Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[OH-].[Na+].[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28]([Cl:30])=[O:29])=[CH:26][CH:25]=1>C1C=CC=CC=1>[ClH:30].[CH3:17][O:16][C:14]1[C:13]([O:18][CH3:19])=[CH:12][C:9]2[CH:10]3[N:5]([CH2:6][CH2:7][C:8]=2[CH:15]=1)[CH2:4][CH2:3][CH:2]([NH:1][C:28](=[O:29])[C:27]1[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=1)[CH2:11]3
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: COc1cc2c(cc1OC)C1CC(N)CCN1CC2
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: COc1ccc(C(=O)NC2CCN3CCc4cc(OC)c(OC)cc4C3C2)cc1
Product: Cl
Reaction time: 1 h
Yield: 9.7 %

Procedure:
A mixture of 2-amino-1,3,4,6,7,11b-hexahydro-9,10-dimethoxy-2H-benzo[a]quinolizine (5 g, 0.019 mole), 200 ml of benzene and 25 ml of 20% NaOH was cooled 10° and a solution of 4-methoxy benzoyl chloride (3.3 g, 0.019 mole) in benzene was added dropwise with stirring. The mixture was stirred in the cold for 30 minutes and at room temperature for 1 hour. The solid was collected after removal of the solvent and chromatographed over silica gel using benzene-methanol (6:1) as eluant. The major fraction (3.8 g) was converted to the HCl salt with hydrogen chloride in 2-propanol. The solvent was removed from the salt in vacuo whereupon the salt was twice recrystallized from methanol-ether, once from 2-propanol and again from absolute ethanol-ethyl acetate to yield 0.8 g of the desired product m.p. (decomposed at 244°-6°). This compound conforms to Formula II where R1 and R2 are --OCH3, R3 is H and R4 is ##STR14##
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([NH2:23])[C:8]([NH2:22])=[CH:9][C:10]=1[O:11][C:12]1[CH:13]=[N:14][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:16][CH:17]=1.[N:28]1[CH:33]=[CH:32][N:31]=[CH:30][C:29]=1[C:34](O)=O>>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[O:4][C:5]1[C:10]([O:11][C:12]2[CH:13]=[N:14][C:15]([S:18]([CH3:21])(=[O:19])=[O:20])=[CH:16][CH:17]=2)=[CH:9][C:8]2[NH:22][C:34]([C:29]3[CH:30]=[N:31][CH:32]=[CH:33][N:28]=3)=[N:23][C:7]=2[CH:6]=1
Reactant: CS(=O)(=O)c1ccc(Oc2cc(N)c(N)cc2Oc2ccccc2F)cn1
Reactant: O=C(O)c1cnccn1
Product: CS(=O)(=O)c1ccc(Oc2cc3[nH]c(-c4cnccn4)nc3cc2Oc2ccccc2F)cn1

Procedure:
The entitled compound was obtained as a colorless solid in the same method as in Example 197 or in accordance with the method or by combining it with an ordinary method but using 4-(2-fluoro-phenoxy)-5-(6-methanesulfonyl-pyridin-3-yloxy)-benzene-1,2-diamine obtained in Example 200 and pyrazine-2-carboxylic acid.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[N:28](COCC[Si](C)(C)C)[CH:29]=[CH:30][C:23]=34)[CH:19]=[N:18]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=2)[CH2:5]1)#[N:2].[F:39][C:40]([F:44])([F:43])[CH2:41][NH2:42]>>[C:1]([CH2:3][C:4]1([N:17]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]4[NH:28][CH:29]=[CH:30][C:23]=34)[CH:19]=[N:18]2)[CH2:7][N:6]([C:8]2[N:9]=[CH:10][C:11]([C:14]([NH:42][CH2:41][C:40]([F:44])([F:43])[F:39])=[O:16])=[N:12][CH:13]=2)[CH2:5]1)#[N:2]
Reactant: NCC(F)(F)F
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn(C4(CC#N)CN(c5cnc(C(=O)O)cn5)C4)c3)ccnc21
Product: N#CCC1(n2cc(-c3ccnc4[nH]ccc34)cn2)CN(c2cnc(C(=O)NCC(F)(F)F)cn2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 34, Step 3 starting from 5-{3-(cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyrazine-2-carboxylic acid and 2,2,2-trifluoroethanamine. LCMS (M+H)+: m/z=482.1.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][Br:26])#[N:21]>>[Br-:26].[C:20]([C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)#[N:21]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: N#Cc1cccc(CBr)c1
Product: N#Cc1cccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Product: [Br-]
Temperature: 80 °C
Reaction time: 5 h
Yield: 72.7 %

