Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].CS(C)=O.[CH3:6][O:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)=[C:10]([CH2:25][CH2:26][CH2:27][OH:28])[CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[CH:27]([CH2:26][CH2:25][C:10]1[CH:9]=[C:8]([O:7][CH3:6])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]=1[O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)=[O:28]
Reactant: COc1cc(CCCO)c(OC2CCCCO2)c2ccccc12
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: COc1cc(CCC=O)c(OC2CCCCO2)c2ccccc12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.3 %

Procedure:
An oven-dried 25 ml 2-necked (14/20) round bottom flask, equipped with magnetic stirring bar, nitrogen inlet and serum cap, is charged with a solution of oxalkyl chloride (61 μl) in 2 ml methylene chloride. This solution is placed under a nitrogen atmosphere and cooled to -60° C. to -50° C. Dimethylsulfoxide (99 μl) is added (neat) dropwise to give a colorless solution. After 2-3 min a solution of 3-[4-methoxy-1-[(tetrahydro-2H-pyran-2-yl)oxy]-2-naphthalenyl]-1-propanol (0.19 g) in 1 ml methylene chloride is added drowpise. The resulting mixture is stirred at -60° C. to -50° C. for 15 min and then treated with triethylamine (0.44 ml). This gives rise to a yellow colored milky suspension. The cooling bath is removed and the stirred mixture is allowed to warm to room temperature at which time the mixture is diluted with water and extracted with ether. The organic phase is washed three times with water (after adjusting the pH to 7 with 10% aqueous sodium bisulfate), dried with magnesium sulfate, filtered and concentrated to give 0.18 g of the crude title compound as an orange colored oil.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([NH:16]C(=O)OC(C)(C)C)[CH2:12][CH2:11]2)[C:6]2[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=2[O:4][CH2:3]1.NC1CCN(CCN2C3C(=CC=C(C#N)C=3)C=CC2=O)CC1>>[NH2:16][CH:13]1[CH2:14][CH2:15][N:10]([CH2:9][CH2:8][N:7]2[C:6]3[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=3[O:4][CH2:3][C:2]2=[O:1])[CH2:11][CH2:12]1
Reactant: CC(C)(C)OC(=O)NC1CCN(CCN2C(=O)COc3ccccc32)CC1
Agent: N#Cc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Product: NC1CCN(CCN2C(=O)COc3ccccc32)CC1

Procedure:
tert-Butyl {1-[2-(3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl)ethyl]piperidin-4-yl}carbamate (Intermediate 98) was reacted as described for Intermediate 14. The crude trifluoro acetate of the title compound was obtained as a colorless solid and used without further purification for the next step (quantitative yield).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9](=[O:23])[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=2)=[C:11]([CH3:14])[C:12]=1O.[NH2:24][NH2:25]>C(O)C>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:10]2[C:9](=[O:23])[NH:24][N:25]=[C:12]([CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[C:11]=2[CH3:14])[CH:20]=[CH:19][CH:18]=1
Reactant: NN
Reactant: COc1cccc(C2=C(C)C(O)=C(c3ccccc3F)C2=O)c1
Solvent: CCO
Product: COc1cccc(-c2c(C)c(Cc3ccccc3F)n[nH]c2=O)c1

Procedure:
A solution of 2-(2-fluorophenyl)-3-hydroxy-4-methyl-5-(3-methoxyphenyl)-2,4-cyclopentadienone (310 mg, 1 mmol) and hydrazine (0.2 mL) in ethanol (5 mL) was heated at reflux for 30 minutes. The resulting solution was concentrated in vacuo and the residue was dissolved in dichloromethane, dried over sodium sulfate, filtered and concentrated in vacuo to give the desired compound as a colorless oil. 1H NMR (CDCl3): 2.14 (s, 3H), 3.27 (d, J=13.8 Hz, 1H), 3.43 (d, J=13.8 Hz, 1H), 6.70-7.25 (m, 8H); MS:325 (MH+).
Reaction SMILES: [F:1][C:2]1[C:3]([OH:12])=[C:4]([O:10][CH3:11])[CH:5]=[C:6]([CH:9]=1)[CH:7]=O.[Cl:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH2:22][C:23]#[N:24])[CH:17]=[CH:18][CH:19]=1>>[Cl:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:25])[C:22]([C:23]#[N:24])=[CH:7][C:6]2[CH:5]=[C:4]([O:10][CH3:11])[C:3]([OH:12])=[C:2]([F:1])[CH:9]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: COc1cc(C=O)cc(F)c1O
Reactant: N#CCC(=O)Nc1cccc(Cl)c1
Product: COc1cc(C=C(C#N)C(=O)Nc2cccc(Cl)c2)cc(F)c1O
Yield: 57 %

