Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][C:12]=1[CH3:18]>>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:13][C:12]=1[CH3:18]
Reactant: OB(O)c1ccccc1
Reactant: Cc1cc(Br)ccc1F
Product: Cc1cc(-c2ccccc2)ccc1F

Procedure:
In the case of Q10-Br, the desired 2-fluoro-5-phenyl-toluene (S1=F) was prepared from phenylboronic acid and 2-fluoro-5-bromo-toluene via a Suzuki reaction, analogously to procedure A2. See scheme A3.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][CH:6]=1)=[O:4].[NH2:16][C@@H:17]1[CH2:26][CH2:25][C:24]2[C:19](=[C:20]([N:27]3[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]3)[CH:21]=[CH:22][CH:23]=2)[CH2:18]1.C(N(CC)CC)C>S(Cl)(Cl)=O.C(Cl)Cl>[CH3:33][N:30]1[CH2:31][CH2:32][N:27]([C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:19]=2[CH2:18][C@H:17]([NH:16][C:9](=[O:11])[C:8]2[CH:7]=[CH:6][C:5]([C:3](=[O:4])[C:2]([F:1])([F:15])[F:14])=[CH:13][CH:12]=2)[CH2:26][CH2:25]3)[CH2:28][CH2:29]1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CC3)CC1
Reactant: O=C(O)c1ccc(C(=O)C(F)(F)F)cc1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(c2cccc3c2C[C@H](NC(=O)c2ccc(C(=O)C(F)(F)F)cc2)CC3)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
4-(Trifluoroacetyl)benzoic acid (0.50 g, 2.4 mmol) was dissolved in thionyl chloride (15 mL) and heated at reflux for 20 min. The excess of thionyl chloride was evaporated in vacuo, the residue was treated with toluene and again the solvent was removed in vacuo. Crude acid chloride (97 mg, 0.43 mmol) was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cooled solution of (R)-2-amino-8-(4-methylpiperazin-1-yl)-1,2,3,4-tetrahydronaphthalene (100 mg, 0.41 mmol) and triethylamine (85 μL, 0.61 mmol) in methylene chloride (35 mL). After the addition, the reaction was allowed to stir at ambient temperature for 15 min and was then washed with dilute aqueous sodium hydrogen carbonate. The phases were separated and the organic phase was dried (Na2SO4), filtered and evaporated in vacuo to give a crude product which was purified on a silica gel column using chloroform/ethanol saturated with NH3 (100:3) as the eluent. Yield: 98 mg (54%) of the title compound as slightly yellow crystals: mp 91-93° C.; [α]21D −47° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 453 (27, M+).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11]([O:13][CH3:14])=[O:12])=[CH:4][CH:3]=1.[CH2:15]([N:18]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41]O)=[CH:37][CH:36]=1)[C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=2)[N:23]=1)[CH2:16][CH3:17].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1(C)C=CC=CC=1.CCCCCC>[CH2:15]([N:18]([CH2:34][C:35]1[CH:40]=[CH:39][C:38]([CH2:41][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH:8]3[CH2:10][CH:9]3[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:7]=2)=[CH:37][CH:36]=1)[C:19]1[S:20][CH:21]=[C:22]([C:24]2[CH:25]=[CH:26][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:29]=2)[N:23]=1)[CH2:16][CH3:17]
Reactant: COC(=O)C1CC1c1ccc(O)cc1
Reactant: CCCN(Cc1ccc(CO)cc1)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCCN(Cc1ccc(COc2ccc(C3CC3C(=O)OC)cc2)cc1)c1nc(-c2ccc(C(F)(F)F)cc2)cs1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
A solution of methyl 2-(4-hydroxyphenyl)cyclopropanecarboxylate (0.158 g, 0.822 mmol), {4-[(propyl{4-[4-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}amino)methyl]phenyl}methanol (0.303 g, 0.745 mmol) and tributylphosphine (0.301 g, 1.49 mmol) in toluene (15 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.375 g, 1.49 mmol) was added, and the mixture was stirred at room temperature for 4 hr. Hexane (15 m1) was added to the reaction mixture, and the precipitated insoluble material was filtrated. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=0:100-30:70) to give the title compound (0.366 g, yield 77%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][N:30]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: O=C(CBr)c1cc(Cl)ccn1
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: COC(=O)Cc1c(C(=O)c2cc(Cl)ccn2)[nH]c2ccc(Cl)cc12

