Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][C:5](=O)[CH3:6])(=[O:3])[CH3:2].[CH3:8][N:9](C)[CH2:10]CO.C(Cl)(Cl)Cl.[OH-].[Na+]>C(O)(=O)C>[C:1]([O:4][CH2:5][CH2:6][N:9]([CH3:10])[CH3:8])(=[O:3])[CH3:2]
Reactant: CN(C)CCO
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CC(=O)OCCN(C)C
Reaction time: 0.5 h
Yield: 77.2 %

Procedure:
With gentle cooling, 168.5 g of acetic anhydride are added dropwise to 133.6 g of 2-dimethylaminoethanol in the course of 20 minutes, whereupon the temperature rises from 20° C. to a maximum of 105° C. The reaction mixture is kept for 30 minutes at 100° C. and then cooled. Then 750 ml of CHCl3 are added and the acetic acid formed is neutralised with 380 ml of 20% sodium hydroxide solution at 30°-35° C. with cooling. The two phases are separated and the organic phase is washed with a small amount of H2O. Distillation of the residue affords 151.7 g (77.7%) of product with a boiling point of 114° C./225 torr.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[OH:12][CH:13]([C:21]([F:24])([F:23])[F:22])[C:14]([F:20])([F:19])[S:15]([O-:18])(=[O:17])=[O:16].[C:25]1([S+:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[F:20][C:14]([F:19])([S:15]([O-:18])(=[O:17])=[O:16])[CH:13]([O:12][C:7](=[O:8])[C:6]1[CH:10]=[CH:11][C:3]([CH:1]=[CH2:2])=[CH:4][CH:5]=1)[C:21]([F:24])([F:22])[F:23].[C:38]1([S+:31]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=1
Reactant: O=S(=O)([O-])C(F)(F)C(O)C(F)(F)F
Reactant: C=Cc1ccc(C(=O)Cl)cc1
Agent: Cl
Agent: c1ccc([S+](c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=Cc1ccc(C(=O)OC(C(F)(F)F)C(F)(F)S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Under ice cooling, 2.0 g (12 mmol) of the resulting 4-vinylbenzoyl chloride in methylene chloride was added dropwise to a mixture of 4.9 g (10 mmol) of triphenylsulfonium 2-hydroxy-1,1,3,3,3-pentafluoropropane-1-sulfonate in Synthesis Example 1-11, 1.21 g (12 mmol) of triethylamine, 0.24 g (2 mmol) of N,N-dimethylaminopyridine, and 20 g of methylene chloride. The reaction mixture was stirred at room temperature for 2 hours. Thereafter, 11 g of 5% dilute hydrochloric acid was added. The organic layer was separated and washed with water whereupon methylene chloride was distilled off under vacuum. The residue was combined with 30 g of methyl isobutyl ketone and washed with dilute aqueous ammonia and then with water, whereupon the methyl isobutyl ketone was distilled off under vacuum. Diisopropyl ether was added to the residue, followed by decantation. The target compound, triphenylsulfonium 1,1,3,3,3-pentafluoro-2-(4-vinyl-benzoyloxy)-propane-1-sulfonate was obtained as colorless oil (5.3 g, yield 85%). The compound has the following structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]#[N:10].Br[CH2:12][CH:13](Br)C.[H-].[Na+].O>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1([C:9]#[N:10])[CH2:13][CH2:12]1
Reactant: CC(Br)CBr
Reactant: N#CCc1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC1(c2ccccc2Cl)CC1

Procedure:
A solution of 13.1 g of 2-chlorophenylacetonitrile and 20.3 g of 1,2-dibromopropane in 142 ml of DMF is mixed with 9 g of sodium hydride [55–65% in oil] at room temperature. It is stirred for several hours and carefully added to water. After extraction with ethyl acetate and filtration by silica gel, the desired product is obtained: 13.1 g
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[N:19]=[C:20]([CH3:23])[S:21][CH:22]=4)=[CH:13][CH:14]=3)[C:9]([S:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:8]2[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([O:33]C)=[O:32])=[CH:4][CH:3]=1.CO.Cl>[Li+].[OH-].C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:17][C:18]4[N:19]=[C:20]([CH3:23])[S:21][CH:22]=4)=[CH:13][CH:14]=3)[C:9]([S:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:8]2[CH2:29][C:30]([CH3:36])([CH3:35])[C:31]([OH:33])=[O:32])=[CH:37][CH:38]=1
Reactant: COC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3csc(C)n3)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(COc2ccc3c(c2)c(SC(C)(C)C)c(CC(C)(C)C(=O)O)n3Cc2ccc(Cl)cc2)cs1