Procedure:
Triphenylphosphine (2.8 g) was added to a Tol (50 ml) solution of 3-cyanobenzyl bromide (2.0 g), followed by stirring at 80° C. for 5 hours. This was cooled to room temperature, and the precipitated solid was collected by filtration, and washed with Tol. This was dried under reduced pressure to obtain (3-cyanobenzyl)(triphenyl)phosphonium bromide (3.4 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:16]([O:18][C:19]4[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=4)[NH2:22])=[N:15][CH:14]=[N:13][C:12]=3[O:11][C:10]=2[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[CH:5][CH:4]=1.[CH3:32][O:33][C:34](=[O:37])[CH2:35]Br.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH3:32][O:33][C:34](=[O:37])[CH2:35][NH:22][C:21]1[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:16]2[C:17]3[C:9]([C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=4)=[C:10]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[O:11][C:12]=3[N:13]=[CH:14][N:15]=2)[CH:20]=1
Reactant: COC(=O)CBr
Reactant: COc1ccc(-c2c(-c3ccccc3)oc3ncnc(Oc4cccc(N)c4)c23)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COC(=O)CNc1cccc(Oc2ncnc3oc(-c4ccccc4)c(-c4ccc(OC)cc4)c23)c1

Procedure:
Stir 450 mg (1.1 mmol) of 3-{[5-(4-methoxyphenyl)-6-phenylfuro[2,3-d]pyrimidin-4-yl]-oxy}aniline, 202 mg (1.32 mmol) of bromoacetic acid methyl ester and 465.5 mg (1.43 mmol) of caesium carbonate in 10 ml of acetone under reflux overnight. Remove the acetone under reduced pressure and take up the residue in water and extract repeatedly with dichloromethane/ethyl acetate (1:1). Dry the combined organic phases over magnesium sulphate and concentrate. Chromatograph the residue twice on silica gel (eluent: dichloromethane/ethyl acetate 1:1). 75.4 mg (13.8% of theory) of the target compound are obtained as a white foam.
Reaction SMILES: [CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:17])([CH3:16])[C:3]=1[C@@H:4]([OH:39])[C:5]([C@@:7]1([CH3:38])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6].[C:40](OC(=O)C)(=[O:42])[CH3:41].C(Cl)Cl.CO>O1CCCC1.FC(F)(F)S([O-])(=O)=O.[Sc+3].FC(F)(F)S([O-])(=O)=O.FC(F)(F)S([O-])(=O)=O>[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([OH:39])[C:5]([C@@:7]1([CH3:38])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6].[CH3:1][C:2]1[C@@H:19]([OH:20])[CH2:18][C@:14]2([OH:21])[C:15]([CH3:16])([CH3:17])[C:3]=1[C@@H:4]([O:39][C:40]([CH3:41])=[O:42])[C:5]([C@@:7]1([CH3:38])[C@H:12]([C@@H:13]2[O:22][C:23]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:24])[C@:11]2([O:33][C:34]([CH3:36])=[O:35])[CH2:31][O:32][C@@H:10]2[CH2:9][C@@H:8]1[OH:37])=[O:6]
Reactant: CC(=O)OC(C)=O
Agent: CC(=O)O[C@@]12CO[C@@H]1C[C@H](O)[C@@]1(C)C(=O)[C@H](O)C3=C(C)[C@@H](O)C[C@@](O)([C@@H](OC(=O)c4ccccc4)[C@H]21)C3(C)C
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CC(=O)O[C@H]1C(=O)[C@@]2(C)[C@H]([C@H](OC(=O)c3ccccc3)[C@]3(O)C[C@H](O)C(C)=C1C3(C)C)[C@]1(OC(C)=O)CO[C@@H]1C[C@@H]2O
Temperature: 25 °C
Reaction time: 48 h
Yield: 58 %