Procedure:
The reaction was effected in the same manner as in Example 1 with 5-fluorovanillin (410 mg, 2.41 mmol) and N-(3-chlorophenyl) cyanoacetamide (469 mg, 2.41 mmol) to give the objective N-(3-chlorophenyl)-2-cyano-3-(3-fluoro-4-hydroxy-5-methoxyphenyl) propenamide (476 mg, 57% in yield) as yellow powders.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[N:12]=[C:11]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)[N:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[F:25])[N:9]=2)[CH:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>C(O)CO.O1CCOCC1.[Cl-].[Na+].O.[Cu-]=O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH2:18][N:10]1[C:11]([C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[N:12][C:8]([C:4]2[CH:3]=[C:2]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:7]=[CH:6][N:5]=2)=[N:9]1
Reactant: C1COCCN1
Reactant: Fc1ccccc1Cn1nc(-c2cc(Br)ccn2)nc1-c1nccs1
Agent: O=[Cu-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: OCCO
Solvent: C1COCCO1
Product: Fc1ccccc1Cn1nc(-c2cc(N3CCOCC3)ccn2)nc1-c1nccs1
Temperature: 100 °C
Yield: 79 %

Procedure:
To a stirring suspension of 2-(3-(4-bromopyridin-2-yl)-1-(2-fluorobenzyl)-1H-1,2,4-triazol-5-yl)thiazole (I-36, 1 eq) and copper(I) oxide (1 eq) in ethylene glycol-dioxane (approx. 4:1) in a sealed tube is added morpholine (30 eq). The resultant reaction mixture was heated at 100° C. for 12 hr. The reaction was cooled to room temperature and treated with brine and then extracted with ethyl acetate. The combined organic layers were dried over sodium sulfate, concentrated and purified using SiO2 chromatography (methylene chloride/acetonitrile/methanol) to afford 4-(2-(1-(2-fluorobenzyl)-5-(thiazol-2-yl)-1H-1,2,4-triazol-3-yl)pyridin-4-yl)morpholine as a solid in 79% yield.
Reaction SMILES: [CH3:1][CH2:2][C:3](=[N:6][OH:7])[CH2:4][CH3:5].[Cl:8][C:9]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:14][C:10]=1[C:11](O)=[O:12].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CN=CC=2)CCCC1>C(OCC)C>[Cl:8][C:9]1[CH:17]=[C:16]([F:18])[C:15]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[N:21]([CH3:30])[C:20]2=[O:31])=[CH:14][C:10]=1[C:11]([O:7][N:6]=[C:3]([CH2:4][CH3:5])[CH2:2][CH3:1])=[O:12]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(C(=O)O)c(Cl)cc2F)c1=O
Reactant: CCC(CC)=NO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1cc(N2CCCC2)ccn1
Solvent: CCOCC
Product: CCC(CC)=NOC(=O)c1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.9 g of 3-pentanone oxime is added at room temperature to a suspension of 3.0 g of 2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4-trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoic acid in 50 ml of diethyl ether. Thereafter, a solution of 1.9 g of dicyclohexylcarbodiimide and 0.1 g of 4-pyrrolidinopyridine in 15 ml of diethyl ether is added dropwise over 10 minutes. The reaction mixture is stirred at room temperature for 12 hours. Subsequently, it is filtered and evaporated to dryness under reduced pressure. The residue is purified by chromatography on silica gel with n-hexane/diethyl ether (4:1) as the eluent. In this manner there is obtained 3-pentanone O-{2-chloro-5-[3,6-dihydro-2,6-dioxo-3-methyl-4 -trifluoromethyl-1(2H)-pyrimidinyl]-4-fluorobenzoyl}oxime, m.p. 128°-130° C.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:10]([NH:12][CH:13]2[CH2:15][CH2:14]2)=[O:11])[N:5]=[CH:4][C:3]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=[O:28])[CH:22]=1.OO.[O-:32]Cl=O.[Na+].[O-]S([O-])=O.[Na+].[Na+]>CC#N>[NH2:1][C:2]1[N:6]([C:7]2[CH:8]=[C:9]([C:10](=[O:11])[NH:12][CH:13]3[CH2:15][CH2:14]3)[CH:16]=[CH:17][C:18]=2[CH3:19])[N:5]=[CH:4][C:3]=1[C:20]([C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[C:27]([OH:32])=[O:28])=[O:29]
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C=O)c2)c1N
Reactant: [O-][Cl+][O-]
Agent: O=S([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1ncc(C(=O)c2cccc(C(=O)O)c2)c1N
Yield: 36.8 %

