Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=3)[N:9]=2)[N:4]([Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[CH:3]=1.[Li]CCCC.CON(C)[C:41]([C:43]1([CH3:46])[CH2:45][CH2:44]1)=[O:42]>O1CCCC1>[CH3:46][C:43]1([C:41]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[C:8]([C:11]4[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=4)[N:9]=3)[N:4]([Si:23]([CH:30]([CH3:32])[CH3:31])([CH:27]([CH3:29])[CH3:28])[CH:24]([CH3:26])[CH3:25])[CH:3]=2)=[O:42])[CH2:45][CH2:44]1
Reactant: COc1cc(-c2cnc3c(n2)c(I)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Reactant: CON(C)C(=O)C1(C)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(-c2cnc3c(n2)c(C(=O)C2(C)CC2)cn3[Si](C(C)C)(C(C)C)C(C)C)cc(OC)c1OC
Reaction time: 0.01 h
Yield: 19.1 %

Procedure:
A solution of 7-iodo-5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazine (116 mg, 0.2 mmol) in anhydrous tetrahydrofuran (3 ml) was cooled to −78° C. and treated with nBuLi (2.13M in hexanes, 0.13 ml, 0.27 mmol) dropwise. The solution was stirred for 30 seconds and 1-methyl-cyclopropanecarboxylic acid methoxy-methyl-amide (88 mg, 0.61 mmol) was added in one portion. The reaction mixture was stirred at −78° C. for 30 minutes. The reaction mixture was quenched with saturated aqueous NaHSO4 and then partitioned between EtOAc/brine. The organic layers were collected, dried over MgSO4, filtered, and concentrated giving a yellow oil. The oil was purified by silica gel chromatography using 2-30% EtOAc in hexanes as eluant to provide 20 mg (19%) of (1-methyl-cyclopropyl)-[5-triisopropylsilanyl-2-(3,4,5-trimethoxy-phenyl)-5H-pyrrolo[2,3-b]pyrazin-7-yl]-methanone.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[SH:9].Cl.Cl[CH2:12][C:13]1[N:14]=[CH:15][NH:16][CH:17]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([S:25]([NH:1][C:2]2[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=2[S:9][CH2:12][C:13]2[N:14]=[CH:15][NH:16][CH:17]=2)(=[O:26])=[O:27])=[CH:21][C:20]=1[C:29]([F:32])([F:30])[F:31]
Reactant: ClCc1c[nH]cn1
Reactant: Nc1cc(Cl)ccc1S
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Product: O=S(=O)(Nc1cc(Cl)ccc1SCc1c[nH]cn1)c1ccc(Cl)c(C(F)(F)F)c1

Procedure:
Following General Procedure A, B, the title compound was prepared from 2-Amino-4-chloro-benzenethiol, 4-chloromethyl-1H-imidazole hydrogen chloride and 4-chloro-3-trifluoromethyl-benzenesulfonyl chloride.
Reaction SMILES: Br[C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[CH2:7]([NH:9][CH2:10][CH2:11][NH2:12])[CH3:8].O>C(O)(C)C.[Cu].[Cu]Cl>[CH2:7]([N:9]([C:2]1[S:3][CH:4]=[CH:5][N:6]=1)[CH2:10][CH2:11][NH2:12])[CH3:8]
Reactant: Brc1nccs1
Reactant: CCNCCN
Agent: Cl[Cu]
Agent: [Cu]
Solvent: CC(C)O
Solvent: O
Product: CCN(CCN)c1nccs1
Temperature: 70 °C
Yield: 8 %

