Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:11]1([S:17]([CH:20]=[CH2:21])(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CC1C(P(C2C(C)=CC=CC=2)C2C(C)=CC=CC=2)=CC=CC=1.C(N(CC)CC)C>CN(C=O)C.ClCCl.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:11]1([S:17](/[CH:20]=[CH:21]/[C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)(=[O:19])=[O:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C=CS(=O)(=O)c1ccccc1
Reactant: Brc1ccc2[nH]ccc2c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=S(=O)(/C=C/c1ccc2[nH]ccc2c1)c1ccccc1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of 5-bromoindole (5.0 g, 25.5 mmol), phenylvinylsulfone (7.50 g, 44.64 mmol), Pd(OAc)2 (0.46 g, 2.05 mmol), tri-O-tolylphosphine (1.55 g, 5.10 mmol) and triethylamine (4.88 g, 48.46 mmol) was heated to 95-105° C. for 6-15 h in DMF. The reaction mixture was cooled to RT, diluted with dichloromethane and filtered over a bed of filter aid. The filtrate was sequentially washed with water and brine, and dried over sodium sulphate. The organic layer was concentrated under vacuum and the product precipitated from dichloromethane and hexane as a solid in about 85-90% yield.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([S:8](Cl)(=[O:10])=[O:9])[CH:7]=1.N1C=CC=CC=1.[NH2:19][C@H:20]1[CH2:25][CH2:24][C@H:23]([OH:26])[CH2:22][CH2:21]1>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([S:8]([NH:19][CH:20]2[CH2:25][CH2:24][CH:23]([OH:26])[CH2:22][CH2:21]2)(=[O:10])=[O:9])[CH:7]=1
Reactant: O=S(=O)(Cl)c1cc(Br)ccc1Cl
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(NC1CCC(O)CC1)c1cc(Br)ccc1Cl
Reaction time: 18 h

Procedure:
5-Bromo-2-chloro-benzenesulfonyl chloride (1.0 g, 3.45 mmol) (Intermediate E, Step 1) and pyridine (2 ml) are added to a stirred suspension of trans-4-aminocyclohexanol (2.0 g, 17.2 mmol) suspended in DCM (20 ml). After 18 h, the solvents are removed and the residue is partitioned between aq. 1M HCl and ethyl acetate. The organic extract is dried over Mg2SO4 and the solvent is removed. The residue is purified by chromatography on silica, eluting with ethyl acetate:hexane (1:1 to 1:0) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[CH:33]1([NH2:43])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35][CH2:34]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:43][CH:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH2:36][CH2:35][CH2:34]1)=[O:31]
Reactant: NC1CCCc2ccccc21
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Product: COc1ccc(CC2c3cc(OC(C)C)c(OC)cc3CCN2CC(=O)NC2CCCc3ccccc32)cc1OC

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 1,2,3,4-tetrahydro-1-naphthylamine
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[C:9]([Cl:14])[CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](N(OC)C)=[O:16])(=[O:3])[CH3:2].[C:21]1([Li])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(OCC)C.O1CCCC1>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[C:9]([Cl:14])[CH:10]=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:15](=[O:16])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CON(C)C(=O)c1[nH]c2c(Cl)cccc2c1NC(C)=O
Reactant: [Li]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(=O)Nc1c(C(=O)c2ccccc2)[nH]c2c(Cl)cccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 26 %

