Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[C:14]2[N:13]3[N:15]=[C:16]([CH3:27])[C:17]([C:18]4[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=4[CH3:26])=[C:12]3[N:11]=[C:10]([CH3:28])[C:9]=2[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].O>CN1CCCC1=O>[CH2:1]([CH:3]([N:6]1[C:14]2[N:13]3[N:15]=[C:16]([CH3:27])[C:17]([C:18]4[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=4[CH3:26])=[C:12]3[N:11]=[C:10]([CH3:28])[C:9]=2[CH:8]=[CH:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)N1CCc2c(C)nc3c(-c4c(C)cc(C)cc4C)c(C)nn3c21
Solvent: CN1CCCC1=O
Solvent: O
Product: CCC(CC)n1ccc2c(C)nc3c(-c4c(C)cc(C)cc4C)c(C)nn3c21
Yield: 36.2 %

Procedure:
A solution of 8-(1-ethylpropyl)-3-mesityl-2,5-dimethyl-7,8-dihydro-6H-pyrazolo[1,5-a]pyrrolo[3,2-e]pyrimidine (468 mg, 1,24 mmol) in N-methyl-2-pyrrolidinone (10 mL) was heated at 200° C. for 15 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate, washed with brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to silica gel column cromatography (10% ethyl acetate/hexane), to give the title compound (168 mg, 36%) as pale yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][N:3]=1.[S:12]([O-:15])([OH:14])=[O:13].[Na+:16].C(O)C>O>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([S:12]([O-:15])(=[O:14])=[O:13])=[N:3][CH:4]=1.[Na+:16]
Reactant: O=S([O-])O
Reactant: FC(F)(F)c1ccc(Cl)nc1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: O=S(=O)([O-])c1ccc(C(F)(F)F)cn1
Yield: 85.6 %

Procedure:
In a flask, 2-chloro-5-(trifluoromethyl)pyridine (54.5 g, 0.3 mol), sodium hydrogen sulfite (125 g, 1.2 mol), ethanol (600 ml) and water (600 ml) were charged and heated under reflux for 198 hours. After evaporating off the solvent, to the solid residue, conc. hydrochloric acid was added. The mixture was evaporated to dryness. The residue was extracted with methanol and filtrated. The filtrate was evaporated to dryness to obtain sodium 5-(trifluoromethyl)pyridine-2-sulfonate (64.0 g). Yield, 86%. Decomposition point, 356°-370° C.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[O:11][CH:10](C(OCC)=O)[C:9](=[O:18])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-].[Na+].S(=O)(=O)(O)O>>[N+:1]([C:4]1[C:12]2[O:11][CH2:10][C:9](=[O:18])[C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)C1Oc2c(cccc2[N+](=O)[O-])C1=O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: O=C1COc2c1cccc2[N+](=O)[O-]
Temperature: 25 °C

Procedure:
In a flask 3.77 g (0.015 mole) of ethyl 2,3-dihydro-7-nitrobenzofuran-3-on-2-ylcarboxylate is suspended in 75 mL of a 5% aqueous solution of sodium hydroxide which is heated at reflux until all solid has gone into solution. The solution is cooled to ambient temperature, and dilute sulfuric acid is added cautiously until there is no further evidence of decarboxylation. The product is extracted with ethyl acetate, and the combined extracts are dried over anhydrous magnesium sulfate and filtered. The filtrate is evaporated under reduced pressure, leaving 2,3-dihydro-7-nitro-3-benzofuranone as a residue.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15](B3OC(C)(C)C(C)(C)O3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1.Br[C:28]1[CH:33]=[C:32]([CH3:34])[N:31]=[C:30]([C:35]#[N:36])[CH:29]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]([C:11]2[CH:16]=[C:15]([C:28]3[CH:29]=[C:30]([C:35]#[N:36])[N:31]=[C:32]([CH3:34])[CH:33]=3)[CH:14]=[C:13]([CH3:26])[N:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cc(Br)cc(C#N)n1
Reactant: Cc1cc(NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)cc(C)n2)ccn1
Product: Cc1cc(NC(=O)c2cc(-c3cc(C)nc(C#N)c3)cc(C)n2)ccn1

