Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])O.[Cs+:5].[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:21]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:20]=1)[C:15]([OH:17])=[O:16])=[O:12])([CH3:9])([CH3:8])[CH3:7]>O.C(#N)C>[Cs+:5].[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:21]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:20]=1)[C:15]([O-:17])=[O:16])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)O
Agent: O=C([O-])O
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(OCc2ccccc2)c1)C(=O)[O-]
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Cesium hydrogencarbonate (194 mg, 1 mmol) was added to a solution of (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propionic acid (297 mg, 1 mmol) in 5 mL water and 5 mL acetonitrile. The resulting mixture was stirred at room temperature for 10 minutes, then frozen and lyophilized to yield (2S)-2-[(tert-butoxy)carbonylamino]-3-[3,4-bis(phenylmethoxy)phenyl]propionic acid cesium salt as a white solid, which was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([OH:6])=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]([O:21][CH3:22])=[O:20].O>CN(C=O)C>[Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[C:5]([OH:6])=[CH:4][C:3]=1[O:10][CH2:18][C:19]([O:21][CH3:22])=[O:20]
Reactant: Oc1cc(O)c(Cl)cc1Cl
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)COc1cc(O)c(Cl)cc1Cl
Temperature: 80 °C
Yield: 23.2 %

Procedure:
A mixture of 4,6-dichlororesorcinol (2 g), potassium carbonate (1.54 g) and methyl bromoacetate (1.71 g) in DMF (10 ml) was heated at 80° C. for 24 h. The resulting mixture was cooled and water (200 ml) added. Solid (bis-alkylated product) was filtered off, then the aqueous was acidified with aq. HCl, which was extracted with ether and the organics were dried and concentrated in vacuo. Purification by RPHPLC (Xterra, gradient 95-5%, ammonia (0.2% aq.) in acetonitrile) gave the subtitle compound (0.65 g) as a solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.NN>C(O)C>[C:1]1([CH:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][NH2:17])[CH2:11][CH2:12]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCCN1CCC(c2ccccc2)CC1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCCN1CCC(c2ccccc2)CC1

Procedure:
20 g (61.2 mmol) 2-[4-(4-phenyl-piperidin-1-yl)-butyl]-isoin-dolin-1,3-dione and 6.1 g (122.5 mmol) hydrazine hydrate are heated under reflux in 250 ml ethanol for 3 hours. The cooled solution is concentrated under vacuum and the residue is taken up in chloroform. The suspension is filtered and the residue is distributed between chloroform and 10% sodium hydroxide solution. The combined organic phases are dried over sodium sulfate and steam evaporated under vacuum until dry. The resin is further processed without further purification: Yield 11.7 g (82%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[N:12][CH:11]=[C:10](Cl)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[Br-].[N:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[Zn+]>>[C:1]([O:5][C:6](=[O:22])[N:7]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=1)[C:8]1[CH:13]=[N:12][CH:11]=[C:10]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][N:24]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: [Zn+]c1ccccn1
Reactant: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(Cl)n1
Agent: [Br-]
Product: CC(C)(C)OC(=O)N(c1ccc(Cl)cc1)c1cncc(-c2ccccn2)n1

Procedure:
Was prepared according to Example 5 from (4-chloro-phenyl)-(6-chloro-pyrazin-2-yl)-carbamic acid tert-butyl ester and 2-pyridylzinc bromide.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)(=O)=O)=CC=1.C([O-])([O-])=O.[K+].[K+].[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[SH:35]>CCO>[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[S:35][CH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccc(C#N)cc2)cc1
Reactant: Nc1ccccc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: N#Cc1ccc(CCSc2ccccc2N)cc1
Yield: 82.4 %