Procedure:
To a solution of 3-acetylamino-7-chloro-2-[(N-methoxy-N-methylamino)carbonyl]indole (step 4, 321 mg, 1.08 mmol) in diethyl ether-tetrahydrofuran (1:1, 10 ml) was added phenyl lithium (1M solution in cyclohexane, 5.4 ml, 5.42 mmol) at −78° C. After stirring for 1 h, the mixture was allowed to warm to 0° C. and stirred for an additional 2 h. The mixture was quenched with saturated aqueous ammonium chloride (20 ml) and extracted with ether (150 ml). The organic layer was washed with water (50 ml) and dried (MgSO4). Removal of solvent gave an oily residue. Purification by flash column chromatography eluting with ethyl acetate/hexane (1:3) afforded yellow crystals. Recrystallization from ethyl acetate gave 87 mg, (26%) of the title compound. m.p.: 185-188° C. IR (KBr) ν: 3240, 1690, 1628, 1543, 1375, 1315, 1250, 725 cm1 1H-NMR (CDCl3) δ: 9.77 (1 H, br s), 8.36 (1 H, br s), 8.18 (1 H, d, J=8.6 Hz), 7.87-7.83 (2 H, m), 7.71-7.57 (3 H, m), 7.40 (1 H, dd, J=1.0, 7.6 Hz), 7.10 (1 H, dd, J=7.6, 8.4 Hz), 2.26 (3 H, s).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[CH:14]=[CH:15][C:16]([O:75][CH2:76][C:77]4[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=4)=[C:17]([CH:74]=3)[CH2:18][C@H:19]([NH:63][C:64]([O:66][CH2:67][C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)=[O:65])[C:20](=[O:62])[NH:21][C@@H:22]([CH2:40][C@@H:41]([O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])[CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])[C:23](=[O:39])[NH:24][C@H:25]([C:29]([O:31]CC3C=CC=CC=3)=[O:30])[CH2:26][C:27]=1[CH:28]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[OH-].[Li+].Cl>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[C:13]3[CH:14]=[CH:15][C:16]([O:75][CH2:76][C:77]4[CH:78]=[CH:79][CH:80]=[CH:81][CH:82]=4)=[C:17]([CH:74]=3)[CH2:18][C@H:19]([NH:63][C:64]([O:66][CH2:67][C:68]3[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=3)=[O:65])[C:20](=[O:62])[NH:21][C@@H:22]([CH2:40][C@@H:41]([O:54][Si:55]([C:58]([CH3:61])([CH3:60])[CH3:59])([CH3:57])[CH3:56])[CH2:42][NH:43][C:44]([O:46][CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)=[O:45])[C:23](=[O:39])[NH:24][C@H:25]([C:29]([OH:31])=[O:30])[CH2:26][C:27]=1[CH:28]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](CNC(=O)OCc1ccccc1)C[C@@H]1NC(=O)[C@@H](NC(=O)OCc2ccccc2)Cc2cc(ccc2OCc2ccccc2)-c2ccc(OCc3ccccc3)c(c2)C[C@@H](C(=O)OCc2ccccc2)NC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)[Si](C)(C)O[C@@H](CNC(=O)OCc1ccccc1)C[C@@H]1NC(=O)[C@@H](NC(=O)OCc2ccccc2)Cc2cc(ccc2OCc2ccccc2)-c2ccc(OCc3ccccc3)c(c2)C[C@@H](C(=O)O)NC1=O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
210 mg (0.19 mmol) of the compound from Example 66A are dissolved in 2 ml of THF, and 1 ml each of water and methanol are added. After the addition of 13 mg (0.56 mmol) of lithium hydroxide the mixture is stirred at RT for 12 h. The reaction solution is then diluted with 30 ml of water and adjusted to pH=3 by adding 1N hydrochloric acid. The precipitate is collected by filtration and dried under high vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.C([Li])CCC.[CH2:16](I)[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].C(OCC)C>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCI
Reactant: COc1cccc(OC)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: O
Product: CCCCCCCc1c(OC)cccc1OC
Temperature: -78 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
1,3-dimethoxybenzene (0.25 mol, 34 ml) was dissolved in THF (1 liter, dried) and the resultant solution was cooled in an ice bath. n-Butyl lithium (200 ml, 0.32 moles) was added over a period of one hour. The resultant solution was stirred for 2 hours in an ice bath. Solution was then cooled to -78° C. and n-heptyl iodide (226 ml, 0.22 moles) was quickly added. The solution was then allowed to warm to room temperature and stirred overnight then refluxed for 2 hours. The solution was cooled and a mixture of diethyl ether and water was added. The ether layer was collected, dried over magnesium sulfate, filtered and evaporated to dryness. The residue was chromatographed by HPLC (eluted with hexane) to yield 34.0 g of the title product.
Reaction SMILES: [CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15](O)=[O:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2].[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:1]([O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([C:15]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:16])=[CH:12][CH:13]=2)[CH:8]=[C:7]([NH:18][C:19]2[CH:23]=[C:22]([CH3:24])[NH:21][N:20]=2)[N:6]=1)([CH3:3])[CH3:2]
Reactant: C1CCNC1
Reactant: Cc1cc(Nc2cc3cc(C(=O)O)ccc3c(OC(C)C)n2)n[nH]1
Product: Cc1cc(Nc2cc3cc(C(=O)N4CCCC4)ccc3c(OC(C)C)n2)n[nH]1

Procedure:
Similar procedure as described in example 384 was used, starting from 1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinoline-6-carboxylic acid and Pyrrolidine to give [1-Isopropoxy-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-yl]-pyrrolidin-1-yl-methanone. LC-MS: m/e 394 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:3](=O)[NH:4][C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.P(Cl)(Cl)([Cl:19])=O>CN(C=O)C>[Br:1][C:2]1[C:3]([Cl:19])=[N:4][C:5]([CH3:15])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1cc(-c2ccc(Cl)cc2)c(Br)c(=O)[nH]1
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(Cl)cc2)c(Br)c(Cl)n1
Temperature: 100 °C
Reaction time: 7 h
Yield: 60 %