Procedure:
The title compound, was prepared from 6-Methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carboxylic acid (2-methyl-pyridin-4-yl)-amide in accordance with the general method of example 131, step 2 using 4-Bromo-6-methyl-pyridine-2-carbonitrile instead of 3-Trifluoromethyl-5-bromopyridine to yield the final compound as a off-white solid, MS (ISP): m/e=344.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17](I)=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[N:6]=1.[CH3:23][N:24]1[CH:28]=[CH:27][N:26]=[CH:25]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][N:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:28]2[N:24]([CH3:23])[CH:25]=[N:26][CH:27]=2)=[CH:16][CH:15]=1)[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[N:6]=1
Reactant: CC(C)(C)CN(Cc1ccc(I)cc1)c1ccnc(C#N)n1
Reactant: Cn1ccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cncc1-c1ccc(CN(CC(C)(C)C)c2ccnc(C#N)n2)cc1
Temperature: 120 °C
Reaction time: 18 h
Yield: 57.7 %

Procedure:
4-{(2,2-Dimethyl-propyl)-[4-iodo-benzyl]-amino}-pyrimidine-2-carbonitrile (200 mg, 0.5 mmoles), 1-methyl imidazole (0.2 ml, 2.5 mmoles), triphenylphosphine (26 mg, 0.10 mmoles) and CsCO3 (160 mg, 0.5 mmoles) are dissolved in 3 ml of DMF and Pd(OAc)2 (10 mg, 0.05 mmoles) is added at rt. The mixture is stirred at 120° C. for 18 h. Water is added and the organic layer is extracted with AcOEt washed with brine, dried over magnesium sulfate and concentrated. The crude product is purified by silica gel column chromatography to give 104 mg of desired 4-{(2,2-dimethyl-propyl)-[4-(3-methyl-3H-imidazol-4-yl)-benzyl]-amino}-pyrimidine-2-carbonitrile in 59% yield.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C@@H:17]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][N:18]2[S:27]([CH3:30])(=[O:29])=[O:28])[CH:12]=[CH:11][C:10]=1[N:31]1[S:35](=[O:37])(=[O:36])[N:34](CC[Si](C)(C)C)[C:33](=[O:44])[CH2:32]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-].[Cs+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13](/[CH:15]=[CH:16]/[C@@H:17]2[CH2:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH2:19][N:18]2[S:27]([CH3:30])(=[O:29])=[O:28])[CH:12]=[CH:11][C:10]=1[N:31]1[S:35](=[O:36])(=[O:37])[NH:34][C:33](=[O:44])[CH2:32]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(/C=C/[C@@H]3Cc4ccccc4CN3S(C)(=O)=O)cc2OCc2ccccc2)S1(=O)=O
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)N1Cc2ccccc2C[C@H]1/C=C/c1ccc(N2CC(=O)NS2(=O)=O)c(OCc2ccccc2)c1
Temperature: 60 °C
Reaction time: 1.25 h

Procedure:
To a solution of 5-{2-benzyloxy-4-[(E)-2-((S)-2-methanesulfonyl-1,2,3,4-tetrahydroisoquinolin-3-yl)-vinyl]-phenyl}-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one (0.107 g, 0.164 mmol) in DMF (10 mL) is added CsF (0.980 g, 6.47 mmol). The mixture is stirred at 60° C. for 1.25 h, and then diluted with EtOAc (20 mL) and washed with 1N HCl (2×15 mL), followed by brine (2×15 mL). The organic layer is dried with Na2SO4 and the solvent removed under reduced pressure to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH:7]([CH3:8])[CH2:6][CH2:5][CH:4]([CH3:9])[C:3]1=[C:10]=[CH:11][CH:12]([OH:16])[CH2:13][CH2:14][CH3:15].[H][H]>C(OCC)(=O)C.[Pd]>[CH3:17][C:2]1([CH3:1])[CH:7]([CH3:8])[CH2:6][CH2:5][CH:4]([CH3:9])[CH:3]1[CH2:10][CH2:11][CH:12]([OH:16])[CH2:13][CH2:14][CH3:15]
Reactant: CCCC(O)C=C=C1C(C)CCC(C)C1(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC(O)CCC1C(C)CCC(C)C1(C)C
Yield: 95 %

