Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5](Cl)=[O:6].C(N(CC)CC)C.[NH2:19][C:20]1[CH:42]=[CH:41][C:23]([C:24]([N:26]2[CH2:32][C:31]3[CH:33]=[CH:34][CH:35]=[CH:36][C:30]=3[CH2:29][C:28]3[CH:37]=[CH:38][CH:39]=[CH:40][C:27]2=3)=[O:25])=[CH:22][CH:21]=1>C(Cl)Cl>[CH:37]1[C:28]2[CH2:29][C:30]3[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=3[CH2:32][N:26]([C:24]([C:23]3[CH:22]=[CH:21][C:20]([NH:19][C:5](=[O:6])[C:4]4[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=4)=[CH:42][CH:41]=3)=[O:25])[C:27]=2[CH:40]=[CH:39][CH:38]=1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1ccc(Cl)c(Cl)c1
Reaction time: 2 h
Yield: 71.9 %

Procedure:
A mixture of 314 mg of 3,4-dichlorobenzoyl chloride and 151 mg of triethylamine in 2 ml of methylene chloride is stirred while 314 mg of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine in 5 ml of methylene chloride is added. Stirring is continued for 2 hours. The reaction mixture is partitioned with water and the organic layer is washed 1N HCl, water, 0.5N NaOH and brine. The organic layer is dried with Na2SO4 and passed through a short pad of hydrous magnesium silicate. Hexane is added to the filtrate at the boil to give 0.35 g of off-white crystalline solid, m.p. 238°-241° C.
Reaction SMILES: CC1(C)[O:6][C:5](=[O:7])[CH:4]([CH:8]([CH2:12][CH2:13][CH2:14][CH3:15])[C:9]([OH:11])=O)[O:3]1.[NH:17]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[CH2:18]1>>[OH:3][C@@H:4]([C@H:8]([C:9]([N:17]1[CH2:21][CH2:20][CH:19]([C:22]2[CH:23]=[CH:24][N:25]=[CH:26][CH:27]=2)[CH2:18]1)=[O:11])[CH2:12][CH2:13][CH2:14][CH3:15])[C:5]([OH:6])=[O:7]
Reactant: CCCCC(C(=O)O)C1OC(C)(C)OC1=O
Reactant: c1cc(C2CCNC2)ccn1
Product: CCCC[C@@H](C(=O)N1CCC(c2ccncc2)C1)[C@H](O)C(=O)O

Procedure:
The title compound is prepared from 2-(2,2-dimethyl-4-oxo-1,3-dioxolan-5-yl)hexanoic acid B-5 and commercially available 4-pyrrolidin-3-yl-pyridine A-5 according to General Procedure B.
Reaction SMILES: [N:1]#[C:2]Br.[CH:4]1[C:14]2[C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][NH:10][CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1>C(Cl)(Cl)Cl>[CH:4]1[C:14]2[C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][N:10]([C:2]#[N:1])[CH2:9][C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: N#CBr
Reactant: c1ccc2c(c1)CNCc1ccccc1-2
Solvent: ClC(Cl)Cl
Product: N#CN1Cc2ccccc2-c2ccccc2C1
Reaction time: 1 h

Procedure:
A solution of 1.91 g of cyanogen bromide in 20 ml of chloroform is added dropwise at 5°-10° C. within 25 minutes to a solution, cooled to 5° C., of 7 g of 6,7-dihydro-5H-dibenz[c,e]azepine in 50 ml of chloroform. The reaction mixture is stirred for a further 1 hour and then a small amount of the hydrobromide salt of the still unreacted azepine is filtered off. The filtrate is washed three times with water, dried over anhydrous sodium sulphate and evaporated. There is obtained solid 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile, m.p. 123°-126° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[CH:17](Br)([CH3:19])[CH3:18]>>[CH:17]([N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([N+:14]([O-:16])=[O:15])[CH:4]=2)[CH2:13][CH2:12]1)([CH3:19])[CH3:18]
Reactant: CC(C)Br
Reactant: Cc1ccc(N2CCNCC2)cc1[N+](=O)[O-]
Product: Cc1ccc(N2CCN(C(C)C)CC2)cc1[N+](=O)[O-]