Procedure:
47 mg (0.74 mmol) of copper and 225 mg (2.27 mmol) of copper(I) chloride were added to a solution of 1.35 g (15.0 mmol) of 2-bromothiazole and 9.48 ml (90.0 mmol) of N-ethylethylenediamine in isopropanol (7.5 ml). The mixture was then heated to 70° C. for 1 h. After cooling to RT, the reaction solution was poured into water and extracted with EA. The organic phase was dried over MgSO4, filtered and evaporated under a vacuum. 200 mg (1.2 mmol, 8%) of N1-ethyl-N1-(thiazol-2-yl)ethane-1,2-diamine were obtained by carrying out CC twice (i. DCE/EtOH 5:1; ii. DCE/EtOH/conc. aq. NH4OH soln. 5:1:0.06) with the residue.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([NH:6][C:7]2[CH:15]=[C:14]([C:16]([OH:18])=O)[C:13]([NH:19][C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[CH:12][C:8]=2[C:9](O)=[O:10])=[CH:4][CH:3]=1.P(=O)(O)(O)O.CO>O.S(N(C1C=C(C(O)=O)C(N(S(=O)(=O)N)C2C=CC=CC=2)=CC=1C(O)=O)C1C=CC=CC=1)(=O)(=O)N.C(N(CC)S(C1C=CC(NC2C=C(C(O)=O)C(NC3C=CC(S(=O)(=O)N(CC)CC)=CC=3)=CC=2C(O)=O)=CC=1)(=O)=O)C>[CH3:1][C:2]1[CH:28]=[CH:27][C:5]2[NH:6][C:7]3[C:8]([C:9](=[O:10])[C:4]=2[CH:3]=1)=[CH:12][C:13]1[NH:19][C:20]2[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][C:21]=2[C:16](=[O:18])[C:14]=1[CH:15]=3
Reactant: Cc1ccc(Nc2cc(C(=O)O)c(Nc3ccc(C)cc3)cc2C(=O)O)cc1
Agent: CCN(CC)S(=O)(=O)c1ccc(Nc2cc(C(=O)O)c(Nc3ccc(S(=O)(=O)N(CC)CC)cc3)cc2C(=O)O)cc1
Agent: NS(=O)(=O)N(c1ccccc1)c1cc(C(=O)O)c(N(c2ccccc2)S(N)(=O)=O)cc1C(=O)O
Agent: O=P(O)(O)O
Solvent: O
Solvent: CO
Product: Cc1ccc2[nH]c3cc4c(=O)c5cc(C)ccc5[nH]c4cc3c(=O)c2c1
Temperature: 92 °C
Reaction time: 0.08 h
Yield: 103.7 %

Procedure:
To 720 g of polyphosphoric acid (117%) heated at 92° C. were added 1.6 g of 2,5-di(sulfamoylanilino)terephthalic acid followed by 8 g of 2,5-di[4-(N,N-diethylsulfamoyl)anilino]terephthalic acid. The mixture was stirred for five minutes, after which 160 g of 2,5-di(4-methylanilino)terephthalic acid were added over a period of approximately 65 minutes, the temperature being maintained below 105° C. by adjustment of the addition rate. The reaction mixture was held at 105° C. for five hours and then cooled to 92° C. To this mixture was added 105.8 g of phosphoric acid (75%) dropwise over a period of approximately 30 minutes. The resultant melt was allowed to stir for 15 minutes at 90° C. and then poured slowly into 1120 g of methanol, the temperature being maintained below reflux using a water bath. The slurry was allowed to cool to room temperature and stand for 16 hours. The pigment slurry was heated at reflux for one hour, cooled below 65° C., diluted with water, collected by filtration, and washed with water until free of acid. The resultant presscake was reslurried in water and heated to 45° C. After the slurry was acidified to pH 2.6, an emulsion of 4.7 g of an anionic surfactant, 69.6 g of a petroleum distillate, and 160 g of water was added, and the slurry was stirred for three hours. The resultant slurry was collected by filtration and washed with water. The wet cake can be dried or used as is for specific applications. Here, the wet cake was dried in an oven at 60° C. to give approximately 150 g of 2,9-dimethylquinacridone as a magenta pigment.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH2:12][CH2:13]Cl)[CH:10]([CH2:15]Cl)[CH2:9][N:8]=[C:7]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[C:6]=2[CH:22]=1.[OH-:23].[Na+].C(Cl)(Cl)Cl>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][O:23][CH2:15][CH:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:21]=[CH:20][S:19][CH:18]=3)[C:6]=2[CH:22]=1
Reactant: ClCCN1c2ccc(Cl)cc2C(c2ccsc2)=NCC1CCl
Reactant: [OH-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: Clc1ccc2c(c1)C(c1ccsc1)=NCC1COCCN21

