Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24](O)=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:59][NH:60][CH2:61][C:62]1[CH:73]=[CH:72][C:65]([CH2:66][N:67]2[CH2:70][CH:69]([OH:71])[CH2:68]2)=[CH:64][CH:63]=1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:60]([CH2:61][C:62]3[CH:63]=[CH:64][C:65]([CH2:66][N:67]4[CH2:70][CH:69]([OH:71])[CH2:68]4)=[CH:72][CH:73]=3)[CH3:59])=[O:25])[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:2][CH2:3]1
Reactant: CNCc1ccc(CN2CC(O)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CC(O)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (40 mg, 0.105 mmol), EDCI (28 mg, 0.158 mmol), HOBt (21 mg, 0.16 mmol), DIPEA (0.04 mL, 0.21 mmol), 1-{4-[(methylamino)methyl]benzyl}azetidin-3-ol dihydrochloride (40 mg, 0.12 mmol) and DCM (10 mL).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18]([NH2:21])(=[O:20])=[O:19].[CH3:22][S-:23].[Na+]>O1CCOCC1>[CH3:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([S:23][CH3:22])=[C:3]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:4]=2)=[O:17])=[CH:10][CH:11]=1
Reactant: COc1ccc(C(=O)c2ccc(F)c(S(N)(=O)=O)c2)cc1
Reactant: C[S-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)c2ccc(SC)c(S(N)(=O)=O)c2)cc1
Temperature: 90 °C
Yield: 67.9 %

Procedure:
To a solution of 2-fluoro-5-(4-methoxy-benzoyl)-benzenesulfonamide (0.15 g, 0.48 mmol) dissolved in dioxane (3 mL) is added sodium thiomethoxide (0.041 g, 0.57 mmol). The reaction mixture is heated at 90° C. for 4 h and then cooled to room temperature and concentrated in vacuo. The residue is partitioned between water and methylene chloride, and the aqueous phase is extracted with methylene chloride three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Purification by silica gel chromatography (50% ethyl acetate-hexane) gives 0.11 g (68%) of the title compound as a white solid. 1H NMR (CDCl3): δ 8.4 (d, J=2 Hz, 1H), 7.90 (dd, J=8, 2 Hz, 1H), 7.80 (d, J=9 Hz, 2H), 7.50 (d, J=8 Hz, 1H), 7.00 (d, J=9 Hz, 2H), 5.20 (s, 2H), 3.90 (s, 3H), 2.65 (s, 3H). Analytics calculated for C15H15NO4S2: C, 53.04; H, 4.48; N, 4.15. Found: C, 52.67; H, 4.57; N, 4.08. MS (m/z): 336 (M−1).
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[NH4+].[Cl-]>ClCCCl>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:1][CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
To a stirred solution of p-bromophenol (30 g, 0.1734 mol) in 1,2-dichloroethane (300 mL) at 23° C. was added imidazole (29.45 g, 0.433 mol). After 15 min, tert-butyldimethylsilylchloride (28.75 g, 0.190 mol) was added, and the resulting solution heated at reflux for 3 h. The mixture was cooled to room temperature and poured onto saturated aqueous NH4Cl and extracted with CH2Cl2 (3×200 mL). The combined extracts were washed with brine (200 mL), dried (NaSO4), filtered and evaporated in vacuo. The crude product was distilled via short-path distillation (0.5 mm Hg, 130° C.) to give (4-bromo-phenoxy)-tert-butyl-dimethylsilane (49.6 g, 99.5% yield) as a colorless oil. Rf=0.80 (1:3 EtOAc/hexanes). IR (thin film) 3390, 2951, 2928, 1584, 1479, 1250 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.34 (1H, d, J=9 Hz), 6.74 (1H, d, J=9 Hz), 1.00 (12H, s), 0.21 (6H, s). 13C NMR (75 MHz, CDCl3) δ 154.76, 132.22, 121.83, 113.55, 25.58, 18.12, −4.54. HRMS calcd. for C12H20BrOSi (MH+) 287.0461. Found 287.0463.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)[N:5]=[C:4]([S:24][CH3:25])[N:3]=1.CO[CH:28](OC)[N:29]([CH3:31])[CH3:30]>>[CH3:28][N:29]([CH3:31])/[CH:30]=[CH:1]/[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:21])[F:22])[CH:15]=2)[N:5]=[C:4]([S:24][CH3:25])[N:3]=1
Reactant: CCOC(=O)c1c(C)nc(SC)nc1Nc1cccc(C(F)(F)F)c1
Reactant: COC(OC)N(C)C
Product: CCOC(=O)c1c(/C=C/N(C)C)nc(SC)nc1Nc1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared as described in Example 1e by starting from ethyl 4-methyl-2-(methylthio)-6-(3-(trifluoromethyl)phenylamino)pyrimidine-5-carboxylate 1.76 g (4.74 mmol) and N,N-dimethyl formamide dimethylacetal (947 uL, 7.1 mmol) and continuing until the reaction yielded the crude title compound. This was used for the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[NH2:28])[C:5]([NH:7][N:8]=[C:9]([C:11]1[C:15]([OH:16])=[C:14]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([Cl:24])[CH:18]=2)[S:13][CH:12]=1)[CH3:10])=[O:6].C[C:30](C)([O-:32])C.[Na+].Cl>O1CCCC1>[Cl:24][C:19]1[CH:18]=[C:17]([C:14]2[S:13][CH:12]=[C:11]([C:9](=[N:8][NH:7][C:5]([C:4]3[CH:25]=[CH:26][C:27]4[NH:28][C:30](=[O:32])[NH:1][C:2]=4[CH:3]=3)=[O:6])[CH3:10])[C:15]=2[OH:16])[CH:22]=[CH:21][C:20]=1[Cl:23]
Reactant: CC(C)(C)[O-]
Reactant: CC(=NNC(=O)c1ccc(N)c(N)c1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=NNC(=O)c1ccc2[nH]c(=O)[nH]c2c1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Temperature: 25 °C
Reaction time: 16 h
Yield: 97 %

