Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][CH2:6][C@H:7]1[NH:14][CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[CH2:10][O:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][C:27]=2[S:29](Cl)(=[O:31])=[O:30])[CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1>[C:1]([O:5][CH2:6][C@H:7]1[N:14]([S:29]([C:27]2[CH:26]=[CH:25][CH:24]=[C:23]3[C:28]=2[N:19]=[CH:20][CH:21]=[CH:22]3)(=[O:30])=[O:31])[CH2:13][C:12]2[CH:15]=[CH:16][CH:17]=[CH:18][C:11]=2[CH2:10][O:9][CH2:8]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Reactant: CC(C)(C)OC[C@@H]1COCc2ccccc2CN1
Solvent: c1ccncc1
Product: CC(C)(C)OC[C@@H]1COCc2ccccc2CN1S(=O)(=O)c1cccc2cccnc12
Reaction time: 16 h
Yield: 45.4 %

Procedure:
To a mixture of compound 14f (crude, 129 mg, 0.5 mmol) in pyridine (4 mL) at rt was added quinoline-8-sulfonyl chloride (142 mg, 0.6 mmol). The reaction mixture was stirred for 16 h and concentrated under reduced pressure. The residue was partitioned between CHCl3 and H2O. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by Prep-TLC to give compound 14 (100 mg, 44% yield). 1H NMR (400 MHz, CDCl3) δ 8.97 (s, 1H), 8.49 (d, 1H, J=8.0 Hz), 8.17 (d, 1H, J=8.0 Hz), 7.97 (d, 1H, J=8.0 Hz), 7.56 (t, 1H, J=8.0 Hz), 7.47-7.44 (m, 1H), 7.21 (d, 1H, J=8.0 Hz), 7.02-7.00 (m, 1H), 6.94-6.93 (m, 1H), 6.87 (d, 1H, J=8.0 Hz), 5.17 (d, 1H, J=8.0 Hz), 4.98-4.93 (m, 2H), 4.66 (d, 1H, J=8.0 Hz), 4.51 (s, 1H), 4.27 (d, 1H, J=8.0 Hz), 3.78 (d, 1H, J=8.0 Hz), 3.53 (t, 1H, J=7.2 Hz), 3.21-3.18 (m, 1H), 1.00 (s, 9H). MS (ESI) calcd for [C24H28N2O4S+H]+ (m/z): 441.56. found: 441.3.
Reaction SMILES: [SH:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Br[CH2:19][CH2:20][Cl:21]>>[Cl:21][CH2:20][CH2:19][S:1][C:2]1[N:7]2[CH:8]=[CH:9][N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Sc1cccc2nccn12
Reactant: ClCCBr
Solvent: CCN(CC)CC
Product: ClCCSc1cccc2nccn12

