Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][N:13]([C:16]2[C:17]([O:22][CH2:23][CH2:24][OH:25])=[N:18][CH:19]=[CH:20][N:21]=2)[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Cl:26][C:27]1[C:32](Cl)=[N:31][CH:30]=[CH:29][N:28]=1.O>O1CCOCC1>[Cl:26][C:27]1[C:32]([O:25][CH2:24][CH2:23][O:22][C:17]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH2:11][CH2:12]3)=[N:21][CH:20]=[CH:19][N:18]=2)=[N:31][CH:30]=[CH:29][N:28]=1
Reactant: Clc1nccnc1Cl
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCOc2nccnc2Cl)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 61.2 %

Procedure:
NaH (50% in mineral oil; 0.153 g, 3.50 mmol) was added to a stirred solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (1.00 g, 3.08 mmol; prepared in Example 52, Step 2) and 2,3-dichloropyrazine (1.0 g, 6.71 mmol) in dioxane (10 mL). The reaction was stirred in a sealed tube at 100° C. overnight. The reaction mixture was poured into water and extracted with diethyl ether. The ether phase was dried (MgSO4), concentrated and purified by column chromatography on silica using toluene/EtOAc (7:3) as eluent to give 0.823 g (61%) of the title product: Pos-EI-MS shows M+ and 14 ions supporting the stated structure. HRMS m/z calcd for C19H25CIN6O4 (M)+436.1626, found 436.1606.
Reaction SMILES: [C:1]([C:3](=[C:9]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].[C:22]([CH:26]1[CH2:31]CC(O)[CH2:28][CH2:27]1)([CH3:25])([CH3:24])[CH3:23].C([O-])([O-])=O.[Na+].[Na+].C(O)C>CO>[C:1]([C:3](=[C:9]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]([O:6][CH:7]1[CH2:28][CH2:27][CH:26]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:31][CH2:8]1)=[O:5])#[N:2]
Reactant: CC(C)(C)C1CCC(O)CC1
Reactant: CCOC(=O)C(C#N)=C(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: CC(C)(C)C1CCC(OC(=O)C(C#N)=C(c2ccccc2)c2ccccc2)CC1
Reaction time: 4 h
Yield: 67 %

Procedure:
139 g (0.5 mol) of ethyl 2-cyano-3,3-diphenylacrylate (Uvinul 3035), 200 ml of 4-tert-butylcyclohexanol and 10 g of Na2CO3 were reacted together at 182° C. with distillative removal of the ethanol formed, assisted by a stream of nitrogen. After about 4 h, the reaction mixture was diluted with 300 ml of methanol and filtered hot in order to remove the Na2CO3. After the filtrate had been cooled, the precipitate which had formed was filtered off, washed with petroleum ether and dried, giving 130 g (67%) of 4-tert-butyl-cyclohexyl 2-cyano-3,3-diphenylacrylate as a colorless solid. [λmax 302 nm; E11 (MeOH) 324]
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:17]3[C:18]4[CH:42]=[CH:41][C:40]([O:43]CC5C=CC=CC=5)=[CH:39][C:19]=4[S:20][C:21]=3[C:22]3[CH:27]=[CH:26][C:25]([O:28][Si](C(C)C)(C(C)C)C(C)C)=[CH:24][CH:23]=3)=O)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH4+:51].[OH-]>C(Cl)(Cl)Cl>[OH:43][C:40]1[CH:41]=[CH:42][C:18]2[C:17]([CH2:15][C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][N:1]4[CH2:2][CH2:3][CH2:4][CH2:5]4)=[CH:14][CH:13]=3)=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:2][CH2:3][CH2:4][C:5]#[N:51])=[CH:24][CH:23]=3)[S:20][C:19]=2[CH:39]=1
Reactant: CC(C)[Si](Oc1ccc(-c2sc3cc(OCc4ccccc4)ccc3c2C(=O)c2ccc(OCCN3CCCC3)cc2)cc1)(C(C)C)C(C)C
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: N#CCCCOc1ccc(-c2sc3cc(O)ccc3c2Cc2ccc(OCCN3CCCC3)cc2)cc1

