Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C:24]2[C:29](=[O:30])[CH2:28][CH:27]([C:31](F)(F)F)[CH2:26][C:25]=2[OH:35])[NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:23])([F:22])[F:21])[CH:15]=2)=[O:12])=[CH:5][CH:4]=1)#[N:2].[CH3:36][O:37][C:38]1[CH:39]=C(C2CC(=O)CC(=O)C2)[CH:41]=[C:42]([O:46][CH3:47])[C:43]=1[O:44][CH3:45]>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C:24]2[C:29](=[O:30])[CH2:28][CH:27]([C:31]3[CH:39]=[C:38]([O:37][CH3:36])[C:43]([O:44][CH3:45])=[C:42]([O:46][CH3:47])[CH:41]=3)[CH2:26][C:25]=2[OH:35])[NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([F:22])([F:21])[F:23])[CH:15]=2)=[O:12])=[CH:7][CH:8]=1)#[N:2]
Reactant: COc1cc(C2CC(=O)CC(=O)C2)cc(OC)c1OC
Reactant: N#Cc1ccc(C(NC(=O)Nc2cccc(C(F)(F)F)c2)C2=C(O)CC(C(F)(F)F)CC2=O)cc1
Product: COc1cc(C2CC(=O)C(C(NC(=O)Nc3cccc(C(F)(F)F)c3)c3ccc(C#N)cc3)=C(O)C2)cc(OC)c1OC

Procedure:
The title compound is prepared in analogy to 1-((4-cyanophenyl)(2-hydroxy-6-oxo-4-(tri-fluoromethyl)cyclohex-1-enyl)methyl)-3-(3-(trifluoromethyl)phenyl)urea (intermediate 12), using 5-(3,4,5-trimethoxyphenyl)cyclohexane-1,3-dione (300 mg, 1.08 mmol) as starting material. Yield: 590 mg; ESI mass spectrum [M+H]+=596, Retention time HPLC: 0.76 min (V011_S01).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][C:12](OCC)=[O:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[AlH4-].[Li+].O.[OH-].[Na+]>CCOCC>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][OH:13])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CC1CCC2(CC1)OCCO2
Agent: [AlH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: OCCC1CCC2(CC1)OCCO2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl 1,4-dioxaspiro[4.5]dec-8-ylacetate (3.40 g, 0.0149 mol) prepared according to the procedure of Itagaki, Noriaki; Kimura, Mari; Sugahara, Tsutomu; Iwabuchi, Yoshiharu. (Organic Letters 2005; 7(19); 4181-4183) was dissolved in ether (30.00 mL) and the mixture was cooled to 0° C. To the reaction was added 1.00 M lithium tetrahydroaluminate in ether (15.0 mL) and the resulting mixture was stirred at 0° C. for 60 minutes and at 25° C. for 2 hours. The reaction was cooled and water (0.40 mL, 0.022 mol) was added, followed by 1.00 M sodium hydroxide (0.40 mL). To the reaction was then added ether (100.00 mL) and the solid that precipitated was filtered off. The filtrate was concentrated using a rotary evaporator to give the product. 1H NMR (CDCl3): 3.94 (s, 4H), 3.67 (t, 2H), 1.20-1.80 (m, 11H).
Reaction SMILES: [Cl:1]Cl.[F:3][C:4]1[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=1[NH:6][C:7](=[O:9])[CH3:8]>>[Cl:1][C:12]1[CH:11]=[CH:10][C:5]([NH:6][C:7](=[O:9])[CH3:8])=[C:4]([F:3])[CH:13]=1
Reactant: CC(=O)Nc1ccccc1F
Reactant: ClCl
Product: CC(=O)Nc1ccc(Cl)cc1F
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Seventy-one parts of liquid chlorine were added to a solution of 140 parts of 2'-fluoroacetanilide in 500 parts glacial acetid acid, during one hour, at 25°-27°, with ice-water cooling. While stirring for 4 hours at 25°-27°, 4'-chloro-2'-fluoroacetanilide precipitated. After collecting the product by filtration, the filtrate was poured over 2000 parts of ice. The resulting second portion of precipitated product was collected by filtration, combined with the first portion and recrystallized from 700 parts of methanol at -45° to yield 199 parts of 4'-chloro-2'-fluoroacetanilide as white crystals melting at 152°-155°.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][C:5]=1Br.[CH2:18]([O:25][C:26]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][CH:29]=[CH:28][N:27]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+].CO>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.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][C:5]=1[C:31]1[C:26]([O:25][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[N:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC1(C)OB(c2cccnc2OCc2ccccc2)OC1(C)C
Reactant: COC(=O)c1cc(OC)c(C(C)(C)C)cc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: COC(=O)c1cc(OC)c(C(C)(C)C)cc1-c1cccnc1OCc1ccccc1
Yield: 79.2 %