Procedure:
Beginning with 1-(4-methyl-3-nitro-phenyl)-piperazine and 1-isopropylbromide, the title compound was recovered by the procedure described in Example 2. MS m/z (rel. intensity, 70 eV) 263 (M+, 31), 249 (15), 248 (bp), 84 (15), 56 (42).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:5]=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:16][CH2:17]Br.CCOC(C)=O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([C:9]([O:11][CH3:12])=[O:10])[CH2:17][CH2:16]2)[CH:5]=[N:6][CH:7]=1
Reactant: BrCCBr
Reactant: COC(=O)Cc1cncc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)C1(c2cncc(Br)c2)CC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a solution of methyl 2-(5-bromopyridin-3-yl)acetate (4.8 g, 20.86 mmol) in DMF (100 mL) was added 60% NaH in mineral oil (1.1 g, 45.9 mmol), and the mixture was stirred at 0° C. for 15 min. A solution of 1,2-dibromoethane (3.92 g, 20.86 mmol) in DMF (20 mL) was added and the mixture was stirred at room temperature for 1 h. Two other portions of 60% NaH in mineral oil (200 and 450 mg) were added sequentially, until conversion was complete. The mixture was poured into EtOAc (1 L) and washed with water (60 mL), dried over Na2SO4 and concentrated in vacuo to give an oil which was used in next step without further purification.
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C:15]#[CH:16].[CH:17]1([C:20](Cl)=[O:21])[CH2:19][CH2:18]1.[Cl-].[Na+]>CCCCCC.C1COCC1>[Cl:6][C:7]1[CH:12]=[C:11]([S:13][CH3:14])[CH:10]=[CH:9][C:8]=1[C:15]#[C:16][C:20]([CH:17]1[CH2:19][CH2:18]1)=[O:21]
Reactant: C#Cc1ccc(SC)cc1Cl
Reactant: O=C(Cl)C1CC1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CSc1ccc(C#CC(=O)C2CC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of n-butyllithium in hexane (4.4 ml) was added to a stirred solution of [2-chloro-4-(methylsulphenyl)phenyl]acetylene (2.0 g) in THF while maintaining the temperature below -70° C. The mixture was stirred for 5 minutes and cyclopropanecarbonyl chloride (2.4 g) was added. The mixture was warmed to room temperature and poured onto aqueous sodium chloride solution. The aqueous layer was extracted with ether and combined organic layers dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was dissolved in methanol and heated at reflux for 5 minutes. Toluene was added and the mixture was evaporated to dryness. The residue was purified by chromatography eluted with a mixture of hexane and ether to give 1-[2-chloro4(methylsulphenyl)phenyl]-3-cyclopropylprop-1-yn-3-one as yellow oil which crystallized on standing, m.p. 46°-50° C. [2-Chloro-4-(methylsulphenyl)phenyl]acetylene was prepared by the reaction of 1-bromo-2-[2-chloro-4-(methylsulphenyl)phenyl]acetylene with n-butyllithium and wet zinc chloride in THF at -70° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2].[F:21][C:22]([Si](C)(C)C)([F:27])[C:23]([F:26])([F:25])[F:24].[F-].Cl>C1COCC1.O>[CH2:1]([O:3][C:4](=[O:20])[C:5]([OH:19])([C:22]([F:27])([F:21])[C:23]([F:26])([F:25])[F:24])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(C)(C)c1cccc(F)c1OC
Reactant: C[Si](C)(C)C(F)(F)C(F)(F)F
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)(C)c1cccc(F)c1OC)C(F)(F)C(F)(F)F
Temperature: -25 °C
Reaction time: 4.5 h
Yield: 115.9 %