Procedure:
A solution of 11 g of 7-chloro-1-(β-chloroethyl)-2-chloromethyl-5-(3-thienyl)-2,3-dihydro-1H-1,4-benzodiazepine in 60 ml of dioxane and 160 ml of 4.5% strength sodium hydroxide solution is heated under reflux for 5 hours. After the solvent has been stripped off in vacuo, the reaction product is isolated from chloroform and is then chromatographed on aluminium oxide of activity level II, using methylene chloride. After the methylene chloride has been stripped off, 6.5 g of 1,2,4,4a-tetrahydro-9-chloro-7-(3-thienyl)-5H-[1,4]oxazino[4,3-a][1,4]benzodiazepine are obtained as an oil. This product is converted into its hydrochloride by reaction with alcoholic hydrogen chloride solution, and the product is crystallised as the hydrochloride.0.3H2O from isopropanol. Melting point: 207° to 212° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:13]=[CH:14][C:15](=[O:25])[N:16]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)=[C:5]([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1.[C:26](O)(=[O:33])[C:27]1[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[CH2:18]([N:16]1[CH:17]=[C:12]([C:4]2[S:3][C:2]([NH:1][C:26]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[O:33])=[N:6][C:5]=2[C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[CH:13]=[CH:14][C:15]1=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccncc1
Reactant: Nc1nc(-c2ccco2)c(-c2ccc(=O)n(Cc3ccccc3)c2)s1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1nc(-c2ccco2)c(-c2ccc(=O)n(Cc3ccccc3)c2)s1)c1ccncc1
Temperature: 80 °C
Reaction time: 1 h
Yield: 28.2 %

Procedure:
2-Amino-5-(1-benzyl-2-oxo-1,2-dihydropyridin-5-yl)-4-(2-furyl)thiazole (349 mg, 1.00 mmol) obtained in Step 1 was dissolved in DMF (4 mL), and isonicotinic acid (246 mg, 2.00 mmol), PyBOP (1.14 g, 2.20 mmol) and triethylamine (0.613 mL, 4.40 mmol) were added thereto, followed by stirring at 80° C. for 1 hour. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was purified through silica gel column chromatography (chloroform:methanol=17:1), followed by reslurrying with a mixed solvent of methanol and diethyl ether to afford the entitled Compound 128 (128 mg, 28%) as a pale brown solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([C:10]2[NH:14][CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1.C1OCCOCCOCCOCCOC1.[F:41][C:42]1[CH:43]=[C:44]([S:48](Cl)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1>O1CCCC1.O>[Cl:3][C:4]1[C:9]([C:10]2[N:14]([S:48]([C:44]3[CH:45]=[CH:46][CH:47]=[C:42]([F:41])[CH:43]=3)(=[O:50])=[O:49])[CH:13]=[C:12]([CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])[C:11]=2[F:25])=[CH:8][CH:7]=[CH:6][N:5]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CN(Cc1c[nH]c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(Cc1cn(S(=O)(=O)c2cccc(F)c2)c(-c2cccnc2Cl)c1F)C(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 95.7 %

Procedure:
To a suspension of sodium hydride (60% in oil, 60 mg) in tetrahydrofuran (5 mL) were added dropwise a solution of tert-butyl {[5-(2-chloropyridin-3-yl)-4-fluoro-1H-pyrrol-3-yl]methyl}methylcarbamate (340 mg) in tetrahydrofuran (5 mL), 15-crown-5 (330 mg) and 3-fluorobenzenesulfonyl chloride (292 mg) under ice-cooling and the mixture was stirred for 10 min. The reaction mixture was diluted with water, and extracted with ethyl acetate. The separated aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=6:1→2:1) to give the title compound as a pale-yellow oil (yield 477 mg, 96%).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C([Li])CCC.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=[O:24])[CH2:20][CH2:19]1>CCCCCC>[OH:24][C:21]1([C:2]2[CH:3]=[N:4][C:5]3[C:10]([CH:11]=2)=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:22][CH2:23][N:18]([CH3:17])[CH2:19][CH2:20]1
Reactant: CN1CCC(=O)CC1
Reactant: Brc1cnc2ccccc2c1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: CN1CCC(O)(c2cnc3ccccc3c2)CC1
Yield: 53.84 %