Procedure:
2 G (8.5 mM) of 1-(2,2,3,6-tetramethyl-1-cyclohexylidene)-1-hexen-3-ol in 20 ml of ethyl acetate were hydrogenated in the presence of 0.2 g of palladium at 5% on charcoal, in an autoclave containing a hydrogen atmosphere maintained at a pressure of 100 atm. After filtration, the mixture was concentrated and distilled by means of a bulb apparatus (bath temp.: about 130°) under reduced pressure. There were thus obtained 1.9 g (yield 95%) of a mixture containing about 80% by weight of 1-(2,2,c-3,t-6-tetramethyl-r-1-cyclohexyl)-3-hexanol and 10% of 1-(2,2,t-3,c-6-tetramethyl-r-1-cyclohexyl)-3-hexanol accompanied by minor amounts of 1-(2,2,c-3,c-6-tetramethyl-r-1-cyclohexyl)-3-hexanol and 1-(2,2,t-3,t-6-tetramethyl-r-1-cyclohexyl)-3-hexanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[C:15]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH:21]=O)[CH:16]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C1(C2C=CC=CC=2)C=CC=CC=1CN1CCN(C2C=CC=CC=2)CC1>>[C:15]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][CH:18]=[C:17]([CH2:21][N:12]2[CH2:11][CH2:10][N:9]([C:4]3[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH3:8])[CH:5]=3)[CH2:14][CH2:13]2)[CH:16]=1
Reactant: Cc1cc(C)cc(N2CCNCC2)c1
Reactant: O=Cc1cccc(-c2ccccc2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: c1ccc(-c2ccccc2CN2CCN(c3ccccc3)CC2)cc1
Product: Cc1cc(C)cc(N2CCN(Cc3cccc(-c4ccccc4)c3)CC2)c1

Procedure:
138.6 mg of the target compound (0.39 mmol, 47.6%) was obtained using 1-(3,5-dimethylphenyl)piperazine (312 mg, 1.64 mmol), biphenyl-3-carbaldehyde (150 mg, 0.82 mmol) and NaBH(OAc)3 (529 mg, 2.46 mmol) according to the synthesis method of Compound 1.
Reaction SMILES: [C:1]1(=[O:14])[O:11]CC[O:8][C:6](=[O:7])[C:5]2[CH:12]=[CH:13][C:2]1=[CH:3][CH:4]=2>C(O)CO>[C:1]([OH:14])(=[O:11])[C:2]1[CH:13]=[CH:12][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1OCCOC(=O)c2ccc1cc2
Solvent: OCCO
Product: O=C(O)c1ccc(C(=O)O)cc1

Procedure:
The polymer composition forming the supporting film of the present invention may be the polyester-a alone. This polyester-a is a copolyester containing ethylene terephthalate units as a main recurring unit and having a melting point of 210 to 250° C. The polyester-a is obtained from terephthalic acid as an acid component, ethylene glycol as a glycol component and further a copolymer component. The copolymer component may be either an acid component or a glycol component. Illustrative examples of the acid component include aromatic dibasic acids such as isophthalic acid, phthalic acid and naphthalenedicarboxylic acid; aliphatic dicarboxylic acids such as adipic acid, azelaic acid, sebacic acid and decanedicarboxylic acid; alicyclic dicarboxylic acids such as cyclohexanedicarboxylic acid; and the the like. Illustrative examples of the glycol component include aliphatic diols such as butane diol and hexane diol; alicyclic diols such as cyclohexane dimethanol; and the like. They may be used alone or in combination of two or more.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28]Br)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:31][N:32]1[CH:40]=[C:35]2[CH2:36][NH:37][CH2:38][CH2:39][C:34]2=[N:33]1>>[CH3:1][O:2][C:3](=[O:30])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:28][N:37]5[CH2:38][CH2:39][C:34]6=[N:33][N:32]([CH3:31])[CH:40]=[C:35]6[CH2:36]5)[C:20]([C:24]([F:27])([F:26])[F:25])=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CBr)ccc21
Reactant: Cn1cc2c(n1)CCNC2
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c3ccc(C(F)(F)F)c4CN3CCc4nn(C)cc4C3)ccc21