Procedure:
4-Toluenesulfonic acid, 2-(4-cyanophenyl)ethyl ester (1.9 g; 6.3 mmol; from Example 18(i) above) and K2CO3 (2.0 g) were added to a solution of 2-aminothiophenol (0.875 g; 7.0 mmol) in EtOH (20 mL). The mixture was heated to reflux for 48 hours, cooled, filtered and concentrated in vacuo to an oil which was dissolved in EtOAc (50 mL) and washed with water (25 mL). The organic portion was dried (MgSO4) and concentrated. The residue was purified by flash chromatography (SiO2; Et2O:hexane (1:1)) to obtain 1.32 g (78%) of the sub-title product as a viscous oil.
Reaction SMILES: [CH3:1][CH2:2][C:3]1([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10](=[O:11])[N-:9][C:7](=[O:8])[NH:6][C:4]1=[O:5].[Na+].Cl[CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>CN(C)C=O>[CH3:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][O:21][CH2:20][N:6]1[C:7](=[O:8])[N:9]([CH2:20][O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[C:10](=[O:11])[C:3]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)([CH2:2][CH3:1])[C:4]1=[O:5]
Reactant: CCCCCCCCCCCCOCCl
Reactant: CCC1(c2ccccc2)C(=O)[N-]C(=O)NC1=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCCOCN1C(=O)N(COCCCCCCCCCCCC)C(=O)C(CC)(c2ccccc2)C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 43.9 %

Procedure:
Powdered phenobarbital sodium (25.4 g) was suspended at room temperature in 250 ml of dimethylformamide and 22.1 g of chloromethyldodecanyl ether was added to the suspension. The reaction mixture was stirred overnight and poured into 1 liter of ice-water; the mixture was then stirred for 3 hours and the waxy solid removed by filtration. The wet solid was dissolved in 150 ml of boiling ethanol; to the hot solution 1 g of activated carbon was added and the boiling solution was filtered through a Buchner funnel which contained a compacted layer of finely-divided diatomaceous silica. The filter cake was washed three times with 15 ml of ethanol and the hot solution together with the washings was allowed to cool overnight. The resulting crystals were filtered and recrystallized in the same manner as described for the first crystallization. There was obtained 13 g of N,N'-dilauryloxymethyl phenobarbital (also known as 1,3-dilauryloxymethyl-5-ethyl-5-phenyl barbituric acid), m.p. 48°-50°. When tested as described above the compound exhibited anticonvulsant activity against maximal electroshock, the peak activity occurring at 2 hours and the ED50 being about 50 mg/kg. The LD50 (oral) was determined to be greater than 500 mg/kg.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[C:9]([CH3:10])=[C:8]([S:11][CH2:12][C:13]2[CH:17]=[CH:16][S:15][CH:14]=2)[CH:7]=[CH:6][N:5]=1.[SH:18][C:19]1[NH:23][C:22]2[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=2[N:20]=1.[OH-].[Na+]>C(O)C>[CH3:10][C:9]1[C:4]([CH2:3][S:18][C:19]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=2)=[N:5][CH:6]=[CH:7][C:8]=1[S:11][CH2:12][C:13]1[CH:17]=[CH:16][S:15][CH:14]=1
Reactant: Cc1c(SCc2ccsc2)ccnc1CCl
Reactant: Sc1nc2ccccc2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(SCc2ccsc2)ccnc1CSc1nc2ccccc2[nH]1
Yield: 62 %

Procedure:
2-Chloromethyl-3-methyl-4-(3-thienylmethylthio)pyridine hydrochloride, 2-mercapto-1H-benzimidazole and sodium hydroxide are reacted in ethanol at 25° C. for 20 h. After crystallization from toluene/methanol, the title compound is isolated. Yield: 62%, m.p. 161°-164° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12]([OH:14])=[O:13])[CH:6]=[CH:7][C:8]=1[CH3:9].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[N:40]12[CH2:47][CH2:46][CH:43]([CH2:44][CH2:45]1)[C@@H:42](O)[CH2:41]2>C(#N)C>[N:40]12[CH2:47][CH2:46][CH:43]([CH2:44][CH2:45]1)[C@@H:42]([O:13][C:12](=[O:14])[CH:11]([NH:10][C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[C:3]([F:2])[CH:4]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:41]2
Reactant: Cc1ccc(NC(C(=O)O)c2ccccc2)cc1F
Reactant: O[C@H]1CN2CCC1CC2
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1ccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.5 %