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(phenylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4-chloropyridine hydrobromide (Preparation is described in Example 33).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([O-:11])=[O:10].[H-].[Na+]>[Cl-].[Na+].O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([O:18][C:15]2[CH:16]=[CH:17][C:12]([N+:9]([O-:11])=[O:10])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: Clc1cc(Cl)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1ccc(Oc2cc(Cl)ncn2)cc1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 55.3 %

Procedure:
After adding 4,6-dichloropyrimidine (750 mg) to a suspension of 4-nitrophenol (700 mg) and sodium hydride (60%) (200 mg) indimethylformamide (13 ml) at 0° C., the mixture was heated and stirred at 80° C. for 1.5 hours. The reaction solution was poured into saturated brine and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated. The obtained residue was passed through an NH silica gel column (Fuji Silysia Chemical), eluted with a solvent (ethyl acetate-hexane=1-4) and concentrated to obtain 700 mg of the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][C:5](=[CH:8][C:9]2[CH:10]=[C:11]([CH:23]=[CH:24][CH:25]=2)[O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][N:14]=2)[CH2:4][CH2:3]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33](=O)[O:34]CC)[N:27]=1.NC1N=NC=CC=1.C(N(CC)CC)C>C(#N)C>[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:33]([N:2]2[CH2:7][CH2:6][C:5](=[CH:8][C:9]3[CH:25]=[CH:24][CH:23]=[C:11]([O:12][C:13]4[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][N:14]=4)[CH:10]=3)[CH2:4][CH2:3]2)=[O:34])[N:27]=1
Reactant: CCOC(=O)Nc1cccnn1
Reactant: FC(F)(F)c1ccc(Oc2cccc(C=C3CCNCC3)c2)nc1
Agent: Cl
Agent: Nc1cccnn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: O=C(Nc1cccnn1)N1CCC(=Cc2cccc(Oc3ccc(C(F)(F)F)cn3)c2)CC1
Temperature: 180 °C

Procedure:
2-(3-Piperidin-4-ylidenemethyl-phenoxy)-5-trifluoromethyl-pyridine hydrochloride (500 mg, 1.35 mmol, from Example 1, Step 5), ethyl pyridazin-3-ylcarbamate (248 mg, 1.48 mmol, prepared according to the procedure described in Synthesis, 1997, 1189-1194 from 3-aminopyridazine) and triethylamine (0.376 mL, 2.7 mmol) were combined in acetonitrile (4.5 mL) and heated in a microwave at 180° C. for 40 minutes. The reaction mixture was cooled to rt and concentrated to form a residue. The residue was purified by silica gel chromatography (50-100% EtOAc in CH2Cl2) to provide the title compound (340 mg). MS (APCI 10 V) AP+ 456.2, 376.2, 335.2; 1H NMR (400 MHz, CD3OD) δ ppm 2.54 (dt, J=50.71, 5.84 Hz, 4H) 3.64 (dt, J=36.50, 5.84 Hz, 4H) 6.47 (s, 1H) 6.96-7.07 (m, 2H) 7.08-7.20 (m, 2H) 7.40 (td, J=7.72, 0.52 Hz, 1H) 7.59 (dd, J=9.13, 4.62 Hz, 1H) 8.08 (dd, J=8.67, 2.68 Hz, 1H) 8.13 (d, J=8.92 Hz, 1H) 8.43 (dt, J=1.79, 0.81 Hz, 1H) 8.79 (d, J=4.19 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][C:10]=2[CH3:16])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:24](Cl)(=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28].O>O1CCCC1>[Cl:1][C:2]1[CH:7]=[N:6][C:5]([O:8][C:9]2[CH:15]=[CH:14][C:12]([NH:13][C:24](=[O:29])[CH2:25][CH2:26][CH2:27][CH3:28])=[CH:11][C:10]=2[CH3:16])=[N:4][CH:3]=1
Reactant: Cc1cc(N)ccc1Oc1ncc(Cl)cn1
Reactant: CCCCC(=O)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCCCC(=O)Nc1ccc(Oc2ncc(Cl)cn2)c(C)c1