Procedure:
Using 3.0 g (20 mmol) of 5-mercaptoimidazo[1,2-a]pyridine, 2.79 ml (20 mmol) of triethylamine and 1.66 ml (20 mmol) of 1-bromo-2-chloroethane, the same procedure as in Reference Example 1 was followed, to yield 2.29 g (54.0%, light brown oily substance) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[C:21](I)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1.[F:23][C:24]1[CH:25]=[N:26][CH:27]=[C:28](B(O)O)[CH:29]=1>>[Cl:1][C:2]1[C:21]([C:28]2[CH:27]=[N:26][CH:25]=[C:24]([F:23])[CH:29]=2)=[CH:20][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]([Cl:19])([F:18])[F:17])=[CH:11][CH:10]=2)=[O:7])=[CH:4][N:3]=1
Reactant: OB(O)c1cncc(F)c1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(I)c1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(Cl)c(-c2cncc(F)c2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 76 using 6-chloro-N-(4-(chlorodifluoromethoxy)phenyl)-5-iodonicotinamide (Stage 76.1) and 3-Fluoropyridine-5-boronic acid pinacolester (80° C. instead of 90° C.) to afford the title compound as a white solid. UPLC-MS (Condition 2)) tR=1.17 min, m/z=425.9/427.9 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 7.42 (d, J=8.68 Hz, 2H) 7.60 (dd, J=7.89, 4.83 Hz, 1H) 7.88 (d, J=9.05 Hz, 2H) 8.07 (dt, J=7.82, 1.90 Hz, 1H) 8.49 (d, J=2.32 Hz, 1H) 8.71 (dd, J=4.83, 1.41 Hz, 1H) 8.81 (d, J=2.08 Hz, 1H) 9.00 (d, J=2.20 Hz, 1H) 10.68 (s, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[C:8]([C@@H:30]3[CH2:32][C@H:31]3[C:33]([O:35]CC)=[O:34])=[N:9][N:10]([C:11]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1.[CH3:38][O:39][CH2:40][C@@H:41]([NH:48][C:49]([NH2:51])=[O:50])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>>[CH3:38][O:39][CH2:40][C@@H:41]([NH:48][C:49](=[O:50])[NH:51][C:2]1[N:7]=[CH:6][C:5]2[C:8]([C@@H:30]3[CH2:32][C@H:31]3[C:33]([OH:35])=[O:34])=[N:9][N:10]([C:11]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:4]=2[CH:3]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CCOC(=O)[C@@H]1C[C@H]1c1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2cc(Cl)ncc12
Reactant: COC[C@@H](NC(N)=O)c1ccccc1
Product: COC[C@@H](NC(=O)Nc1cc2c(cn1)c([C@@H]1C[C@H]1C(=O)O)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
In a manner similar to that described in Example 30 (Step 1), trans-ethyl 2-(6-chloro-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)cyclopropanecarboxylate was reacted with (S)-1-(2-methoxy-1-phenylethyl)urea (BrettPhos precatalyst, KOtBu, dioxane, 80° C.) to provide trans-2-(6-(3-((S)-2-methoxy-1-phenylethyl)ureido)-1-trityl-1H-pyrazolo[4,3-c]pyridin-3-yl)cyclopropanecarboxylic acid. MS ESI calc'd. for C39H35N5O4[M+1]+ 638, found 638.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=1.[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1>>[F:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[C:11]2[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH:16]=2)=[O:25])=[CH:22][CH:21]=1
Reactant: CCN1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Reactant: O=C(Cl)c1ccc(F)cc1
Product: CCN1CC=C(c2c[nH]c3ccc(NC(=O)c4ccc(F)cc4)cc23)CC1
Yield: 59.2 %

Procedure:
Beginning with 2.69 gm (11.1 mMol) 5-amino-3-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indole and 1.45 mL (12.3 mMol) 4-fluorobenzoyl chloride, 2.39 gm (59.0%) of the title compound were recovered as a burnt orange powder.
Reaction SMILES: [F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25](B4OC(C)(C)C(C)(C)O4)=[CH:24][N:23]=[C:22]([S:35][CH3:36])[N:21]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Br[C:41]1[CH:42]=[C:43]([C:49]2[C:58]([CH3:59])=[CH:57][C:52]([C:53]([O:55][CH3:56])=[O:54])=[CH:51][C:50]=2[CH3:60])[CH:44]=[N:45][C:46]=1[O:47][CH3:48].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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.O1CCOCC1>[F:1][C:2]([F:39])([F:38])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[C:25]([C:41]4[CH:42]=[C:43]([C:49]5[C:58]([CH3:59])=[CH:57][C:52]([C:53]([O:55][CH3:56])=[O:54])=[CH:51][C:50]=5[CH3:60])[CH:44]=[N:45][C:46]=4[O:47][CH3:48])=[CH:24][N:23]=[C:22]([S:35][CH3:36])[N:21]=3)[C@H:14]2[CH3:37])[CH:6]=[C:7]([C:9]([F:10])([F:12])[F:11])[CH:8]=1
Reactant: COC(=O)c1cc(C)c(-c2cnc(OC)c(Br)c2)c(C)c1
Reactant: CSc1ncc(B2OC(C)(C)C(C)(C)O2)c(CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1cc(C)c(-c2cnc(OC)c(-c3cnc(SC)nc3CN3C(=O)O[C@H](c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H]3C)c2)c(C)c1