Procedure:
step 2—A microwave vial was charged with 64 (903 mg, 3.00 mmol), 2-benzyloxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)pyridine (1.12 g, 3.60 mmol), Pd(PPh3)4 (173 mg, 0.15 mmol), Na2CO3 (950 mg, 9.00 mmol), MeOH (10 mL) and DCM (3 mL). The vial was sealed and irradiated at 115° C. for 30 min in microwave synthesizer. The reaction was quenched with H2O and extracted with DCM. The combined organics were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by SiO2 chromatography eluting with a EtOAc/hexane gradient (10% to 20% EtOAc) to afford 964 mg (80%) of 2-(2-benzyloxypyridin-3-yl)-4-tert-butyl-5-methoxybenzoic acid methyl ester (66) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[O:4][N:3]=1.Br[CH2:14][CH2:15]Br.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:15][CH2:14]2)[O:4][N:3]=1
Reactant: CCOC(=O)Cc1cc(C)no1
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1(c2cc(C)no2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of ethyl 2-(3-methylisoxazol-5-yl)acetate (8.22 g, 48.6 mmol) in toluene (85 mL) was sequentially added n-tetrabutylammonium bromide (1.67 g, 5.18 mmol), 1,2-dibromoethane (7.0 mL, 81 mmol), and NaOH (30 mL, 582 mmol, ˜19.4 M). The reaction mixture was vigorously stirred at room temperature. After 1 h, the reaction mixture was cooled to 0° C. and diluted with water (50 mL). The aqueous phase was extracted with MTBE (3×). The combined organic phases were washed 1 N HCl, water (2×), dried over Na2SO4, and concentrated to give the product ethyl 1-(3-methylisoxazol-5-yl)cyclopropanecarboxylate (9.49 g, 48.6 mmol, 100% yield) as a clear oil. LC/MS m/z 196 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:32]=[C:33]([CH2:35][O:36][C:37]4[CH:46]=[CH:45][C:44]5[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=5)[N:38]=4)[N:34]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([CH:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.[C:47]([OH:53])([C:49]([F:52])([F:51])[F:50])=[O:48]>>[F:50][C:49]([F:52])([F:51])[C:47]([OH:53])=[O:48].[NH:22]1[CH2:21][CH2:20][CH:19]([C:16]2[N:17]=[CH:18][C:13]([C:10]3[N:9]4[CH:32]=[C:33]([CH2:35][O:36][C:37]5[CH:46]=[CH:45][C:44]6[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=6)[N:38]=5)[N:34]=[C:8]4[C:7]([N:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[N:12][CH:11]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cnc(N4CCOCC4)c4nc(COc5ccc6ccccc6n5)cn34)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Product: c1ccc2nc(OCc3cn4c(-c5ccc(C6CCNCC6)nc5)cnc(N5CCOCC5)c4n3)ccc2c1