Procedure:
To a stirred solution of 3-[5-amino-4-(3-formylbenzoyl)-pyrazol-1-yl]-N-cyclopropyl-4-methylbenzamide (900 mg) in CH3CN (25 mL) were added NaH2PO4 (55 mg in 2 mL water) and H2O2 (1.3g, 30% solution in water) followed by the dropwise addition of an aqueous solution of NaClO2 (365 mg) at 10° C. The mixture was stirred at this temperature for 4h before Na2SO3 was added. Solvent was removed and residue was dissolved in EtOAc, the organic layer was washed with water and brine and concentrated. The crude product was purified by column chromatography on silica gel eluted with EtOAc followed by EtOAC: AcOH=100 :1), to provide the desired intermediate as a beige foam (345 mg, 37%).
Reaction SMILES: N1CCCCC1.C(O)(=O)C.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1.[C:20]([O:28][CH2:29][CH3:30])(=[O:27])[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>C1(C)C=CC=CC=1>[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:20]([O:28][CH2:29][CH3:30])=[O:27])=[CH:14][CH:13]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1ccc(O)cc1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1ccc(O)cc1)C(=O)OCC
Temperature: 125 °C
Reaction time: 5 h
Yield: 46.2 %

Procedure:
To a 100 mL RB flask fitted with magnetic stirrer was charged with piperidine (0.426 g, 0.5 mL, 5 mmol) and acetic acid (0.3 g, 0.3 mL, 5 mmol). To this, toluene (25 mL) was added, followed by 4-hydroxybenzaldehyde (2 g, 16.4 mmol) and diethyl malonate (3.15 g, 19.7 mmol). The RM was heated at 125° C., by fitted with a dean-stark's apparatus for 5 h. After 5 h, the RM was concentrated; water (50 mL) was added and extracted with ethyl acetate (50 mL×2)). The organic layer was washed with saturated brine solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and the solvent was removed under reduced pressure. The product was obtained as yellow solid. (2 g, yield: 46.2%); MS (ESI, 120 eV): m/z=263.1 (M−H)+; 1H NMR (300 MHz, DMSO-d6): δ 10.27 (s, 1H), 7.58 (s, 1H), 7.36-7.38 (d, 2H), 6.81-6.84 (d, 2H), 4.17-4.32 (m, 4H), 4.06-4.14 (q, 1H), 1.21-1.26 (t, 6H).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[NH2:11][CH2:12][CH2:13][CH2:14][N:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.O>CS(C)=O>[N:15]1([CH2:14][CH2:13][CH2:12][NH:11][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH:19]=[CH:18][N:17]=[CH:16]1
Reactant: NCCCn1ccnc1
Reactant: O=[N+]([O-])c1cccc(F)c1
Solvent: CS(C)=O
Solvent: O
Product: O=[N+]([O-])c1cccc(NCCCn2ccnc2)c1
Temperature: 100 °C
Reaction time: 60 h

Procedure:
28.2 g 3-fluoronitrobenzene and 137.5 g 1-(3-aminopropyl)imidazole were dissolved in 300 ml dimethyl sulfoxide, and the batch was stirred for 60 h at 100° C. After cooling, the batch was poured into 1 l water. The precipitated product was suction-filtered and dried overnight under vacuum.
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]([OH:32])([CH2:29][CH:30]=[CH2:31])[CH2:26][CH:27]=[CH2:28])[CH3:21])=[CH:16][CH:15]=1.C(N(C(C)C)C(C)C)C>ClCCl>[CH2:29]([C:25]1([CH2:26][CH:27]=[CH2:28])[O:32][C:2](=[O:4])[N:22]([C@H:20]([C:17]2[CH:16]=[CH:15][C:14]([Br:13])=[CH:19][CH:18]=2)[CH3:21])[CH2:23][CH2:24]1)[CH:30]=[CH2:31]
Reactant: C=CCC(O)(CC=C)CCN[C@@H](C)c1ccc(Br)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C=CCC1(CC=C)CCN([C@@H](C)c2ccc(Br)cc2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Triphosgene (6.90 g) is added to a solution of 4-{2-[(S)-1-(4-bromo-phenyl)-ethylamino]-ethyl}-hepta-1,6-dien-4-ol (7.86 g) and ethyl-diisopropyl-amine (4 mL) in dichloromethane (150 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 then separated. The organic phase is dried (Na2SO4) and concentrated to give the crude title compound that is used without further purification. Yield: 8.65 g (ca. 90% pure); LC (method 1): tR=4.03 min; Mass spectrum (ESI+): m/z=364/366 (Br) [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])=[N:5][S:4][N:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23].O>CN(C)C=O>[C:22]([NH:1][C:2]1[C:6]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=2[Cl:14])=[N:5][S:4][N:3]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: Nc1nsnc1-c1c(Cl)cccc1Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)Nc1nsnc1-c1c(Cl)cccc1Cl
Temperature: 60 °C
Reaction time: 12 h
Yield: 43.6 %