Procedure:
95.01 g of 3-bromoquinoline were treated with 200 ml of a 2.5 M solution of butyllithium in hexane and 51.62 g of 1-methylpiperid-4-one in accordance with the procedure described in Stage A of Example 1, in order to obtain the expected product.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:8][C:9](=O)[CH3:10])[S:5][C:6]=1[CH3:7].[H-].[Na+].Cl.[CH3:15][N:16](CCCl)[CH3:17]>CN(C)C=O>[CH3:15][N:16]([CH3:17])[CH2:10][CH2:9][NH:8][C:4]1[S:5][C:6]([CH3:7])=[C:2]([CH3:1])[N:3]=1
Reactant: CC(=O)Nc1nc(C)c(C)s1
Reactant: CN(C)CCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(NCCN(C)C)sc1C
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Dissolve 30.0 g. (0.176 moles) of N-(4,5-dimethyl-2-thiazolyl) acetamide in 375 ml. of dimethylformamide under nitrogen followed by 7.7 g. of 50% sodium hydride in 2 portions at room temperature. When gas evolution ceases, 27.5 g. (0.191 moles) of dimethylaminoethylchloride hydrochloride is added along with 8.35 g. of 50% sodium hydride. The mixture is stirred at 60°-70° C. for 1/2 hour, 90° C. for 2 hours, cooled to room temperature, and concentrated in vacuo. The residue is taken up in 200 ml. of 6 N hydrochloric acid and refluxed for 24 hours. The mixture is extracted with hexane and made basic with sodium hydroxide with cooling. The aqueous layer is extracted with methylene chloride, the organic layer washed with saturated sodium chloride, dried over sodium sulfate and evaporated. The residue is distilled and the fraction boiling at 110°-113° C./0.7 mm. of Hg. collected (29.2 g.) and identified as N,N-dimethyl-N'-(4,5-dimethyl-2-thiazolyl)-1,2-ethanediamine.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH3:7])=[CH:5][N:6]=1.[Cl:8][CH2:9][C:10](=O)[CH2:11][C:12](OCC)=[O:13].C1(COC2C(OC)=CC=CC=2/C=C/C2N=C3SC=CN3C(=O)C=2I)CC1>>[Cl:8][CH2:9][C:10]1[N:1]=[C:2]2[S:3][C:4]([CH3:7])=[CH:5][N:6]2[C:12](=[O:13])[CH:11]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Cc1cnc(N)s1
Agent: COc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Product: Cc1cn2c(=O)cc(CCl)nc2s1
Yield: 63.9 %

Procedure:
This compound was synthesized from 2-amino-5-methyl thiazole (5.0 g, 43.710 mmol) and ethyl chloroacetoacetate (9.893 g, 59.561 mmol) in polyphosphoric acid (40.0 g) according to the procedure described in Step 1, Intermediate 2 to afford 6.0 g of the desired compound as a black solid; 1H NMR (300 MHz, DMSO-d6) δ 2.43 (s, 3H), 4.58 (s, 2H), 6.39 (s, 1H), 7.87 (s, 1H); ESI-MS (m/z) 215.37 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([OH:5])[C:3]#[CH:4].[H-].[Na+].C([Li])CCC.Cl[Si:14]([CH3:17])([CH3:16])[CH3:15]>CCOCC.CCCCCC>[CH3:15][Si:14]([CH3:17])([CH3:16])[C:4]#[C:3][CH:2]([OH:5])[CH3:1]
Reactant: C#CC(C)O
Reactant: C[Si](C)(C)Cl
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(O)C#C[Si](C)(C)C

Procedure:
Referring to Flowchart II, 3-butyn-2-ol (formula 21) is treated in step H with sodium hydride in ether at -20° C. and then with 2.0 n-butyllithium in hexane, followed by chlorotrimethylsilane, to produce (+)-4-trimethylsilyl-3-butyn-2-ol (formula 22), which is then reacted in step I with lithium aluminum hydride in ether at reflux for several hours, basified and distilled, to produce (±)-trans-4-(trimethylsilyl)-3-buten-2-ol (formula 23). The reaction in step J of (23) in ether with a mixture of sodium dichromate hydrate and sulfuric acid at <5° C. or below produces trans-4-(trimethylsilyl)-3-buten-2-one (formula 24), which upon distillation with selected solvents gives trans-4-(trimethylsilyl)-2-acetoxy-1,3-butadiene (formula 25).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5](OC2CCN(C(OC(C)(C)C)=O)CC2)=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:31][CH:30]([C:32]([OH:34])=O)[CH2:29]2)[N:23]=1.[CH2:35]([O:42][C:43](N1CC(C(O)=O)C1)=[O:44])C1C=CC=CC=1>>[N:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH2:31][CH:30]([C:32]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:43]([O:42][CH3:35])=[O:44])=[CH:20][CH:21]=3)=[O:34])[CH2:29]2)[N:23]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2)CC1
Reactant: O=C(O)C1CN(c2cccnn2)C1
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)C1
Product: COC(=O)c1ccc(NC(=O)C2CN(c3cccnn3)C2)cc1