Procedure:
(4S,5R)-5-[3,5-Bis(trifluoromethyl)phenyl]-4-methyl-3-{[2-(methylthio)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-4-yl]methyl}-1,3-oxazolidin-2-one (INTERMEDIATE 21, 1.12 g, 1.940 mmol), methyl 4-(5-bromo-6-methoxypyridin-3-yl)-3,5-dimethylbenzoate (INTERMEDIATE 33, 0.815 g, 2.328 mmol) and Pd(Ph3P)4 (0.224 g, 0.194 mmol) were evacuated and charged with nitrogen. Added 1,4-dioxane (9.70 mL) and 2N tribasic potassium phosphate (2.91 mL, 5.82 mmol), then stirred at 170° C. for 10 minutes in a microwave reactor. LCMS showed significant product formation. The crude was purified directly by silica gel chromatography, eluting with a gradient of 5-40% ethyl acetate/hexanes over 10 column volumes to give the title compound. 1H NMR (CDCl3, 500 MHz): δ 8.36 (s, 1H), 8.07 (d, 1H), 7.89 (s, 1H), 7.81 (s, 2H), 7.74 (s, 2H), 7.33 (d, 1H), 5.73 (d, 1H), 4.81 (d, 1H), 4.44 (br, 1H), 4.08 (m, 1H), δ4.01 (s, 3H), 3.93 (s, 3H), 2.62 (s, 3H), 2.16 (s, 3H), 2.14 (s, 3H), 0.75 (d, 3H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:15]=[CH:14][CH:13]=[C:12]3[C:8]=2[CH2:9][C:10](=[O:16])[NH:11]3)[CH2:3][CH2:2]1.[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]([CH:33]=O)=[C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:26]=1[CH3:27])=[O:21])[CH3:18]>>[CH2:17]([O:19][C:20]([C:22]1[NH:23][C:24]([CH:33]=[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[CH:15][C:7]=3[CH:4]3[CH2:3][CH2:2][NH:1][CH2:6][CH2:5]3)[NH:11][C:10]2=[O:16])=[C:25]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:26]=1[CH3:27])=[O:21])[CH3:18]
Reactant: CCOC(=O)c1[nH]c(C=O)c(CCC(=O)O)c1C
Reactant: O=C1Cc2c(cccc2C2CCNCC2)N1
Product: CCOC(=O)c1[nH]c(C=C2C(=O)Nc3cccc(C4CCNCC4)c32)c(CCC(=O)O)c1C

Procedure:
4-Piperidin-4-yl-1,3-dihydroindol-2-one (45 mg, 0.2 mmol) was condensed with 4-(2-carboxyethyl)-5-formyl-3-methyl-1H-pyrrole-2-carboxylic acid ethyl ester (55 mg, 0.23 mmol) to give the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]5[NH:32][CH:33]=[C:34]([CH2:36][OH:37])[N:35]=5)[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.C([O-])(O)=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:14]2[CH2:23][CH2:22][C:21]3[C:16](=[CH:17][C:18]([O:24][C:25]4[CH:30]=[CH:29][N:28]=[C:27]([C:31]5[NH:32][CH:33]=[C:34]([CH:36]=[O:37])[N:35]=5)[CH:26]=4)=[CH:19][CH:20]=3)[CH2:15]2)=[O:13])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(-c5nc(CO)c[nH]5)c4)cc3C2)c1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(-c5nc(C=O)c[nH]5)c4)cc3C2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of N-(3-tert-butylphenyl)-7-({2-[4-(hydroxymethyl)-1H-imidazol-2-yl]pyridin-4-yl}oxy)-1,2,3,4-tetrahydronaphthalene-2-carboxamide (I-3) (1.24 g, 2.50 mmol) in DCM (10 mL) was added Dess-Martin periodinane (1.27 g, 3.00 mmol) at rt. The resulting suspension was allowed to stir at rt for 30 min, and then aqueous NaHCO3/Na2SO3 solution (1:1) was added and the mixture was extracted with DCM (30 mL×3). The combined organic solutions were washed with brine, dried over Na2SO4, filtered and concentrated to give N-(3-tert-butylphenyl)-7-{[2-(4-formyl-1H-imidazol-2-yl)pyridin-4-yl]oxy}-1,2,3,4-tetrahydronaphthalene-2-carboxamide as a yellow foam which was used without further purification. LCMS: (FA) ES+ 495.5.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5]([C:7]#[N:8])=[O:6].Cl.[OH2:14]>>[Cl:1][CH2:2][C:3]1[CH:12]=[CH:11][CH:10]=[CH:9][C:4]=1[C:5](=[O:6])[C:7]([NH2:8])=[O:14]
Reactant: O
Reactant: N#CC(=O)c1ccccc1CCl
Agent: Cl
Product: NC(=O)C(=O)c1ccccc1CCl
Temperature: 25 °C
Reaction time: 5 h
Yield: 74 %