Procedure:
By essentially following the proceedure described in Example 14, Part D, the title compound was prepared as a foam starting from 6-benzyloxy-2-(4-triisopropylsilyloxyphenyl)benzo[b]thiophene-3-yl 4-[2-(1-pyrrolidinyl)ethoxy]phenyl ketone (Part B) in quantitative yield following MPLC (SiO2; 0.5% in CHCl3 sat'd with NH4OH).
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[NH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C(O)C>O>[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1)=[NH:11]
Reactant: NCc1ccccn1
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Agent: I
Solvent: O
Solvent: CCO
Product: N=C(NCc1ccccn1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A solution of 5.85 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydriodide (U.S. Pat. No. 3,657,337) and 3.24 g. of 2-(aminomethyl)pyridine in 25 ml. of absolute ethanol is heated under reflux for 20 hours and diluted while hot with 75 ml. of water, causing the separation of an oil. On standing, the oil crystallizes and filtration gives 5.00 g. of pale yellow crystals, m.p. 125°-140° C. Recrystallization from aqueous ethanol gives the desired compound as pale yellow crystals, m.p. 159.5°-161° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=3)[N:12](C(OCC)=O)[N:11]=2)[CH2:3][CH2:2]1.[OH-].[K+]>CCO.O>[N+:19]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[O:9][CH2:8][CH2:7][N:4]1[CH2:3][CH2:2][O:1][CH2:6][CH2:5]1)([O-:21])=[O:20]
Reactant: CCOC(=O)n1nc(OCCN2CCOCC2)c2cc([N+](=O)[O-])ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]nc(OCCN3CCOCC3)c2c1
Temperature: 25 °C
Yield: 86 %

Procedure:
To a solution of the morpholinoethoxy indazole described above (combined with a previous batch made in an identical manner) (309 mg, 0.848 mmol) in EtOH (2.0 mL) was added a solution of KOH (48 mg, 0.848 mmol) in water (1.0 mL) and the reaction mixture maintained at RT for 16 hr. The reaction mixture was then purified directly, without work-up, by SCX capture and release to afford 4-(2-((5-nitro-1H-indazol-3-yl)oxy)ethyl)morpholine as a bright yellow solid (221 mg, 86%); Rt 0.94 min (Method 2, acidic); m/z 293 (M+H)+ (ES+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([CH:16]([F:18])[F:17])=[CH:14][NH:13][C:12](=[O:19])[CH:11]=2)[CH:3]=1.Br[CH:21]([CH3:25])[C:22]([OH:24])=[O:23]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]2[C:15]([CH:16]([F:17])[F:18])=[CH:14][N:13]([CH:21]([CH3:25])[C:22]([OH:24])=[O:23])[C:12](=[O:19])[CH:11]=2)[CH:3]=1
Reactant: N#Cc1ccc(Cl)cc1-c1cc(=O)[nH]cc1C(F)F
Reactant: CC(Br)C(=O)O
Product: CC(C(=O)O)n1cc(C(F)F)c(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
215 mg (purity 64%, 0.5 mmol) of 4-chloro-2-[5-(difluoromethyl)-2-oxo-1,2-dihydropyridin-4-yl]benzonitrile and 1.5 eq. of 2-bromopropanoic acid (racemate) were reacted according to General Method 4A at 50° C. Yield: 256 mg of crude product (purity 64%, 95% of theory)
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH3:11].[CH3:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@H:24]([OH:32])[CH2:25][N:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[CH:18][C:16]=2[N:17]=1.CCN(C(C)C)C(C)C>CCO>[CH3:12][C:13]1[S:14][C:15]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@H:24]([OH:32])[CH2:25][N:26]3[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][O:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[CH3:11])[CH2:30][CH2:31]3)=[CH:18][C:16]=2[N:17]=1
Reactant: Cc1nc2cc(OC[C@H](O)CN3CCNCC3)ccc2s1
Reactant: Cc1ccccc1OCCBr
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(OC[C@H](O)CN3CCN(CCOc4ccccc4C)CC3)ccc2s1