Procedure:
1.0 g (3.54 mmol) of ethyl-4-(3-fluoro-2-methoxyphenyl)-2-oxo-4-methyl-valerate and 0.98 g (5.1 mmol) of (pentafluoroethyl)-trimethylsilane in 7 ml of THF are mixed with 65 mg (0.7 mmol) of tetramethylammonum fluoride at −40° C. The reaction mixture is heated to −25° C. and stirred at this temperature. After 4.5 hours, 1 ml of 2N hydrochloric acid is added, and the reaction mixture is added to water. It is extracted several times with ethyl acetate, washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. 1.65 g of ethyl-4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(pentafluoroethyl)valerate is obtained as a crude product. The ester is mixed in 80 ml of diethyl ether at 0° C. with 300 mg (8 mmol) of lithium aluminum hydride and stirred for 3.5 more hours at room temperature. A little water is carefully added to the batch at 0° C., and it is stirred vigorously for 15 more minutes. It is filtered by Cellite, and the precipitate is rewashed thoroughly with ethyl acetate. The filtrate is dried with sodium sulfate and concentrated by evaporation in a vacuum. After chromatographic purification on silica gel (hexane/ethyl acetate 10%-15%), 800 mg of 4-(3-fluoro-2-methoxyphenyl)-4-methyl-2-(pentafluoroethyl)pentane-1,2-diol is obtained. 1.8 ml (13 mmol) of triethylamine and, in portions over 10 minutes, 1.6 g (10 mmol) of pyridine SO3 complex are added to 800 mg (2.2 mmol) of diol in 25 ml of dichloromethane and 8.9 ml of DMSO. It is stirred for 2.5 hours, and saturated ammonium chloride solution is added. The mixture is stirred for another 15 minutes, the phases are separated, and it is extracted with dichloromethane. It is washed with water and dried on sodium sulfate. The solvent is removed in a vacuum, and the desired aldehyde is obtained quantitatively.
Reaction SMILES: O.Cl.[CH2:3]([NH:7][NH2:8])[CH2:4][CH2:5][CH3:6].[OH-].[K+].[CH2:11]([N:15]=[C:16]=[O:17])[CH2:12][CH2:13][CH3:14]>O1CCCC1>[CH2:11]([NH:15][C:16]([N:7]([CH2:3][CH2:4][CH2:5][CH3:6])[NH2:8])=[O:17])[CH2:12][CH2:13][CH3:14]
Reactant: CCCCN=C=O
Reactant: CCCCNN
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCNC(=O)N(N)CCCC
Yield: 53.4 %

Procedure:
To a cooled (water bath), stirred mixture of 2.42 g n-butylhydrazine hydrochloride in 15 mL tetrahydrofuran was added 1.7 g powdered potassium hydroxide. The resulting mixture was stirred and maintained under a nitrogen atmosphere as n-butyl isocyanate (1.49 g, 0.015 moles) in 30 mL tetrahydrofuran was added dropwise. After addition, the solution was stirred overnight at ambient temperature. Work up as in Example 5 above yielded 1.5 g N,1-dibutylhydrazinecarboxamide b.p. 135°-6° C. at 0.08 torr, m.p. 34°-36° C. This structure was confirmed by NMR analysis.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[CH2:8][NH:9][C@@H:10]1[C@@H:15]([OH:16])[C@H:14]([CH2:17][C:18]2[CH:23]=[C:22](F)[C:21]([N+:25]([O-:27])=[O:26])=[C:20]([F:28])[CH:19]=2)[CH2:13][S:12](=[O:30])(=[O:29])[CH2:11]1)([CH3:4])([CH3:3])[CH3:2].[F:34][C:35]([F:42])([F:41])[C@H:36]([OH:40])[CH2:37][O:38][CH3:39]>>[C:1]([C:5]1[CH:6]=[C:7]([CH:31]=[CH:32][CH:33]=1)[CH2:8][NH:9][C@@H:10]1[C@@H:15]([OH:16])[C@H:14]([CH2:17][C:18]2[CH:23]=[C:22]([O:40][C@H:36]([CH2:37][O:38][CH3:39])[C:35]([F:42])([F:41])[F:34])[C:21]([N+:25]([O-:27])=[O:26])=[C:20]([F:28])[CH:19]=2)[CH2:13][S:12](=[O:29])(=[O:30])[CH2:11]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)c1cccc(CN[C@H]2CS(=O)(=O)C[C@@H](Cc3cc(F)c([N+](=O)[O-])c(F)c3)[C@@H]2O)c1
Reactant: COC[C@@H](O)C(F)(F)F
Product: COC[C@@H](Oc1cc(C[C@@H]2CS(=O)(=O)C[C@H](NCc3cccc(C(C)(C)C)c3)[C@H]2O)cc(F)c1[N+](=O)[O-])C(F)(F)F