Procedure:
2.0 g of 4-(5-chloro-2-pyrimidinyloxy)-3-methylaniline and 1.3 ml of triethylamine were dissolved in 20 ml of tetrahydrofuran, and 1.12 ml of valeryl chloride was dropwise added thereto under cooling with ice. The mixture was reacted at room temperature for 40 minutes under stirring. After completion of the reaction, the reaction product was poured into water and extracted with ethyl acetate. The extract layer was washed with a saturated aqueous solution of sodium chloride and dried over Glauber's salt. Then, ethyl acetate was distilled off to obtain 2.8 g of N-[4-(5-chloro-2-pyrimidinyloxy)-3-methylphenyl]valeramide (Intermediate Compound No. 13) (melting point: 146°-150° C.)
Reaction SMILES: [C:1]1([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:23])C=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]1([S:7]([CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:23])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CSc2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: O=S(Cc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 110.7 %

Procedure:
To a solution of benzyl phenyl sulfide (Aldrich; 1.068 g, 5.33 mmol) in 25 mL of CH2Cl2 at -78° C. was slowly added a solution of m-chloroperbenzoic acid (Aldrich, 50-60%; 760 mg, 2.64 mmol if 60%) in 10 mL of CH2Cl2. After warming to room temperature and stirring overnight, the solution was added to 20 mL of a saturated NaHCO3 solution. The aqueous layer was separated and extracted with CH2Cl2 (2×10 mL). The pooled organic layers were then dried (MgSO4) and concentrated. The residue was subjected to flash column chromatography (silica gel, 10% acetone/hexane and 15% acetone/hexane) affording the sulfoxide (632 mg, 55%) as a white solid, mp 123-126° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:5][CH:4]([C:6]([NH2:8])=[O:7])[CH2:3]1.C(Cl)(=O)[C:11](Cl)=[O:12].[CH3:16][C:17]1[N:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:18]=1[O:24][C:25]1[CH:30]=[CH:29][N:28]=[C:27]([C:31]2[O:35][N:34]=[C:33]([CH3:36])[CH:32]=2)[CH:26]=1.N1C=CC=CC=1>ClCCCl.C1COCC1>[CH3:1][C:2]1([CH3:9])[CH2:5][CH:4]([C:6]([NH:8][C:11](=[O:12])[NH:23][C:21]2[CH:20]=[CH:19][C:18]([O:24][C:25]3[CH:30]=[CH:29][N:28]=[C:27]([C:31]4[O:35][N:34]=[C:33]([CH3:36])[CH:32]=4)[CH:26]=3)=[C:17]([CH3:16])[N:22]=2)=[O:7])[CH2:3]1
Reactant: Cc1cc(-c2cc(Oc3ccc(N)nc3C)ccn2)on1
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)CC(C(N)=O)C1
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cc1cc(-c2cc(Oc3ccc(NC(=O)NC(=O)C4CC(C)(C)C4)nc3C)ccn2)on1
Temperature: 83 °C
Reaction time: 2 h
Yield: 63.6 %

Procedure:
A solution of Example B1 (0.028 g, 0.221 mmol) in DCE (4 mL) was treated with oxalyl chloride (0.019 mL, 0.221 mmol), heated at 83° C. for 2 h, cooled to RT, added drop-wise to a solution of Example A7 (0.052 g, 0.184 mmol) and pyridine (0.074 mL, 0.921 mmol) in THF (4.0 mL) and stirred at RT for 2 h. The mixture was treated with satd. NaHCO3, extracted with EtOAc (3×) and the combined organics were dried over MgSO4 and concentrated to dryness. The resulting material was treated with MeCN and the solid collected via filtration and dried to afford 3,3-dimethyl-N-((6-methyl-5-((2-(3-methylisoxazol-5-yl)pyridin-4-yl)oxy)pyridin-2-yl)carbamoyl)cyclobutanecarboxamide (51 mg, 64%) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.08 (s, 1H), 10.70 (s, 1H), 8.56 (d, J=5.7 Hz, 1H), 7.92 (d, J 8.8 Hz, 1H), 7.68 (d, J=8.8 Hz, 1H), 7.35 (d, J=2.5 Hz, 1H), 6.98-6.95 (m, 2H), 3.25 (m, 1H), 2.28 (s, 3H), 2.26 (s, 3H), 2.02-1.88 (m, 4H), 1.13 (s, 3H), 1.05 (s, 3H); MS (ESI) m/z: 436.2 (M+H+).
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]1(=[O:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br>C1(C)C=CC=CC=1>[C:7]1(=[O:13])[C:12]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C1CCCCC1
Reactant: BrCCCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1CCCCC12CCCCC2
Temperature: 25 °C
Yield: 65.6 %

