Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](I)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Sn](C)(C)[C:20]1[O:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:24]=1>COCCOC>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:20]2[O:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:24]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1nn(Cc2ccccc2)c2ccccc12
Reactant: COC(=O)c1ccc([Sn](C)(C)C)o1
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A solution of methyl 5-bromofuranoate (0.75 g, 3.66 mmol), hexamethylditin (1.0 g, 3.05 mmol) and Pd(PPh3)4 (90 mg, 0.078 mmol) in DME (50 mL) was heated to reflux overnight. The initial amber coloured solution became black The solution was allowed to cool and then filtered and concentrated under reduced pressure. The crude stannane was purified by passage through a plug of silica (1:9 EtOAc:cyclohexane) to give methyl 2-trimethylstannyl-5-furanoate (0.17 g, 19%): 1H-NMR (CDCl3); The low yield of the product may be due to its suspected volatility. Pd(PPh3), (9 mg, 0.008 mmol) was added to a solution of 1-benzyl-3-iodo-1H-indazole (0.13 g, 0.39 mmol) and methyl 2-trimethylstannyl-5-furanoate (0.17 g, 0.588 mmol) in DME (20 mL) and the mixture was heated to reflux overnight. The reaction mixture was allowed to cool to rt, filtered and concentrated under reduced pressure. Purification of the residue by chromatography on silica (3:7 EtOAc:cyclohexane) gave the product as a slightly contaminated yellow solid (88.6 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[CH:32]=[CH:31][C:5]([O:6][CH2:7][C:8]2[N:12]=[C:11]([C@H:13]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])[O:10][N:9]=2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:12]=[C:11]([C@H:13]([CH2:22][CH2:23][CH2:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)[CH2:14][C:15]([OH:17])=[O:16])[O:10][N:9]=2)=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(COc2ccc(Cl)cc2)no1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)C[C@@H](CCCC1CCCCC1)c1nc(COc2ccc(Cl)cc2)no1
Temperature: 25 °C
Reaction time: 4 h
Yield: 101 %

Procedure:
tert-Butyl (3R)-3-{3-[(4-chlorophenoxy)methyl]-1,2,4-oxadiazol-5-yl}6-cyclohexylhexanoate (Preparation 56) (215 mg, 0.46 mmol) was treated with trifluoroacetic acid (5 ml) and the resulting mixture was stirred at room temperature under a nitrogen atmosphere for 4 hours. The solvent was removed under reduced pressure and the residue azeotroped from toluene to afford the title compound (189 mg).
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][CH2:11][CH2:12][N:13]=2)=[CH:5][CH:4]=1.[C:14](NC1C=CC=CC=1)(=[O:19])[CH2:15][C:16]([CH3:18])=[O:17]>>[CH3:1][N:2]([C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:10][CH2:11][CH2:12][N:13]=2)=[CH:7][CH:8]=1)[C:14](=[O:19])[CH2:15][C:16]([CH3:18])=[O:17]
Reactant: CNc1ccc(C2=NCCO2)cc1
Reactant: CC(=O)CC(=O)Nc1ccccc1
Product: CC(=O)CC(=O)N(C)c1ccc(C2=NCCO2)cc1

Procedure:
This compound was prepared by treating 4-aminobenzonitrile with a slight excess, on a molar equivalents basis, of methyl iodide in tetrahydrofuran solvent for 4 hrs at room temperature. Removal of the THF and other volatiles, followed by recrystallization, gave a 76% yield of 4-(N-methyl)aminobenzonitrile, mp 85-87° C. Using Example 1 procedure, the aforesaid substituted nitrile was treated with ethanolamine to obtain a 70% yield of 2-[4-(N-methyl)aminophenyl]oxazoline, mp 145-147° C. Following the Example 6 procedure, the aforesaid compound was treated with TDO to form the oxazoline shown below, having a methyl group attached to the nitrogen in the acetoacetanilide segment. The product was recrystallized from ethyl acetate, mp 102-105° C. Elemental analysis, FT-IR, exhibiting 1726 (C—O) and 1635 (—C═N—) cm−1 absorptions, and with 1H NMR confirmed the below drawn structure.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:13])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[CH2:14](Br)[C:15]#[CH:16].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([F:13])[C:11]=1[O:12][CH2:16][C:15]#[CH:14])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(F)c(O)c(F)c1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C#CCOc1c(F)cc(C(=O)OC)cc1F
Yield: 101.7 %