Procedure:
16.5 g (92 mmol) of 2-(chloromethyl)benzoyl cyanide, 150 ml of concentrated hydrochloric acid and 150 ml of saturated ethereal hydrogen chloride solution were mixed together and stirred at room temperature for 5 hours. The mixture was then poured into water, the organic phase was separated off and the aqueous phase was extracted with methyl tert-butyl ether. The combined organic phases were washed with water, dried over sodium sulfate and concentrated. After purification by column chromatography on silica gel (methyl tert-butyl ether/n-hexane), 13.4 g (74% yield) of the title compound were obtained as a beige powder of melting point 105°-107° C.
Reaction SMILES: [C:1]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][C:4]([OH:7])=[CH:3][CH:2]=1.[Br:14][CH2:15][CH2:16][CH2:17]Br.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[Br:14][CH2:15][CH2:16][CH2:17][O:7][C:4]1[CH:3]=[CH:2][C:1]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][CH:5]=1
Reactant: Oc1ccc(-c2ccccc2)cc1
Reactant: BrCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: BrCCCOc1ccc(-c2ccccc2)cc1
Reaction time: 24 h
Yield: 63.9 %

Procedure:
To a solution of 4-biphenylol (0.0514 g, 0.302 mmol) in acetonitrile (4 mL) was added 1,3-dibromopropane (0.310 mL, 3.05 mmol) followed by Cs2CO3 (0.154 g, 0.472 mmol). The reaction mixture was stirred for 24 h and then concentrated under vacuum. The resulting residue was treated with H2O (4 mL) and extracted with DCM (8 mL). The organic layer was dried through a phase separator and concentrated under vacuum. The residue was taken up in DMSO and purified by preparatory HPLC (without TFA) to give the title compound (0.0562 g, 64.0%). ELMS Rt (2.62 min).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C@@H:20]([NH:22][CH2:23][CH2:24][C:25]2([OH:38])[CH2:37][CH2:36][C:28]3([O:33]CC(C)(C)CO3)[CH2:27][CH2:26]2)[CH3:21])=[CH:16][CH:15]=1.C(N(C(C)C)C(C)C)C.Cl>ClCCl.CC(C)=O>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C@@H:20]([N:22]2[CH2:23][CH2:24][C:25]3([CH2:26][CH2:27][C:28](=[O:33])[CH2:36][CH2:37]3)[O:38][C:2]2=[O:4])[CH3:21])=[CH:18][CH:19]=1
Reactant: C[C@H](NCCC1(O)CCC2(CC1)OCC(C)(C)CO2)c1ccc(Br)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](c1ccc(Br)cc1)N1CCC2(CCC(=O)CC2)OC1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphosgene (2.51 g) is added to a solution of 9-{2-[(S)-1-(4-bromo-phenyl)-ethylamino]-ethyl}-3,3-dimethyl-1,5-dioxa-spiro[5.5]undecan-9-ol (4.00 g) and ethyl-diisopropyl-amine (1.7 mL) in dichloromethane (40 mL) chilled in an ice bath. The cooling bath is removed and the solution is stirred at room temperature overnight. Water is added and the organic phase is separated. The organic phase is dried (Na2SO4) and concentrated to give an oil that is dissolved in acetone (20 mL). 1 M Hydrochloric acid (19 mL) is added and the solution is stirred at room temperature for 3 h. The acetone is then evaporated, and the residue is diluted with saturated aqueous K2CO3 solution and extracted with ethyl acetate. The combined extracts are washed with water and brine, dried (MgSO4), and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate 1:1→0:1) to give the title compound. Yield: 1.89 g (52% of theory); LC (method 8): tR=1.27 min; Mass spectrum (ESI+): m/z=366/368 (Br) [M+H]+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:32]=[CH:31][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)=[C:16]([CH3:30])[NH:15][CH:14]=2)=[O:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].I[CH2:40][CH3:41]>CN(C=O)C.CO>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][NH:10][C:11]([C:13]2[C:18](=[O:19])[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:28])([F:27])[F:29])[CH:21]=3)=[C:16]([CH3:30])[N:15]([CH2:40][CH3:41])[CH:14]=2)=[O:12])=[CH:31][CH:32]=1)(=[O:4])=[O:3]
Reactant: Cc1[nH]cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)c1-c1cccc(C(F)(F)F)c1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)NCc2ccc(S(C)(=O)=O)cc2)c(=O)c(-c2cccc(C(F)(F)F)c2)c1C
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-methyl-4-oxo-5-(3-trifluoromethyl-phenyl)-1,4-dihydro-pyridine-3-carboxylic acid 4-methanesulfonyl-benzylamide (preparation 1, 100 mg, 0.215 mmol), K2CO3 (48 mg, 0.344 mmol) and iodoethane (20 μL, 0.250 mmol) in DMF (1 mL) is stirred for 30 min at 80° C. (microwave). The reaction mixture is diluted with MeOH, filtered and purified by preparative reversed-phase HPLC (XBridge, gradient of methanol in water, 0.3% NH4OH, 60° C.). Yield: 52 mg (49% of theory); ESI mass spectrum: [M+H]+=493; Retention time HPLC: 1.03 min (Z003_001).
Reaction SMILES: C(O[C:6]1[CH:15]=[C:14]2[C:9]([CH:10]=[CH:11][C:12]([OH:16])=[CH:13]2)=[CH:8][CH:7]=1)CCC>C1C2C(=CC=CC=2)C=CC=1O.C(Cl)(Cl)(Cl)Cl>[CH:7]1[CH:8]=[C:9]2[CH:10]=[CH:11][C:12]([OH:16])=[C:13]([C:13]3[C:14]4[C:9](=[CH:8][CH:7]=[CH:6][CH:15]=4)[CH:10]=[CH:11][C:12]=3[OH:16])[C:14]2=[CH:15][CH:6]=1
Reactant: CCCCOc1ccc2ccc(O)cc2c1
Agent: Oc1ccc2ccccc2c1
Solvent: ClC(Cl)(Cl)Cl
Product: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Reaction time: 0.17 h
Yield: 99 %

