Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[N:7]1([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.CS(O[CH:25]1[CH2:28][N:27]([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26]1)(=O)=O>C(#N)C.O1CCCC1>[C:30]1([CH:29]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[N:27]2[CH2:28][CH:25]([N:10]3[CH2:11][CH2:12][N:7]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9]3)[CH2:26]2)[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CS(=O)(=O)OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Temperature: 100 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
Potassium carbonate (26 g) was added to a solution of tert-butyl piperazine-1-carboxylate (7.7 g) in acetonitrile (100 ML), to which a suspension of 1-(diphenylmethyl)azetidin-3-yl methanesulfonate (12.05 g) in tetrahydrofuran (30 mL) was added at room temperature, and the mixture was stirred for 4 hours at 100° C., and then concentrated. To the resulting residue was added water, and the mixture was extracted with ethyl acetate twice. The extract was dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to column chromatography on silica gel (hexane:ethyl acetate=3:1→1:2), and the product was washed with tert-butyl methyl ether and collected by filtration to give the title compound (10.68 g) having the following physical data.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH:16][CH3:17])=[CH:9][C:8]=1Cl.[F:22][C:23]([F:31])([F:30])[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1.Cl.CCN(C(C)C)C(C)C>CC#N>[F:1][C:2]([F:21])([F:20])[CH2:3][CH2:4][NH:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[C:10]([NH:16][CH3:17])=[CH:9][C:8]=1[N:27]1[CH2:28][CH2:29][CH:24]([C:23]([F:31])([F:30])[F:22])[CH2:25][CH2:26]1
Reactant: CNc1cc(Cl)c(C(=O)NCCC(F)(F)F)cc1[N+](=O)[O-]
Reactant: FC(F)(F)C1CCNCC1
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CNc1cc(N2CCC(C(F)(F)F)CC2)c(C(=O)NCCC(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The sub-title compound is prepared in analogy to 6a from N-(3,3,3-trifluoro-propyl)-2-chloro-4-methylamino-5-nitro-benzoic acid amide (compound 81a; 2.0 g, 6.5 mmol), 4-trifluormethyl-piperidine×HCl (2.45 g, 13 mmol), DIPEA (4.9 mL, 29 mmol) and MeCN (25 mL) in a pressure flask at 80° C.
Reaction SMILES: C[N:2](CC(C1(O)CCCCC1)C1C=CC(O)=CC=1)C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29]#N)=[CH:24][CH:23]=1.[C:31]1(=[O:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1.[OH-].[Na+]>>[C:32]([C:31]1([OH:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH:29]1[CH2:28][C:25]1[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=1)#[N:2]
Reactant: CN(C)CC(c1ccc(O)cc1)C1(O)CCCCC1
Reactant: COc1ccc(CC#N)cc1
Reactant: O=C1CCCCC1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(CC2CCCCC2(O)C#N)cc1