Procedure:
To a suspension of 3,4-diamino-N′-[1-{5-(3,4-dichlorophenyl)-4-hydroxythiophen-3-yl}ethylidene]-benzohydrazide (30 mg, 0.064 mmol, see the synthetic example 176) in tetrahydrofuran (3.0 mL) was added sodium tert-butoxide (12 mg, 0.13 mmol) and N,N′-carbonyl diimidazole (15 mg, 0.095 mmol). The reaction mixture turned clear orange and was stirred at room temperature for 16 hours, and then N,N′-carbonyl diimidazole (15 mg, 0.095 mmol) was added. The reaction mixture was stirred further for 12 hours, acidified with 1M aqueous HCl solution (0.7 mL) and concentrated under the reduced pressure. To the residue was added water (4 mL), then the precipitated solid was collected by filtration and dried by means of a vacuum pump to give the desired product as a pale yellow solid (yield 97%).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH2:8].[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1>C(Cl)Cl>[C:9]1([CH3:19])[CH:14]=[CH:13][C:12]([S:15]([NH:1][C@@H:2]2[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]2[NH2:8])(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N[C@@H]1CCCC[C@H]1N
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N[C@@H]2CCCC[C@H]2N)cc1
Temperature: -7.5 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a stirred solution of (R,R)-1,2-diaminocyclohexane (300 g, 2.63 mole) in CH2Cl2 (5.00 l) at −10° C. was added a solution of p-toluenesulfonylchloride (209 g, 1.10 mole) in CH2Cl2 (5.00 l) dropwise over a 7 h period, maintaining the temp at −5 to −10° C. The mixture was allowed to warm to room temp while stirring overnight. The mixture was concentrated in vacuo to a volume of 3 l and the white solid was removed by filtration. The solution was then washed with H2O (10×1 l) and was dried over MgSO4. Removal of the solvent in vacuo gave 286 g (97.5% yield) of the product as a yellow crystalline solid: 1H NMR (CDCl3) δ 0.98-1.27 (m, 4H), 1.54-1.66 (m, 2H), 1.81-1.93 (m, 2H), 2.34 (dt, J=4.0, 10.7 Hz, 1H), 2.42 (s, 3H), 2.62 (dt, J=4.2, 9.9 Hz, 1H), 7.29 (d, J=8.1 Hz, 2H), 7.77 (d, J=8.3 Hz, 2H); MS (LRFAB-DTT-DTE) m/z 269 [M+H]+.
Reaction SMILES: C([O:4][C:5]1[CH:10]=CC(OC(=O)C)=[CH:7][C:6]=1[O:15]C(=O)C)(=O)C.[CH2:19]([CH:26]([C:32]([CH3:34])=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.S(=O)(=O)(O)O>>[OH:4][C:5]1[CH:10]=[C:31]2[C:30](=[CH:7][C:6]=1[OH:15])[O:29][C:27](=[O:28])[C:26]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[C:32]2[CH3:34]
Reactant: CC(=O)Oc1ccc(OC(C)=O)c(OC(C)=O)c1
Reactant: CCOC(=O)C(Cc1ccccc1)C(C)=O
Agent: O=S(=O)(O)O
Product: Cc1c(Cc2ccccc2)c(=O)oc2cc(O)c(O)cc12
Temperature: 0 °C
Reaction time: 16 h