Procedure:
To 80 ml of acetonitrile were added 4.5 g of methyl 3,5-difluoro-4-hydroxybenzoate, 3.5 g of propargyl bromide and 9.4 g of cesium carbonate, and the mixture obtained was heated under reflux for 2 hours. The reaction mixture was filtered through Celite. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 5.5 g of methyl 3,5-difluoro-4-(2-propynyloxy)benzoate represented by the formula:
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][C:14]=1[O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])[CH:10]=[O:11].[CH3:26][Mg]Cl.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:10]([OH:11])[CH3:26])[CH:12]=[CH:13][C:14]=1[O:15][Si:16]([CH:23]([CH3:25])[CH3:24])([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:18])[CH3:19]
Reactant: C[Mg]Cl
Reactant: COCCCOc1cc(C=O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCCOc1cc(C(C)O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Temperature: 0 °C
Yield: 99.9 %

Procedure:
3-(3-methoxypropoxy)-4-[(triisopropylsilyl)oxy]benzaldehyde (12 g, 32.7 mmol) was dissolved in tetrahydrofuran (300 mL) and the solution was cooled to 0° C. Methyl magnesium chloride (109 mL, 327 mmol) was added dropwise. The temperature was then allowed to rise to room temperature and the mixture was stirred an hour. At 0° C., saturated aqueous ammonium chloride was added to hydrolyze the reaction mixture. The aqueous layer was extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 12.5 g (quantitative yield) of the desired product as a yellow oil.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH:8]=[O:9])=[CH:6][C:5]([O:10][CH3:11])=[N:4][CH:3]=1.[CH2:12](O)[CH2:13][OH:14].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:9]1[CH2:12][CH2:13][O:14][CH:8]1[C:7]1[CH:6]=[C:5]([O:10][CH3:11])[N:4]=[CH:3][C:2]=1[OH:1]
Reactant: OCCO
Reactant: COc1cc(C=O)c(O)cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cc(C2OCCO2)c(O)cn1
Temperature: 25 °C
Yield: 76 %

Procedure:
To 5-hydroxy-2-methoxyisonicotinaldehyde (1.0 g, 6.54 mmol, 1.0 eq.) in toluene (50.0 mL) were added ethane-1,2-diol (10.0 mL) and PTSA (248 mg, 1.31 mmol, 0.2 eq.). The mixture was heated to reflux O/N, cooled to rt, neutralized to pH 8, and extracted with EtOAc three times. The combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give 4-(1,3-dioxolan-2-yl)-6-methoxypyridin-3-ol (980 mg, 76%) as an off-white solid. LRMS (M+H+) m/z 198.1.
Reaction SMILES: Cl.[CH:2]1([NH:8][OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:17][C:18]1[O:19][CH:20]=[CH:21][C:22]=1[C:23](Cl)=[O:24]>C1C=CC=CC=1>[CH:2]1([N:8]([C:23]([C:22]2[CH:21]=[CH:20][O:19][C:18]=2[CH3:17])=[O:24])[OH:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1occc1C(=O)Cl
Reactant: ONC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: Cc1occc1C(=O)N(O)C1CCCCC1
Reaction time: 1 h

Procedure:
57 parts (by weight) of N-cyclohexylhydroxylamine hydrochloride is added to 800 parts of benzene; 71 parts of triethylamine is then introduced into this mixture. After the mixture has been stirred for 1 hour, a solution of 50 parts of 2-methylfuran-3-carboxylic chloride in 100 parts of benzene is dripped in at room temperature. After the mixture has been stirred for 3 hours the precipitate is filtered and washed with benzene. The filtrate is washed with water, dried over sodium sulfate and evaporated. The crystalline residue is recrystallized from cyclohexane. There is obtained 33 parts of N-cyclohexyl-2-methylfuran-3-hydroxamic acid, m.p.: 108°-110° C.
Reaction SMILES: [C:1]1([S:7]([O:10][C:11]2[C:18]([O:19][CH3:20])=[C:17]([N+:21]([O-])=O)[CH:16]=[CH:15][C:12]=2[CH:13]=[O:14])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)(=O)C.O.[Fe]>[C:1]1([S:7]([O:10][C:11]2[C:18]([O:19][CH3:20])=[C:17]([NH2:21])[CH:16]=[CH:15][C:12]=2[CH:13]=[O:14])(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1c([N+](=O)[O-])ccc(C=O)c1OS(=O)(=O)c1ccccc1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: COc1c(N)ccc(C=O)c1OS(=O)(=O)c1ccccc1
Yield: 66.9 %