Procedure:
WO 2007/094008 application discloses a process for the preparation of O-desmethylvenlafaxine, wherein p-methoxyphenyl acetonitrile is reacted with cyclohexanone in presence of sodium hydroxide and phase transfer catalyst selected from polyethyleneglycol-400 or ALIQUATE 336™ (N-methyl-N,N-dioctyloctan-1-ammonium chloride) to give 1-cyano[(4-methoxyphenyl)methyl] cyclohexanol, which is further subjected to reduction reaction in the presence of reducing agent such as borane-dimethylsulphide complex, aluminum chloride-sodium borohydride to give 1-[2-amino-1-(4methoxyphenyl)ethyl]cyclohexanol. Subsequently, 1-[2-amino-1-(4-methoxyphenyl)ethyl]cyclohexanol is subjected to reductive aviation reaction in presence of formic acid and formaldehyde to give venlafaxine.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[N:11][N:12]([CH:14]([CH3:16])[CH3:15])[CH:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[CH3:17][N:18]1[C:26]2[C:21](=[CH:22][C:23](B(O)O)=[CH:24][CH:25]=2)[CH:20]=[CH:19]1.O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.CCOC(C)=O.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>[CH:14]([N:12]1[CH:13]=[C:9]([C:4]2[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:23]3[CH:22]=[C:21]4[C:26](=[CH:25][CH:24]=3)[N:18]([CH3:17])[CH:19]=[CH:20]4)[CH:3]=2)[N:10]=[N:11]1)([CH3:16])[CH3:15]
Reactant: Cn1ccc2cc(B(O)O)ccc21
Reactant: CC(C)n1cc(-c2cc(Br)cnc2N)nn1
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: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: CC(C)n1cc(-c2cc(-c3ccc4c(ccn4C)c3)cnc2N)nn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of 5-bromo-3-(1-isopropyl-1H-[1,2,3]triazol-4-yl)-pyridin-2-ylamine (200 mg, 0.708 mmol) and N-methylindole-5-boronic acid (124 mg, 0.708 mmol) in 1,4-dioxane (6.0 mL)/water (3.0 mL) was added K2CO3 (293 mg, 2.126 mmol) at room temperature. The reaction mixture was purged with argon for 30 min. Then Pd(PPh3)4 (41 mg, 0.035 mmol) was added and the mixture was allowed to stir at 100° C. for 16 h. The reaction mixture was cooled to RT, diluted with EtOAc (20 mL) and washed with water (20 mL). The organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4 and solvent was evaporated under reduced pressure to afford crude compound. Crude compound was purified by column using 100-200 mesh silica gel. The column was eluted with 80% EtOAc in Pet. Ether to afford the title compound as pale yellow solid.
Reaction SMILES: C[Si](C)(C)CC[O:5][NH:6][C:7]([C@H:9]1[CH2:13][N:12]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:17][CH:16]=2)[C:11](=[O:29])[NH:10]1)=[O:8].B(F)(F)F.CCOCC>C(Cl)Cl>[OH:5][NH:6][C:7]([C@H:9]1[CH2:13][N:12]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([O:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[CH:19][CH:20]=2)[C:11](=[O:29])[NH:10]1)=[O:8]
Reactant: C[Si](C)(C)CCONC(=O)[C@H]1CN(Cc2ccc(Oc3ccc(F)cc3)cc2)C(=O)N1
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(NO)[C@H]1CN(Cc2ccc(Oc3ccc(F)cc3)cc2)C(=O)N1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 0.5 %

Procedure:
To a solution of (4R)-1-[4-(4-fluorophenoxy)benzyl]-2-oxo-imidazolidine-4-carboxylic acid (2-trimethylsilanylethoxy)amide (85 mg, 0. 19 mmol) in methylene chloride (5 mL) was added boron trifluoride etherate (0.073 mL, 0.58 mmol). The reaction mixture was stirred at room temperature for 1.5 hours and then quenched by addition of aqueous saturated NH4Cl solution. The mixture was diluted with water and ethyl acetate and the organic phase was washed with brine, dried over MgSO4 and concentrated to a white solid. The title compound (31 mg, 47%) was isolated by recrystallization from a mixture of ethyl acetate and methanol.
Reaction SMILES: [CH:1]1([C:6]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][C:15]1[N:24]=[C:23]([NH:25][NH2:26])[C:22]2[C:17](=[CH:18][C:19]([O:29][CH3:30])=[C:20]([O:27][CH3:28])[CH:21]=2)[N:16]=1>>[ClH:14].[NH:25]([C:23]1[C:22]2[C:17](=[CH:18][C:19]([O:29][CH3:30])=[C:20]([O:27][CH3:28])[CH:21]=2)[N:16]=[C:15]([N:11]2[CH2:10][CH2:9][N:8]([C:6]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[O:7])[CH2:13][CH2:12]2)[N:24]=1)[NH2:26]
Reactant: COc1cc2nc(Cl)nc(NN)c2cc1OC
Reactant: O=C(C1CCCC1)N1CCNCC1
Product: COc1cc2nc(N3CCN(C(=O)C4CCCC4)CC3)nc(NN)c2cc1OC
Product: Cl