Procedure:
To a suspension of potassium tert-butoxide (24.4 g) in toluene (100 mL) was added a solution of cyclohexanone (10.67 g) and 1,5-dibromopentane (25 g) in toluene (50 mL) while stirring. The mixture was stirred at 100° C. for 4 hours. After cooling down to room temperature, the resulting solid was filtered and washed with toluene. The filtrate was concentrated and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane (volume ratio)=1:15) to give spiro[5.5]undecan-1-one (11.85 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][O:10][CH2:11][O:12][CH3:13])=[C:7]([C:14]([CH2:18][CH3:19])=[CH:15][CH2:16][OH:17])[CH:6]=[CH:5][N:4]=1.C([C@@](C([O-])=O)(O)[C@@](CC)(O)C([O-])=[O:25])C.C(OO)(C)(C)C>C(Cl)Cl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[CH2:18]([C@:14]1([C:7]2[CH:6]=[CH:5][N:4]=[C:3]([O:2][CH3:1])[C:8]=2[CH2:9][O:10][CH2:11][O:12][CH3:13])[O:25][CH:15]1[CH2:16][OH:17])[CH3:19]
Reactant: CCC(=CCO)c1ccnc(OC)c1COCOC
Reactant: CC[C@](O)(C(=O)[O-])[C@](O)(CC)C(=O)[O-]
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: CC(C)(C)OO
Solvent: ClCCl
Product: CC[C@]1(c2ccnc(OC)c2COCOC)OC1CO
Yield: 88.7 %

Procedure:
Following the procedure in Example 5, the reaction was carried out with 5b (0.80 g, 3 mmol), Ti(OiPr)4 (0.71 mL, 2.4 mmol), diethyl-L(+)-tartrate (0.51 mL, 3 mmol), tBuOOH (0.95 mL, 5.0-6.0M in decane) and 4 Å molecular sieves (241 mg) in dry CH2Cl2 for 24 h to afford 6b as a yellow oil (754 mg, 89%) with 96% ee. The crude product was sufficiently pure for the subsequent reaction. Epoxide 6b was analyzed for enantiomeric purity using a Chiralcel OD-H column with 98:2 hexane/iPrOH as the eluent with the racemate as the standard. IR (CH2Cl2, NaCl,cm−1) 3408, 2980, 1765, 1607, 1457, 1410, 1393, 1266, 1040, 742, 546; 1H NMR (300 MHz, CDCl3) δ0.92 (t, J=7.6 Hz, 3H), 1.82 (m, 1H), 1.99 (m, 1H), 3.24 (t, J=5.8 Hz, 1H), 3.46 (s, 3H), 3.90 (m, 2H), 3.99 (s, 3H), 4.71 (s, 2H), 4.73 (s, 2H), 6.93 (d,J=5.2 Hz, 1H), 8.12 (d, J=5.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ9.41, 25.73, 25.98, 54.06, 55.82, 60.80, 61.33, 63.72, 64.72, 96.70, 116.46, 116.83, 146.60, 150.98, 163.10; HRMS (EI) m/z calcd for C14H22NO5 (M+H) 284.1498, found 284.1507; LRMS (EI) m/z 284(M+H, 58), 190(100), 178(73), 162(27), 148(27), 77(13); [α]D23=+65.6(c=0.25, CH2Cl2).
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH3:19][O:20][CH2:21][CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[NH:23]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:19][O:20][CH2:21][CH:22]1[CH2:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]1[C:15](=[O:17])[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: COCC1Cc2ccccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COCC1Cc2ccccc2N1C(=O)Cc1nc(N2CCOCC2)cc(=O)[nH]1
Yield: 37.2 %