Procedure:
To a solution containing 0.49 g of 3-amino-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole and 0.22 g of triethylamine in N,N-dimethylformamide, 0.20 g of acetyl chloride was added and the mixture was stirred at 60° C. for 12 hours. After allowing to cool, the mixture was poured into water and was extracted with ether. The ether layer was washed twice with dilute hydrochloric acid, twice with water and twice with saturated aqueous sodium chloride solution. The resultant was dried over anhydrous sodium sulfate, concentrated and purified by silica gel chromatography to obtain 0.25 g of 3-acetylamino-4-(2,6-dichlorophenyl)-1,2,5-thiadiazole.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:31][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]3[CH2:20][CH2:19][N:18]([C:21](=[O:23])[CH3:22])[CH2:17][CH2:16]3)[CH:8]=2)[N:3]=1
Reactant: CC(=O)N1CCN(c2ccc3nc(N)c(C#N)c(Cl)c3c2)CC1
Reactant: NCc1ccccc1
Solvent: O
Product: CC(=O)N1CCN(c2ccc3nc(N)c(C#N)c(NCc4ccccc4)c3c2)CC1

Procedure:
5 g 2-amino-3-cyano-4-chloro-6-(4-acetylpiperazin-1-yl)quinoline and 15 ml benzylamine is stirred at 125° C. for 1 h. The reaction mixture is then poured onto 30 ml water, the resulting precipitate is filtered off, washed with 20 ml water and dried to obtain 4 g of the title compound (MH+: 401).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6](Cl)[N:5]=2.[CH:20]1([CH:25]([OH:28])[C:26]#[CH:27])[CH2:24][CH2:23][CH2:22][CH2:21]1>CN(C)C=O.C(N(CC)CC)C.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[NH2:1][C:2]1[N:3]([CH2:18][CH3:19])[C:4]2[C:9]([C:10](=[O:16])[C:11]=1[C:12]([NH:14][CH3:15])=[O:13])=[CH:8][CH:7]=[C:6]([C:27]#[C:26][CH:25]([CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1)[OH:28])[N:5]=2
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(Cl)nc21
Reactant: C#CC(O)C1CCCC1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(C#CC(O)C3CCCC3)nc21

