[C:3]=12.[CH3:23][C:24]1[CH:25]=[C:26]([CH3:49])[C:27]2[O:31][C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36](B4OC(C)(C)C(C)(C)O4)=[CH:35][CH:34]=3)=[N:29][C:28]=2[CH:48]=1.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>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]3[CH2:15][N:14]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:13]3)[N:9]=[C:10]([C:36]3[CH:35]=[CH:34][C:33]([NH:32][C:30]4[O:31][C:27]5[C:26]([CH3:49])=[CH:25][C:24]([CH3:23])=[CH:48][C:28]=5[N:29]=4)=[CH:38][CH:37]=3)[C:3]=12
Reactant: Cc1cc(C)c2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1
Reactant: CC(C)(C)OC(=O)N1CC(n2nc(I)c3c(N)ncnc32)C1
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: COCCOC
Solvent: O
Product: Cc1cc(C)c2oc(Nc3ccc(-c4nn(C5CN(C(=O)OC(C)(C)C)C5)c5ncnc(N)c45)cc3)nc2c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 16.7 %

Procedure:
A mixture of tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-azetanecarboxylate (0.15 g, 0.00036 mol), N-(5,7-dimethyl-1,3-benzoxazol-2-yl)-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine (0.16 g, 0.00045 mol), tetrakis(triphenylphosphine)palladium (0.021 g, 0.000018 mol) and sodium carbonate (0.095 g, 0.0009 mol) in ethylene glycol dimethyl ether (5 mL) and water (2 mL) was heated at 80° C. for 16 hours under an atmosphere of nitrogen. The reaction was cooled to room temperature. Additional tetrakis(triphenylphosphine)palladium (0.021 g, 0.000018 mol) was added to the mixture. The reaction was stirred at 80° C. for 3 hours. The mixture was allowed to cool to ambient temperature, and the solvent was removed under the reduced pressure. The residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane (3×50 mL). The combined organic extracts were washed with water, saturated aqueous sodium bicarbonate solution, and brine, and dried over magnesium sulfate. The solvents were evaporated under the reduced pressure to leave a brownish solid which was purified by flash column chromatography on silica using 5%-50% methanol t dichloromethane as a mobile phase to give tert-butyl 3-(4-amino-3-{4-[(5,7-dimethyl-1,3-benzoxazol-2-yl)amino]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-1-yl)-1-azetanecarboxylate (0.033 g, 0.00006 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-95% acetonitrile-0.1 M ammonium acetate over 10 min, 1 mL/min) Rt 11.6 min. MS: MH+ 527.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[C:18]([CH3:27])[CH:17]=3)[CH2:13][CH:12]([C:28]([OH:30])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:32]=[C:33]([CH:35]1[CH2:37][CH2:36]1)[NH2:34]>>[CH:35]1([C:33]2[N:34]=[C:28]([CH:12]3[CH2:13][CH:14]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[C:18]([CH3:27])[CH:17]=4)[CH2:15][N:10]([C:8]([N:5]4[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]4)=[O:9])[CH2:11]3)[O:30][N:32]=2)[CH2:37][CH2:36]1
Reactant: Cc1cc(C2CC(C(=O)O)CN(C(=O)N3CCC(O)CC3)C2)ccc1OC(F)(F)F
Reactant: NC(=NO)C1CC1
Product: Cc1cc(C2CC(c3nc(C4CC4)no3)CN(C(=O)N3CCC(O)CC3)C2)ccc1OC(F)(F)F