Procedure:
A solution of the ester from Step 1 (22.5 g) in 118 mL 1N LiOH, 120 mL THF, and 65 mL MeOH was heated at 60° C. for 2 hours. The mixture was cooled, poured onto 1N HCl, and extracted with EtOAc (3×). After washing the organic phase twice with brine, the solution was dried (MgSo4) and evaporated. The residue was swished with ether/hexane 1:2 to give the title compound as a solid; m.p. 196.5°-198° C.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].I[CH3:24]>C1COCC1.CN1CCCN(C)C1=O>[CH3:24][N:8]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]3[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]([C:14]=23)=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: Cn1c(-c2ccccc2)c2c3c(cccc31)C(=O)NCC2
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of compound 12 (51.3 mg, 0.20 mmol) in THF (1 mL) and 0.1 mL 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) was cooled with an ice/water bath and treated dropwise with a suspension of NaH (0.45 mmol) in THF (0.5 mL). The yellow mixture was allowed to stir at 0° C. for 10 min., and was treated dropwise with a 1M solution of iodomethane in THF (0.22 mL, 0.22 mmol). The mixture was allowed to warm to ambient temperature and stirred for 30 min. The reaction was quenched at 0° C. with saturated aqueous NH4Cl, and extracted with EtOAc (5 mL×3). The organic solution was washed with water and brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by radial chromatography (2 mm SiO2; 1-5% MeOH in CH2Cl2) to yield 18 as a white solid, 44.9 mg (81%). mp 254-256° C. (dec.); 1H NMR (DMSO-d6) δ 2.88 (m, 2H), 3.40 (m, 2H), 3.74 (s, 3H), 7.34 (t, 1H, J=7.7 Hz), 7.56 (m, 5H), 7.73 (d, 1H, J=7.7 Hz), 7.80 (d, 1H, J=7.7 Hz), 8.15 (bt, 1H); Anal. (C18H16N2O.0.75 H2O) C, H, N.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:46])([CH:43]([F:45])[F:44])[CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[CH2:30][CH2:29][N:28]([C:31]3[CH:36]=[CH:35][C:34]([N:37]4[CH:41]=[CH:40][NH:39][C:38]4=[O:42])=[CH:33][CH:32]=3)[CH2:27][CH2:26]2)=[CH:21][CH:20]=1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:39]1[CH:40]=[CH:41][N:37]([C:34]2[CH:33]=[CH:32][C:31]([N:28]3[CH2:27][CH2:26][N:25]([C:22]4[CH:21]=[CH:20][C:19]([O:18][CH2:17][C:16]([F:15])([F:46])[CH:43]([F:45])[F:44])=[CH:24][CH:23]=4)[CH2:30][CH2:29]3)=[CH:36][CH:35]=2)[C:38]1=[O:42])[CH3:13]
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Reactant: O=c1[nH]ccn1-c1ccc(N2CCN(c3ccc(OCC(F)(F)C(F)F)cc3)CC2)cc1
Product: C[C@@H](n1ccn(-c2ccc(N3CCN(c4ccc(OCC(F)(F)C(F)F)cc4)CC3)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 16.3 %

Procedure:
In the same manner as in Reference Example 5, starting from 0.44 g of (1S)-1-[(2R)-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 0.48 g of 1-[4-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1-piperazinyl]phenyl]-2(1H,3H)imidazolone, 0.11 g of 1-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-3-[4-[4-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-1-piperazinyl]phenyl]-2(1H,3H)-imidazolone was obtained as a colorless powder.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([C@@H:18]([C:28]3[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=3)[C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([OH:24])=[O:23])[CH2:15]2)[C:10]([F:13])([CH3:12])[CH3:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[CH3:36][CH2:37]O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@H:9]([CH:14]2[CH2:17][N:16]([C@@H:18]([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][CH:27]=3)[C:22]([O:24][CH2:36][CH3:37])=[O:23])[CH2:15]2)[C:10]([F:13])([CH3:11])[CH3:12])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(F)[C@H](c1cc(F)cc(Br)c1)C1CN([C@@H](c2ccc(Cl)cc2)c2cccc(C(=O)O)c2)C1
Reactant: CCO
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)c1cccc([C@H](c2ccc(Cl)cc2)N2CC([C@@H](c3cc(F)cc(Br)c3)C(C)(C)F)C2)c1