Procedure:
N-(Cyclopentylcarbonyl)piperazine (0.02 mole) and 2-chloro-4-hydrazino-6,7-dimethoxyquinazoline (0.02 mole) reacted according to the procedure of Example 7 provides 4-hydrazino-2-[4-(cyclopentylcarbonyl)-1-piperazinyl]-6,7-dimethoxyquinazolinehydrochloride, m.p. 282°-284° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:8]([OH:10])=O)=[C:5]([CH3:7])[N:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:42]=[CH:43][C:44]=1[CH3:45])[O:26][C:27]1[CH:28]=[CH:29][C:30]2[N:31]([CH:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=2)[N:32]=1>CN(C)C=O.CN(C)C(=O)C>[CH:39]1([C:37]([NH:36][C:34]2[N:35]=[C:30]3[CH:29]=[CH:28][C:27]([O:26][C:25]4[CH:42]=[CH:43][C:44]([CH3:45])=[C:23]([NH:22][C:8]([C:4]5[O:3][C:2]([CH3:1])=[N:6][C:5]=5[CH3:7])=[O:10])[CH:24]=4)=[N:32][N:31]3[CH:33]=2)=[O:38])[CH2:40][CH2:41]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1nc(C)c(C(=O)O)o1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)o1
Yield: 82.8 %

Procedure:
In the same manner as in Example 259 and using 2,4-dimethyl-1,3-oxazole-5-carboxylic acid (85 mg, 0.60 mmol), tetrahydrofuran (5 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (62 μL, 0.72 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (170 mg, 81%) was obtained as a white solid.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][CH:5]1[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]2[CH:14]=[CH:15][CH:16]=[N:17][C:7]=2[O:6]1.S(Cl)([Cl:21])(=O)=O>CN(C)C=O>[Cl:21][C:15]1[CH:16]=[N:17][C:7]2[O:6][CH:5]([CH2:4][CH2:3][Cl:2])[CH2:11][N:10]([CH3:12])[C:9](=[O:13])[C:8]=2[CH:14]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: CN1CC(CCCl)Oc2ncccc2C1=O
Agent: Cl
Solvent: CN(C)C=O
Product: CN1CC(CCCl)Oc2ncc(Cl)cc2C1=O
Yield: 6.4 %

Procedure:
A sample of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f][1,4]-oxazepin-5-(4H)-one hydrochloride (10 g, 136 mole) was dissolved in dimethylformamide (150 ml) and heated to reflux. Sulfuryl chloride (20 g, 0.148 mole) was then added dropwise over a period of 40-50 minutes. The reaction was allowed to stir at reflux for 30 minutes following the addition of SO2CL2. After cooling, the contents of the flask were partitioned between water (150 ml) and benzene (150 ml). The benzene layer was saved and the water layer extracted with an additional amount of benzene (2×50 ml). The benzene extracts were combined and washed with dilute aqueous potassium hydroxide (2×50 ml) followed by dilute aqueous hydrochloric acid (2×50 ml). The benzene layer was dried over sodium sulfate and concentrated by rotary evaporation (~70° C., water aspirator) yielding 2.61 g of crude material. The crude material was recrystallized from isopropyl ether giving 1.25 g (12.6%) of off-white crystals, m.p. 78°-79° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[S:13])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15])=[O:4].O.[NH2:18][NH2:19].O>O1CCCC1>[NH:18]([C:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]([N+:14]([O-:16])=[O:15])[CH:7]=1)=[S:13])[NH2:19]
Reactant: NN
Reactant: COC(=O)c1ccc(N=C=S)cc1[N+](=O)[O-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc(NC(=S)NN)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 84.7 %

Procedure:
A solution of the above synthesized 4-methoxycarbonyl-3-nitrophenyl isothiocyanate (149 mg, 0.62 mmol) in tetrahydrofuran (2.2 ml) was added dropwise to a solution of hydrazine monohydrate (94 mg, 1.87 mmol) in tetrahydrofuran (4.0 ml) at 000 over 20 minutes. After stirring at 0° C. for further 40 minutes, water was added, and the precipitated solid was filtered to obtain 142 mg of the desired product as a colorless solid (yield 85%).
Reaction SMILES: O.[NH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[S:11][CH2:12][C:13]1[C:14]([NH2:19])=[N:15][CH:16]=[CH:17][CH:18]=1.N1[C:24]2C=CC=C[C:23]=2N=C1SCC1C(N)=NC=CC=1.ClCC=O.C(=O)(O)[O-].[Na+]>C(O)C>[N:19]1[CH:23]=[CH:24][N:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH2:12][S:11][C:3]3[NH:4][C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=4[N:2]=3)[C:14]=12
Reactant: Nc1ncccc1CSc1nc2ccccc2[nH]1
Agent: O=C([O-])O
Agent: O=CCCl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: c1ccc2[nH]c(SCc3cccn4ccnc34)nc2c1
Temperature: 25 °C
Yield: 71.3 %