Procedure:
1,2,4-triacetoxybenzene (6.3 g, 25 mmol) and ethyl 2-benzylacetoacetate (5.5 g, 25 mmol) were heated together as described in Example 1. 75% sulphuric acid (35 ml) was added to the stirred solution and stirring continued for 16 hours. The dark coloured suspension was poured into ice/water (350 ml) with good stirring and the grey suspension filtered and the residue washed with abundant water. The residual solid was air dried and recrystallised from hot ethanol with subsequent addition of a little water to aid crystallisation. The esculetin derivative formed small white needles (5.5 g, 75.3%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([B:10]([OH:12])[OH:11])[CH:5]=[C:6]([F:9])[C:7]=1[F:8].[CH3:13][C:14]([CH2:18]O)([CH2:16]O)[CH3:15]>>[CH3:13][C:14]1([CH3:18])[CH2:16][O:11][B:10]([C:4]2[CH:5]=[C:6]([F:9])[C:7]([F:8])=[C:2]([F:1])[CH:3]=2)[O:12][CH2:15]1
Reactant: CC(C)(CO)CO
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Product: CC1(C)COB(c2cc(F)c(F)c(F)c2)OC1
Yield: 34 %

Procedure:
The title compound (34%, yellow oil) was prepared from 3,4,5-trifluorophenylboronic acid and neopentylglycol.
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:16]([NH:18][C@H:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][CH:22]=3)[CH3:20])=[O:17])[CH:9]=[CH:8]2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:44][S:45]([CH2:48][CH2:49][CH2:50][O:51][C:52](=[O:54])[CH3:53])(=[O:47])=[O:46].N12CCCN=C1CCCCC2.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C=O)C>[Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][C:14]=3[C:16]([NH:18][C@H:19]([C:21]3[CH:29]=[CH:28][C:24]([C:25](=[O:26])[NH:44][S:45]([CH2:48][CH2:49][CH2:50][O:51][C:52](=[O:54])[CH3:53])(=[O:46])=[O:47])=[CH:23][CH:22]=3)[CH3:20])=[O:17])[CH:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: CC(=O)OCCCS(N)(=O)=O
Reactant: C[C@H](NC(=O)c1cccc2ccn(Cc3ccc(Cl)cc3)c12)c1ccc(C(=O)O)cc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CC(=O)OCCCS(=O)(=O)NC(=O)c1ccc([C@H](C)NC(=O)c2cccc3ccn(Cc4ccc(Cl)cc4)c23)cc1
Reaction time: 0.08 h
Yield: 61 %

Procedure:
To a mixture of 4-[(1S)-1-({[1-(4-chlorobenzyl)-1H-indol-7-yl]carbonyl}amino)ethyl]benzoic acid (250 mg) and DMF (5 mL) was added 1,1′-carbonyldiimidazole (187 mgl) at room temperature, followed by stirring for 5 minutes, and then 3-(aminosulfonyl)propylacetate (209 mg) and 1,8-diazabicyclo[5.4.0]undec-7-ene (173 μL) were added in this order, followed by stirring for 3 days. The reaction mixture was ice-cooled, and 10% aqueous citric acid (30 mL) was added thereto, followed by stirring for 30 minutes. The precipitated solid was collected by filtration and washed with cold ethanol (4 mL) to obtain 1-(4-chlorobenzyl)-N-[(1S)-1-(4-{[(3-acetoxypropyl)sulfonyl]carbamoyl}phenyl)ethyl]-1H-indole-7-carboxamide (210 mg) as a pale yellow solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=[O:11])[CH2:2]1.[Cl:12][CH2:13][CH2:14][CH2:15]I.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N>[Cl:12][CH2:13][CH2:14][CH2:15][N:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][CH2:2][C:3]1=[O:11]
Reactant: ClCCCI
Reactant: O=C1COc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=C1COc2ccccc2N1CCCCl
Temperature: 25 °C
Reaction time: 40 h
Yield: 87.3 %