Procedure:
100 mg (0.22 mmol) of the compound from Example 170A and 33 mg (0.331 mmol) of N′-hydroxycyclopropanecarboximidamide were reacted according to the General Method 2. Yield: 41 mg (37% of theory)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[N:11]/[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:6][CH:5]=1.[P:20]([O-:25])([O:23][CH3:24])[O:21][CH3:22]>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[P:20]([O:23][CH3:24])([O:21][CH3:22])=[O:25])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(/C=N/Cc2ccccc2)cc1
Reactant: COP([O-])OC
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C(NCc2ccccc2)P(=O)(OC)OC)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-[(E)-Benzylimino-methyl]-benzoic acid methyl ester (0.50 g, 1.97 mmol) was made 0.3 M in dimethyl phosphite (6.5 mL) and to this stirring solution was added catalytic N,N,N,′,N′-tetramethyl-guanidine (0.02 g, 0.20 mmol). After stirring at ambient temperature for 4 hours the reaction mixture was diluted with EtOAc and washed with 1M aqueous NaOH (3×). The organic layer was washed further with brine, then dried (MgSO4) and concentrated in vacuo. MPLC purification (10-70% EtOAc in CH2Cl2) gave the title compound: MS: cal'd 364 (MH+), exp 364 (MH+)
Reaction SMILES: C(C1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=CC=1)(C)(C)C.[CH3:37][CH:38]([CH3:74])[C@H:39]([N:44]1[CH2:52][C:51]2[C:46](=[CH:47][C:48]([C:53]3[CH:58]=[CH:57][C:56]([NH:59][C:60](=[O:72])[C:61]4[CH:66]=[CH:65][C:64]([CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:63][CH:62]=4)=[CH:55][N:54]=3)=[CH:49][CH:50]=2)[C:45]1=[O:73])[C:40]([O:42]C)=[O:41]>>[CH3:74][CH:38]([CH3:37])[C@H:39]([N:44]1[CH2:52][C:51]2[C:46](=[CH:47][C:48]([C:53]3[CH:58]=[CH:57][C:56]([NH:59][C:60](=[O:72])[C:61]4[CH:62]=[CH:63][C:64]([CH2:67][CH2:68][CH2:69][CH2:70][CH3:71])=[CH:65][CH:66]=4)=[CH:55][N:54]=3)=[CH:49][CH:50]=2)[C:45]1=[O:73])[C:40]([OH:42])=[O:41]
Reactant: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)OC)C(C)C)C4)nc2)cc1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)nc2)cc1
Yield: 88 %

Procedure:
The compound of example 406 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 405.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:19]#[C:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:8][C:9]=1[NH:10][CH2:11][CH2:12][P:13]([O:16][CH2:17][CH3:18])([CH3:15])=[O:14])=[O:4].[CH3:25][CH:26]1[CH2:31][CH2:30][CH:29]([C:32](Cl)=[O:33])[CH2:28][CH2:27]1>N1C=CC=CC=1.CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:19]#[C:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[CH:8][C:9]=1[N:10]([CH2:11][CH2:12][P:13]([O:16][CH2:17][CH3:18])([CH3:15])=[O:14])[C:32]([CH:29]1[CH2:30][CH2:31][CH:26]([CH3:25])[CH2:27][CH2:28]1)=[O:33])=[O:4]
Reactant: CC1CCC(C(=O)Cl)CC1
Reactant: CCOP(C)(=O)CCNc1cc(C#CC(C)(C)C)sc1C(=O)OC
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CCOP(C)(=O)CCN(C(=O)C1CCC(C)CC1)c1cc(C#CC(C)(C)C)sc1C(=O)OC
Temperature: 100 °C
Reaction time: 7 h
Yield: 80.5 %

Procedure:
5-(3,3-Dimethyl-but-1-ynyl)-3-[2-(ethoxy-methyl-phosphinoyl)-ethylamino]-thiophene-2-carboxylic acid methyl ester (233 mg, 0.629 mmol) was dissolved in pyridine (4 mL) and then 4-methyl-cyclohexanecarbonyl chloride (506 mg, 3.15 mmol) was added. The reaction was stirred for 7 hours at 100° C., the heat to the oil bath was shut off and the reaction was allowed to stir for a further 9 hours. The reaction was diluted with EtOAc and extracted with H2O. The organic phase was then extracted with brine and dried over Na2SO4. The drying agent was removed by vacuum filtration and the filtrate was concentrated. 5-(3,3-Dimethyl-but-1-ynyl)-3-[[2-(ethoxy-methyl-phosphinoyl)-ethyl]-(4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (251 mg, 78%) was isolated from the residue by silica gel column chromatography.
Reaction SMILES: CO[C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][C:5]=1/[N:11]=[C:12]1\C(Cl)=NSS\1.[CH3:19][C:20]([CH3:25])([CH2:23][NH2:24])[CH2:21][NH2:22]>C1COCC1>[Br:10][C:7]1[CH:6]=[C:5]2[C:4]([C:3](=[O:18])[N:22]3[CH2:21][C:20]([CH3:25])([CH3:19])[CH2:23][NH:24][C:12]3=[N:11]2)=[CH:9][CH:8]=1
Reactant: CC(C)(CN)CN
Reactant: COC(=O)c1ccc(Br)cc1/N=c1/ssnc1Cl
Solvent: C1CCOC1
Product: CC1(C)CNc2nc3cc(Br)ccc3c(=O)n2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.1 %