Procedure:
To a solution of 50 mg (91.9 μmol) of 10-deacetylbaccatin III and 13 μL (1.5 eq.) of acetic anhydride in 2.0 mL of freshly distilled tetrahydrofuran 100 μL of a solution of 4.5 mg of commercial scandium trifluoromethanesulfonate in 1.0 mL of tetrahydrofuran was added. The reaction mixture was stirred at room temperature for 48 hours. Usual workup and isolation of the product by means of preparative TLC (Silica 60, CH2Cl2/MeOH 10:1) afforded 9 mg of unreacted 10-deacetylbaccatin III (18%) along with 31 mg of baccatin III (58%). 1H-NMR and Rf-value (TLC) were in accordance with the product from example 1.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=O)=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].C1C2[C:38](=CC=CC=2)[CH:37]=[C:36](N)N=1>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[N:17]=[CH:18][C:19]3[C:23]([CH:24]=1)=[CH:38][CH:37]=[CH:36][CH:20]=3)=[O:14])[N:8]([CH2:25][C:26]1[CH:27]=[CH:28][C:29]([F:32])=[CH:30][CH:31]=1)[C:7]2=[O:33]
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Reactant: Nc1cc2ccccc2cn1
Product: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1cc2ccccc2cn1

Procedure:
The product from Example 11, Part D (200 mg, 0.6 mmol) and isoquinolin-3-amine (131 mg, 0.91 mmol) were converted to the title compound in a manner analogous to the method described in Example 7, Part E, using CH2Cl2 in place of THF in the reaction and EtOAc in the workup, and without crystallization (95 mg, 35%). 1HNMR (300 MHz, CDCl3) δ 8.28 (d, J=9 Hz, 1H), 8.15 (d, J=9 Hz, 1H), 7.91 (s, 1H), 7.75 (m, 2H), 7.70 (d, J=8 Hz, 1H), 7.64 (m, 1H), 7.45 (m, 2H), 7.32 (m, 2H), 7.20 (t, J=9 Hz, 1H), 7.02 (m, 2H), 5.29 (d, J=15 Hz, 1H), 4.71 (m, 1H), 4.26 (d, J=15 Hz, 1H), 2.55 (m, 2H), 2.00 (m, 2H). MS: m/z (MH+) 458.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH2:5].[Cl:6][C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][N:8]=1>>[Cl:6][C:7]1[CH:12]=[C:11]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][N:8]=1.[Cl:13][C:11]1[C:10]([C:14]([F:17])([F:15])[F:16])=[CH:9][N:8]=[C:7]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH:12]=1
Reactant: COCCN
Reactant: FC(F)(F)c1cnc(Cl)cc1Cl
Product: COCCNc1cc(Cl)c(C(F)(F)F)cn1
Product: COCCNc1cc(Cl)ncc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
2-Methoxyethylamine (1.0 ml, 11.57 mmol) was added drop wise to 2,4-dichloro-5-(trifluoromethyl)pyridine (500 mg, 2.32 mmol) at 0° C. and the mixture stirred at room temperature for 2.5 h. The reaction mixture was partitioned between saturated aqueous NaHCO3 solution and DCM, the organic layer dried over Na2SO4 and evaporated. The residue was applied to a 120 g RediSep® silica column as a DCM solution and purified by normal phase chromatography, eluting with a gradient from DCM to 50% EtOAc in DCM. The title compound was obtained as the major regioisomer and elutes before the 4-chloro-N-(2-methoxyethyl)-5-(trifluoromethyl)pyridin-2-amine (ratio 2:1). Product containing fractions were combined and evaporated to give the title compound as a yellow-white solid. (UPLC-MS 6) tR 0.96; ESI-MS 255.1 [M+H]+.
Reaction SMILES: C(Cl)(Cl)Cl.[O:5]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]([CH:24]3[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][N:32]4[C:41]5[C:36](=[C:37]([NH2:42])[CH:38]=[CH:39][CH:40]=5)[CH:35]=[CH:34][C:33]4=[O:43])[CH2:26][CH2:25]3)[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][C:9]=2[O:8][CH2:7][CH2:6]1.Cl[C:45]([O:47][CH3:48])=[O:46]>C(N(CC)CC)C>[CH3:48][O:47][C:45](=[O:46])[NH:42][C:37]1[CH:38]=[CH:39][CH:40]=[C:41]2[C:36]=1[CH:35]=[CH:34][C:33](=[O:43])[N:32]2[CH2:31][CH2:30][N:27]1[CH2:28][CH2:29][CH:24]([N:16]([C:17]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:23])[CH2:15][C:13]2[CH:12]=[CH:11][C:10]3[O:5][CH2:6][CH2:7][O:8][C:9]=3[CH:14]=2)[CH2:25][CH2:26]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(N)cccc32)CC1
Reactant: COC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cccc2c1ccc(=O)n2CCN1CCC(N(Cc2ccc3c(c2)OCCO3)C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 45.1 %