Procedure:
The 4-nitrobenzaldehyde from Procedure 3 (82.0 g, 243 mM) in glacial acetic acid (323 ml) and H2O (332 ml) at 90°-95° C. was treated with iron powder (103 g, 40 mesh) added in 10-12 portions during 3/4 hour with vigorous stirring. When addition was complete the suspension was heated at 90°-95° C. for 3 hours. The reaction mixture was cooled and H2O (380 ml) added. The mixture is then filtered and the dark brown solid washed with EtOAc. Removal of solvent afforded 50 g of crude product. Crystallization from EtOAc and treatment with charcoal afford a yellow solid, 50 g (67%), mp 280°-282° C. dec.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH3:17][CH2:18][O:19][C:20]([CH3:22])=[O:21]>CN(C=O)C>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][CH:22]2[CH2:17][CH2:18][O:19][C:20]2=[O:21])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CCOC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1OCCC1Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54 %

Procedure:
To a solution of 4-nitrophenol (278 mg, 2.0 mmol) in DMF (6 mL) at room temperature under a nitrogen atmosphere was added powdered K2CO3 (552 mg, 2.0 mmol) followed by3-bromo-dihydrofuran-2-one (330 mg, 2.0 mmol). After stirring at room temperature under a nitrogen atmosphere for 16 hours, the mixture was diluted to 30 mL with EtOAc and washed with water (4×30 mL) and brine (30 mL). The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to provide the product (240 mg, 54%) as tan oil that later solidified.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11][CH2:12][CH3:13])[C:9]=1[OH:10])[CH:5]=[O:6].[NH2:14][C:15]1[C:20]([CH2:21]O)=[CH:19][CH:18]=[CH:17][N:16]=1>>[NH2:14][C:15]1[C:20]([CH2:21][O:10][C:9]2[C:8]([O:11][CH2:12][CH3:13])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[Br:1])=[CH:19][CH:18]=[CH:17][N:16]=1
Reactant: CCOc1cc(C=O)cc(Br)c1O
Reactant: Nc1ncccc1CO
Product: CCOc1cc(C=O)cc(Br)c1OCc1cccnc1N

Procedure:
Mitsunobu reaction of 3-bromo-5-ethoxy-4-hydroxy benzaldehyde (490 mg) with (2-amino-pyridin-3-yl)-methanol (250 mg) was preformed according to the method described for example 21d. The residue was chromatographed on silica gel in dichloromethane/methanol=99/1 (v/v) as eluent. Yield: 500 mg. MS-ESI: [M+H]+=351/353.
Reaction SMILES: [OH:1][C@@H:2]([CH3:35])[CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:8]=[C:7]([C:17]2[C:18]([C:25]3[CH:30]=[C:29]([CH2:31]C)[CH:28]=[C:27]([O:33]C)[CH:26]=3)=[N:19][N:20]([CH2:22][C:23]#[N:24])[CH:21]=2)[CH:6]=1.B(F)(F)F.CSC>ClCCl>[OH:1][C@@H:2]([CH3:35])[CH2:3][NH:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[N:8]=[C:7]([C:17]2[C:18]([C:25]3[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([OH:33])[CH:26]=3)=[N:19][N:20]([CH2:22][C:23]#[N:24])[CH:21]=2)[CH:6]=1
Reactant: CCc1cc(OC)cc(-c2nn(CC#N)cc2-c2cc(NC[C@H](C)O)nc(-c3cccnc3)n2)c1
Agent: FB(F)F
Solvent: ClCCl
Solvent: CSC
Product: Cc1cc(O)cc(-c2nn(CC#N)cc2-c2cc(NC[C@H](C)O)nc(-c3cccnc3)n2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44.5 %