Procedure:
The product is prepared according to the procedure described in example 5, using 261 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 326 mg of 2-(methoxymethyl)indoline and 249 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 162 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 143 mg of 2-{2-[2-(methoxymethyl)-2,3-dihydro-1 H-indol-1-yl]-2-oxoethyl}-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a beige powder, the characteristics of which are the following:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:21])=[C:9]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=2)[N:10]=1.O1CCCC1.CO.[BH4-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:21])=[C:9]([CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH2:17][OH:18])=[CH:15][CH:14]=2)[N:10]=1
Reactant: Cc1oc(-c2ccco2)nc1COc1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccco2)nc1COc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
To a mixture of 4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]benzaldehyde (37.8 g), tetrahydrofuran (140 ml) and methanol (60 mL) was added sodium borohydride (2.53 g) under ice-cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into iced water, and the precipitated solid was collected by filtration, and dried with air to give crystals (34.6 g, 91%) of [4-[[2-(2-furyl)-5-methyl-4-oxazolyl]methoxy]phenyl]methanol. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 91-92° C.
Reaction SMILES: [OH:1][C:2]1[CH:36]=[CH:35][C:5]([C:6]([CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([O:28]C(=O)C(C)(C)C)[CH:22]=[CH:21][C:20]=3[CH2:19]2)=O)=[CH:4][CH:3]=1.Cl[CH2:38][C:39]([N:41]([CH3:43])[CH3:42])=O>>[CH3:42][N:41]([CH3:43])[CH2:39][CH2:38][O:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][CH2:8][NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=2[CH:18]2[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([OH:28])[CH:22]=[CH:21][C:20]=3[CH2:19]2)=[CH:4][CH:3]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCC(=O)c2ccc(O)cc2)c1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(NCCc2ccc(OCCN(C)C)cc2)c1
Yield: 22.9 %

Procedure:
Synthesized from pivalic acid 6-{2-[(4-hydroxybenzoyl)methylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg) and 2-chloro-N,N-dimethylacetamide (13 mg) according to an analogous synthetic method to Example 404 and purified by LC-MS, the title compound (5.4 mg) was obtained.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][O:11][C@@H:10]([CH2:14][N:15]=[N+:16]=[N-:17])[CH2:9]1)=[O:7])(C)(C)C.Cl.FC1C(OC([C:29]2[N:30]=[N:31][C:32]([CH2:48][CH2:49][CH2:50][CH3:51])=[C:33]([C:35]3[CH:40]=[CH:39][C:38]([O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:37][CH:36]=3)[CH:34]=2)=O)=C(F)C(F)=C(F)C=1F>C(Cl)Cl.O1CCOCC1.C(OCC)(=O)C>[N:15]([CH2:14][C@@H:10]1[O:11][CH2:12][CH2:13][N:8]([C:6]([C:29]2[N:30]=[N:31][C:32]([CH2:48][CH2:49][CH2:50][CH3:51])=[C:33]([C:35]3[CH:36]=[CH:37][C:38]([O:41][CH:42]4[CH2:47][CH2:46][CH2:45][CH2:44][CH2:43]4)=[CH:39][CH:40]=3)[CH:34]=2)=[O:7])[CH2:9]1)=[N+:16]=[N-:17]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](CN=[N+]=[N-])C1
Reactant: CCCCc1nnc(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1-c1ccc(OC2CCCCC2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCCCc1nnc(C(=O)N2CCO[C@@H](CN=[N+]=[N-])C2)cc1-c1ccc(OC2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 105.8 %

Procedure:
To a stirred solution of (R)-2-azidomethyl-morpholine-4-carboxylic acid tert-butyl ester (0.82 mmol, 0.2 g) in DCM (2 mL) was added 4 N HCl in dioxane (4 mL) and continued stirring at ambient temperature for 45 min. The volatiles were removed under reduced pressure, and the residue was dissolved in NMP (4 mL). To this was added 6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazine-3-carboxylic acid pentafluorophenyl ester (Example 93, 0.77 mmol, 0.4 g) followed by TEA (0.5 mL) and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate (20 mL) and washed with water, followed by saturated sodium bicarbonate. The organic layer was dried, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography using ethyl 30% acetate in hexanes to provide ((R)-2-azidomethyl-morpholin-4-yl)-[6-butyl-5-(4-cyclohexyloxy-phenyl)-pyridazin-3-yl]-methanone (0.39 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1.[C:26](C1C=C2C(=CC=1)NC(=O)/C/2=C\C1NC=CC=1)#C.IC1C=CC(OC)=CC=1.C(N(CC)CC)C>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C=O)C>[CH3:26][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[NH:15][C:14](=[O:19])/[C:13]/3=[CH:20]\[C:21]2[NH:22][CH:23]=[CH:24][CH:25]=2)=[CH:4][CH:3]=1
Reactant: C#Cc1ccc2c(c1)/C(=C/c1ccc[nH]1)C(=O)N2
Reactant: O=C1Nc2ccc(C#Cc3ccc(O)cc3)cc2/C1=C/c1ccc[nH]1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: COc1ccc(I)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc(C#Cc2ccc3c(c2)/C(=C/c2ccc[nH]2)C(=O)N3)cc1