Procedure:
(3-Fluoro-4-methyl-phenylamino)-phenyl-acetic acid hydrochloride (I48) (250 mg, 0.84 mmol), 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate (V) (321 mg, 0.84 mmol), and HOBT (129 mg, 0.84 mmol) are dissolved in acetonitrile (6 mL). DIPEA (0.29 mL, 1.69 mmol) is added, followed by (R)-quinuclidin-3-ol (215 mg, 1.69 mmol) and the resulting yellow solution is stirred at RT overnight (Conversion complete by UPLC/MS-UV). MeCN is evaporated, the residue is dissolved in EtOAc and washed with sat. NaHCO3, water and brine. The organic layer is recovered, dried over Na2SO4, filtered and evaporated. The crude compound is purified by filtration through a pad of silica using DCM/MeOH=9/1 as the eluent to obtain the title compound as a yellow oil (311 mg, quantitative yield, mixture of diastereoisomers).
Reaction SMILES: [Na].Cl[C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])=[O:17])[C:4]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35].Cl.[CH3:37][OH:38]>>[CH3:37][O:38][C:3]1[N:8]=[C:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[N:6]=[C:5]([NH:15][S:16]([CH:19]=[CH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:18])=[O:17])[C:4]=1[O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[O:34][CH3:35]
Reactant: COc1ccccc1Oc1c(Cl)nc(-c2ncccn2)nc1NS(=O)(=O)C=Cc1ccccc1
Reactant: CO
Agent: Cl
Agent: [Na]
Product: COc1ccccc1Oc1c(NS(=O)(=O)C=Cc2ccccc2)nc(-c2ncccn2)nc1OC
Temperature: 25 °C

Procedure:
Sodium (181 mg) was dissolved in 10 ml of methanol and 400 mg of N-[6-chloro-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide was added with stirring at room temperature. The reaction mixture was stirred at room temperature for three hours and poured into a mixture of 1N hydrochloric acid and ice. The crystals separated out therefrom were collected by filtration and the resulting crystals were purified by a silica gel column chromatography (chloroform-methanol=40:1). The resulting yellow amorphous substance was crystallized in ether and collected by filtration to give 273 mg of N-[6-methoxy-5-(2-methoxyphenoxy)-2-(2-pyrimidinyl)-4-pyrimidinyl]-2-phenylethenesulfonamide.
Reaction SMILES: F[C:2](F)(F)[C:3](O)=[O:4].[F:8][C:9]1[C:10]([C:33]([F:36])([F:35])[F:34])=[C:11]([CH:16]2[CH2:21][CH2:20][N:19]([C:22]([C:24]3[C:32]4[CH2:31][CH2:30][NH:29][CH2:28][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:18][CH2:17]2)[CH:12]=[CH:13][C:14]=1[F:15].C(Cl)(=O)C>>[F:8][C:9]1[C:10]([C:33]([F:34])([F:35])[F:36])=[C:11]([CH:16]2[CH2:17][CH2:18][N:19]([C:22]([C:24]3[C:32]4[CH2:31][CH2:30][N:29]([C:3](=[O:4])[CH3:2])[CH2:28][C:27]=4[NH:26][N:25]=3)=[O:23])[CH2:20][CH2:21]2)[CH:12]=[CH:13][C:14]=1[F:15]
Reactant: O=C(O)C(F)(F)F
Reactant: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2ccc(F)c(F)c2C(F)(F)F)CC1
Solvent: CC(=O)Cl
Product: CC(=O)N1CCc2c(C(=O)N3CCC(c4ccc(F)c(F)c4C(F)(F)F)CC3)n[nH]c2C1
Yield: 80 %