Procedure:
Compound 49c was deprotected using TFA using the methods described in the Example 48, Step B to obtain the title compound. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.99-2.14 (m, 6H), 2.20-2.32 (m, 4H), 3.02-3.20 (m, 3H), 3.56-3.67 (m, 2H), 3.85-3.95 (m, 4H), 4.32-4.45 (m, 4H), 5.68 (s, 2H), 6.95 (d, J=8.8 Hz, 1H), 7.33-7.45 (m, 3H), 7.63 (td, J=7.7, 1.5 Hz, 1H), 7.69-7.75 (m, 1H), 7.76 (s, 1H), 7.83 (d, J=8.6 Hz, 1H), 7.89 (dd, J=8.1, 2.2 Hz, 1H), 8.00 (d, J=8.8 Hz, 1H), 8.70-8.79 (m, 1H), 9.34 (br. s., 1H), 9.79 (br. s., 1H). Mass Spectrum (LCMS, ESI pos.) Calcd. for C30H31N7O2: 522.2 [M+H]. found 522.2.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[C:28]([CH2:32]O)[N:29]([CH3:31])[N:30]=2)=[CH:22][CH:21]=1.CN(C)C(N=NC(N(C)C)=O)=O.C(P(CCCC)CCCC)CCC>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:32][C:28]3[N:29]([CH3:31])[N:30]=[C:26]([C:23]4[CH:24]=[CH:25][C:20]([Cl:19])=[CH:21][CH:22]=4)[CH:27]=3)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nc(-c2ccc(Cl)cc2)cc1CO
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: Cn1nc(-c2ccc(Cl)cc2)cc1COc1ccc2ccn(CC(=O)OC(C)(C)C)c2c1

Procedure:
In analogy to the procedure described for example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester (example 1 d]) was reacted with [5-(4-chloro-phenyl)-2-methyl-2H-pyrazol-3-yl]-methanol in the presence of N,N,N′,N′-tetramethyl azodicarboxamide and tributylphosphine to give {6-[5-(4-chloro-phenyl)-2-methyl-2H-pyrazol-3-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester as colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)N)=[CH:4][CH:3]=1.[N:19]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C:22](=O)[CH2:21][CH2:20]2>>[F:16][C:13]1[CH:14]=[CH:15][C:10]2[N:8]([CH2:7][CH2:6][C:5]3[CH:17]=[CH:18][C:2]([F:1])=[CH:3][CH:4]=3)[C:22]3[CH:23]4[CH2:26][CH2:27][N:19]([CH2:20][C:21]=3[C:11]=2[CH:12]=1)[CH2:25][CH2:24]4
Reactant: O=C1CCN2CCC1CC2
Reactant: NN(CCc1ccc(F)cc1)c1ccc(F)cc1
Product: Fc1ccc(CCn2c3c(c4cc(F)ccc42)CN2CCC3CC2)cc1

Procedure:
General procedure C was used to convert 1-(4-fluorophenethyl)-1-(4-fluorophenyl)-hydrazine (276 mg, 1.1 mmol; Example 85A) and 1-azabicyclo[3.2.2]nonan-4-one (144 mg, 1.1 mmol; Example 2A) into the title compound as the trifluoroacetic acid salt: 1H NMR (300 MHz, CDCl3) δ ppm 1.60-1.77 (m, 2H) 1.96-2.15 (m, 2H) 2.92 (s, 1H) 3.05 (t, J=6.54 Hz, 2H) 3.24 (d, J=28.16 Hz, 2H), 3.51-3.74 (m, 2H) 4.31 (t, J=6.35 Hz, 2H) 4.57 (s, 2H) 6.81-6.89 (m, 2H) 6.89-6.95 (m, 2H) 6.99-7.07 (m, 2H) 7.21-7.34 (m, 1H); MS (DCI/NH3) m/z 353 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11]1>>[CH:11]1[S:10][CH:14]=[CH:13][C:12]=1[CH2:15][NH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccsc1
Reactant: N#Cc1ccc(N)cc1
Product: N#Cc1ccc(NCc2ccsc2)cc1
Yield: 38.6 %