Procedure:
To a suspension of 3-bromo-4-(4-chlorophenyl)-6-methylpyridin-2(1H)-one (280 mg, 0.94 mmol) in phosphorus oxychloride (5 mL) was added anhydrous DMF (a few drops). The mixture was stirred at 100° C. for 7 h. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure to remove most of the phosphorus oxychloride. The remaining liquid was cooled at 0° C. and carefully quenched by addition of water. The resulting mixture was then adjusted to pH 7-8 by addition of saturated aqueous NaHCO3. The mixture was then extracted with EtOAc (30 mL×3). The combined EtOAc extracts were washed with saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified using a silica gel cartridge (12 g) eluted with a gradient of EtOAc (0-70%) in hexanes to obtain 180 mg (60%) of the title compound as a white solid. HPLC/MS: retention time=3.95 min, [M+H]+=316.0.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:38]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)(=[O:40])=[O:39])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Reactant: O=S(=O)(Cl)c1ccccc1
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4ccccc4)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and -benzenesulfonyl chloride. Purity (ELSD, based on MW=561.6)=95%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].S(O[CH2:22][CH:23]1[CH2:28][CH2:27][CH:26]=[CH:25][O:24]1)(C1C=CC(C)=CC=1)(=O)=O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:22][CH:23]2[CH2:28][CH2:27][CH:26]=[CH:25][O:24]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC=CO2)cc1
Reactant: Oc1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1ccc(OCC2CCC=CO2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24.5 %

Procedure:
A mixture of a solution of 247 mg of p-fluorophenol in 1 ml of dimethylformamide with 87 mg of 55% sodium hydride was stirred at room temperature for 30 minutes. 537 mg of 2-tosyloxymethyl-3,4-dihydro-2H-pyran were then added to the mixture, which was allowed to react at 90° C. for 3 hours. Thereafter, the mixture was treated and the product purified essentially as described in Example 34(a) to give 102 mg of 2-(4-fluorophenoxymethyl)-3,4-dihydro-2H-pyran as a colourless oil.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([Si:15](Cl)([CH2:18][CH3:19])[CH2:16][CH3:17])[CH3:14].[CH3:21][Si:22]([O:25][C:26](=[O:33])[CH2:27][O:28][Si:29]([CH3:32])([CH3:31])[CH3:30])([CH3:24])[CH3:23]>C1COCC1>[CH2:13]([Si:15]([CH2:18][CH3:19])([CH2:16][CH3:17])[O:33][CH:26]([O:25][Si:22]([CH3:24])([CH3:23])[CH3:21])[CH2:27][O:28][Si:29]([CH3:30])([CH3:32])[CH3:31])[CH3:14]
Reactant: CC[Si](Cl)(CC)CC
Reactant: C[Si](C)(C)OCC(=O)O[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC[Si](CC)(CC)OC(CO[Si](C)(C)C)O[Si](C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (15.5 mL, 0.11 mol) in THF (100 mL) at −78° C. was added a 1.6 M hexanes solution of n-butyl lithium (70 mL, 0.11 mol) over 15 minutes. After stirring for an additional 15 minutes at this temperature, triethylsilylchloride (16.7 mL, 0.1 mol) was added over 10 minutes followed by the addition of trimethylsilyl-2 -(trimethylsiloxy)acetate (24.4 mL, 0.1 mol) over 30 minutes. The reaction was stirred at −78° C. for 30 minutes and warmed to ambient temperature by removing the cryogenic bath. The THF solvent was removed by vacuum rotary evaporation at 40° C. to precipitate out the lithium chloride. The mixture was taken up in 300 mL of hexanes and 5 mL of triethylamine and stirred for 5 min and the salt was allowed to settle. The supernatant was twice filtered through a pad of diatomaceous earth to give clear solution. The solution was concentrated under rotary evaporation to give the lightly yellow colored oil product as a mixture of geometrical isomers (4:1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[F:11][C:12]1[CH:23]=[CH:22][C:15]([CH2:16][C@@H:17]([C:19]([OH:21])=[O:20])[NH2:18])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CS(C)=O>[Cl:1][C:2]1[CH:9]=[C:8]([NH:18][C@H:17]([C:19]([OH:21])=[O:20])[CH2:16][C:15]2[CH:14]=[CH:13][C:12]([F:11])=[CH:23][CH:22]=2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1Cl
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#Cc1ccc(N[C@@H](Cc2ccc(F)cc2)C(=O)O)cc1Cl
Temperature: 90 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of 2-chloro-4-fluorobenzonitrile (1.8 g) in dimethyl sulfoxide (30 mL) were added 4-fluorophenylalanine (2.54 g) and cesium carbonate (4.90 g), and the mixture was stirred at 90° C. overnight. After allowing to room temperature, ethyl acetate was added, and the mixture was extracted twice with saturated aqueous sodium hydrogen carbonate solution. The aqueous layers were combined, and acidified with citric acid, and the mixture was extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound as a brown oil (yield: 3.69 g, 100%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[N:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)[C:21]([C:22]#[N:23])=[C:17]2[N:16]=[CH:15][CH:14]=1>CO.O1CCOCC1.O.NN>[NH2:3][CH2:12][C:13]1[N:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[CH:26][CH:25]=3)[C:21]([C:22]#[N:23])=[C:17]2[N:16]=[CH:15][CH:14]=1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c(CN3C(=O)c4ccccc4C3=O)ccnc12
Agent: NN
Solvent: O
Solvent: CO
Solvent: C1COCCO1
Product: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c(CN)ccnc12
Temperature: 60 °C
Yield: 70.9 %