Procedure:
Following general procedure GP-G1, (4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone TFA salt (34) and acetyl chloride were converted to give 1-(3-(4-(3,4-difluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridin-6(7H)-yl)ethanone as a white solid (29.2 g, 80%): 1H NMR (500 MHz, CDCl3) δ10.59 (br, 1H), 7.36-7.29 (m, 1H), 7.15 (m, 1H), 4.81 (br, 2H), 4.77 and 4.65 (s, 2H), 3.85 (br, 1H), 3.68 (m, 1H), 3.26-2.69 (m, 5H), 2.21 and 2.19 (s, 3H), 1.89-1.73 (m, 4H) MS (ESI+) m/z 457 [M+H]+.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH:12]=O.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Cl:9][C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][NH:8][C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=1
Reactant: Nc1cccc(F)n1
Reactant: O=Cc1ccccc1Cl
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: Fc1cccc(NCc2ccccc2Cl)n1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To 6-fluoro-pyridin-2-ylamine (43, 2.47 g, 22.0 mmol) in 60.0 mL of acetonitrile, 2-chloro-benzaldehyde (44, 3.09 g, 22.0 mmol), triethylsilane (14.0 mL, 87.6 mmol) and trifluoroacetic acid (7.00 mL, 90.9 mmol) were added. The reaction was stirred at 80° C. for 4 hours, then solvents removed under vacuum, and the residue was combined with aqueous potassium carbonate and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound, which was used in the next step without further purification. MS (ESI) [M+H+]+=272.1.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([NH:9][C:10]3[N:14]([CH3:15])[C:13]4[CH:16]=[CH:17][C:18]([C:20](O)=[O:21])=[CH:19][C:12]=4[N:11]=3)[S:8][C:4]=2[CH:3]=1.[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[C:25]([O:29][C:30]([N:32]1[CH2:37][CH2:36][CH:35]([NH:38][C:20]([C:18]2[CH:17]=[CH:16][C:13]3[N:14]([CH3:15])[C:10]([NH:9][C:7]4[S:8][C:4]5[CH:3]=[C:2]([Cl:1])[CH:24]=[CH:23][C:5]=5[N:6]=4)=[N:11][C:12]=3[CH:19]=2)=[O:21])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1c(Nc2nc3ccc(Cl)cc3s2)nc2cc(C(=O)NC3CCN(C(=O)OC(C)(C)C)CC3)ccc21
Yield: 74.1 %

Procedure:
4-{[2-(6-Chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester (800 mg) was prepared by following General Procedure F starting from 2-(6-chloro-benzothiazol-2-ylamino)-1-methyl-1H-benzoimidazole-5-carboxylic acid (716 mg), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (500 mg), HBTU (952 mg), and DIEA (700 uL) in DMF (5 mL).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[N:6][C:7]=1[CH:8]=[CH2:9].Br[CH2:12][C:13]#[C:14][CH3:15].[Na].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:12]([O:10][C:4]1[CH:3]=[C:2]([CH3:1])[C:7]([CH:8]=[CH2:9])=[N:6][CH:5]=1)[C:13]#[C:14][CH3:15]
Reactant: C=Cc1ncc(O)cc1C
Reactant: CC#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [Na]
Solvent: CN(C)C=O
Product: C=Cc1ncc(OCC#CC)cc1C
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A reaction mixture of 5-methyl-6-vinylpyridin-3-ol (100 mg, 0.00074 mmol), sodium 1-bromobut-2-yne (118 mg, 0.00088 mol, Alfa-Aesar) and cesium carbonate (361 mg, 0.0011 mol) in DMF (2 mL) was stirred for 2 h at 80° C. After completion of the reaction, reaction mixture was cooled to ambient temperature, poured into ice-cold water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The crude residue was purified by column chromatography using silica gel and eluting with 0-10% ethyl acetate in petroleum ether to give 5-(but-2-yn-1-yloxy)-3-methyl-2-vinylpyridine as an off white solid (85 mg, 61.5%). MS m/z=188.3 [M+H]+.
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[NH:18][C:17]3=[O:25])[CH2:10][CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[N:11]1([CH2:14][CH2:15][N:16]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[NH:18][C:17]2=[O:25])[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: O=c1[nH]c2ccccc2n1CCN1CCN(Cc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=c1[nH]c2ccccc2n1CCN1CCNCC1