Procedure:
A mixture of (E)-methyl-4-bromo-2-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)benzoate (0.1 g, 0.27 mmol) and 2,2-dimethylpropane-1,3-diamine (28 mg, 0.27 mmol) in dry THF was stirred for 2 h at room temperature, then the solvent was evaporated to give the crude product, which was purified by column chromatography to give 80 mg of the title compound. MS (ESI): 308, 310 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][C:11]([C:18]([OH:21])([CH3:20])[CH3:19])([C:14]([O:16]C)=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.O.O.[OH-].[Li+]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:13][CH2:12][C:11]([C:18]([OH:21])([CH3:20])[CH3:19])([C:14]([OH:16])=[O:15])[CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1(C(C)(C)O)CC[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CCC(C(=O)O)(C(C)(C)O)C1
Temperature: 110 °C
Yield: 49.6 %

Procedure:
To a solution of methyl (3S)-3-[(tert-butoxycarbonyl)amino]-1-(1-hydroxy-1-methylethyl)cyclopentanecarboxylate (1.0 g, 3.3 mmol) in a mixture of THF (30 mL), methanol (30 mL) and water (6 mL) was added lithium hydroxide monohydrate (0.22 g, 5.3 mmol) and the mixture refluxed overnight (110 ° C). The organic solvents were evaporated and the aqueous layer was washed with ether one time. The aqueous layer was then acidified with 6 N HCl to about pH 4 and extracted with methylene chloride three times. The combined extracts were dried, filtered, and concentrated to provide the desired product (0.47 g, 49%).
Reaction SMILES: [C:1]1(=[N:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26](OCC)=O)[CH2:19][CH2:18]2)=[CH:13][C:12]=1[C:31]([F:34])([F:33])[F:32]>>[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]3[O:9][N:8]=[C:1]4[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]=34)[CH2:19][CH2:18]2)=[CH:13][C:12]=1[C:31]([F:34])([F:32])[F:33]
Reactant: ON=C1CCCCCC1
Reactant: CCOC(=O)CCCN1CCC(c2ccc(Cl)c(C(F)(F)F)c2)CC1
Product: FC(F)(F)c1cc(C2CCN(CCCc3onc4c3CCCCC4)CC2)ccc1Cl

Procedure:
By the same reaction and treatment as in Example 48 using cycloheptanone oxime and ethyl 4-(4-(4-chloro-3-trifluoromethylphenyl)piperidin-1-yl)-n-butyrate, 3-(3-(4-(4-chloro-3-trifluoromethylphenyl)piperidin-1-yl)propyl)-5,6,7,8-tetrahydro-4H-cyclohepta[c]isoxazole is obtained.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:13]([CH3:18])[C:14]([O:16]C)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br>C(O)(=O)C.[OH-].[Na+]>[OH:2][C:3]1[CH:4]=[C:5]([CH:13]([CH3:18])[C:14]([OH:16])=[O:15])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: COC(=O)C(C)c1cc(OC)cc(C(F)(F)F)c1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(C(=O)O)c1cc(O)cc(C(F)(F)F)c1
Temperature: 100 °C
Yield: 70 %

Procedure:
The product from step (ii) (0.8 g) was dissolved in glacial acetic acid (20 ml) and treated with 48% aqueous HBr (20 ml). The mixture was heated at 100° C. for 16 h. The mixture was cooled and diluted with 2M NaOH, extracted with ethyl acetate, dried (MgSO4) and evaporated under reduced pressure to give an oil, which was purified by RPHPLC to give a colourless oil (0.5 g).
Reaction SMILES: O[C:2]1C=C2C(=CC=1)NC(=O)CC2.N1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[NH:33][C:32](=[O:37])[CH2:31][CH2:30]2)(=[O:21])=[O:20]>>[C:14]1([S:19]([CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:28]=[C:29]3[C:34](=[CH:35][CH:36]=2)[NH:33][C:32](=[O:37])[CH2:31][CH2:30]3)(=[O:21])=[O:20])[CH:2]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C1CCc2cc(O)ccc2N1
Reactant: O=C1CCc2cc(OCCCCS(=O)(=O)c3ccccn3)ccc2N1
Product: O=C1CCc2cc(OCCCCS(=O)(=O)c3ccccc3)ccc2N1

Procedure:
Prepared analogous to Example 4 from 6-hydroxy-3,4-dihydro-carbostyril and 4-phenylsulfonyl-butyl bromide (prepared from 4-(phenylmercapto)-butyl bromide by oxidation analogous to Example 3).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1>CCOC(C)=O>[ClH:2].[Cl:2][C:3]1[C:8]([Cl:9])=[CH:7][CH:6]=[CH:5][C:4]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Cl)c2Cl)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: Clc1cccc(N2CCNCC2)c1Cl
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 167.3 %