Procedure:
To a solution of 2-bromo-1-(2-methylphenoxy)ethane (1.09 g, 5.09 mmol, crude) in EtOH (15 mL) was added (2R)-3-(2-methylbenzothiazol-5-yloxy)-1-piperazinylpropan-2-ol as prepared in Example 3A (250 mg, 0.81 mmol) and DIEA (1.5 mL, 8.6 mmol). The solution was stirred at reflux for 14 hours. Upon cooling, the solution was concentrated to an oil and then purified on an Isco™ (100% EtOAc hold 2 min, 8 min. gradient to 20% MeOH/EtOAc, hold 10 min) to afford (2R)-1-(2-methylbenzothiazol-5-yloxy)-3-{4-[2-(2-methylphenoxy)ethyl]piperazinyl}prop an-2-ol.
Reaction SMILES: [OH:1][C:2]1[C:7]2[O:8][C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[C:4]([C:23]([OH:25])=O)[CH:3]=1.S(Cl)([Cl:28])=O>C(Cl)(Cl)Cl.C(N(CC)CC)C>[OH:1][C:2]1[C:7]2[O:8][C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:10][C:6]=2[CH:5]=[C:4]([C:23]([Cl:28])=[O:25])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1cc(O)c2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Cl)c1cc(O)c2c(c1)OC(c1ccccc1)(c1ccccc1)O2
Temperature: 70 °C
Reaction time: 6 h

Procedure:
7-Hydroxy-2,2-diphenyl-benzo[1,3]dioxole-5-carboxylic acid (334 mg, 1 mmol) was dissolved in chloroform (5 ml). One drop of triethyl amine was added. At 45 to 50° C. thionylchloride (0.33 ml, 4.5 mmol) was added within 30 minutes. The solution was than stirred for 6 hours at 70° C. The exccess thionyl chloride was removed by evaporation. The crude 7-hydroxy-2,2-diphenyl-benzo[1,3]dioxole-5-carbonyl chloride was used without further purification in the next step.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:9])=[CH:3]\[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:10]1([N:13]=[C:14]=[S:15])[CH2:12][CH2:11]1.C(OCC)C>CCCCCCC>[CH2:7]([O:6][C:4](=[O:5])[C:3]([C:14](=[S:15])[NH:13][CH:10]1[CH2:12][CH2:11]1)=[C:2]([NH2:1])[CH3:9])[CH3:8]
Reactant: S=C=NC1CC1
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CCOCC
Solvent: CCCCCCC
Product: CCOC(=O)C(C(=S)NC1CC1)=C(C)N
Temperature: 100 °C
Yield: 44.9 %

Procedure:
A mixture of 2.03 ml of ethyl 3-aminocrotonate (16 mmol) and 1.59 g of cyclopropyl iso-thiocyanate (16 mmol) was heated to 100° C. for 5 h. The reaction mixture was then cooled to 0° C. and diethyl ether (5 ml) and a small amount of heptane were added. An oily precipitate formed and after 5 min the solvents were decanted off. The remaining residue was triturated with a small amount of diethyl ether at 0° C. The precipitate was then filtered off and dried to give 1.64 g (45%) of 3-amino-2-cyclopropylthiocarbamoyl-but-2-enoic acid ethyl ester as a yellow solid. 1HNMR (DMSO-d6, 300 MHz): δ 0.60 (m, 2H), 0.76 (m, 2H), 1.11 (t, J=7.1 Hz, 3H), 1.90 (s, 3H), 3.28 (m, 1H), 3.97 (q, J=7.1 Hz, 2H), 7.24 (br s, 1H), 8.21 (br s, 1H), 9.79 (d, J=5.5 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([Cl:9])[C:3]=1[NH2:4].Cl.N([O-])=O.[Na+].[N-:15]=[N+:16]=[N-].[Na+]>C(OCC)(=O)C.O>[N:4]([C:3]1[C:2]([Cl:1])=[CH:8][CH:7]=[CH:6][C:5]=1[Cl:9])=[N+:15]=[N-:16]
Reactant: Nc1c(Cl)cccc1Cl
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=Nc1c(Cl)cccc1Cl
Reaction time: 0.17 h
Yield: 90.9 %