Procedure:
To anhydrous dichloromethane (5 mL) was added [4-[6-(2(S)-hydroxypropylamino)-2-pyridin-3-yl-pyrimidin-4-yl]-3-(3-methoxy-5-ethylphenyl)pyrazol-1-yl]acetonitrile (150 mg, 0.33 mmol) and boron trifluoride-dimethylsulfide (344 μL, 3.27 mmol) under nitrogen atmosphere. The reaction mixture was stirred for 12 hours at room temperature under nitrogen atmosphere. After completion of the demethylation, the solvent was removed by vacuum distillation, and the reaction mixture was dissolved, extracted with ethyl acetate, washed with brine, dried over anhydrous magnesium sulfate, and concentrated through vacuum distillation. Column chromatography gave the title compound (64.89 mg, 45%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][NH:8]2)=[CH:4][C:3]=1[C:11]([CH3:14])([CH3:13])[CH3:12].[N:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]=[C:22]=[O:23])[CH:16]=1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][N:8]2[C:22](=[O:23])[NH:21][C:17]2[CH:16]=[N:15][CH:20]=[CH:19][CH:18]=2)=[CH:4][C:3]=1[C:11]([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)c1cc2c(cc1Cl)NCC2
Reactant: O=C=Nc1cccnc1
Product: CC(C)(C)c1cc2c(cc1Cl)N(C(=O)Nc1cccnc1)CC2
Yield: 35 %

Procedure:
6-Chloro-5-tert-butylindoline (D56) (0.21 g, 1.01 mmol) was treated with 3-pyridylisocyanate as in the procedure described in Example 1. The product was recrystallised from ethanol/diethyl ether to give the title compound (0.12 g, 35%) as a white crystalline solid m.p.=200° C.
Reaction SMILES: [OH:1][C:2]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6].[H-].[Na+].[F:21][C:22]1[CH:23]=[C:24]([CH:27]=[C:28]([F:30])[CH:29]=1)[CH2:25]Br.[Na+].[I-]>CN(C=O)C.O>[F:21][C:22]1[CH:23]=[C:24]([CH2:25][O:18][C:15]2[CH:14]=[CH:13][C:12]([C:2]([OH:1])([CH3:11])[CH2:3][NH:4][S:5]([CH:8]([CH3:10])[CH3:9])(=[O:7])=[O:6])=[CH:17][CH:16]=2)[CH:27]=[C:28]([F:30])[CH:29]=1
Reactant: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(O)cc1
Reactant: Fc1cc(F)cc(CBr)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)S(=O)(=O)NCC(C)(O)c1ccc(OCc2cc(F)cc(F)c2)cc1
Temperature: 25 °C
Yield: 140.3 %

Procedure:
Into a 100 mL-3 neck flask fitted with a stirrer and thermometer, 200 mg of [2-hydroxy-2-(4-hydroxyphenyl)propyl][(methylethyl)sulfonyl]amine in DMF (5 mL) was added dropwise to 35 mg of NaH in DMF (20 mL) while stirring at room temperature under a nitrogen atmosphere. After stirring at this temperature for 30 minutes, 153 mg of 3,5-difluorobenzyl bromide in DMF (5 mL) was added dropwise followed by the addition of 92 mg of NaI portion wise. The reaction was then heated at 100° C. for 2 hours. The mixture was cooled to room temperature and poured into H2O and the desired product was extracted with ethyl acetate. This organic layer was washed with H2O, dried over K2CO3, and concentrated under reduced vacuum to yield 410 mg of a brown oil. This two spot material was purified via silica gel chromatography employing the Chromatotron and using a 4000 micron rotor while eluting with a solvent of hexane/ethyl acetate 1:1. Collection of the bottom spot provided the intermediate title compound (70 mg, 24%) as an oil. Ion spray M.S. 398.1 (M*−1).
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=2[Cl:18])[N:5]=[C:4]([C:19]#[N:20])[C:3]=1[S:21]([CH3:23])=[O:22].C[O-].[Na+].[C:27](=O)=[O:28]>CO>[CH3:27][O:28][C:19]([C:4]1[C:3]([S:21]([CH3:23])=[O:22])=[C:2]([NH2:1])[N:6]([C:7]2[C:12]([Cl:13])=[CH:11][C:10]([C:14]([F:15])([F:16])[F:17])=[CH:9][C:8]=2[Cl:18])[N:5]=1)=[NH:20]
Reactant: O=C=O
Reactant: CS(=O)c1c(C#N)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=N)c1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1S(C)=O
Temperature: 0 °C