Procedure:
A mixture of 9.6 g (63 mmole) of 2-mercaptobenzimidazole and 7.7 g (62 mmole) of 3-hydroxymethyl-2-pyridinamine was dissolved in 60 ml of 48% aqueous hydrobromic acid and 60 ml of acetic acid and heated to reflux. After being cooled to room temperature, the mixture was poured into water and make alkaline with potassium carbonate. The oil that separated solidified upon addition of diethyl ether to the aqueous mixture. The solid was collected by filtration, washed with portions of diethyl ether and water, and air dried to yield 12.4 g of analytically pure 3-[(1H-benzimidazol-2-ylthio)methyl]-2-pyridinamine hemihydrate, as confirmed by the nmr and infrared spectra and by elemental analysis. [Calcd. for C13H12N4S.1/2H2O: C, 58.84; H, 4.93; N, 21.11; S, 12.08. Found: C, 59.06; H, 4.48; N, 20.82; S, 12.16.]A mixture of 4.0 g (15 mmole) of 3-[(1H-benzimidazol-2-ylthio)methyl]-2-pyridinamine hemihydrate, 1.9 ml (ca. 18 mmole) of 50% aqueous chloroacetaldehyde, and 1.5 g (18 mmole) of sodium bicarbonate in 25 ml of ethanol was stirred at room temperature. After three days the mixture was filtered and the filtrate was concentrated in vacuo. Trituration of the residue from the filtrate with a mixture of water and dichloromethane induced crystallization. The solid was collected, washed sequentially with water and dichloromethane, and air dried to yield 3.0 g of the title compound. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:15][CH3:16])=[CH:5][C:6]2[NH:11][C:10](=[O:12])[O:9][C:8](=[O:13])[C:7]=2[CH:14]=1.[H-].[Na+].[CH3:19]I>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([O:15][CH3:16])=[CH:5][C:6]2[N:11]([CH3:19])[C:10](=[O:12])[O:9][C:8](=[O:13])[C:7]=2[CH:14]=1
Reactant: COc1cc2[nH]c(=O)oc(=O)c2cc1OC
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(=O)oc(=O)n(C)c2cc1OC
Reaction time: 0.17 h

Procedure:
To a solution of 500 mg (3.06 mmol) of 6,7-dimethoxy-1,2-dihydro-4H-3,1-benzoxazine-2,4-dione (XV), in 6 ml of anhydrous DMF, add under an inert atmosphere 134 mg (3.37 mmol) of 60% NaH in oil. After 10 minutes at room temperature, add dropwise 219 μl (3.52 mmol) of MeI. Allow to stand at room temperature for 3 hours.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:29])[CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:27])[CH3:26])[CH:20]=[CH:21][CH:22]=3)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1O)(=[O:32])[CH3:31]>>[C:30]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[O:29][CH:8]([C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH:14]([C:17]2[CH:18]=[C:19]([NH:23][C:24](=[O:28])[CH:25]([CH3:26])[CH3:27])[CH:20]=[CH:21][CH:22]=2)[CH2:13][CH2:12]1)(=[O:32])[CH3:31]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCC(O)c3ccc(Br)cc3)CC2)c1
Reactant: CC(=O)c1ccccc1O
Product: CC(=O)c1ccccc1OC(CCN1CCC(c2cccc(NC(=O)C(C)C)c2)CC1)c1ccc(Br)cc1

Procedure:
Prepared by Procedure A and Scheme AN using N-(3-{1-[3-(4-bromophenyl)-3-hydroxypropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 2-acetylphenol: ESMS m/e: 576.6 (M+H)+.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH:6]=2)[CH2:3][CH2:2]1.[CH3:25][N:26]1[C:30](=[O:31])[CH2:29][NH:28][C:27]1=[O:32].N1CCCCC1>CCO.O>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13](/[CH:14]=[C:29]4\[NH:28][C:27](=[O:32])[N:26]([CH3:25])[C:30]\4=[O:31])=[C:9]3[N:8]=[C:7]([NH:16][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH:6]=2)[CH2:2][CH2:3]1
Reactant: N#Cc1ccc(Nc2cc(NC3CC3)n3ncc(C=O)c3n2)cc1
Reactant: CN1C(=O)CNC1=O
Solvent: CCO
Solvent: O
Solvent: C1CCNCC1
Product: CN1C(=O)N/C(=C\c2cnn3c(NC4CC4)cc(Nc4ccc(C#N)cc4)nc23)C1=O
Temperature: 80 °C
Reaction time: 15 h
Yield: 67.9 %