Procedure:
Excess HCl in EtOAc was added dropwise to a solution of intermediate 40 (11.1 g, 33.5 mmol) in EtOAc and the reaction mixture was stirred at rt for 1.5 h. Filtration gave 1-(2,3-dichlorophenyl)piperazine hydrochloride salt (intermediate 41) (7.5 g, 78%) as a white solid. HPLC: 99%, RT 2.052 min. MS (ESI) m/z 231.0[M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[C:14]([C:19]([O:21][CH3:22])=[O:20])=[N:15][CH:16]=[CH:17][N:18]=1.C([O-])(O)=O.[Na+]>CN(C=O)C.C(Cl)Cl>[CH3:22][O:21][C:19]([C:14]1[C:13]2[N:18]([CH:2]=[C:3]([C:5]3[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=3)[N:12]=2)[CH:17]=[CH:16][N:15]=1)=[O:20]
Reactant: O=C(CBr)c1ccc(F)cc1
Reactant: COC(=O)c1nccnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1nccn2cc(-c3ccc(F)cc3)nc12
Temperature: 80 °C
Yield: 80.1 %

Procedure:
A mixture of 2-bromo-1-(4-fluorophenyl)ethanone (30.0 g, 138 mmol) and methyl 3-aminopyrazine-2-carboxylate (21.2 g, 138 mmol) in DMF (200 mL) was heated at about 80° C. for about 16 h. The mixture was allowed to cool to ambient temperature and was neutralized with saturated aqueous NaHCO3. The mixture was diluted with DCM. The layers were separated and the aqueous layer was washed with DCM. The combined organic layers were washed with brine, dried over MgSO4, and eluted through a silica gel plug with EtOAc as the eluent. The combined organic layers were concentrated under reduced pressure to yield 30 g black oil. The material was diluted with DCM and the insoluble materials were removed by filtration to yield 2.0 g of the title compound. A second crop was obtained similarly to yield 1.8 g. The remaining filtrate was purified by flash silica gel chromatography using EtOAc as an eluent to yield an additional 3.1 g of the title compound (6.9 g, 15%): LC/MS (Table 1, Method b) Rt=1.7 min; MS m/z: 272.3 (M+H)+.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8](/[C:10](=[N:21]/[O:22][CH3:23])/[CH2:11][O:12][C:13]3[CH:18]=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][CH:14]=3)=[CH:9][C:4]=2[CH2:3][CH2:2]1.[C:24]([CH:26]([C:32]1[CH:37]=[CH:36][C:35](O)=[CH:34][CH:33]=1)[CH2:27][C:28]([O:30]C)=[O:29])#[N:25]>>[C:24]([CH:26]([C:32]1[CH:37]=[CH:36][C:35]([O:20][CH2:19][C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11]/[C:10](/[C:8]3[CH:7]=[CH:6][C:5]4[O:1][CH2:2][CH2:3][C:4]=4[CH:9]=3)=[N:21]\[O:22][CH3:23])=[CH:14][CH:15]=2)=[CH:34][CH:33]=1)[CH2:27][C:28]([OH:30])=[O:29])#[N:25]
Reactant: COC(=O)CC(C#N)c1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccc2c(c1)CCO2
Product: CO/N=C(\COc1ccc(COc2ccc(C(C#N)CC(=O)O)cc2)cc1)c1ccc2c(c1)CCO2
Yield: 56.2 %

Procedure:
Compound 102 was synthesized from ((4-{[(2Z)-2-(2,3-dihydro-1-benzofuran-5-yl)-2-(methoxyimino)ethyl]oxy}phenyl)methanol (0.330 g, 1.0 mmol) and methyl 3-cyano-3-(4-hydroxyphenyl)propanoate (0.216 g, 1.0 mmol) by following the procedure described in scheme 5 (0.008 g, yield: 56.2%); Purity: 94.55%.
Reaction SMILES: C[O:2][C:3](=[O:21])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:20].[O:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[OH:35])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[CH3:20][C:7]1[CH:8]=[C:9]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:35][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[O:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:14]=2)[CH:10]=[CH:11][C:6]=1[CH2:5][CH2:4][C:3]([OH:2])=[O:21]
Reactant: COC(=O)CCc1ccc(Oc2cccc(Br)c2)cc1C
Reactant: Oc1ccccc1Oc1ccccc1
Product: Cc1cc(Oc2cccc(Oc3ccccc3Oc3ccccc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 2-phenoxy-phenol as in Example 18 to afford 0.106 g (42%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C28H24O5 440, found 441 (M+1).