Procedure:
The procedure of Example 40 was repeated, except that 1.43 g of 4-aminobenzonitrile was used in place of aniline, and 1.57 g of 3-thiophenecarbaldehyde was used in place of 4-formyl-phenyl sulfamate. The resulting crude product was purified by silica gel column chromatography (using a 2:1 mixture of hexane and ethyl acetate as the eluent) to obtain 1.00 g of 4-[N-(3-thenyl)amino]-benzonitrile.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([B:9]([OH:11])[OH:10])=[CH:5][CH:4]=1.[CH3:12][C:13]([N:16]1[C:20]([C:21](Cl)=[O:22])=[CH:19][C:18]([CH3:24])=[N:17]1)([CH3:15])[CH3:14].C(N(CC)CC)C>CN(C=O)C>[CH3:15][C:13]([N:16]1[C:20]([C:21]([NH:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([B:9]([OH:11])[OH:10])=[CH:7][CH:8]=2)=[O:22])=[CH:19][C:18]([CH3:24])=[N:17]1)([CH3:12])[CH3:14]
Reactant: Cc1cc(C(=O)Cl)n(C(C)(C)C)n1
Reactant: NCc1ccc(B(O)O)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)NCc2ccc(B(O)O)cc2)n(C(C)(C)C)n1
Reaction time: 2 h

Procedure:
To a solution of [4-(aminomethyl)phenyl]boronic acid (145 mg, 0.966 mmol) in DMF (2 mL) was added 1-(1,1-dimethylethyl)-3-methyl-1H-pyrazole-5-carbonyl chloride (290 mg, 1.45 mmol) and triethylamine (403 μL, 2.90 mmol). The reaction was stirred for 2 h. It was then quenched and partitioned between EtOAc and H2O and the organic layer was concentrated to give {4-[({[1-(1,1-dimethylethyl)-3-methyl-1H-pyrazol-5-yl]carbonyl}amino)methyl]phenyl}boronic acid.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:11]=2[C:12]#[N:13])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.N>C(O)C.[Pd].O>[N:1]1([CH2:7][CH2:8][O:9][C:10]2[CH:17]=[C:16]([C:18]([F:20])([F:19])[F:21])[CH:15]=[CH:14][C:11]=2[CH2:12][NH2:13])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: N#Cc1ccc(C(F)(F)F)cc1OCCN1CCOCC1
Agent: [Pd]
Agent: N
Solvent: O
Solvent: CCO
Product: NCc1ccc(C(F)(F)F)cc1OCCN1CCOCC1
Reaction time: 0.75 h
Yield: 96.4 %

Procedure:
To a solution of 2-(2-morpholin-4-ylethoxy)-4-(trifluoromethyl)benzonitrile (Description 124, 0.5 g, 1.67 mmol) in ethanol (30 ml) was added aqueous ammonia (33% aq soln, 5 ml) and a slurry of 10% Pd/C catalyst in water. The reaction was hydrogenated at 43 psi. After 45 min the reaction was complete. The catalyst was filtered off, the reaction condensed and the product azeotroped with toluene to give the desired amine (0.49 g, 96%).
Reaction SMILES: C([O:3][CH:4](OCC)[CH:5]([OH:15])[CH2:6][C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14])C.Cl>C(O)C>[Cl:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:14])[C:7]=1[CH2:6][C:5](=[O:15])[CH2:4][OH:3]
Reactant: CCOC(OCC)C(O)Cc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCO
Product: O=C(CO)Cc1c(Cl)cccc1Cl