Procedure:
A reaction flask was charged with 4H-benzo[1.4]oxazin-3-one (1.48 g, 10 mmol), 1-chloro-3-iodopropane (2.04 g, 10 mmol), and Cs2CO3 (4.88 g, 15 mmol) in MeCN (10 mL) and stirred at rt for 40 h. The reaction mixture was quenched with water and the product extracted into EtOAc. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The product was purified by flash column chromatography (SiO2; n-heptane/EtOAc 2:1) to give the title compound (1.97 g, 88%). 1H NMR (CDCl3) d 7.06-7.02 (m, 2H), 7.01-6.99 (m, 2H), 4.58 (s, 2H), 4.12-4.07 (m, 2H), 3.64-3.60 (m, 2H), 2.19-2.12 (m, 2); 13C NMR (CDCl3) d 164.7, 145.6, 128.6, 124.2, 123.2, 117.5, 114.9, 67.8, 42.6, 39.1, 30.3.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:11][CH2:10]2)[CH:3]=1.[O:23]=[C:24]([C:28]1[N:36]2[C:31]([CH2:32][CH2:33][CH2:34][CH2:35]2)=[CH:30][C:29]=1[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:25](Cl)=[O:26].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]2[CH2:15][CH2:14][CH2:13][N:12]([C:16]3[CH:17]=[CH:18][C:19]([NH:22][C:25](=[O:26])[C:24](=[O:23])[C:28]4[N:36]5[C:31]([CH2:32][CH2:33][CH2:34][CH2:35]5)=[CH:30][C:29]=4[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[CH:20][CH:21]=3)[CH2:11][CH2:10]2)[CH:3]=1
Reactant: Cc1cc(C)nc(N2CCCN(c3ccc(N)cc3)CC2)c1
Reactant: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2n1CCCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)nc(N2CCCN(c3ccc(NC(=O)C(=O)c4c(-c5ccccc5)cc5n4CCCC5)cc3)CC2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.8 %

Procedure:
To a solution of 4-[4-(4,6-dimethyl-pyridin-2-yl)-[1,4]diazepan-1-yl]-phenyl amine (prepared as described in Reference Example 90, 800 mg, 2.70 mmol) in DCM (30 mL) was added oxo-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetyl chloride (prepared as described in Reference Example 21, 930 mg, 3.24 mmol) and triethylamine (0.75 mL, 5.4 mmol). The mixture was stirred for 2 h at room temperature then concentrated in vacuo to give a residue which was purified by flash chromatography on silica gel (60-120 mesh) eluting with 30% ethyl acetate/n-hexane to afford N-{4-[4-(4,6-dimethyl-pyridin-2-yl)-[1,4]diazepan-1-yl]-phenyl}-2-oxo-2-(2-phenyl-5,6,7,8-tetrahydro-indolizin-3-yl)-acetamide (500 mg, 35%) as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH3:2].[CH2:17]([C:19]1[CH:27]=[CH:26][CH:25]=[C:24]2[C:20]=1[CH2:21][CH2:22][CH:23]2O)[CH3:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH2:1]([O:3][C@H:4]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH:23]2[C:24]3[C:20](=[C:19]([CH2:17][CH3:18])[CH:27]=[CH:26][CH:25]=3)[CH2:21][CH2:22]2)=[CH:12][CH:11]=1)[CH2:5][C:6]([O:8][CH3:9])=[O:7])[CH3:2]
Reactant: CCO[C@@H](CC(=O)OC)c1ccc(O)cc1
Reactant: CCc1cccc2c1CCC2O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCO[C@@H](CC(=O)OC)c1ccc(OC2CCc3c(CC)cccc32)cc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Methyl (3S)-3-ethoxy-3-(4-hydroxyphenyl)propionate (100 mg, 0.446 mmol) produced in Example 41 (41C) and 4-ethylindan-1-ol (109 mg, 0.669 mmol) synthesized in (44B) were dissolved in tetrahydrofuran (10 mL), and triphenylphosphine (178 mg, 0.680 mmol) and a 40% diethyl azodicarboxylate toluene solution (309 μL, 0.680 mmol) were added thereto at room temperature, and then, the resulting mixture was stirred under a nitrogen atmosphere at 50° C. for 4 hours.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.[H-].[Na+].Cl[CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17]>CN(C=O)C>[CH3:17][Si:16]([CH2:15][CH2:14][O:13][CH2:12][C:5]1[C:6]([C:7]#[N:8])=[C:2]([NH2:1])[NH:3][N:4]=1)([CH3:19])[CH3:18]
Reactant: N#Cc1c[nH]nc1N
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCc1n[nH]c(N)c1C#N
Temperature: 0 °C
Yield: 17 %