Procedure:
To a 0° C. solution of 2,6-dichloroaniline (2.00 g) in ethyl acetate (40 mL) is added concentrated hydrochloric acid (12 mL). The reaction is stirred for 10 min. To this solution is added a solution of sodium nitrite (2.55 g) in water (7.5 mL) over 3 min. Upon completion of the addition, the reaction is stirred for an additional 30 min. A solution of sodium azide (2.41 g) in water (8 mL) is added over 5 min. After 30 min, pH 7 buffer (50 mL) is added and the reaction is transferred to a separatory funnel. The layers are separated and the aqueous layer is extracted with ethyl acetate. The organic layers are combined and washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound (2.11 g). 1H NMR (400 MHz, CDCl3) δ 7.3-7.27 (d, 2H), 7.07-7.02 (t, 1H)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[N:3]=1.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40].CCN(C(C)C)C(C)C>C1COCC1>[C:39]([O:38][C:37]([NH:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[N:5]=[C:4]([NH:14][C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][CH:16]=2)[N:3]=1)=[O:43])([CH3:42])([CH3:41])[CH3:40]
Reactant: COC(=O)c1ccc(Nc2nc(Cl)nc(OCC(F)(F)F)n2)cc1
Reactant: CC(C)(C)OC(=O)NCCCCCCCCCCN
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(Nc2nc(NCCCCCCCCCCNC(=O)OC(C)(C)C)nc(OCC(F)(F)F)n2)cc1
Temperature: 70 °C
Yield: 67.7 %

Procedure:
To a suspension of methyl 4-(4-chloro-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (600 mg) in THF (20 mL) was added tert-butyl 10-aminodecylcarbamate (451 mg) and iPr2NEt (0.578 mL). The mixture was heated at 70° C. for 16 hours. The solvent was removed under vacuum. The residue was purified by silica gel column (EtOAC/Hexanes=4:1) to give methyl 4-(4-(10-(tert-butoxycarbonylamino)decylamino)-6-(2,2,2-trifluoroethoxy)-1,3,5-triazin-2-ylamino)benzoate (0.67 g).
Reaction SMILES: C([Li:5])CCC.[CH3:6][Si:7]([CH3:20])([CH3:19])[CH:8]1[C:17]2[N:16]=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1>CCCCCC.C1COCC1>[Li:5][C:8]1([Si:7]([CH3:19])([CH3:20])[CH3:6])[C:17]2[N:16]=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=2[CH2:11][CH2:10][CH2:9]1
Reactant: [Li]CCCC
Reactant: Cc1cnc2c(c1)CCCC2[Si](C)(C)C
Solvent: CCCCCC
Solvent: C1CCOC1
Product: [Li]C1([Si](C)(C)C)CCCc2cc(C)cnc21

Procedure:
A mixture of a 1.55 molar solution of butyl lithium in hexane (6.45 ml, 1O mM) and THF (10 ml) maintained below 10° was treated with a solution of 5,6,7,8-tetrahydro-8-trimethylsilyl-3-methylquinoline (2.2 g, 10 mM) in THF (1O ml) to obtain 5,6,7,8-tetrahydro- -8-lithio-8-trimethylsilyl-3-methylquinoline. After 0.5 hour a 22% solution of t-butyldimethylsilyl isothiocyanate in benzene (6.9 g, 1O mM) was added dropwise. After 0.5 hour the reaction mixture was quenched with 2N hydrochloric acid (25 ml) and after 1 hour the aqueous layer was separated, basified (to pH9) and extracted with dichloromethane (2×50 ml). The organic extracts were dried and evaporated to give the title thioamide (2.1 g, c 100%). Recrystallisation from benzene gave analytically pure material (1.9 g, 88%) m.p. 153°, identical to authentic material (Found: C63.7; H,6.9; N,13.4% C11H14N2S requires: C64.0; H,6.8; N,13.6%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[N:7][CH:6]=[CH:5]2.[B-](F)(F)(F)F.C1C=CN=CC=1.C1C=CN=CC=1.[IH2+:29].FC(F)(F)S(O)(=O)=O>ClCCl>[I:29][C:3]1[C:2]([OH:1])=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[CH:6][N:7]=[CH:8]2
Reactant: [IH2+]
Reactant: Oc1ccc2cnccc2c1
Agent: F[B-](F)(F)F
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: Oc1ccc2cnccc2c1I
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.8 %