Procedure:
10 g of 1,1-diethoxy-2-hydroxy-3-(2',6'-dichlorophenyl)propane are dissolved in 40 ml of ethanol, 20 ml of concentrated hydrochloric acid are added, and the mixture is refluxed for 4 hours, then is evaporated to dryness. 10 ml of toluene are added and the solution is again evaporated to dryness in order to remove the water. The residue, crude 1-(2',6'-dichlorophenyl)-3-hydroxy-2-propanone, is used in Example 49 (d) below. After recrystallization from diisopropyl ether, the product melts at 111°-114° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][OH:14].N1C=CC=CC=1.[C:21](Cl)([Cl:23])=[O:22]>C1C=CC=CC=1>[Cl:23][C:21]([O:14][CH2:13][CH2:12][O:11][CH2:10][CH2:9][O:8][CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[O:22]
Reactant: COCCOCCOCCOCCO
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: COCCOCCOCCOCCOC(=O)Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 12.9 g. (62 mmoles) of tetraethylene glycol monomethyl ether and 4.9 g. (62 mmoles) of pyridine is added dropwise to 77 ml. (124 mmoles) of a 17.2% solution of phosgene in benzene stirred in an ice bath with protection from moisture. The pyridine hydrochloride precipitates during the 35 to 40 minute addition and stirring is continued in the ice bath for an additional 2 hours. The reaction mixture is allowed to warm to room temperature and stirred overnight. The benzene solution is decanted from the pyridine hydrochloride which is washed with additional benzene. A stream of nitrogen is passed through the solution to remove excess phosgene as well as most of the benzene. The residual oil is dissolved in benzene-hexane and filtered to remove additional pyridine hydrochloride. The filtrate is evaporated to dryness in vacuo affording 17.1 g. of a residual oil, the infrared analysis of which reveals a strong carbonyl absorption and minimal hydroxyl absorption. The oil is used as is in the next step.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[S:10][C:9]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]3)=[O:12])=[N:8][C:6]=2[N:7]=1.B(O)(O)[C:30]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:31]=1[CH:32]=[N:33][NH:34]2.C(=O)([O-])[O-].[Na+].[Na+].C(#N)C>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.O>[NH:34]1[C:35]2[C:31](=[C:30]([C:2]3[N:3]=[C:4]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:5]4[S:10][C:9]([C:11]([N:13]5[CH2:18][CH2:17][N:16]([S:19]([CH3:22])(=[O:21])=[O:20])[CH2:15][CH2:14]5)=[O:12])=[N:8][C:6]=4[N:7]=3)[CH:38]=[CH:37][CH:36]=2)[CH:32]=[N:33]1
Reactant: OB(O)c1cccc2[nH]ncc12
Reactant: CS(=O)(=O)N1CCN(C(=O)c2nc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CS(=O)(=O)N1CCN(C(=O)c2nc3nc(-c4cccc5[nH]ncc45)nc(N4CCOCC4)c3s2)CC1

Procedure:
(5-Chloro-7-morpholinothiazolo[4,5-d]pyrimidin-2-yl)(4-methylsulfonylpiperazin-1-yl)methanone, 1H-indazol-4-yl-4-boronic acid (2.5 eq), and trans-dichlorobis(triphenylphosphine)palladium(II) (0.1 eq) were slurried with equal parts 1M sodium carbonate aqueous solution (3 eq) and acetonitrile. The solution was microwaved at 140° C. for 10 minutes. Water was added and the solution was filtered. The resulting precipitate was washed with methylene chloride and the organic layer was purified by silica gel chromatography followed by reverse phase silica gel chromatography to give the product 141.
Reaction SMILES: CS(Cl)(=O)=O.[CH3:6][C:7]1[CH:18]=[CH:17][CH2:16][C:15]2[C:8]=1[CH:9]=[C:10]1[C:14]=2[CH:13]=[N:12][N:11]1[CH2:19][CH:20](O)[CH3:21].C(N(CC)CC)C.[N-:30]=[N+:31]=[N-:32].[Na+].[Cl-].[Na+]>ClCCl.CN(C)C=O>[N:30]([CH:20]([CH3:21])[CH2:19][N:11]1[C:10]2=[CH:9][C:8]3[C:15]([CH2:16][CH:17]=[CH:18][C:7]=3[CH3:6])=[C:14]2[CH:13]=[N:12]1)=[N+:31]=[N-:32]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1=C2C=c3c(cnn3CC(C)O)=C2CC=C1
Agent: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1=C2C=c3c(cnn3CC(C)N=[N+]=[N-])=C2CC=C1
Yield: 73.1 %