Procedure:
A suspension of 1 g (3.56 mmol) of 2-amino-7-chloro-1-ethyl-N-methyl-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxamide in 25 ml of a dimethylformamide/triethylamine mixture (V/V; 2.5/1) is placed in a 10 ml microwave tube. This suspension is sparged with argon for 10 minutes and then 0.931 g (7.5 mmol) of (±)-1-cyclopentylprop-2-yn-1-ol, 0.068 g of CuI (0.36 mmol) and 0.125 g of bis(triphenylphosphine) palladium(II)dichloride (0.18 mmol) are successively added.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([N+:15]([O-])=O)[CH:9]=2)[CH2:7][CH2:6]1)=[O:4]>CO.[Ni]>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[C:10]([NH2:15])[CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: COC(=O)C1(c2ccc(O)c([N+](=O)[O-])c2)CC1
Agent: [Ni]
Solvent: CO
Product: COC(=O)C1(c2ccc(O)c(N)c2)CC1
Temperature: 35 °C
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a solution of 1-(4-hydroxy-3-nitro-phenyl)-cyclopropanecarboxylic acid methyl ester (8.3 g, 35 mmol) in MeOH (100 mL) was added Raney Nickel (0.8 g) under nitrogen atmosphere. The mixture was stirred under hydrogen atmosphere (1 atm) at 35° C. for 8 hours. The catalyst was filtered off through a Celite pad and the filtrate was evaporated under vacuum to give crude product, which was purified by column chromatography on silica gel (petroleum ether/ethyl acetate 1:1) to give 1-(3-amino-4-hydroxy-phenyl)-cyclopropanecarboxylic acid methyl ester (5.3 g, 74%). 1H NMR (CDCl3, 400 MHz) δ 6.77 (s, 1H), 6.64 (d, J=2.0 Hz, 2H), 3.64 (s, 3H), 1.55-1.52 (m, 2H), 1.15-1.12 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[C:18](/[CH:20]=[CH:21]/[CH:22]([C:27]2[CH:32]=[C:31]([Cl:33])[CH:30]=[C:29]([Cl:34])[CH:28]=2)[C:23]([F:26])([F:25])[F:24])[CH:17]=[CH:16][C:3]=1[CH2:4][N:5]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>CCO>[Cl:1][C:2]1[CH:19]=[C:18](/[CH:20]=[CH:21]/[CH:22]([C:27]2[CH:28]=[C:29]([Cl:34])[CH:30]=[C:31]([Cl:33])[CH:32]=2)[C:23]([F:25])([F:26])[F:24])[CH:17]=[CH:16][C:3]=1[CH2:4][NH2:5]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1ccc(/C=C/C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)cc1Cl
Temperature: 80 °C
Yield: 100 %

Procedure:
To a stirred solution of (E)-2-(2-chloro-4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-1-en-1-yl)benzyl)isoindoline-1,3-dione (0.4 g, 0.76 mmol) in EtOH was added hydrazine hydrate (0.38 g, 7.6 mmol), and the resultant reaction mixture was heated at 80° C. for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2, washed with brine, dried over Na2SO4, and concentrated under reduced pressure to afford the title compound as a gummy liquid (0.3 g), which was carried on to the next step without further purification.
Reaction SMILES: O1C(C2C=C(N[C:13]3[N:18]=[C:17]([C:19]4[C:20]([C:28]5[CH:29]=[C:30]([NH:34][C:35](=[O:42])[CH2:36]C6SC=CC=6)[CH:31]=[CH:32][CH:33]=5)=[N:21][N:22]5[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=45)[CH:16]=[CH:15][N:14]=3)C=CC=2)=CN=C1.[S:43]1[CH:47]=[CH:46][C:45](CC(O)=O)=[CH:44]1.[ClH:52].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C1COCC1.C(Cl)Cl>[Cl:52][C:13]1[N:18]=[C:17]([C:19]2[C:20]([C:28]3[CH:29]=[C:30]([NH:34][C:35](=[O:42])[CH2:36][C:45]4[CH:46]=[CH:47][S:43][CH:44]=4)[CH:31]=[CH:32][CH:33]=3)=[N:21][N:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=23)[CH:16]=[CH:15][N:14]=1
Reactant: O=C(Cc1cccs1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Nc3cccc(-c4cnco4)c3)n2)c1
Reactant: Cl
Reactant: O=C(O)Cc1ccsc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cc1ccsc1)Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1
Reaction time: 20 h
Yield: 69 %

Procedure:
To solution of {3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}amine (125 mg, 0.4 mmol) (see Example 2, step A) in THF (5 mL) were added 3-thienylacetic acid (67 mg, 0.47 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (90 mg, 0.47 mmol), N-hydroxybenzotriazole (63 mg, 0.47 mmol), and diisopropylethylamine (200 μL, 1.2 mmol). After 20 h at rt, the reaction mixture was diluted with DCM, washed with water, dried over Na2SO4, filtered, and adsorbed onto silica gel. The crude product was purified by column chromatography to generate the title compound in 69% yield. ES-LC/MS m/z=446 [M+H]+.
Reaction SMILES: O[CH2:2][C:3]12[CH2:8][CH:7]1[CH2:6][CH2:5][CH2:4]2.[CH2:9]([NH2:11])C>>[C:3]12([CH2:2][CH2:9][NH2:11])[CH2:8][CH:7]1[CH2:6][CH2:5][CH2:4]2
Reactant: CCN
Reactant: OCC12CCCC1C2
Product: NCCC12CCCC1C2