Procedure:
To a mixture of 5.72 g (10.4 mmol) of 3-[(S)-{3-[(1S)-1-(3-bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]azetidin-1-yl}(4-chlorophenyl)methyl]benzoic acid in 230 mL of EtOH, was added a solution of 25 mL of 4N HCl in dioxane. After 7.5 h at reflux, the solution was cooled and concentrated to remove solvents. To the residue were added 150 mL of CH2Cl2 and 30 mL of H2O and the pH was adjusted to 7-8 with aq NaHCO3. The aqueous layer was extracted with three 100 mL portions of CH2Cl2 and the combined organic layer was dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography with hexanes/ethyl acetate to afford the title compound as a white solid; 1H-NMR(CDCl3) δ 1.25 (d, 3H, J1=22 Hz), 1.27 (d, 3H, J1=22 Hz), 1.40(t, 3H, J=7.1 Hz), 2.34(t, 1H, J=7.5 Hz), 2.83-2.89(m, 2H), 3.10-3.15(m, 2H), 3.62 (m, 1H), 4.30(s, 1H), 4.38 (q, 2H, J1=14.2 Hz, J2=7.1 Hz), 6.85 (d, 1H, J=9.4 Hz), 7.10-7.11(m, 2H), 7.26-7.38 (m, 5H), 7.55 (d, 1H, J=7.8 Hz), 7.86 (d, 1H, J=7.7 Hz), 8.05 (s, 1H); Mass Spectrum: m/e=576, (M+1, 35Cl 79Br), 578 (M+1, 37Cl79Br/35Cl 81Br), 580 (M+1, 37Cl 81Br).
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:16])(=[O:15])[N:4]([CH3:17])[C:3]=1[C:18](OC)=[O:19].[S:22]1[CH:26]=[CH:25][N:24]=[C:23]1[NH2:27]>C1(C)C(C)=CC=CC=1>[OH:1][C:2]1[C:7]2[S:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:6]=2[S:5](=[O:15])(=[O:16])[N:4]([CH3:17])[C:3]=1[C:18]([NH:27][C:23]1[S:22][CH:26]=[CH:25][N:24]=1)=[O:19]
Reactant: COC(=O)C1=C(O)c2sc3ccccc3c2S(=O)(=O)N1C
Reactant: Nc1nccs1
Solvent: Cc1ccccc1C
Product: CN1C(C(=O)Nc2nccs2)=C(O)c2sc3ccccc3c2S1(=O)=O

Procedure:
25.0 gm (0.0768 mol) of methyl 4-hydroxy-2-methyl-2H-[1]benzothieno-[2,3-e]-1,2-thiazine-3-carboxylate-1,1-dioxide and 10.0 gm (0.12 mol) of 2-thiazolamine were refluxed for 16 hours in 300 cc of anhydrous xylene in an atmosphere of nitrogen. The released methanol was removed by means of 4 A-molecular sieve filled in a Soxhlet apparatus. After cooling and standing for several hours, the reaction product was filtered off. After recrystallization from a mixture of dimethylformamide and 1,2-dichloroethane 19.9 gm (66% of theory) of light-yellow 4-hydroxy-2-methyl-N-(2-thiazolyl)-2H-[1]benzothieno[2,3-e]-1,2-thiazine-3-carboxamide-1,1-dioxide were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]3)=[CH:4][CH:3]=1.[C:26]([C:30]1[CH:38]=[CH:37][C:33]([C:34](Br)=[O:35])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:30]1[CH:31]=[CH:32][C:33]([C:34]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[CH:9]=[C:10]4[C:14](=[CH:15][CH:16]=3)[C:13](=[O:17])[N:12]([C@@H:18]([CH:23]([CH3:25])[CH3:24])[C:19]([O:21][CH3:22])=[O:20])[CH2:11]4)=[CH:4][CH:3]=2)=[O:35])=[CH:37][CH:38]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Reactant: CC(C)(C)c1ccc(C(=O)Br)cc1
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cc3)ccc2C1=O