Procedure:
Under argon atmosphere 1.77 g (12.2 mmol) of compound 7 were added to a solution of 5.0 g (13.5 mmol) bis(pyridin)iodonium tetrafluoroborate in 100 mL of dry dichloromethane. A solution of 2.4 mL (4 g, 26.8 mmol) trifluoromethane sulfonic acid in 20 mL dry dichloromethane was added dropwise at 0° C. and the mixture was stirred for 3 hours at room temperature. The solvents were removed by distillation and the remainder was treated with aqueous NaHCO3 solution. The precipitate was filtered, washed with water and dried to yield 3.2 g (97%) of compound 10 as a beige solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9].[CH2:12](Br)[CH3:13]>>[Cl:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][CH3:13])[CH:5]=[C:6]([F:10])[C:7]=1[CH2:8][OH:9]
Reactant: OCc1c(F)cc(O)cc1Cl
Reactant: CCBr
Product: CCOc1cc(F)c(CO)c(Cl)c1
Yield: 60 %

Procedure:
This compound was prepared from 3-chloro-5-fluoro-4-hydroxymethyl-phenol and ethylbromide according to the procedure described in Example 179 to give the product as a yellowish oil (209 mg, 60%); MS (EI): 204.1 (M)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[Cl:13]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].Cl>CC#N.O>[Cl:13][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:10]([OH:12])=[O:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1ccc2[nH]ncc2c1
Agent: Cl
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: O=C(O)c1ccc2[nH]nc(Cl)c2c1
Yield: 83.2 %

Procedure:
To a suspension of 1H-indazole-5-carboxylic acid (155 mg, 0.96 mmol) in CH3CN (8 mL) was added N-chlorosuccinimide (142 mg, 1.06 mmol). The mixture was heated at reflux overnight before concentration. The solid was suspended in water and aqueous sodium thiosulfate solution, acidified with 1 N HCl and the solids were isolated by filtration. The solids were then washed with water and dried under vacuum at 50° C. to provide the title compound as an off-white solid (157 mg, 84%).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[N:9]=[CH:8][C:7]=2[N:6]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:5]=1.[CH2:30](I)[CH3:31]>>[CH2:30]([O:1][CH2:2][CH2:3][C:4]1[C:12]2[C:11](=[O:13])[N:10]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:20])[CH3:21])[N:9]=[CH:8][C:7]=2[N:6]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:28])([CH3:27])[CH3:29])[CH:5]=1)[CH3:31]
Reactant: C[Si](C)(C)CCOCn1ncc2c(c(CCO)cn2COCC[Si](C)(C)C)c1=O
Reactant: CCI
Product: CCOCCc1cn(COCC[Si](C)(C)C)c2cnn(COCC[Si](C)(C)C)c(=O)c12
Yield: 63.1 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Reference example 57-(f) except for using 1.15 g (2.61 mmol) of 3-(2-hydroxyethyl)-1,5-bis(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained by the same manner as in Reference example 57-(e), and using 1.3 ml (18.7 mmol) of ethyl iodide in place of methyl iodide, whereby 0.77 g of the title compound was obtained as a slightly yellowish oil. (Yield: 63%)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@@H:11]([CH3:22])[CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[Li]CCCC.[B:28](OC)([O:31]C)[O:29]C.[NH4+].[Cl-]>C1COCC1.O>[CH3:19][C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][N:9]([CH2:8][C:4]2[CH:3]=[C:2]([B:28]([OH:31])[OH:29])[CH:7]=[CH:6][CH:5]=2)[CH2:10][C@@H:11]1[CH3:22])=[O:16])([CH3:21])[CH3:20]
Reactant: COB(OC)OC
Reactant: C[C@H]1CN(Cc2cccc(Br)c2)CCN1C(=O)OC(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]1CN(Cc2cccc(B(O)O)c2)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 103.8 %