Procedure:
1.15 ml (14.8 mmol) of methanesulfonyl chloride were added dropwise while stirring to a solution, cooled to 0°, of 1.7 g (7.45 mmol) of (RS)-1-(7-methyl-1,4-dihydro-indeno[2,1-c]pyrazol-1-yl)-propan-2-ol and 4.12 ml (29.7 mmol) of triethylamine in 60 ml of dichloromethane and the mixture was stirred at this temperature for a further 1.5 hours. The reaction mixture was subsequently diluted with 100 ml of dichloromethane, washed twice with 50 ml of saturated sodium hydrogen carbonate solution each time and the combined aqueous phases were extracted once with 50 ml of dichloromethane. The combined organic phases were washed with 50 ml of saturated sodium chloride solution, dried over magnesium sulfate and evaporated in a vacuum. The yellow oil obtained was dissolved in 40 ml of anhydrous dimethylformamide, treated with 0.96 g (14.8 mmol) of sodium azide and the reaction mixture was heated to 70° for 15 hours while stirring. After cooling, the solution was poured into 100 ml of semi-saturated sodium chloride solution and extracted twice with 100 ml of diethyl ether each time. The combined organic phases were washed once with 80 ml of water and once with 80 ml of saturated sodium chloride solution, dried over magnesium sulfate and the solution was concentrated in a vacuum. The brown oil obtained was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.38 g (73%) of (RS)-1-(2-azido-propyl)-7-methyl-1,4-dihydro-indeno[2,1-c]pyrazole were obtained as a light yellow solid with m.p. 70°-72°.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[C:3]=1[C:4]#[N:5].O=[C:19]([CH3:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22].CO[2H]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH2:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[N:1]=[C:19]([CH3:26])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)CC(C)=O
Reactant: N#Cc1c(N)cccc1OCC1CCCCC1
Agent: [2H]OC
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCCCC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(cyclohexylmethoxy)benzonitrile (Example 115b) and ethyl 3-oxobutanoate as a pale yellow solid (47%). 1H NR (400 MHz, MeOD) δ 1.12-1.37 (m, 6H), 1.42 (t, J=4.0 Hz, 3H), 1.73-2.01 (m, 5H), 2.68 (s, 3H), 4.06 (d, J=4.0 Hz, 2H), 4.42 (q, J=8.0 Hz, 2H), 6.96 (d, J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.58 (t, J=8.0 Hz, 1H). MS 343 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:17]=1[NH2:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:18][C:17]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:16]=2[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cc1ccc(C)c(N)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cc1ccc(C)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 16 h
Yield: 98.2 %