Procedure:
The title compound is prepared from {(S)-6-[(R)-4-bromomethyl-5-trifluoromethyl-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-methyl-4,5,6,7-tetrahydro-2H-pyrazolo[4,3-c]pyridine following a procedure analogous to that described for Intermediate 42. LC (method 1): tR=0.92 min; Mass spectrum (ESI+): m/z=542 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][CH:15]=[C:16]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Cl.[CH3:25][CH:26]1[CH2:30][CH2:29][CH2:28][NH:27]1.[I-].[Na+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[O:14][CH:15]=[C:16]([CH2:18][N:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[N:17]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:27]1[CH2:28][CH2:29][CH2:30][CH:26]1[CH3:25]
Reactant: CC1CCCN1
Reactant: ClCCCOc1ccc(-c2nc(CN3CCCCC3)co2)cc1Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CC1CCCN1CCCOc1ccc(-c2nc(CN3CCCCC3)co2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
A solution of 1-({2-[3-chloro-4-(3-chloropropoxy)phenyl]-1,3-oxazol-4-yl}methyl)piperidine i71 (0.12 g, 0.32 mmol, 1 eq) and 2-methylpyrrolidine (63 PI, 0.65 mmol, 2 eq) in acetonitrile (10 ml) is treated with sodium iodide (5 mg, 0.03 mmol, 0.1 eq) and stirred at room temperature overnight. The mixture is then washed with water, dried over magnesium sulfate, and concentrated to give the crude product. Purification by chromatography over silicagel (eluent: dichloromethane/methanol/ammonia 90:10:0.1) gives 75 mg of 1-[(2-{3-chloro-4-[3-(2-methylpyrrolidin-1-yl)propoxy]phenyl}-1,3-oxazol-4-yl)methyl]piperidine 124 as an orange oil.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:8]=1)[NH2:5].[CH3:15][S:16](Cl)(=[O:18])=[O:17]>>[I:1][C:2]1[CH:3]=[C:4]([NH:5][S:16]([CH3:15])(=[O:18])=[O:17])[CH:6]=[C:7]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[CH:8]=1
Reactant: Nc1cc(I)cc(N2CCOCC2)c1
Reactant: CS(=O)(=O)Cl
Product: CS(=O)(=O)Nc1cc(I)cc(N2CCOCC2)c1
Yield: 105 %

Procedure:
3-Iodo-5-morpholinoaniline (279 mg, 0.76 mmol) was treated with methanesulfonyl chloride (82 μl, 1.06 mmol) according to the method described in Preparation 15b to give 305 mg (95% yield) of the title compound as an oil. Purity 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([O:11][CH3:12])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.Cl.[CH3:27][NH:28][O:29][CH3:30]>CN(C=O)C.C(Cl)Cl>[CH3:30][O:29][N:28]([CH3:27])[C:7](=[O:9])[C:6]1[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[O:11][CH3:12]
Reactant: COc1ccc(Cl)cc1C(=O)O
Reactant: CNOC
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(Cl)cc1C(=O)N(C)OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 0.1 %

Procedure:
A mixture of 5-chloro-o-anisic acid (50 g, 0.27 mol), oxalyl chloride (23 mL, 0.27 mol) and methylene chloride was stirred 1 hour at approximately 25° C. and then treated with DMF (2 drops). The mixture was stirred an additional hour, heated 45 minutes at reflux and then concentrated. The residue was dissolved in THF and the solution was reconcentrated. The residue was dissolved in THF-(approximately 200 mL) and the solution was added in a thin stream to a mixture of triethylamine (96 mL, 0.7 mol), N,O-dimethylhydroxylamine hydrochloride (26.3 g, 0.27 mol) and methylene chloride (approximately 300 mL). After an exothermic reaction had ensued, the mixture was allowed to cool to 25° C. and stirred approximately 16 hours. The mixture was filtered, concentrated and then partitioned between ethyl acetate and water. The organic layer was separated, washed with water (2×), sodium bicarbonate. (2×), 2% hydrochloric acid (1×) and brine (1×), dried (K2CO3), filtered and concentrated to give N-methoxy-N-methyl-5-chloro-2-methoxy-benzamide (52.3 g, 0.23 mmol), m.p. 80°-83° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.Cl.[NH2:15][C:16]1[C:17]([C:21]2[N:22]([CH2:38][CH3:39])[C:23]3[C:28]([C:29]([N:31]4[CH2:36]C[NH:34][CH2:33][CH2:32]4)=[O:30])=[CH:27][N:26]=[CH:25][C:24]=3[N:37]=2)=[N:18][O:19][N:20]=1.CCOCC>CN(C=O)C>[NH2:15][C:16]1[C:17]([C:21]2[N:22]([CH2:38][CH3:39])[C:23]3[C:28]([C:29]([N:31]4[CH:32]=[CH:33][N:34]=[CH:36]4)=[O:30])=[CH:27][N:26]=[CH:25][C:24]=3[N:37]=2)=[N:18][O:19][N:20]=1
Reactant: CCn1c(-c2nonc2N)nc2cncc(C(=O)N3CCNCC3)c21
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCn1c(-c2nonc2N)nc2cncc(C(=O)n3ccnc3)c21
Reaction time: 18 h
Yield: 84.7 %