Procedure:
The title compound was prepared in analogous manner as described for example 24j) from (3R,4S,5S)-3-(3-tert-butyl-benzylamino)-5-(3,5-difluoro-4-nitro-benzyl)-1,1-dioxo-hexahydro-1lambda*6*-thiopyran-4-ol (example 24i) and (R)-1,1,1-trifluoro-3-methoxy-propan-2-ol to yield the title compound as a colorless foam: TLC (EtOAc-MeOH 19:1) Rf=0.47; HPLC RtA=2.13 min; ESIMS [M+H]+=607; 1H NMR (600 MHz, DMSO-d6): δ 7.34 (s, 1H), 7.28 (s, 1H), 7.24 (m, 2H), 7.143 (d, 1H), 7.10 (d, 1H), 5.59 (m, 1H), 5.30 (d, 1H), 3.80 (m, 2H), 3.70 (dd, 1H), 3.64 (d, 1H), 3.40 (dt, 1H), 3.29 (s, 3H), 3.21 (m, 1H), 3.12 (dd, 1H), 3.03 (m, 2H), 2.81 (m, 1H), 2.62 (dd, 1H), 2.42 (m, 1H), 2.14 (m, 1H), 1.27 (s, 9H).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[CH2:14]([N:16](CC)[CH2:17][CH3:18])[CH3:15].N1CCCC1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C(C)=CC=CC=1>[N+:11]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:2]=1[N:16]1[CH2:17][CH2:18][CH2:15][CH2:14]1)[C:6]([OH:8])=[O:7])([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCN(CC)CC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: Cc1ccccc1C
Solvent: C1CCNC1
Product: O=C(O)c1ccc(N2CCCC2)c([N+](=O)[O-])c1
Yield: 96 %

Procedure:
4-Chloro-3-nitrobenzoic acid (5.0 g) is suspended in xylene (50 ml), and thereto are added triethylamine (2.5 g) and pyrrolidine (2.0 g), and the mixture is refluxed for 2 hours. To the reaction mixture is added 10% aqueous citric acid solution, and the precipitated crystals are separated by filtration, washed with water and dried to give 3-nitro-4-(1-pyrrolidinyl)benzoic acid (5.6 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10](Cl)=[O:11])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:13][CH:14]([CH2:16][CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[CH3:15]>>[CH3:13][CH:14]([CH2:16][CH:17]([NH:21][C:10]([C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][O:3][C:4]=2[CH:9]=1)=[O:11])[CH2:18][CH2:19][CH3:20])[CH3:15]
Reactant: CCCC(N)CC(C)C
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Product: CCCC(CC(C)C)NC(=O)c1ccc2c(c1)OCO2

Procedure:
Prepared in a similar manner to example 1 using benzo[d][1,3]dioxole-5-carbonyl chloride and 2-methylheptan-4-amine (example 2a). 1H NMR (500 MHz, CDCl3): δ 0.93 (m, 9H); 1.38 (m, 5H); 1.53 (m, 1H); 1.66 (m, 1H); 4.21 (m, 1H); 5.61 (d, 1H); 6.01 (s, 2H); 6.82 (d, 1H); 7.26 (m, 2H). MS (278, M+H).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N:8]([CH3:25])[C:9](=[O:24])[C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=1.[CH:26]1([CH2:29][O:30][C:31]2[C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:28][CH2:27]1>CCCCCCC.CCOC(C)=O>[CH:26]1([CH2:29][O:30][C:31]2[C:36]([C:2]3[CH:7]=[CH:6][N:5]=[CH:4][C:3]=3[N:8]([CH3:25])[C:9](=[O:24])[C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[C:12]([C:20]([F:23])([F:22])[F:21])[CH:11]=3)=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:27][CH2:28]1
Reactant: CC1(C)OB(c2cccnc2OCC2CC2)OC1(C)C
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1I
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cnccc1-c1cccnc1OCC1CC1