Procedure:
4-(7-(cyclopropylamino)-3-formylpyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (51 mg, 0.16 mmol) was suspended in EtOH (1.6 mL). 3-methylimidazolidine-2,4-dione (28 mg, 0.24 mmol) and piperidine (24 μL, 0.24 mmol) were added and the reaction was heated to 80° C. After 15 h, the solution was diluted with H2O (2 mL) and filtered. The filter cake was washed with 50% H2O/50% EtOH (3 mL) and then dried in vacuo (˜1 mmHg) to furnish (Z)-4-(7-(cyclopropylamino)-3-((1-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)pyrazolo[1,5-a]pyrimidin-5-ylamino)benzonitrile (45 mg, 68%) as a bright yellow solid. LCMS (ES): >90% pure, tm/z 415 [M+1]+.
Reaction SMILES: I[C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C(NC(C)C)(C)C.[CH3:14][Si:15]([C:18]#[CH:19])([CH3:17])[CH3:16].O>C1COCC1.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.[Cu]I>[CH3:14][Si:15]([CH3:17])([CH3:16])[C:18]#[C:19][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1
Reactant: C#C[Si](C)(C)C
Reactant: Ic1cccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cccs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69747.9 %

Procedure:
A mixture of 2-iodothiophene (500 mg, 2.38 mmol), Pd(PPh3)2Cl2 (52.95 mg, 0.0754 mmol), CuI (28.1 mg, 0.14756 mmol) and diisopropylamine (0.62 ml, 4.4744 mmol) in THF (4 ml) was degassed thoroughly with argon, and trimethylsilyl acetylene (0.453 ml, 3.284 mmol) was added at room temperature. After stirring the reaction mixture for 16 hours at room temperature, it was poured into water and extracted with dichloromethane. The combined organic layers were washed with brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The crude material was purified by column chromatography (100-200 mesh silica gel) using hexane as eluent to yield 300 mg of trimethyl(thiophen-2-ylethynyl)silane (300 mg, 1.66 mol, yield 70.02%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]([NH:14][NH2:15])=[O:13].C(Cl)Cl.IC.[CH2:25]([OH:27])[CH3:26]>>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[CH:19]=[N:18][CH:17]=[CH:16][C:11]=1[C:12]1[O:13][C:17]([NH:18][CH2:19][CH2:10][N:9]2[CH2:3][CH2:2][O:27][CH2:25][CH2:26]2)=[N:15][N:14]=1
Reactant: CCO
Reactant: NNC(=O)c1ccncc1Nc1ccc(I)cc1F
Solvent: CI
Solvent: ClCCl
Product: Fc1cc(I)ccc1Nc1cnccc1-c1nnc(NCCN2CCOCC2)o1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2-Fluoro-4-iodo-phenylamino)-isonicotinic acid hydrazide (500 mg; 1.34 mmol; 1 eq) in DCM (5 mL) 4-(3-Isothiocyanato-ethyll)-morpholine (255 mg; 1.61 mmol; 1.2 eq) was added. The reaction mixture was refluxed for 4 hrs under argon. A yellow solid precipitated out, which was filtered to afford an intermediate that was suspended in ethanol (5 mL). Iodomethane (190 mg; 1.34 mmol; 1.0 eq) was then added and the reaction mixture was stirred overnight at RT. It was then heated to 80° C. and stirred for another 2 hr. Filtration afforded the yellow solid product 153 mg. LC/MS (Method A) [0.41 min; 511(M+1)]
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][C:12]1[C:16]([CH3:17])=[CH:15][NH:14][C:13]=1[CH:18]=O>N1CCCCC1.C(O)C>[CH3:11][C:12]1[C:16]([CH3:17])=[CH:15][NH:14][C:13]=1[CH:18]=[C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][C:2]1=[O:10]
Reactant: Cc1c[nH]c(C=O)c1C
Reactant: O=C1Cc2ccccc2N1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1c[nH]c(C=C2C(=O)Nc3ccccc32)c1C
Temperature: 90 °C
Reaction time: 3 h
Yield: 73.6 %