Procedure:
To a stirred suspension of 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carbonitrile (5.0 g) in anhydrous methanol was added a 25% w/w solution of sodium methoxide (8.95 ml) in methanol, at 20° C. The mixture was stirred for 16-hours, cooled to 0° C. and diluted with ice-cold anhydrous methanol. Carbon dioxide was passed into the solution for 15-minutes until a pH of 8 was attained. The precipitate was filtered off, washed (ethyl acetate) and evaporated to give 5-amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-methylsulfinyl-1H-pyrazole-3-carboximidic acid methyl ester (3.65 g), 1H NMR (CDCl3) in ppm: 8.34 (s, 1H), 7.79 (s, 2H), 5.11 (brs, 2H), 3.93 (s, 3H), 2.94 (s, 3H). By proceeding in a similar manner the following compound was prepared: 5-Amino-1-[2,6-dichloro-4-(trifluoromethyl)phenyl]-4-trifluoromethylsulfinyl-1H-pyrazole-3-carboximidic acid methyl ester, m.p.179-180° C.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15]C(=O)[C@@H]3C(C)C)=[CH:8][C:6]=2[N:7]=1.[CH2:28]1[C@H:33]2[CH2:34]NCCN2[CH2:31][CH2:30][O:29]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]4[C@@H:33]([CH2:28][O:29][CH2:30][CH2:31]4)[CH2:34]3)=[CH:8][C:6]=2[N:7]=1
Reactant: CC(C)[C@H]1C(=O)NCCN1Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Reactant: C1CN2CCOC[C@H]2CN1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN4CCOC[C@H]4C3)cc2n1

Procedure:
Prepared according to the method used in the preparation of (S)-4-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-3-isopropyl-piperazin-2-one using (R)-octahydro-pyrazino[2,1-c][1,4]oxazine in place of (S)-3-isopropyl-piperazin-2-one. The title compound was obtained as a pale yellow solid (57 mg, 62%).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]2.[OH:14][C:15]1([C:21]2[CH:22]=[C:23]([SH:26])[S:24][CH:25]=2)[CH2:19][CH2:18][O:17][CH:16]1[CH3:20]>>[OH:14][C:15]1([C:21]2[CH:22]=[C:23]([S:26][C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[N:8]([CH3:12])[C:7](=[O:13])[CH2:6][CH2:5]4)[S:24][CH:25]=2)[CH2:19][CH2:18][O:17][CH:16]1[CH3:20]
Reactant: CN1C(=O)CCc2cc(I)ccc21
Reactant: CC1OCCC1(O)c1csc(S)c1
Product: CC1OCCC1(O)c1csc(Sc2ccc3c(c2)CCC(=O)N3C)c1
Yield: 42 %

Procedure:
Using an analogous procedure to that described in Example 5, 6-iodo-1-methyl-1,2,3,4-tetrahydroquinolin-2-one was reacted with (2RS,3SR)-3-hydroxy-3-(2-mercaptothien-4-yl)-2-methyltetrahydrofuran to give (2RS,3SR)-3-hydroxy-2-methyl-3-[2-(1-methyl-2-oxo-1,2,3,4-tetrahydroquinolin-6-ylthio)thien-4-yl]tetrahydrofuran in 42% yield as a foam;
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[Si](C)(C)CC[Si]2(C)C)=[N:6][CH:7]=1.[CH2:17]([SH:19])[CH3:18].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[CH2:17]([S:19][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1)[CH3:18]
Reactant: CCS
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1ccc(Br)cn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCSc1ccc(N)nc1
Temperature: 110 °C
Reaction time: 17 h