Procedure:
The title compound was prepared in analogy to example 72, from N-(4-iodo-pyridin-3-yl)-N-methyl-3,5-bis-trifluoromethyl-benzamide (example 98, intermediate a) and 2-(cyclopropylmethoxy)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (CAS RN 848243-26-5) and using a gradient of n-heptane:EtOAc (100:0 to 30:70) for the chromatographic purification. Light yellow oil (63%). MS (ESI): m/z=498.146 [M+H]+.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.CCN(C(C)C)C(C)C.[NH2:34][C:35]1[CH:57]=[CH:56][C:38]([CH2:39][NH:40][C:41]2[C:46]3[CH:47]4[O:55][CH2:54][CH2:53][CH2:52][N:48]4[C:49](=[O:51])[NH:50][C:45]=3[N:44]=[CH:43][CH:42]=2)=[CH:37][C:36]=1[F:58]>CN(C=O)C>[F:58][C:36]1[CH:37]=[C:38]([CH2:39][NH:40][C:41]2[C:46]3[CH:47]4[O:55][CH2:54][CH2:53][CH2:52][N:48]4[C:49](=[O:51])[NH:50][C:45]=3[N:44]=[CH:43][CH:42]=2)[CH:56]=[CH:57][C:35]=1[NH:34][C:1](=[O:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1
Reactant: Nc1ccc(CNc2ccnc3c2C2OCCCN2C(=O)N3)cc1F
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(CNc2ccnc3c2C2OCCCN2C(=O)N3)cc1F)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 9.2 %

Procedure:
Benzoic acid (35 mg; 0.17 mmol), Bop-Cl (39 mg; 0.16 mmol), DIEA (0.04 mL; 0.25 mmol), and 45 (55mg, 0.26 mmol) were suspended in DMF (2 mL), and stirred overnight at room temperature. The crude reaction mixture was purified directly via HPLC to provide 52 (7 mg, 10% yield) as a solid. LC-MS (M+H=448, obsd.=448).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23]([OH:25])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:26][CH:27]1[C:32]2([C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33]2)[CH2:31][CH2:30][NH:29][CH2:28]1>>[CH2:1]([NH:8][C:9]1[N:14]2[N:15]=[CH:16][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:13]2[N:12]=[CH:11][C:10]=1[C:23]([N:29]1[CH2:30][CH2:31][C:32]2([C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:34]=[CH:33]2)[CH:27]([CH3:26])[CH2:28]1)=[O:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)O)cnc12
Reactant: CC1CNCCC12C=Cc1ccccc12
Product: CCOC(=O)c1cnn2c(NCc3ccccc3)c(C(=O)N3CCC4(C=Cc5ccccc54)C(C)C3)cnc12
Yield: 89.9 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-benzylamino-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.066 g, 0.194 mmol) obtained in Example 21, step 4 and 3′-methylspiro[inden-1,4′-piperidine] (WO2004/028459, 0.043 g, 0.213 mmol), the title compound (0.091 g, 90%) was obtained.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[CH:11][C:10]([CH2:25]Cl)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)=[CH:11][C:10]([CH2:25][N:27]2[CH2:32][CH2:31][N:30]([CH2:25][C:10]3[CH:11]=[C:12]([C:13]4[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=4)[N:8]([CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[N:9]=3)[CH2:29][CH2:28]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(-c2cc(CCl)nn2Cc2ccccc2)cc(OC)c1OC
Reactant: C1CNCCN1
Product: COc1cc(-c2cc(CN3CCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)n(Cc5ccccc5)n4)CC3)nn2Cc2ccccc2)cc(OC)c1OC

Procedure:
1-Benzyl-3-chloromethyl-5-(3,4,5-trimethoxy-phenyl)pyrazole (559 mg) and piperazine (59 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: O[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1.O=P(Cl)(Cl)[Cl:15]>>[Cl:15][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([Br:12])=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1ncc(Br)cc1C(F)(F)F
Product: FC(F)(F)c1cc(Br)cnc1Cl
Temperature: 0 °C