Procedure:
A solution of 1,1-dimethylethyl (2S)-4-[(3-bromophenyl)methyl]-2-methyl-1-piperazine carboxylate (1.8 g, 4.9 mmol) in THF (4.9 mL) was mixed with nBuLi (3.7 mL, 1.6 M in Hexane, 5.9 mmol) at −78° C. and stirred for 30 min before B(OMe)3 (2.2 mL, 19.6 mmol) was added. After addition, the resulting solution was warmed up to room temperature within 2 hours. The mixture was then mixed with saturated aqueous NH4Cl solution (10 mL), stirred for 25 minutes at room temperature, diluted with H2O (5 mL) and extracted with Et2O (2×30 mL). The organic layers were collected, dried over Na2SO4, filtered and concentrated to afford the crude title compound (1.7 g, quantitative yield): LC/MS: m/z 335 (M+H); 1H-NMR (MeOD) δ 1.24 (d, 3H), 1.46 (s, 9H), 2.00 (m, 1H), 2.13 (m, 1H), 2.68 (d, 1H), 2.82 (d, 1H), 3.12 (m, 1H), 3.44 (m, 1H), 3.56 (m, 1H), 3.80 (d, 1H), 4.18 (m, 1H), 7.33 (m, 1H), 7.38 (m, 1H), 7.51 (d, 1H), 7.59 (s, 1H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[CH2:7][CH2:8][C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].Cl.[NH2:14][C@H:15]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=1)[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(Cl)Cl>[Br:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][C@@H:15]([NH:14][C:9](=[O:11])[CH2:8][CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:12])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:28][CH:27]=1
Reactant: CCOC(=O)C[C@H](N)Cc1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)CCC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)C[C@@H](Cc1ccc(Br)cc1)NC(=O)CCC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
To a solution of 4-tert-butoxy-4-oxobutanoic acid (2.38 g, 13.64 mmol) in DMF (30 mL) and DCM (30 mL) is added (R)-ethyl 3-amino-4-(4-bromophenyl)butanoate hydrochloride (4 g, 12.4 mmol), HATU (5.19 g, 13.64 mmol), and TEA (6.91 mL, 49.6 mmol). After stirring at room temperature for 2 hours, the reaction is quenched with H2O, and the crude is diluted with EtOAc, the organic layer is washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give (R)-tert-butyl 4-(1-(4-bromophenyl)-4-ethoxy-4-oxobutan-2-ylamino)-4-oxobutanoate (4.0 g). HPLC retention time=1.70 minutes (condition A); MS (m+1)=444.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[C:20]1([CH2:26][C:27](Cl)=[O:28])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:13][CH2:14]2)[C:27](=[O:28])[CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCC(Nc2ccc(Cl)cc2)CC1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC(N(C(=O)Cc2ccccc2)c2ccc(Cl)cc2)CC1

Procedure:
To a stirred solution of 58 parts of ethyl 4-[(4-chlorophenyl)amino]-1-piperidinecarboxylate in 240 parts of benzene is added dropwise a solution of 46.2 parts of benzeneacetyl chloride in 80 parts of benzene at a temperature between 40°-70° C. Upon completion, the whole is stirred and refluxed for 6h.15. The reaction mixture is cooled and filtered. The filtrate is washed successively with water, sodium hydrogen carbonate solution and water, then dried and evaporated in vacuo. The residue is crystallized from 1,1'-oxybisethane, yielding 47 parts of ethyl 4-[N-(4-chlorophenyl)-N-(phenylacetyl)amino]-1-piperidinecarboxylate; mp. 108° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[CH:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH2:8][O:9]2)=[CH:4][CH:3]=1.[C:21](OC(=O)C)(=[O:23])[CH3:22].N1C=CC=CC=1>O>[C:21]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:20])[C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1)(=[O:23])[CH3:22]
Reactant: CC(=O)OC(C)=O
Reactant: COc1ccc(C2COc3cc(O)ccc3C2=O)cc1
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(-c2coc3cc(OC(C)=O)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
A mixture of 7-hydroxy-4′-methoxyisoflavanone (2.0 g, 7.5 mmol), acetic anhydride (10 ml) and pyridine (2 ml) was heated on an oil bath at 105-110 C. for 1 hour. After cooling the mixture to room temperature, it was poured into water (100 ml), stirred for 2 hours and then extracted with dichloromethane (3×50 ml). The dichloromethane layer was washed with water, dried over anhydrous sodium sulfate and evaporated. The white residue was crystallised from methanol to yield 7-acetoxy-4′-methoxyisoflavone as colourless prisms (2.1 g, 91%). 1H NMR (CDCl3): δ 2.36 (s, 3H, OCOCH3), 3.84 (s, 3H, OCH3), 6.98 (d, 2H, J 8.7 Hz, ArH), 7.16 (dd, 1H, J 1.9 Hz 8.6 Hz, H6), 7.30 (d, 1H, J 1.9 Hz H8), 7.50 (d, 2H, J 8.7 Hz, ArH), 8.00 (s, 1H, H2), 8.32 (d, 1H, J 8.6 Hz, H5).