Procedure:
The compound of example 322 was prepared analogous to compound of example 304 by reaction of compound of example 223 with 4-(t-butyl)benzoyl bromide. The compound of example 322 was used directly without isolation, for the preparation of compound of example 323.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1>>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(SC(F)(F)Cl)cc1)c1cnc(Cl)c(Br)c1
Product: O=C(Nc1ccc(SC(F)(F)Cl)cc1)c1cnc(N2CC[C@@H](O)C2)c(Br)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 9.2 using 5-bromo-6-chloro-N-(4-((chlorodifluoromethyl)thio)phenyl)nicotinamide (Stage 18.2) and (R)-pyrrolidin-3-ol to afford an off-white crystalline solid. HPLC (Condition 4) tR=5.97 min, UPLC-MS (Condition 3) tR=1.19 min, m/z=478.2/480.1 [M+H]+.
Reaction SMILES: C(N)CC1C=CC=CC=1.C(Cl)(=O)CC.[CH2:15]([CH:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20][CH2:19][NH:18]1)[CH3:16].C1C2C(=CC=CC=2)C=CN=1.[Cl:37][CH:38]([Cl:42])[C:39](Cl)=[O:40]>C1(C)C=CC=CC=1>[Cl:37][CH:38]([Cl:42])[C:39]([N:18]1[CH2:19][CH2:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:17]1[CH2:15][CH3:16])=[O:40]
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CCC1NCCc2ccccc21
Agent: CCC(=O)Cl
Agent: NCCc1ccccc1
Solvent: c1ccc2cnccc2c1
Solvent: Cc1ccccc1
Product: CCC1c2ccccc2CCN1C(=O)C(Cl)Cl

Procedure:
By procedures described in Example 1 (Method A), phenethylamine and propionyl chloride were converted to 1-ethyl-1,2,3,4-tetrahydroisoquinoline. A reaction vessel was charged with 2.5 g of this isoquinoline compound in 50 ml toluene. With this mixture stirred, 1.5 ml dichloroacetyl chloride was added dropwise to the mixture. The mixture was refluxed until a clear solution appeared. The mixture was stripped of solvent and subjected to Kugelrohr distillation (150° C. @ 0.25 mm Hg) to provide 2.7 g of product having the elemental analysis reported in Table I.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[CH2:11][C:10]3[CH:19]=[CH:20][CH:21]=[CH:22][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.Cl.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[CH:19]1[C:10]2[CH2:11][C:12]3[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=3[CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:26]([C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[O:33])=[CH:24][CH:23]=3)=[O:7])[C:9]=2[CH:22]=[CH:21][CH:20]=1
Reactant: Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=C(Cl)c1cccnc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1)c1cccnc1
Yield: 14.3 %

Procedure:
A mixture of 0.628 g (2 mmol) of 5-(4-aminobenzoyl)-6,11-dihydro-5H-dibenz[b,e]azepine, 0.551 g (3 mmol) of nicotinoyl chloride, hydrochloride, 0.606 g (6 mmol) of triethylamine and 15 mg of 4-(dimethylamino)pyridine in 17 ml of dichloromethane is refluxed for 7 hours. The mixture is washed with H2O, 2N citric acid, H2O, 1N NaHCO3, brine and dried (Na2SO4). The solvent is removed and the solid recrystallized from hexane-dichloromethane to give 0.12 g of crystals,. m.p. 217°-220° C. Anal Calc'd for C27H21N3O2H2O: C,74.1; H,5.3; N,9.6. Found: 73.6; H,4.7; N,9.8.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1)(=O)OCC)C.[CH3:22][CH:23]([N:27]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:31]([CH:36]=O)[C:30]=2[CH:29]=[CH:28]1)[CH2:24][CH2:25][CH3:26]>COC>[C:12]1(/[CH:11]=[CH:36]\[C:31]2[CH:32]=[CH:33][CH:34]=[C:35]3[C:30]=2[CH:29]=[CH:28][N:27]3[CH:23]([CH2:24][CH2:25][CH3:26])[CH3:22])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: CCOP(=O)(Cc1cccc2ccccc12)OCC
Reactant: CCCC(C)n1ccc2c(C=O)cccc21
Agent: COC
Agent: [H-]
Agent: [Na+]
Product: CCCC(C)n1ccc2c(/C=C\c3cccc4ccccc34)cccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.4 %