Procedure:
This compound was also prepared in a manner analogous to the preparation of (Z)-1,3-dihydro-5-(4-hydroxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one in Example 83 above. In this example, (Z)-1,3-dihydro-5-ethynyl-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (60 mg, 0.26 mmol) (Example 82) was coupled with 4-iodoanisole (30 mg, 0.34 mmol) (Aldrich) using CuI (6 mg, 0.031 mmol) (Aldrich) and (Ph3P)2PdCl2 (14 mg, 0.020 mmol) (Aldrich) as catalyst in 1 mL DMF and 2 mL triethylamine at 70° C. for 16 hours to give (Z)-1,3-dihydro-5-(4-methoxyphenyl)ethynyl-3-[(1H-pyrrol-2-yl)-methylene]-2H-indol-2-one as a yellow powder. (Yield 63 mg, 71%).
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)([CH3:5])[CH2:3][CH3:4].[H-].[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][C:26]2[C:29]([CH2:34]Cl)=[C:30]([Cl:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[I-].[Na+]>CN(C=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][C:26]2[C:29]([CH2:34][S:12][C:9]3[CH:8]=[CH:7][C:6]([C:2]([CH3:1])([CH3:5])[CH2:3][CH3:4])=[CH:11][CH:10]=3)=[C:30]([Cl:33])[CH:31]=[CH:32][C:25]=2[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCC(C)(C)c1ccc(S)cc1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(CCl)c2CC1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(C)(C)c1ccc(SCc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 45 °C
Reaction time: 0.08 h
Yield: 40.3 %

Procedure:
Dissolve 4-(1,1-dimethyl-propyl)-benzenethiol (100 mg, 0.55 mmol) in anhydrous DMF (2 mL). Add sodium hydride (32 mg, 0.78 mmol, 60% dispersion in mineral oil) at room temperature under a nitrogen atmosphere. Stir the mixture for 5 min, then add a solution of 3-tert-butoxycarbonyl-7-chloro-6-chloromethyl-2,3,4,5-tetrahydro-1H-benzo[d]azepine (214 mg, 0.55 mmol) in anhydrous DMF (2 mL). Heat the mixture to 45° C., add catalytic sodium iodide and stir the mixture at 45° C. for 6 h. Cool the reaction mixture to room temperature and quench with water. Extract the mixture with EtOAc (4×25 mL). Wash the combined organic extracts with brine. Dry the organic layer over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (20:1 to 17:3 gradient) to obtain 3-tert-butoxycarbonyl-7-chloro-6-[4-(1,1-dimethyl-propyl)-phenylthiomethyl]-2,3,4,5-tetrahydro-1H-benzo[d]azepine (105 mg, 40%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][N:3]=1.[C:11]1([CH2:17][NH:18][S:19]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)(=[O:21])=[O:20])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:11]1([CH2:17][NH:18][S:19]([CH:22]2[CH2:27][CH2:26][N:25]([C:2]3[N:3]=[CH:4][C:5]([NH2:8])=[CH:6][CH:7]=3)[CH2:24][CH2:23]2)(=[O:21])=[O:20])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=S(=O)(NCc1ccccc1)C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Product: Nc1ccc(N2CCC(S(=O)(=O)NCc3ccccc3)CC2)nc1

Procedure:
Intermediate B-25 was prepared by the general procedure for intermediate B-2, by using 2-chloro-5-nitropyridine and 4-((phenylmethylamino)sulfonyl)piperidine as starting materials. MS (M+1): 347.