Procedure:
To a solution of 7-((1,3-dioxoisoindolin-2-yl)methyl)-2-(4-phenoxyphenyl) pyrazolo[1,5-a]pyrimidine-3-carbonitrile (290 mg, 0.62 mmol) in 5 mL of MeOH and 5 mL of dioxane was added 12 drops of hydrazine hydrate. The reaction mixture was stirred and heated to 60° C. for 3 hr. The mixture was concentrated and suspended in 20 mL of solvent (DCM/MeOH=10/1). The mixture was filtered and the filtrate was concentrated and purified by the flash chromatography eluting with EA followed by DCM/MeOH (10/1) to give 150 mg (71%) of 7-(aminomethyl)-2-(4-phenoxyphenyl) pyrazolo[1,5-a]pyrimidine-3-carbonitrile as a solid. MS (ESI) m/e [M+1]+ 342.1.
Reaction SMILES: [Na].[C:2](#[N:4])[CH3:3].[F:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1>O>[NH2:11][C:10]([C:9]1[CH:12]=[CH:13][C:6]([F:5])=[CH:7][CH:8]=1)=[CH:3][C:2]#[N:4]
Reactant: N#Cc1ccc(F)cc1
Reactant: CC#N
Agent: [Na]
Solvent: O
Product: N#CC=C(N)c1ccc(F)cc1

Procedure:
The procedure of Example 1 was used to react 2.7 grams (0.117 mole) of sodium and 5.2 grams (0.126 mole) of acetonitrile with 10.0 grams (0.083 mole) of p-fluorobenzonitrile. After the addition of water, the reaction mixture was extracted three times with chloroform. The combined chloroform extracts were concentrated to obtain a dark-colored crystalline mass which was recrystallized four times from a mixture of chloroform and hexane to obtain yellow plates of β-amino-β-(p-fluorophenyl)acrylonitrile, mleting point 110°-112°C. Analysis: -- Calculated for C9H7N2F (percent): C, 66.66; H, 4.35; N, 17.27; F, 11.72. Found (percent): C, 66.48; H, 4.34; N, 17.21; F, 11.19.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([CH3:23])[CH:15]=1.[C:24](=O)([O:27]C)[O:25]C>C1COCC1>[Br:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[C:16]([CH2:23][C:24]([OH:27])=[O:25])[CH:15]=1
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: COC(=O)OC
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)Cc1cc(Br)ccc1C(=O)O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 93.8 %

Procedure:
To a solution of diisopropylamine (13.26 mL, 93 mmol, 4.0 equiv.) in THF (50 mL) was slowly added n-BuLi (37.2 mL, 93 mmol, 4.0 equiv.) at −78° C. The mixture was allowed to warm to 0° C. and stirred at that temperature for 5 min. The reaction was cooled back to −78° C. and to this mixture was slowly added 4-bromo-2-methylbenzoic acid (5.0 g, 23.25 mmol) and dimethyl carbonate (3.91 mL, 46.5 mmol, 2.0 equiv.) in THF (50 mL) and the mixture was stirred at −78° C. for 5 min. The dry ice bath was removed and the reaction was allowed to stir at room temperature for 4 h. Upon completion of the reaction, the mixture was quenched by the addition of 75 mL water and allowed to stir overnight. The aqueous layer was separated from the organic layer. The aqueous layer was acidified with conc. HCl until pH 2, extracted with EtOAc (2×50 mL), dried over Na2SO4, filtered and evaporated to dryness to yield a white solid. The solid was recrystallized from hot EtOAc/hexanes to yield 5.65 g of 4-bromo-2-(carboxymethyl)benzoic acid as a white solid.
Reaction SMILES: [CH2:1]([O:8][NH:9][C@H:10]1[CH2:15][NH:14][C@H:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[O:30]=[C:31](Cl)OC(Cl)(Cl)Cl>C(#N)C.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][N:9]1[C:31](=[O:30])[N:14]2[CH2:15][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)[C@@H]1CC[C@@H](NOCc2ccccc2)CN1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95.1 %