Procedure:
To 2 mL of a chloroform solution containing 80 mg of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-amino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 45 mg of triethylamine and 42 mg of methyl chloroformate were added, and stirred at room temperature for 3 days. To the reaction mixture, 225 mg of triethylamine and 210 mg of methyl chloroformate were added, and stirred at room temperature overnight. The reaction mixture was purified by silica gel column chromatography [Silica Gel; Fuji Silysia Chemical Ltd., Chromatorex-NH, eluent; hexane:ethyl acetate=1:4], to give 40 mg of N-(1-(2-(4-((tert-butoxycarbonyl) (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-2-oxo-1,2-dihydroquinolin-5-yl)carbamic acid methyl ester as a pale yellow oil.
Reaction SMILES: C(N(CC)CC)C.Cl[CH:9]([C:35](=[O:48])[NH:36][C:37]1[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[CH:39][C:38]=1[Cl:47])[C:10]([O:12][C:13]1[CH:34]=[CH:33][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:15][CH:14]=1)=[O:11].[S:49]([C:59]1[CH:64]=[CH:63][C:62]([OH:65])=[CH:61][CH:60]=1)([C:52]1[CH:57]=[CH:56][C:55]([OH:58])=[CH:54][CH:53]=1)(=[O:51])=[O:50]>CN(C=O)C>[Cl:47][C:38]1[CH:39]=[CH:40][C:41]([C:43]([F:46])([F:45])[F:44])=[CH:42][C:37]=1[NH:36][C:35]([CH:9]([O:58][C:55]1[CH:54]=[CH:53][C:52]([S:49]([C:59]2[CH:64]=[CH:63][C:62]([OH:65])=[CH:61][CH:60]=2)(=[O:51])=[O:50])=[CH:57][CH:56]=1)[C:10]([O:12][C:13]1[CH:34]=[CH:33][C:16]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:15][CH:14]=1)=[O:11])=[O:48]
Reactant: CCOC(=O)CCCCCCCCCCOc1ccc(OC(=O)C(Cl)C(=O)Nc2cc(C(F)(F)F)ccc2Cl)cc1
Reactant: O=S(=O)(c1ccc(O)cc1)c1ccc(O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCCCCCOc1ccc(OC(=O)C(Oc2ccc(S(=O)(=O)c3ccc(O)cc3)cc2)C(=O)Nc2cc(C(F)(F)F)ccc2Cl)cc1
Reaction time: 1 h
Yield: 41 %