Procedure:
A mixture of 79 parts of 1,3-dihydro-1-{2-[4-(phenylmethyl)-1-piperazinyl]ethyl}-2H-benzimidazol-2-one and 320 parts of methanol is hydrogenated at normal pressure and at room temperature with 10 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated. The oily residue is alkalized with ammonium hydroxide and a small amount of water is added. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The oily residue solidifies on triturating in 4-methyl-2-pentanone. The product is filtered off and dried, yielding 1,3-dihydro-1-[2-(1-piperazinyl)ethyl]-2H-benzimidazol-2-one; mp. 122.6° C.
Reaction SMILES: Cl[CH:2]([CH2:19][CH2:20][CH2:21]Cl)[CH2:3][NH:4][C:5](=[O:18])[C:6]1[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:9]=[CH:8][C:7]=1[O:16][CH3:17].[CH:23]1([NH2:26])[CH2:25][CH2:24]1>O>[CH:23]1([N:26]2[CH2:21][CH2:20][CH2:19][CH:2]2[CH2:3][NH:4][C:5](=[O:18])[C:6]2[CH:11]=[C:10]([S:12](=[O:15])(=[O:14])[NH2:13])[CH:9]=[CH:8][C:7]=2[O:16][CH3:17])[CH2:25][CH2:24]1
Reactant: COc1ccc(S(N)(=O)=O)cc1C(=O)NCC(Cl)CCCCl
Reactant: NC1CC1
Solvent: O
Product: COc1ccc(S(N)(=O)=O)cc1C(=O)NCC1CCCN1C1CC1
Temperature: 0 °C
Yield: 189.6 %

Procedure:
36.9 g (0.1 mole) of N-(2,5-dichloropentyl)-2-methoxy-5-sulphamoyl-benzamide and 57 g of cyclopropylamine are placed in 250 ml bottle. They are brought to reflux for 6 hours, left to stand for 1 night then brought back to reflux for 5 hours. The suspension obtained is poured into 300 ml of water and 50 g of ice. The white precipitate is washed with water and dried in an oven at 60° C. It melts at 163° C. and weighs 29.5 g (83.6%). It is dissolved in 2 liters of acetonitrile and filtered in the presence of carbon black. The filtrate is left to crystallise. The crystals obtained are filtered, washed with acetonitrile and dried at 40° C. 67 g (yield 74.9%) of N-(1-cyclopropyl-2-pyrrolidinylmethyl)-2-methoxy-5-sulphamoylbenzamide is collected, melting at 180° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.Br[C:12]1[S:13][CH:14]=[CH:15][N:16]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:12]2[S:13][CH:14]=[CH:15][N:16]=2)=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1nccs1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(-c2nccs2)cc1
Temperature: 95 °C
Reaction time: 5 h
Yield: 82.5 %