Procedure:
1,1′-Carbonyldiimdazole (0.89 g) was added to a solution of the product from Example 250 Step 1 (0.5 g, 1.82 mmol) in dry DMF (10 ml) at room temperature under argon. The mixture was stirred for 18 h resulting in the precipitation of a colourless solid. Ether (10 ml) was added and the solid filtered to give the title compound, (0.5 g, 85%); MS (ES+) m/e 325 [M+H]+.
Reaction SMILES: C=C[C:3]1[CH:8]=CC=CC=1.[C:9]([O:14]CCCCCC)(=[O:13])[C:10](C)=[CH2:11].C(O)(=O)C(C)=C.C(OCCOC(=O)C(C)=C)(=O)C(C)=C.C(OSCCCCCC(C)C)(=O)CO.S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].[NH2:67][C:68]([O:70]CC)=[O:69].[OH-].[K+]>O>[C:9]([OH:14])(=[O:13])[CH:10]=[CH2:11].[NH2:67][C:68]([O:70][CH2:8][CH3:3])=[O:69]
Reactant: C=C(C)C(=O)OCCCCCC
Reactant: C=Cc1ccccc1
Agent: C=C(C)C(=O)O
Agent: C=C(C)C(=O)OCCOC(=O)C(=C)C
Agent: CC(C)CCCCCSOC(=O)CO
Solvent: O
Product: C=CC(=O)O
Temperature: 90 °C

Procedure:
In a round-bottom flask, 76 g of styrene, 276 g of hexyl methacrylate, 24 g of methacrylic acid, 4 g of ethylene glycol dimethacrylate, 1.6 g of isooctylthio glycolate as a chain transfer agent, and 33.28 g of 30% Rhodafac RS 710 as an emulsifying agent are mixed in 136 ml of water forming an emulsion. An initiator solution is prepared by adding 1.39 g of potassium persulfate to 160 ml of water. A hot water solution is prepared by adding 32 ml of the initiator solution to 1160 ml of water preheated to 90° C. Simultaneous addition of the remaining initiator solution with the emulsion is added to the hot water solution over a period of 32 minutes to form a reaction mixture. After about 60% of the emulsion addition, another component, aliphatic urethane acrylate CN968 from Sartomer, is added to the reaction mixture for the incorporation of urethane linkages on the surface of the latex particle. The reaction mixture is maintained at 90° C. for 1.75 hours and then cooled to ambient temperature. The reaction mixture is then neutralized with 50% potassium hydroxide solution and filtered using 200 μm filter to obtain a latex with a rigid polymer shell containing urethane linkages.
Reaction SMILES: [CH2:1]([O:3][CH:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:5]([OH:7])=O)[CH3:2].[NH2:14][CH2:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>>[C:15]([C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:21][C:5](=[O:7])[CH:4]([O:3][CH2:1][CH3:2])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:18][CH:17]=1)#[N:14]
Reactant: CCOC(C(=O)O)c1ccccc1
Reactant: N#Cc1ccc(CN)cc1
Product: CCOC(C(=O)NCc1ccc(C#N)cc1)c1ccccc1