Procedure:
Triethylamine (12.12 g, 120 mmol) was added to a solution of the chloro-coupler (24.5 g, 40.5 mmol) from (e) and 4,4'-sulfonyldiphenol (40.5 g, 162 mmol) in dry DMF (130 ml) which has been degassed with nitrogen. After stirring at 45°-50° C. under nitrogen for 1 h, the suspension was cooled and poured slowly into cold water (300 ml) and conc. hydrochloric acid (10 ml), with rapid stirring. The whole mixture was extracted with ethyl acetate (500 ml) and the organic solution washed with 3N sodium carbonate (2×400 ml), 3N hydrochloric acid (300 ml), dried over MgSO4 and evaporated under reduced pressure. The crude material was purified by silica gel column chromatography (gradient elution from 20% ethyl acetate in petrol (b.p. 60°-80° C.) to 60% ethyl acetate in petrol (b.p. 60°-80° C.) followed by recrystallization from methanol to give a white solid (13.5 g, 41%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([CH3:26])[C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)[C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.[Cl:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].CO.[C:44](OCC)(=O)[CH3:45]>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.O.C1(C)C=CC=CC=1>[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:2]2[CH:3]=[C:4]([CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH:22]([CH3:26])[C:23]([O:25][CH2:44][CH3:45])=[O:24])=[CH:17][CH:16]=3)[C:5]3[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=3[CH:12]=2)=[CH:30][CH:29]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CC(Cc1ccc(OCc2cc(Br)cc3c2OC(C)(C)C3)cc1)C(=O)O
Reactant: CCOC(C)=O
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: CO
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)Cc1ccc(OCc2cc(-c3ccc(Cl)cc3)cc3c2OC(C)(C)C3)cc1

Procedure:
A solution of ethyl 3-(4-((5-bromo-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-methylpropanoate (110) (80 mg, 0.179 mmol), 4-chlorophenyl boronic acid (30.8 mg, 0.197 mmol), Pd(PPh3)4 (7 mg, 00.006 mmol), saturated sodium bicarbonate (0.64 mL), methanol (1.5 mL), and toluene (0.64 mL) was heated in a microwave reactor for 40 minutes at 110° C. To the solution was added water and ethyl acetate and the two layers were separated. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (30%) to afford ethyl 3-(4-((5-(4-chlorophenyl)-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-methylpropanoate. The ester was dissolved in tetrahydrofuran (1.0 mL), methanol (1.0 mL) and water (3 mL). Lithium hydroxide was added and the reaction was stirred at room temperature for 24 hours. The mixture was acidified with 1M HCl and diluted with EtOAc (3 mL). The organic layer was washed with brine (3 mL), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to yield 3-(4-((5-(4-chlorophenyl)-2,2-dimethyl-2,3-dihydrobenzofuran-7-yl)methoxy)phenyl)-2-methylpropanoic acid (111). 1H NMR (400 MHz, CDCl3) δ 7.43-7.39 (m, 3H), 7.34 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.3 Hz, 1H), 7.09 (d, J=8.2 Hz, 2H), 6.94 (d, J=8.3 Hz, 2H), 5.05 (s, 2H), 3.07 (s, 2H), 3.00 (dd, J=13.4, 6.4 Hz, 1H), 2.73-2.67 (m, 1H), 2.62-2.58 (m, 1H), 1.51 (s, 6H), 1.17 (d, J=6.8 Hz, 3H). LC-MS ESI m/z: found 449.1 [M−H]−.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([F:28])([F:27])[F:26])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO.O.C(Cl)Cl>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[CH2:9]2)[O:7][NH:32]1
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](Cc2ccccc2C(F)(F)F)C1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1ccccc1C(F)(F)F
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 122.4 %

Procedure:
Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-(trifluoromethyl)benzyl)piperidine-1-carboxylate (0.661 g, 1.59 mmol) was dissolved in MeOH (5 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.064 g, 1.59 mmol) dissolved in water (0.500 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.098 mL, 1.59 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3.5 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (8 mL, 48.00 mmol) and the mixture continued to stir at 80° C. for 20 min. DCM and water were added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield crude trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(2-(trifluoromethyl)benzyl)piperidine-1-carboxylate (0.748 g, 122%) as a yellow semi-solid. MS m/z 385 (M+H)+
Reaction SMILES: C(#N)C.[Cl:4][C:5]1[C:13]2[C:12](=[O:14])[NH:11][N:10]=[CH:9][C:8]=2[N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:6]=1.[Br:23]N1C(=O)CCC1=O>C(OCC)(=O)C>[Br:23][C:6]1[N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]2[CH:9]=[N:10][NH:11][C:12](=[O:14])[C:13]=2[C:5]=1[Cl:4]
Reactant: C[Si](C)(C)CCOCn1cc(Cl)c2c(=O)[nH]ncc21
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1c(Br)c(Cl)c2c(=O)[nH]ncc21
Reaction time: 8.5 h
Yield: 83 %