Procedure:
The title compound was prepared as described in Example 1A, substituting methyl 4-aminobenzoate for tert-butyl 4-(4-aminophenoxy)piperidine-1-carboxylate and 1-(pyridazin-3-yl)azetidine-3-carboxylic acid for 1-(benzyloxycarbonyl)azetidine-3-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][NH:6][C:5](=[S:8])[NH:4][CH2:3]1.[I:10][CH3:11]>CO>[IH:10].[CH3:1][C:2]1([CH3:9])[CH2:7][NH+:6]=[C:5]([S:8][CH3:11])[NH:4][CH2:3]1
Reactant: CI
Reactant: CC1(C)CNC(=S)NC1
Solvent: CO
Product: CSC1=[NH+]CC(C)(C)CN1
Product: I

Procedure:
The reaction mixture comprising one equivalent of 5,5-dimethyl-3,4,5,6-tetrahydro(1H)pyrimidine-2-thione and 1.2 equivalents of iodomethane in methanol (10 ml/g of thio-urea) is heated under reflux for 5 hours. After cooling down, the methanol is evaporated off under reduced pressure in order to quantitatively produce the product. The precipitate can then be washed in acetone or petroleum ether.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19](O)=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:26][CH2:25]1)=[O:23].[CH:38]1([S:41]([NH2:44])(=[O:43])=[O:42])[CH2:40][CH2:39]1>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:44][S:41]([CH:38]3[CH2:40][CH2:39]3)(=[O:43])=[O:42])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][C:27]2([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=3[O:31][CH2:30]2)[CH2:28][CH2:29]1)=[O:23]
Reactant: NS(=O)(=O)C1CC1
Reactant: Cc1ccc(C)c(Nc2c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc3c(C(=O)O)cnn23)c1
Product: Cc1ccc(C)c(Nc2c(C(=O)N3CCC4(CC3)COc3ccccc34)cnc3c(C(=O)NS(=O)(=O)C4CC4)cnn23)c1
Yield: 55.1 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2,5-dimethylphenylamino)-6-(2H-spiro[benzofuran-3,4′-piperidine]-1′-ylcarbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.065 g, 0.13 mmol) obtained in Example 129, step 2 and cyclopropanesulfonamide (0.079 g, 0.65 mmol), the title compound (0.043 g, 55%) was obtained.
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][N:4]=1.[NH2:20][C:21]1[N:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][N:30]([C:33](=[O:35])[CH3:34])[CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C>[C:33]([N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([NH:20][C:16](=[O:18])[CH2:15][C:12]3[CH:11]=[CH:10][C:9]([C:7]4[CH:6]=[CH:5][N:4]=[C:3]([CH:2]([F:1])[F:19])[CH:8]=4)=[CH:14][CH:13]=3)=[N:26][CH:25]=2)[CH2:32][CH2:31]1)(=[O:35])[CH3:34]
Reactant: O=C(O)Cc1ccc(-c2ccnc(C(F)F)c2)cc1
Reactant: CC(=O)N1CCN(c2ccc(N)nc2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(=O)N1CCN(c2ccc(NC(=O)Cc3ccc(-c4ccnc(C(F)F)c4)cc3)nc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(4-(2-(difluoromethyl)pyridin-4-yl)phenyl)acetic acid 203-5 (30 mg, 0.11 mmol), 1-(4-(6-aminopyridin-3-yl)piperazin-1-yl)ethanone 111-4 (28 mg, 0.13 mmol), N,N-diisopropylethylamine (99 μL, 0.57 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (65 mg, 0.17 mmol) in DMF (2 mL) was stirred at room temperature for 3 hours. The solvent was removed by rotary evaporation. The crude product was purified by reverse phase HPLC to give 2 N-(5-(4-acetylpiperazin-1-yl)pyridin-2-yl)-2-(4-(2-(difluoromethyl)pyridin-4-yl)phenyl)acetamide 201. MS m/z 418.2 (M+1); 1H NMR 400 MHz (MeOD) δ 8.61(d, 1H), 8.25(d, 1H), 7.91(d, 1H), 7.80-7.72(m, 4H), 7.49(d, 2H), 6.79(d, 1H), 6.73(t, 1H), 3.70(s, 2H), 3.66-3.58(m, 4H), 3.52-3.47(m, 2H), 3.45-3.40(m, 2H), 2.09(s, 3H).
Reaction SMILES: [CH:1]1([C:7](Cl)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N:18]1[CH2:23][CH2:22][N:21]([CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]2)[CH2:20][CH2:19]1.C(N(CC)CC)C>C(Cl)Cl>[CH:1]1([C:7]([N:27]2[CH2:28][CH2:29][CH2:30][CH:25]([CH2:24][N:21]3[CH2:22][CH2:23][N:18]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[O:11][CH3:10])[CH2:19][CH2:20]3)[CH2:26]2)=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: COc1ccccc1N1CCN(CC2CCCNC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(CC2CCCN(C(=O)C3CCCCC3)C2)CC1
Temperature: 0 °C
Reaction time: 16 h
Yield: 80.8 %