Procedure:
In a 100 mL round-bottomed flask, 5-bromo-2-(2,2,5,5-tetramethyl-1,2,5-azadisilolidin-1-yl)pyridine (519 mg, 1.65 mmol), ethanethiol (102 mg, 122 μl, 1.65 mmol), xantphos (47.6 mg, 82.3 μmol) and Hunig's base (425 mg, 575 μl, 3.29 mmol) were combined with dioxane (10.0 ml) to give a light yellow solution. Pd2(dba)3 (37.7 mg, 41.1 μmol) was added and the mixture was evacuated and filled with Argon. The reaction mixture was heated to 110° C. and stirred for 17 h under argon. The mixture was cooled to 25° C. and conc. in vacuo. The residue was partitioned between 1M HCl and ether. Separated and basified aqueous phase with 3M NaOH. The aqueous layer was extracted with EtOAc (2×125 mL). The organic layers were combined, washed with H2O (1×50 mL), sat NaCl (1×25 mL), dried over Na2SO4 and concentrated in vacuo to an orange oil. The oil was dried overnight at 25° C. under vacuum to give an orange gum that was used crude in the subsequent oxidation. (M+H)+=155 m/e.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[CH3:32]>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([NH:24][C:1]([C:4]23[CH2:5][CH2:6][C:7]([NH:12][CH2:13][C:14]([N:16]4[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]4[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]2)[CH2:10][CH2:11]3)=[O:3])=[C:26]([CH3:32])[CH:27]=1
Reactant: Cc1cc(Cl)ccc1N
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Product: Cc1cc(Cl)ccc1NC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2
Yield: 24.3 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-amino-5-chlorotoluene (48.2 mg) were used to obtain (2S,4S)-1-[[N-[4-[N-(4-chloro-2-methylphenyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (16.8 mg).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16](I)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.COCCOC>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]3[CH:17]=[C:16]([C:23]4[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=4)[CH:15]=[CH:14][N:13]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: Ic1ccnc(Nc2ccc3c(c2)OCCO3)c1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: Fc1ccc(-c2ccnc(Nc3ccc4c(c3)OCCO4)c2)cc1
Temperature: 150 °C

Procedure:
Following the same procedure described for Example 401 (c), the mixture of (2,3-dihydro-benzo[1,4]dioxin-6-yl)-(4-iodo-pyridin-2-yl)-amine (Example 401 (b), 75 mg, 0.2 mmol), tetrakis (triphenylphosphine) palladium (0) (Aldrich Chemical Company) (12 mg, 0.011 mmol), 4-fluorobenzeneboronic acid (Avocado Chemical Company) (35 mg, 0.25 mmol) and 1,2-dimethoxyethane (2 mL) gave, after heated in the Microwave Smith Synthesizer at 150° C. for 10 min and purification on a Biotage 40S column (3:1 hexane:EtOAc), the title compound as an off-white solid. MS (ESI, pos. ion) m/z: 323 (M+1). Mp: 134.5-135.0° C.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10](Cl)=[O:11].[CH3:13][CH2:14][CH2:15][CH:16]([NH2:20])[CH2:17][CH2:18][CH3:19]>>[CH2:15]([CH:16]([NH:20][C:10]([C:2]1[O:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=1)=[O:11])[CH2:17][CH2:18][CH3:19])[CH2:14][CH3:13]
Reactant: O=C(Cl)c1cc2ccccc2o1
Reactant: CCCC(N)CCC
Product: CCCC(CCC)NC(=O)c1cc2ccccc2o1
Yield: 73 %

Procedure:
Prepared in a similar manner to example 1 using benzofuran-2-carbonyl chloride and heptan-4-amine. Yield: 73%. 1H NMR (500 MHz, CDCl3): δ 0.93 (t, 6H, J=7.2 Hz), 1.41 (m, 8H), 3.01 (s, 3H), 4.18 (m, 1H), 6.29 (d, 1H, J=9.94 Hz), 7.20 (d, 1H, J=8.62 Hz), 7.37 (m, 2H), 7.44 (s, 1H). MS (M+H, 260)
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[C:5]([CH2:16][CH3:17])[C:4]=1[CH:18]([C:20]1[NH:21][CH:22]=[CH:23][N:24]=1)O)[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>>[CH2:1]([C:3]1[CH:8]=[C:7]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[C:5]([CH2:16][CH3:17])[C:4]=1[CH2:18][C:20]1[NH:24][CH:23]=[CH:22][N:21]=1)[CH3:2]
Reactant: CCc1cc(Oc2ccccc2)cc(CC)c1C(O)c1ncc[nH]1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(Oc2ccccc2)cc(CC)c1Cc1ncc[nH]1

Procedure:
2-(2,6-Diethyl-4-phenoxy-benzyl)-1H-imidazole was prepared from rac-(2,6-diethyl-4-phenoxy-phenyl)-(1H-imidazol-2-yl)-methanol, triethylsilane and trifluoroacetic acid in analogy to Example 191e): white crystals; MS (ISP): 307.4 ([M+H]+, 100%).