Procedure:
To a stirred solution of (4-fluorophenyl)boronic acid (10 g, 60.9 mmol) in toluene (70 mL) and ethanol (200 mL) was added 2-bromothiazole (12.7 g, 91.4 mmol) and Na2CO3 (2M, 100 mL, 19.39 g). The reaction mixture was purged with argon for 45 min, Pd(PPh3)4 (3.5 g, 3.04 mmol) added, and the mixture stirred at 95° C. for 5 h. The reaction mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution (2×100 mL), and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with ice-cold water (2×100 mL), followed by brine solution (50 mL). The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to obtain crude product. The crude product was purified by column chromatography (100-200 mesh silica gel; using 10% ethyl acetate in hexane) to obtain 2-(4-fluorophenyl)thiazole as white solid (9.0 g, 82% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.98 (dd, 2H), 7.88 (d, 1H); 7.91 (d, 1H), 7.88 (d, 1H), 7.31 (t, 2H); LC-MS m/z calculated for [M+H]+ 180.02 found 179.91.
Reaction SMILES: [C:1]1([C:7]2[O:11][N:10]=[C:9]([O:12][CH2:13][C:14]([OH:16])=O)[C:8]=2[Cl:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+]([O-])(O)=O.[O:22]([CH2:26][CH2:27][NH2:28])[N+:23]([O-:25])=[O:24].C(OC(C)C)(C)C>>[O:22]([CH2:26][CH2:27][NH:28][C:14](=[O:16])[CH2:13][O:12][C:9]1[C:8]([Cl:17])=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:11][N:10]=1)[N+:23]([O-:25])=[O:24]
Reactant: O=C(O)COc1noc(-c2ccccc2)c1Cl
Reactant: NCCO[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(C)OC(C)C
Product: O=C(COc1noc(-c2ccccc2)c1Cl)NCCO[N+](=O)[O-]
Yield: 45.2 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.70 g of 5-phenyl-4-chloro-3-isoxazolyloxyacetic acid and 0.46 g of nitroxyethylamine nitrate, 0.42 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1.[OH-].[K+].[C:23]1(C)C=CC(S(OCC)(=O)=O)=C[CH:24]=1>CN(C)C=O>[CH2:23]([O:1][C:2]1[CH:3]=[C:4]([O:8][CH2:9][C@@H:10]2[CH2:13][CH2:12][N:11]2[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH:5]=[N:6][CH:7]=1)[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc(O)c1
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CCOc1cncc(OC[C@@H]2CCN2C(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 97.8 %

Procedure:
A solution of 5-hydroxy-3-(1-Boc-2-(S)-azetidinylmethoxy)pyridine (500 mg, 1.78 mmol, from step 120f) in dimethylformamide (15 mL) was treated with ground KOH (170 mg, 1.7 mmol) and stirred for 30 minutes at room temperature. To this mixture was rapdily added ethyl p-toluenesulfonate (430 mg, 2.14 mmol), and the resultant was stirred at 80° C. overnight. The mixture was concentrated to remove the dimethylformamide, and the residue was diluted with water and extracted with EtOAc. The organic extracts were combined, dried (MgSO4), filtered and concentrated under vacuum to give 1.0 g of unpurified product. This material was purified by chromatography (silica gel: hexane/EtOAc, 1:1) to give 537 mg (98%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ: 1.40 (s, 9H), 1.42 (t, J=6 Hz, 3H), 2.30 (m, 2H), 3.92 (t, J=9 Hz, 2H), 4.05 (q, J=6 Hz, 2H), 4.16 (m, 1H), 4.30 (m, 1H), 4.54 (m, 1H), 6.80 (m, 1H), 7.95 (m, 2H). MS (CI/NH3) m/e: 309 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9]Br)[C:3]=1[CH2:11]Br.C(=O)([O-])O.[K+].[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CC#N>[CH2:18]([N:25]1[CH2:11][C:3]2[C:4](=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[Br:1])[CH2:9]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCc1ccccc1
Reactant: Fc1ccc(Br)c(CBr)c1CBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: CC#N
Product: Fc1ccc(Br)c2c1CN(Cc1ccccc1)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 46.7 %

Procedure:
To a mixture of 1-bromo-2,3-bis(bromomethyl)-4-fluorobenzene (7.59 g, 21.0 mmol) and potassium hydrogen carbonate (5.26 g, 52.6 mmol) in 800 mL CH3CN was added benzylamine (2.25 g, 21.0 mmol). The resulting suspension was refluxed for 8 h then stirred at 25° C. for 18 h. The mixture was filtered, and the residue was purified by column chromatography on silica gel (gradient elution, 10 to 60% DCM in hexanes) and concentrated to give 2-benzyl-4-bromo-7-fluoroisoindoline (3.00 g, 46% yield) as colorless oil. LRMS (ESI) m/z 306.3 [(M+H)+; calcd for C15H14NBrF: 306.2].