Procedure:
3-Amino-1H-pyrazole-4-carbonitrile (10 g, 92.5 mmol) was dissolved in 100 mL of DMF and the solution was stirred at 0° C. Sodium hydride (60% in mineral oil, 7.4 g, 185 mmol) was added in small portions. The mixture was stirred for 30 minutes and (2-(chloromethoxy)ethyl)trimethylsilane (90% purity, 17.1 g, 92.5 mmol) was added. The mixture was stirred at room temperature for 1 hr and then extracted with chloroform and aqueous ammonium chloride solution. The organic layer was washed with brine and dried over sodium sulfate, filtered and concentrated. The residue was purified through ISCO flash column chromatography (220 g silica gel, ethyl acetate in hexanes 5% to 40% in 25 minutes). The fractions with a slightly larger Rf as the major component were evaporated and then crystallized from 7% ethyl acetate in hexanes to give a white crystalline pure compound as 1N-trimethylsilylethoxymethyl-5-amino-4-cyanopyrazole (3.75 g). The fractions with a slightly lower Rf as the major component were evaporated and then crystallized from 4% ethyl acetate in hexanes to give a pure crystalline compound as 1N-trimethylsilylethoxymethyl-3-amino-4-cyanopyrazole (3.50 g). The mother liquor and fractions containing both components were combined and evaporated to give a mixture (7.4 g, total yield for this step 67%). For 1N-trimethylsilylethoxymethyl-5-amino-4-cyanopyrazole: LC/MS calcd for C10H18N4OSi (m/e) 238.12, obsd 237.2 (M−H, ES−); 1H NMR (400 MHz, DMSO-d6) δ ppm 0.00 (s, 9H), 0.82 (t, J=8.0 Hz, 2H), 3.53 (t, J=8.0 Hz, 2H), 5.24 (s, 2H) 6.80 (s, 2H) 7.58 (s, 1H); For 1N-trimethylsilylethoxymethyl-3-amino-4-cyanopyrazole: 1H NMR (400 MHz, DMSO-d6) δ ppm 0.00 (s, 9H), 0.83 (t, J=8.0 Hz, 2H), 3.51 (t, J=8.0 Hz, 2H), 5.15 (s, 2H), 5.65 (s, 2H), 8.28 (s, 1H).
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[I-].[Na+].Br[CH2:23][C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=1[O:34][CH:35]([CH3:37])[CH3:36]>CN(C)C=O.C(OCC)(=O)C>[C:1]1([C:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:9]([CH2:23][C:24]3[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=3[O:34][CH:35]([CH3:37])[CH3:36])[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2cc(-c3ccccc3)[nH]n2)cc1
Reactant: COC(=O)c1ccc(CBr)c(OC(C)C)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Cn2nc(-c3ccccc3)cc2-c2ccccc2)c(OC(C)C)c1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
To a solution of 3,5-diphenyl-1H-pyrazole (0.36 g, 1.65 mmol) in N,N-dimethylformamide (8.6 mL) was added sodium hydride (60% in oil, 66 mg, 1.65 mmol) under stirring at room temperature, and the mixture was stirred at the same temperature for 30 min. To the reaction mixture was added sodium iodide (22 mg, 0.15 mmol) and a solution of methyl 4-(bromomethyl)-3-isopropoxybenzoate (0.43 g, 1.50 mmol) in N,N-dimethylformamide (4.3 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=4/1) to give the title compound (0.59 g, yield 92%) as a colorless oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27]Br)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:3][CH:2]=1.[N:29]1([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[N:36]=2)[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>>[N:1]1[CH:6]=[CH:5][C:4]([CH2:7][NH:8][C:9]([C:11]2([CH2:24][CH2:25][CH2:26][CH2:27][N:32]3[CH2:33][CH2:34][N:29]([C:35]4[CH:44]=[CH:43][C:42]5[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=5)[N:36]=4)[CH2:30][CH2:31]3)[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:17]3[C:12]2=[CH:13][CH:14]=[CH:15][CH:16]=3)=[O:10])=[CH:3][CH:2]=1
Reactant: O=C(NCc1ccncc1)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: c1ccc2nc(N3CCNCC3)ccc2c1
Product: O=C(NCc1ccncc1)C1(CCCCN2CCN(c3ccc4ccccc4n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 from 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(pyridin-4-ylmethyl)-amide and 2-piperazin-1-yl-quinoline.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10]([C:13](=[O:17])[C:14]([OH:16])=O)[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.[NH2:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH:7]2[CH2:8][CH2:9][N:10]([C:13](=[O:17])[C:14]([NH:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[NH:26][C:25](=[O:30])[CH2:24]4)=[O:16])[CH2:11][CH2:12]2)=[CH:18][CH:19]=1
Reactant: O=C(O)C(=O)N1CCC(Oc2ccc(F)cc2)CC1
Reactant: Nc1ccc2c(c1)CC(=O)N2
Product: O=C1Cc2cc(NC(=O)C(=O)N3CCC(Oc4ccc(F)cc4)CC3)ccc2N1