Procedure:
A reaction flask described in example 9 was charged with a solution of catalyst 1c (12.2 mg, 0.02 mmol) in anhydrous CCl4 (1 mL). The solution was stirred for 10 min under an oxygen atmosphere and then treated with a solution of 7-n-butyloxy-2-naphthol (43 mg, 0.2 mmol) in anhydrous CCl4 (1 mL) under 0° C. The reaction mixture was stirred at 0° C. until the reaction was complete (monitored by TLC). The crude mixture was concentrated under reduced pressure, and purified by column chromatography (Ethyl acetate/Petroleum ether=⅓) to give (R)-BINOL 3h, Yield 99%. [α]D25=−168.4 (c=0.4 in EtOAc), 1HNMR (300 MHz, CDCl3) δ (ppm) 7.87 (d, J=9.0 Hz, 2H, 2×HC (5)), 7.78 (d, J=9.0 Hz, 2H, 2×HC (4)), 7.21 (d, J=9.0 Hz, 2H, 2×HC (3)), 7.03 (dd, J=9.0 Hz, 3.0 Hz, 2H, 2×HC (6)), 6.49 (s, 2H, 2×HC (8)), 5.08 (s, 2H, 2×OH), 3.68 (m, 4H, 4×OCH2), 1.58–1.67 (m, 4H, 4×OCH2CH2), 1.28–1.40 (m 4H, 4×CH3 CH2), 0.85–0.89 (t, 6H, 6×CH3). e.e. 94%.
Reaction SMILES: [NH2:1][C:2]1[C:24]([C:25](=[O:32])[NH:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)=[C:5]2[N:6]=[CH:7][C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])=[C:9]([C:10]3[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=3)[N:4]2[N:3]=1.Cl[CH2:34][CH2:35][O:36][CH2:37][CH2:38]Cl>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:8]1[CH:7]=[N:6][C:5]2[N:4]([N:3]=[C:2]([N:1]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:24]=2[C:25](=[O:32])[NH:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:9]=1[C:10]1[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=1
Reactant: ClCCOCCCl
Reactant: Nc1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Product: O=C(NC1CCCC1)c1c(N2CCOCC2)nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc12
Yield: 33 %