Procedure:
To a solution of 4.14 g (13.51 mmol) of (2S,5R)-tert-butyl 5-(benzyloxyamino)piperidine-2-carboxylate in dehydrated acetonitrile (615 mL), under argon atmosphere, at 0° C., was added triethylamine 4.9 mL (35.16 mmol), and subsequently 1.18 mL (9.78 mmol) of diphosgene was added dropwise within 5 minutes, followed by stirring at the same temperature for 10 minutes. 182 mg (1.623 mmol) of 4-dimethylaminopyridine was added to this solution, and the temperature was raised to room temperature, followed by allowing to react for 3 hours. After the reaction mixture was concentrated under reduced pressure to the volume of one tenth thereof, the resulting concentrated solution was diluted with ethyl acetate, washed sequentially with water, 5% aqueous citric acid solution, 6.5% aqueous sodium hydrogencarbonate solution and saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was applied to silica gel column chromatography (hexane/ethyl acetate=2/1) to afford 3.09 g of the title compound (yield 69%). The resulting solid was recrystallized from ethyl acetate-hexane, and the generated precipitate was filtered off. The wet crystal was washed with hexane, and subsequently dried under reduced pressure at room temperature to afford the title compound as a colorless crystalline powder. Enantiomeric excess: 99.4% ee (CHIRALPAK AD-H, 4.6×150 mm, hexane/ethanol=2/1, UV 210 nm, flow rate 1 mL/min., retention time 8.0 min.).
Reaction SMILES: [CH3:1][CH2:2][O:3][P:4]([O:9][CH2:10][CH3:11])([CH2:6][C:7]#[N:8])=[O:5].C(N(CC)CC)C.N1C=CC=CC=1.[SH2:25]>>[CH2:10]([O:9][P:4]([CH2:6][C:7]([NH2:8])=[S:25])(=[O:5])[O:3][CH2:2][CH3:1])[CH3:11]
Reactant: S
Reactant: CCOP(=O)(CC#N)OCC
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: CCOP(=O)(CC(N)=S)OCC
Reaction time: 8 h
Yield: 84.7 %

Procedure:
A 250-mL round-bottom flask equipped with a dry-ice condenser and drying tube filled with potassium hydroxide pellets, was charged with 50.0 g (0.2822 mol) of diethyl cyanomethyl phosphonate (Aldrich Lot HY0151136Y), 79.0 mL (0.5668 mol) of triethylamine and 53.0 mL (0.6553 mol) of pyridine. To the resulting solution was added 3.3 g (0.390 mol) of hydrogen sulfide via submerged tube. The reaction flask was stoppered and stirred overnight (small samples were withdrawn, evaporated at 55° C. and 10 torr, redissolved in CDCl3 and checked by NMR spectroscopy for completion of reaction). After about 16 hours, the reaction mixture was evaporated at 55° C. and 10 torr, the crystalline residue was taken up in 200 mL of dichloromethane and the resulting solution was washed with 200 mL of a 1:1 water-saturated sodium chloride solution. The aqueous phase was reextracted with 100 mL of dichloromethane. 50 mL of 1:1 water-saturated sodium chloride solution was used to wash the first extract and then the second. The extracts were combined, dried over sodium sulfate, and evaporated to yield 50.46 g of (2-amino-2-thioxoethyl)phosphonic acid diethyl ester as an off-white, crystalline material after drying at 45° C. and 10 tort, 85% yield.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1.[CH2:17](Br)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cc(O)c2ccccc2c1
Product: CCOC(=O)c1cc(OCc2ccccc2)c2ccccc2c1

Procedure:
By alkylating ethyl 4-hydroxy-naphthalene-2-carboxylate [J. Agric. Chem Soc. Japan 24, 313 (1950)] with benzyl bromide in an analogous manner to that described in Example 14(a) there was obtained ethyl 4-benzyloxy-naphthalene-2-carboxylate as an almost colourless solid; MS: 21 6 (M)+.