Procedure:
Cyclohexanecarbonyl chloride (0.506 g, 3.5 mmol) was added to a solution of 1-(2-methoxyphenyl)-4-piperidin-3-ylmethyl-piperazine (1.0 g, 3.5 mmol) from example 6 and triethylamine (2 equivalents, 1 mL) in CH2Cl2 (30 mL) and the solution stirred under N2 at 0° C. for 16 hours. The mixture was concentrated under vacuum, water (50 mL) added and the product extracted into ethyl acetate (3×25 mL). The combined organics were washed with water (25 mL), saturated sodium bicarbonate (20 mL) and brine (25 mL). After drying over sodium sulfate, filtration and concentration under vacuum afforded the titled product (1.13 g, 81% yield). An ethanolic solution of the product was treated with a hot ethanolic solution of fumaric acid (1.0 equivalents) and afforded the fumarate salt of the titled compound as a light yellow colored solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:9]2[O:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:12][N:13]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[N:26]1[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=1>CN(C=O)C.[Cu]>[NH2:8][C:5]1[N:6]=[CH:7][C:2]([N:26]2[CH:31]=[CH:30][C:29](=[O:32])[CH:28]=[CH:27]2)=[N:3][C:4]=1[C:9]1[O:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:12][N:13]=1
Reactant: Oc1ccncc1
Reactant: Nc1ncc(Br)nc1-c1nnc(-c2ccccc2)o1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Nc1ncc(-n2ccc(=O)cc2)nc1-c1nnc(-c2ccccc2)o1
Temperature: 160 °C
Yield: 25 %

Procedure:
To a solution of 5-bromo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)pyrazin-2-amine (150.0 mg, 0.4715 mmol) in DMF (3.000 mL) was added copper (5.992 mg, 0.09430 mmol) and cesium carbonate (307.2 mg, 0.9430 mmol) followed by pyridin-4-ol (448.4 mg, 4.715 mmol) and the reaction mixture heated at 160° C. in the microwave for 1 h. The reaction mixture was filtered and washed with DMF (2 mL). Ethyl acetate and water were added to the filtrate and the layers separated. The aqueous layer was extracted further with ethyl acetate (3×5 mL) and the combined organic extracts were washed with water (3×5 mL). The organic extracts were dried over Na2SO4, filtered and concentrated in vacuo. The material was triturated with a mixture of methanol and ether to leave the product. (42.6 mg, 25% yield); 1H NMR (400 MHz, DMSO) d 6.33 (d, 2H), 7.69 (s, 2H), 8.15-8.18 (m, 2H), 8.35 (d, 2H) and 8.78 (s, 1H) ppm; MS (ES+) 333.11
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=2)=[C:5]([O:19][CH3:20])[CH:4]=1)=O.[CH3:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[CH2:24][CH2:25][NH2:26]>>[CH3:20][O:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:26][CH2:25][CH2:24][C:23]2[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=2[CH3:21])[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([NH2:14])=[O:13])=[CH:10][N:9]=1
Reactant: Cc1ccccc1CCN
Reactant: COc1cc(C=O)ccc1Oc1ccc(C(N)=O)cn1
Product: COc1cc(CNCCc2ccccc2C)ccc1Oc1ccc(C(N)=O)cn1
Yield: 81.1 %

Procedure:
Using a method similar to Example 405, a reaction of 6-(4-formyl-2-methoxyphenoxy)nicotinamide (Example 414, Part B) (0.050 g, 0.184 mmol) and 2-methylphenethylamine (0.0248 g, 0.184 mmol) gives the title compound (0.0584 g, 81.2%): TOF MS ES+ 392.2 (M+H)+, HRMS calcd for C23H26N3O3 392.1974 (M+H)+, found 392.1966, time 0.39 min; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/min, 20-99% over 23 min], tR=7.5 min, 97.6% purity.