Procedure:
To 30 ml of acetonitrile solution containing 903 mg (3.00 mmol) of 3-chloro-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in Reference example 16-(c) was added 703 mg (3.95 mmol) of N-bromosuccinimide at room temperature, and the mixture was stirred for 8.5 hours. After completion of the reaction, ethyl acetate was added to the reaction mixture, and the mixture was washed successively with a saturated aqueous solution of sodium hydrogencarbonate, 5% aqueous sodium hydrogen sulfite solution and then a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. To the obtained concentrate were added diisopropyl ether and cyclohexane, precipitated solid was collected by filtration. The obtained solid was washed with cyclohexane and then with hexane, and dried under reduced pressure to obtain 943 mg of the title compound as a pale yellowish solid. (Yield: 83%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([OH:13])=O)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1.O>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:11]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][N:16]=1)=[O:13])[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: Nc1ccc(Br)cn1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: c1ccncc1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Br)cn1
Temperature: 25 °C
Reaction time: 15 h
Yield: 35.8 %

Procedure:
In 20 ml of pyridine was dissolved 2.19 g of N-t-butoxycarbonyl-L-alanine and the solution was added with 1 g of 2-amino-5-bromopyridine, 2.77 g of 1-(3-dimethyl(aminopropyl)-3-ethylcarbodimide hydrochloride and 1.41 g of 4-dimethylaminopyridine individually and stirred at room temperature for 15 hours. Water was then added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer thus separated was washed with brine, dehydrated, filtered, and concentrated in vacuo to give 0.713 g of 2-(N-t-butoxycarbonyl-L-alanylamino)-5-bromopyridine. This compound was dissolved, along with 0.714 g of (S)-[N-3-(4-trimethylstannyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl acetamide, in 20 ml of dimethylformamide. Reaction was conducted at 100° C. for 4 hours in the presence of 0.6 ml of triethyl amine with the catalytic aid of 0.36 g of dichlorobistriphenylphosphine palladium (II) with stirring after their addition at room temperature. Water was then added to the reaction mixture, followed by the extraction with ethyl acetate. The organic layer thus separated was washed with brine, dehydrated, filtered and concentrated in vacuo. Recrystallization of the concentrate gave 0.27 g of (S)-[N-3-(4-(2-(N-t-buxotycarbonyl-L-alanylaminopyridin-5-yl)-3-fluorophenyl)-2-oxo-5-oxazolidinyl)methyl acetamide. This compound was reacted with 0.15 ml of trimethylsilyl iodide in chloroform at room temperature for 30 min under a nitrogen atmosphere. Following the addition of chloroform, the organic layer thus separated was washed with brine, dehydrated, filtered, and concentrated in vacuo. The concentrate was subjected to column chromatography to produce the title compound. 50 mg.
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([CH3:20])([O-:19])=[O:18].C([O-])(=O)C.[NH4+]>C(O)(=O)C>[N+:17](/[CH:20]=[CH:13]/[C:12]1[CH:15]=[CH:16][C:9]([CH2:8][O:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)([O-:19])=[O:18]
Reactant: O=Cc1ccc(COc2ccccc2)cc1
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC(=O)O
Product: O=[N+]([O-])/C=C/c1ccc(COc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 4-phenoxymethyl-benzaldehyde described in Manufacturing Example 86-1-2 (3.8 g, 17.8 mmol), nitromethane (4.79 mL, 89 mmol), ammonium acetate (2.74 g, 35.6 mmol) and acetic acid (38 mL) was stirred for 3 hours at 100° C. This mixture was cooled to room temperature, concentrated under a reduced pressure, and diluted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (4.1 g).