Procedure:
A reaction mixture of 67.0 mg (0.5 mmoles) of oxindole, 73.0 mg (0.6 mmoles) of the 3,4-dimethylpyrrole-2-carboxaldehyde, and 2 drops of piperidine in 2 mL of ethanol was stirred at 90° C. for 3 h. After cooling, the precipitate was filtered, washed with cold ethanol, and dried to yield 87.7 mg (37%) of the title compound as a yellow solid.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23]([C:25](O)=[O:26])=[C:22]([CH3:28])[C:21]=3[CH:29]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30].C(Cl)CCl.Cl.C[O:40][C:41](=[O:44])[CH2:42][NH2:43]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:33][C:2]([CH3:1])([CH3:32])[C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([C:17]2[CH:18]=[CH:19][C:20]3[O:24][C:23]([C:25]([NH:43][CH2:42][C:41]([OH:40])=[O:44])=[O:26])=[C:22]([CH3:28])[C:21]=3[CH:29]=2)([CH2:15][CH3:16])[CH2:13][CH3:14])=[CH:8][C:7]=1[CH3:30]
Reactant: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)O)c(C)c2c1
Reactant: COC(=O)CN
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CCC(CC)(c1ccc(OCC(=O)C(C)(C)C)c(C)c1)c1ccc2oc(C(=O)NCC(=O)O)c(C)c2c1
Yield: 66.6 %

Procedure:
5-{1-[4-(3,3-Dimethyl-2-oxo-butoxy)-3-methyl-phenyl]-1-ethyl-propyl}-3-methyl-benzofuran-2-carboxylic acid (520 mg, 1.154 mmol) in CH2Cl2 (10 mL) and DMAP (422 mg, 3.46 mmol), EDC (332 mg, 1.73 mmol), and glycine methyl ester hydrochloride (217 mg, 1.73 mmol) are reacted and hydrolyzed analogous to Example 7 to yield title compound (390 mg, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:18][CH:19]([CH3:36])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:24]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:33]2[CH2:34][CH2:35][CH:30]([C:25]3[CH:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:36])[CH:28]=[CH:27][C:26]=3[CH3:29])[CH2:31][CH2:32]2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccc(F)c(F)c2)cc1
Reactant: Cc1ccc(NC(=O)C(C)C)cc1C1CCNCC1
Product: Cc1ccc(NC(=O)C(C)C)cc1C1CCN(Cc2ccc(Oc3ccc(F)c(F)c3)cc2)CC1

Procedure:
Prepared by Procedure AA and Scheme AJ using 4-(3,4-difluorophenoxy)benzaldehyde and using 2-methyl-N-[4-methyl-3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 479.1 (M+H)+.
Reaction SMILES: [C:1]1(=[O:7])[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[C:8]1([Li])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O>CCOCC>[OH:6][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:4][CH2:5][C:1]1=[O:7]
Reactant: [Li]c1ccccc1
Reactant: O=C1CCCC1=O
Solvent: CCOCC
Solvent: O
Product: O=C1CCCC1(O)c1ccccc1
Yield: 58.4 %

Procedure:
A solution of 73.5 g (0.75 mole) of 1,2-cyclopentanedione in 400 ml of ether was added to 1.5 moles of phenyl lithium in 1.2 liter of ether, and the mixture was stirred under N2 for one half hour. After careful addition of water, the ethereal layer was separated, dried over magnesium sulfate and the solvent evaporated. The residue was distilled under reduced pressure and gave 77.2 g of 2-hydroxy-2-phenylcyclopentanone, b.p. 122°-126° C. (1.5 mm), nD25 1.5551. The oxime was prepared by known procedures, m.p. 110°-112° C., and was reduced by hydrogenation over Raney nickel in 20% alcoholic ammonia. Removal of catalyst, evaporation of solvent and addition of HCl gave 2-hydroxy-2-phenylcyclopentylamine hydrochloride, m.p. 198°-199° C.