Procedure:
A mixture of 1.83 g (7.6 mmol) of 2-hydroxy-3-trifluoromethyl-5-bromopyridine (from Step A) in 15 mL of POCl3 was heated at reflux for 3 h. The mixture was cooled and poured onto 200 g of ice. The resulting mixture was extracted with 200 mL of CH2Cl2. The extract was dried and concentrated. Chromatography on a Biotage 40 M cartridge using hexanes as the eluant afforded 1.11 g of the title compound: 1H NMR (500 MHz, CDCl3) δ 8.14 (d, J=2.0, 1H), 8.64 (d, J=2.0, 1H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:23])[CH:6]=1)[CH3:2].Br[C:26]1[CH:27]=[N:28][N:29]([CH2:31][CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])[CH:30]=1>>[CH2:1]([O:3][C:4](=[O:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[C:16]([F:22])[C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:26]3[CH:27]=[N:28][N:29]([CH2:31][CH2:32][O:33][Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:35])[CH3:36])[CH:30]=3)[C:13]=2[CH3:23])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3c(F)c(Cl)ccc23)c1
Reactant: CC(C)(C)[Si](C)(C)OCCn1cc(Br)cn1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(CCO[Si](C)(C)C(C)(C)C)c3)c3c(F)c(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 55, Step 2 using the following starting materials: 3-(6-chloro-7-fluoro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-Bromo-1-[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]-1H-pyrazole.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[C:4]([C:11](=[O:13])[CH3:12])=[CH:3][CH:2]=1.N1C(C)=CC=CC=1C.O([Si:30]([CH3:33])([CH3:32])[CH3:31])S(C(F)(F)F)(=O)=O>C(Cl)Cl>[CH3:31][Si:30]([CH3:33])([CH3:32])[O:13][C:11]([C:4]1[C:5]2[C:10](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1)=[CH2:12]
Reactant: CC(=O)c1ccnc2ncccc12
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: C=C(O[Si](C)(C)C)c1ccnc2ncccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-[1,8]Naphthyridin-4-yl-ethanone from Preparation 18 (250 mg, 1.45 mmol), 2,6-lutidine (0.254 ml, 2.18 mmol) in DCM (3.6 ml) was treated with trimethylsilyl triflate (0.276 ml, 1.53 mmol) and allowed to stir at RT overnight. Mixture diluted with DCM and washed with satd. NaHCO3. Organics dried over Na2SO4 and concentrated, furnished 350 mg 4-(1-trimethylsilanyloxy-vinyl)-[1,8]-naphthyridine as an oil. MS (ESI+) for m/z 245 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br[CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:39][CH3:40])=[O:32].CN(C)C=O.[H-].[Na+]>C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:30][C:31]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=3[O:39][CH3:40])=[O:32])[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: COc1ccccc1C(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccccc3OC)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.6 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (5 g), 2-bromo-1-(2-methoxyphenyl)ethanone (3.3 g) and N,N-dimethylformamide (200 mL) was added 60% sodium hydride (1 g), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% potassium hydrogensulfate and then saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as colorless crystals (4.12 g, 60%).
Reaction SMILES: [CH:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CS(O[CH2:18][CH2:19][C@@:20]1([C:36]2[CH:41]=[CH:40][C:39]([Cl:42])=[C:38]([Cl:43])[CH:37]=2)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:34])[CH2:21]1)(=O)=O.C(#N)C>>[Cl:43][C:38]1[CH:37]=[C:36]([C@@:20]2([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][N:7]([CH:1]4[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]4)[CH2:8][CH2:9]3)[CH2:24][CH2:23][N:22]([C:25](=[O:35])[CH2:26][C:27]3[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=3[Cl:34])[CH2:21]2)[CH:41]=[CH:40][C:39]=1[Cl:42]
Reactant: CS(=O)(=O)OCC[C@@]1(c2ccc(Cl)c(Cl)c2)CCN(C(=O)Cc2c(F)cccc2Cl)C1
Reactant: C1CCC(N2CCNCC2)CC1
Solvent: CC#N
Product: O=C(Cc1c(F)cccc1Cl)N1CC[C@](CCN2CCN(C3CCCCC3)CC2)(c2ccc(Cl)c(Cl)c2)C1

Procedure:
In 30 ml of acetonitrile (R)-3-(2-methanesulfonyloxyethyl)-3-(3,4-dichlorophenyl)-1-[(2-chloro-6-fluorophenyl)acetyl]pyrrolidine (3.17 g), prepared as described, supra, is mixed with an equimolar amount of 1-cyclohexylpiperazine. The reaction mixture is then heated to reflux and refluxed for about ten hours. The mixture is then concentrated under vacuum and the residue is taken up in methylene chloride and washed with a 3N solution of hydrochloric acid, followed by a wash with brine. The organic fraction is dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue precipitates from an acetone/diethyl ether mixture to give the desired title product.