Procedure:
The title compound is prepared from [4-(4-fluoro-phenoxy)-piperidin-1-yl]-oxo-acetic acid and 5-amino-1,3-dihydro-indol-2-one according to the method described in Example 2. The filtered crystals are purified by column chromatography using Kieselgel 60 (Merck) as adsorbent and toluene:methanol=4:1 as eluent. Melting Point: 209-211° C. (diethyl ether)
Reaction SMILES: C([O:3][C:4](=[O:39])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[CH:17]=[C:16]([CH3:37])[CH:15]=2)=[CH:9][C:8]=1[CH3:38])C.[OH-].[Na+].Cl>C(O)C.O>[CH3:38][C:8]1[CH:9]=[C:10]([O:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:23][C:22]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=3)[CH:17]=[C:16]([CH3:37])[CH:15]=2)[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][C:4]([OH:39])=[O:3]
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3-c3ccccn3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2-c2ccccn2)c1
Yield: 38 %

Procedure:
A mixture of 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester (0.155 g, 0.289 mmol) and 2-tributylstannyl pyridine (0.210 g, 0.571 mmol) in dry toluene (8 mL) is purged with N2 and then tetrakis(triphenylphospine)pallium (0) (0.033 g, 0.029 mmol) is added. The reaction is heated to 100° C. and stirred for 20 hours under N2. The reaction is cooled, and the solvent is removed in vacuo to give crude 3-{2-methyl-4-[3-methyl-5-(2-pyridin-2-yl-4-trifluoromethyl-phenoxy)-phenoxy]-phenyl}-propionic acid ethyl ester. This ester is dissolved in ethanol (8 mL), treated with 5 N NaOH (2 mL) and heated to reflux until saponification is complete. The mixture is cooled, and the solvent is removed in vacuo to afford a residue that is acidified with 1 N HCl. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried (Na2SO4), and the solvent is removed in vacuo to give crude product that is purified by preparative HPLC to afford 0.056 g (38%) of the title compound. 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H24NO4F3 507, found 508 (M+1, 100%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1>CC#N>[N:10]1([C:2]2[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=2)[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: N#Cc1ccc(F)cc1
Reactant: C1COCCN1
Solvent: CC#N
Product: N#Cc1ccc(N2CCOCC2)cc1
Temperature: 82 °C
Reaction time: 50 h
Yield: 65.4 %

Procedure:
Under nitrogen atmosphere, to a solution of 4-fluorobenzonitrile (24.9 g) in CH3CN (500 mL) was added morpholine (53.8 g), and the mixture was stirred at 82° C. for 50 hours. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (hexane/ethyl acetate=10/1→4/1) to give 4-morpholin-4-yl-benzonitrile (25.3 g, 65%).