Procedure:
In this preparation 1-(hydroxymethyl)-bicyclo[3.1.0]hexane is treated in the same manner as described in paragraphs b.-d. of Preparation A affording 2-bicyclo[3.1.0]hex-1-yl)ethylamine.
Reaction SMILES: C(O[C:4]([C:6]1([CH2:20][CH2:21]OC)[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH:7]1[OH:19])=[O:5])C.[F:24][C:25]([F:37])([F:36])[CH:26]([CH3:35])[O:27][C:28]1[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=1>>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:5])[N:34]([C:31]3[CH:32]=[CH:33][C:28]([O:27][CH:26]([CH3:35])[C:25]([F:24])([F:36])[F:37])=[CH:29][CH:30]=3)[CH2:21][CH2:20]2)[CH:7]([OH:19])[CH2:8]1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(Oc1ccc(N)cc1)C(F)(F)F
Reactant: CCOC(=O)C1(CCOC)CCN(Cc2ccccc2)CC1O
Product: CC(Oc1ccc(N2CCC3(CCN(Cc4ccccc4)CC3O)C2=O)cc1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 1 step C from a mixture of (3RS,4SR)-1-benzyl-3-hydroxy-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester and (rac)-4-(2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine. Light yellow solid. MS (ESI): 449.2 (MH+)
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH2:19][CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].[Br:28]Br.CCOC(C)=O>C(O)(=O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[C:15]([CH3:18])=[N:16][S:17][C:11]=2[N:10]=[C:9]1[CH:19]([Br:28])[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nsc2nc(CC(C)C)n(Cc3ccccc3)c(=O)c12
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1nsc2nc(C(Br)C(C)C)n(Cc3ccccc3)c(=O)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
To a solution of 5-benzyl-6-isobutyl-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (method 27) (1.3 g, 4.2 mmol) and sodium acetate (2 g) in acetic acid (10 mL) at 100° C., a solution of the bromine (1.32 g, 8.4 mmol) in acetic acid (10 mL) was added dropwise over a period of 20 minutes. The reaction mixture was stirred at that temperature for 30 min and cooled and the TLC (eluent 10% EtOAc in hexanes) and MS showed the complete disappearance of the SM and only the product. The reaction mixture was poured into ice water and extracted with EtOAc (3×60 mL) and the organic layers were combined and washed with 2% sodium thiosulfate solution (60 mL), water (100 mL), brine (100 mL) and dried over Na2SO4. Concentration of the organic layer provided 5-benzyl-6-(1-bromo-2-methyl-propyl)-3-methyl-5H-isothiazolo[5,4-d]pyrimidin-4-one (1.61 g, 99%) as white crystalline solid. m/z 392, 394 (MH+), 1H NMR (300 MHz) δ 0.54 (d, 3H), 1.11 (d, 3H), 2.62-2.76 (m, 1H), 2.83 (s, 3H), 4.42 (d, 1H), 4.80 (d, 1H), 6.22 (d, 1H), 7.12-7.42 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][C:8](Br)=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:27][Si:28]([C:31]#[CH:32])([CH3:30])[CH3:29].[Cl-]>[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(Cl)Cl>[CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][C:8]([C:32]#[C:31][Si:28]([CH3:30])([CH3:29])[CH3:27])=[CH:9][CH:10]=2)[N:5]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:4][CH2:3]1
Reactant: CC1(C)CCN(c2ccccc2)c2cc(Br)ccc21
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)CCN(c2ccccc2)c2cc(C#C[Si](C)(C)C)ccc21
Temperature: 70 °C

Procedure:
To a solution of 0.10 g (0.32 mmol) of 4,4-dimethyl-1,2,3,4-tetrahydro-N-phenyl-7-bromoquinoline (Compound 6) and 5.0 g (4.0 mL, 36 mmol) triethylamine were added 0.032 g (0.17 mmol) of copper(I) iodide, 0.70 g (1.0 mL, 7.1 mmol) of (trimethylsilyl)acetylene, and 0.050 g (0.07 mmol) of bis(triphenylphosphine)palladium(ID chloride. The resulting mixture was heated at 70° C. for 22 hours. The reaction was cooled, methylene chloride was added, and the mixture was adsorbed onto silica gel. The mixture was purified by flash chromatography (hexanes) to give the title compound as a yellow solid. PNMR (300 MHz, CDCl3) d 0.17 (9 H, s), 1.32 (6 H, s), 1.82 (2 H, t, J=6.0 Hz), 3.61 (2 H, t, J=6.0 Hz), 6.85 (2 H, overlapping d's), 7.15-7.41 (6 H, m).