Procedure:
The compound obtained in Example 40 and 2-chloroethylether were treated in the same manner as described in Example 43 to obtain 6-(2-chlorophenyl)-7-(4-chlorophenyl)-2-morpholino-3-(N-cyclopentylcarbamoyl)pyrazolo[1,5-a]pyrimidine (23 mg, yield: 33%) as a powder.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][N:3]=1.[H-].[Na+].[CH3:10][Si:11]([CH3:18])([CH3:17])[CH2:12][CH2:13][O:14][CH2:15]Cl>O1CCCC1.C(OCC)(=O)C.O>[Br:1][C:2]1[CH:6]=[C:5]([CH3:7])[N:4]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:18])([CH3:17])[CH3:10])[N:3]=1
Reactant: Cc1cc(Br)n[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(Br)nn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 103 %

Procedure:
To a solution of 3-bromo-5-methyl-1H-pyrazole (from Ark Pharm, 6.4 g, 40 mmol) in tetrahydrofuran (263 mL) at 0° C. was added sodium hydride (3.2 g, 80 mmol). After stirring for 30 min, [β-(trimethylsilyl)ethoxy]methyl chloride (8.4 mL, 48 mmol) was added and the reaction mixture was allowed to warm to room temperature over 2 h. The reaction mixture was diluted with ethyl acetate and water. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated. The crude was purified with flash chromatography (eluting with a gradient of 0-15% ethyl acetate in hexanes) to give the desired product as colorless oil (12 g, 100%). LCMS calculated for C10H20BrN2OSi (M+H)+: m/z=291.1. Found: 291.0.
Reaction SMILES: C([NH:4][CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([NH2:16])[CH:10]=1)([CH3:8])[CH3:7])(=O)C.C(N(CC)CC)C.Cl.[C:25](Cl)(=O)[C:26]1[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=1.N>O.ClCCl>[NH2:4][CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]2[N:15]=[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)[NH:16][C:11]=2[CH:10]=1)([CH3:7])[CH3:8]
Reactant: O=C(Cl)c1ccncc1
Reactant: CC(=O)NCC(C)(C)c1ccc(N)c(N)c1
Agent: Cl
Agent: N
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(CN)c1ccc2nc(-c3ccncc3)[nH]c2c1
Temperature: 0 °C

Procedure:
To 22.1 g. 4-(2-acetamidomethylprop-2-yl)-1,2-diaminobenzene and 42 ml. triethylamine in 500 ml. dichloromethane are added, while cooling with ice water, 27 g. isonicotinic acid chloride hydrochloride. Stirring is continued at ambient temperature until the reaction of the diamine is complete (thin layer chromatography, silica gel, dichloromethane:methanolic ammonia=10:1 v/v). It is shaken with water and the organic phase is separated off and evaporated to dryness in a vacuum. The residue (24.3 g.) is taken up in 200 ml. ethanol, mixed with 60 ml. concentrated hydrochloric acid and boiled under reflux for 3 days. It is evaporated to dryness in a vacuum, the residue is digested with aqueous ammonia solution at pH=6, 50 ml. dichloromethane are added thereto, filtered off with suction and then washed with iced water and dichloromethane to give 14.1 g. of colourless crystals which are purified by column chromatography (column: diameter 6 cm., length 40 cm., filled with 1 liter silica gel, elution agent dichloromethane:methanolic ammonia 15:1 v/v). After combining the appropriate fractions, removing the elution agent in a vacuum and triturating with ethyl acetate, there are obtained 9.2 g. of the title compound as colourless crystals; m.p. 199°-202° C. 2.7 g. thereof are recrystallised from dioxan to give 2.3 g. of colourless crystals; m.p. 203°- 204° C.
Reaction SMILES: CN(C)C=O.[OH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1.[H-].[Na+].[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1F)[CH:20]=[O:21]>O>[F:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[CH:20]=[O:21]
Reactant: OCc1ccccn1
Reactant: O=Cc1ccc(F)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(OCc2ccccn2)c(F)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 45.6 %

Procedure:
To an N,N-dimethylformamide (40.0 mL) solution of 2-(hydroxymethyl)-pyridine (3.00 g, 27.5 mmol) was added sodium hydride (1.00 g, 25.0 mmol, 60% in oil) under nitrogen atmosphere at 0° C., which was stirred for 20 minutes at room temperature. 3,4-Difluorobenzaldehyde (4.69 g, 33.0 mmol) was then added at 0° C., and stirred for 20 minutes at room temperature. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:1→2:1) to obtain the title compound (2.90 g, 45.6%).