Procedure:
(RS)-Ethoxy-phenyl-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-ethoxy-2-phenyl-acetamide. Light yellow semisolid. MS 295.3 ([M+H]+)
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][N:25]=1>O1CCOCC1>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:24]2[N:25]=[CH:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:29]=2)[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCOC(=O)c1cnc(Cl)nc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To a solution of tert-butyl piperazine-1-carboxylate (10.0 g, 53.7 mmol) and diisopropylethylamine (23.4 mL, 134.25 mmol) in dioxane (80 mL) was added ethyl 2-chloropyrimidine-5-carboxylate (10 g, 53.7 mmol), and the reaction mixture was stirred at RT for 3 h. LCMS showed the reaction was completed. The reaction was concentrated to afford the title compound (17 g, crude), which was directly used in the next step without the further purification. MS (ES+) C16H24N4O4 requires: 336. found: 237, 281 [M−56+H]+.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([N:17]3[N:18]=[C:19]([C:24]4[CH:29]=[CH:28][C:27]([O:30][C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=5)=[CH:26][CH:25]=4)[C:20]([C:21]([NH2:23])=[O:22])=[C:16]3[NH:15][C:14]2=[O:37])[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[OH-].[Pd+2]>[O:37]=[C:14]1[C:11]2([CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:17]2[N:18]=[C:19]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)[C:20]([C:21]([NH2:23])=[O:22])=[C:16]2[NH:15]1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NC(=O)C21CCN(Cc2ccccc2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NC(=O)C21CCNCC1
Reaction time: 16 h
Yield: 289.2 %

Procedure:
To a solution of 1′-benzyl-2-oxo-6-(4-phenoxyphenyl)-1,2-dihydrospiro[imidazo[1,2-b]pyrazole-3,4′-piperidine]-7-carboxamide (120 mg, 0.24 mmol) in MeOH (10 mL) was added 10% w/w Pd(OH)2/C (5 mg) and stirred for 16 hr under H2. The mixture was filtered and the filtrate was concentrated to give the crude product (280 mg, 58.9%) as a yellow solid. MS (ESI, m/e) [M+1]+ 403.9.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[O:4][CH2:5][C@H:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.I[CH2:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1>>[CH:17]1([CH2:16][C@@:2]2([CH3:1])[C:3](=[O:14])[O:4][CH2:5][C@H:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[NH:7]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC1=N[C@@H](c2ccccc2)COC1=O
Reactant: ICC1CCCC1
Product: C[C@@]1(CC2CCCC2)N[C@@H](c2ccccc2)COC1=O

Procedure:
The compound was prepared according to the procedure outlined in Preparation 1 using (5S)-3-methyl-5-phenyl-5,6-dihydro-2H-1,4-oxazin-2-one (1 g, 5.28 mmol, see WO-A-02/051983) and (iodomethyl)cyclopentane. The total amount of compound synthesised was 0.426 g.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:13])([F:12])[F:11])=[CH:5][C:4]=1[NH2:14].[CH2:15]([S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](O)=O)[CH3:16].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>O.N1C=CC=CC=1>[CH2:15]([S:17][C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]1[N:2]([CH3:1])[C:3]2[C:8]([NH2:9])=[CH:7][C:6]([C:10]([F:11])([F:12])[F:13])=[CH:5][C:4]=2[N:14]=1)[CH3:16]
Reactant: CCSc1ccccc1C(=O)O
Reactant: CNc1c(N)cc(C(F)(F)F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Solvent: O
Product: CCSc1ccccc1-c1nc2cc(C(F)(F)F)cc(N)c2n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 15.2 %

Procedure:
To a mixture of N′-methyl-5-trifluoromethyl-benzene-1,2,3-triamine (1.3 g), 2-ethylsulfanylbenzoic acid (1.3 g), and pyridine (12 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.4 g) and 1-hydroxybenzotriazole (86 mg) were added at room temperature. The mixture was stirred at room temperature for 5 hours, then heated to 110° C., and stirred with heating for 8 hours. After the reaction mixture was allowed to cool to room temperature, the reaction mixture was diluted with water, and extracted with ethyl acetate. The combined organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 339 mg of 2-(2-ethylsulfanyl-phenyl)-3-methyl-6-trifluoromethyl-3H-benzimidazole-4-ylamine (hereinafter, Present Compound 336).