Procedure:
A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1 g, 0.00502 mole) in dry 1,2-dichloroethane (10 mL) was stirred under an atmosphere of nitrogen for 10 minutes. 2,5-dimethylaniline (0.73 g, 0.00602 mole), acetic acid (0.301 g, 0.005 mole) and sodium triacetoxyborohydride (1.596 g, 0.00753 mole) were then added portionwise and stirring was continued at ambient temperature for 16 hours. The reaction mixture was basified with sodium bicarbonate solution and the product was extracted with dichloromethane. The dichloromethane layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting transparent viscous liquid was purified by column chromatography using neutral aluminium oxide (1% ethyl acetate in hexane) to afford 1.5 g (82%) of 4-(2,5-dimethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3): δ 7.0 (t, 1H), 6.6 (d, 2H), 4.2 (dd, 2H), 3.5 (m, 1H), 2.9 (t, 2H), 2.3 (t, 3H), 2.15 (s, 3H), 2.05 (s, 3H), 1.5 (s, 9H), 1.3 (t, 2H). A solution of 4-(2,5-dimethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 0.00492 mole) in ethyl acetate.HCl (7 mL) was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was washed with ether and dried to afford 1.1 g (80%) of (2,5-dimethyl-phenyl)-piperidin-4-yl-amine dihydrochloride. LCMS: 205.16 (M+1)+, 92.74%, 1H NMR (DMSO-d6): δ 9.4 (d, 1H), 9.0 (d, 1H), 7.2 (d, 2H), 7.1 (s, 1H), 3.7 (m, 1H), 3.6 (s, 1H), 3.4 (d, 2H), 3.2 (bs, 1H), 2.9 (m, 2H), 2.4 (s, 3H), 2.3 (s, 3H), 2.1 (m, 4H).
Reaction SMILES: Br[C:2]1[C:6]2[CH:7]=[N:8][C:9]([NH2:23])=[C:10]([O:11][C@@H:12]([C:14]3[C:19]([Cl:20])=[CH:18][CH:17]=[C:16]([F:21])[C:15]=3[Cl:22])[CH3:13])[C:5]=2[O:4][CH:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH2:33][CH2:34][O:35][CH2:36][CH:37]=2)O1>>[Cl:22][C:15]1[C:16]([F:21])=[CH:17][CH:18]=[C:19]([Cl:20])[C:14]=1[C@H:12]([O:11][C:10]1[C:5]2[O:4][CH:3]=[C:2]([C:32]3[CH2:37][CH2:36][O:35][CH2:34][CH:33]=3)[C:6]=2[CH:7]=[N:8][C:9]=1[NH2:23])[CH3:13]
Reactant: C[C@@H](Oc1c(N)ncc2c(Br)coc12)c1c(Cl)ccc(F)c1Cl
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCOCC3)coc12)c1c(Cl)ccc(F)c1Cl

Procedure:
The title compound was prepared according to General procedure A with starting materials 3-Bromo-7-[(R)-1-(2,6-dichloro-3-fluorophenyl)-ethoxy]-furo[3,2-c]pyridin-6-ylamine and 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran. 1H-NMR (CDCl3, 400 MHz): δ=1.86 (d, 3H), 2.40-2.52 (m, 2H), 3.94 (t, J=5.6 Hz, 2H), 4.36 (q, J=2.5 Hz, 2H), 4.77 (br. s., 2H), 6.24 (br. s., 1H), 6.52 (q, J=6.6 Hz, 1H), 7.01-7.10 (m, 1H), 7.29 (t, 1H), 7.37 (s, 1H), 8.24 (s, 1H). MS (ES+): m/z 423.02 (MH+, 35Cl, 37Cl), 424.94 (MH+, 37Cl, 37Cl). HPLC: tR=3.34 min (polar—5 min, ZQ3).
Reaction SMILES: CC1N=C(N2CCN(C3C=CC=CC=3)C2=O)SC=1C(OCC)=O.[CH2:24]([N:31]1[CH2:35][CH2:34][N:33]([C:36]2[S:37][C:38]([C:42]([O:44]CC)=[O:43])=[C:39]([CH3:41])[N:40]=2)[C:32]1=[O:47])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([N:31]1[CH2:35][CH2:34][N:33]([C:36]2[S:37][C:38]([C:42]([OH:44])=[O:43])=[C:39]([CH3:41])[N:40]=2)[C:32]1=[O:47])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccccc3)C2=O)nc1C
Agent: CCOC(=O)c1sc(N2CCN(c3ccccc3)C2=O)nc1C
Product: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Yield: 84 %

Procedure:
Following the procedure as described in Example 6, making variations as required to replace ethyl 4-methyl-2-(2-oxo-3-phenylimidazolidin-1-yl)thiazole-5-carboxylate with ethyl 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate, the title compound was obtained in 84% yield: mp 248-249° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.36-7.22 (m, 5H), 4.47 (s, 2H), 3.97 (t, J=7.5 Hz, 2H), 3.42 (t, J=7.5 Hz, 2H), 2.49 (s, 3H); MS (ES+) m/z 318.3 (M+1).