Procedure:
To a suspension of 95% sodium hydride (NaH, 347 mg, 13.76 mmol) in dimethyl ether (DME, 17 mL) was added diethyl(naphthalen-1-ylmethyl)phosphonate (4) (960 mg, 3.44 mmol) dropwise at 0° C. The resulting solution was stirred at room temperature for 1 h, then semi-pure 1-(pentan-2-yl)-1H-indole-4-carbaldehyde (3) (˜3.44 mmol) in DME (2 mL) was added dropwise and the reaction mixture was stirred for 8 h at room temperature. After the reaction completed as indicated by thin layer chromatography, the reaction mixture was poured into ice-cold water (30 mL), extracted with ethyl acetate (3×30 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography (6:1 hexane/ethyl acetate) gave (Z)-4-(2-(naphthalen-1-yl)vinyl)-1-(pentan-2-yl)-1H-indole (5) (580 mg, 1.70 mmol) in 50% yield. 1H NMR (CDCl3): 8.30 (d, 1H, J=8.0 Hz), 8.09 (d, 1H, J=16.0 Hz), 7.91 (dd, 1H, J=7.5, 1.5 Hz), 7.86 (d, 1H, J=7.0 Hz), 7.84 (d, 1H, J=8.0 Hz), 7.59 (d, 1H, J=16.0 Hz), 7.58-7.52 (m, 3H), 7.48 (d, 1H, J=7.0 Hz), 7.39 (d, 1H, J=8.0 Hz), 7.32 (d, 1H, J=3.5 Hz), 7.29 (d, 1H, J=7.5 Hz), 6.91 (d, 1H, J=3.0 Hz), 4.61-4.53 (m, 1H), 2.00-1.92 (m, 1H), 1.88-1.80 (m, 1H), 1.56 (d, 3H, J=7.0 Hz), 1.36-1.20 (m, 4H), 0.93 (t, 3H, J=7.5 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][CH:4]=1)#[CH:2].I[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cu](I)I.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.C(N(CC)CC)C>[C:6]1([CH3:9])[CH:7]=[CH:8][C:3]([C:1]#[C:2][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:4][CH:5]=1
Reactant: Oc1ccc(I)cc1
Reactant: C#Cc1ccc(C)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(C#Cc2ccc(O)cc2)cc1
Reaction time: 0.5 h

Procedure:
50 g of 4-ethynyltoluene, 94.6 g of 4-iodophenol and 250 ml of triethylamine were mixed at RT under a nitrogen atmosphere, and 0.35 g of triphenylphosphine and 0.2 g of copper iodide were added. 0.25 g of bis(triphenylphosphine)palladium(II) chloride were then introduced with stirring. After 30 minutes, a further 0.25 g of bis(triphenylphosphine)palladium(II) chloride and after a further 15 minutes a further 0.25 g of bis(triphenylphosphine)palladium(II) chloride were introduced, during which the temperature was held at between 40 and 55° C. After the reaction mixture had been stirred overnight, it was poured into conc. HCl/ice and subjected to conventional work-up, giving 4-p-tolylethynylphenol in the form of a solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[CH:22]=[C:21]([CH2:23]Br)[CH:20]=[CH:19][C:18]=1[O:25][CH3:26]>CN(C=O)C>[Br:16][C:17]1[CH:22]=[C:21]([CH:20]=[CH:19][C:18]=1[O:25][CH3:26])[CH2:23][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1ccc(CBr)cc1Br
Reactant: c1ccc2[nH]cnc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cnc3ccccc32)cc1Br
Temperature: 45 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
A suspension of 1H-benzoimidazole (317 mg, 2.68 mmol) and potassium carbonate (495 mg, 3.58 mmol) in DMF (10 mL) was stirred at 45° C. for 1 h. To the heated suspension was added 2-Bromo-4-bromomethyl-1-methoxy-benzene (500 mg, 1.79 mmol) and the reaction was stirred at 45° C. for 4 h, cooled to room temperature and stirred at room temperature overnight. About half of the solvent was removed under vacuum, and ethyl acetate (30 mL) was added. The organic solution was washed with saturated aqueous ammonium chloride (3×30 mL), water (2×15 mL), and brine (15 mL). The organic extract was dried over anhydrous sodium sulfate and the solvent removed under vacuum to give crude product as an orange oil. The product was purified by flash silica gel column chromatography eluting with 5% methanol in dichloromethane to give the title compound (282.5 mg; 48% yield) and a second crop of 50% pure 2-Bromo-4-bromomethyl-1-methoxy-benzene (207.1 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].CO[CH2:28][CH2:29]OC>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:28]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[CH:4][CH:3]=1)=[CH2:29]
Reactant: O=C1c2ccccc2C(=O)N1Nc1ccc(Br)cc1
Reactant: COCCOC
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: O
Product: C=Cc1ccc(NN2C(=O)c3ccccc3C2=O)cc1
Temperature: 150 °C
Yield: 13 %

Procedure:
To a solution of 2-(4-bromophenylamino)isoindoline-1,3-dione (2 g, 6 mmol) in 1,2-dimethoxyethane (20 mL) and H2O (4 mL) were added vinyl boronic anhydride pyridine complex (4.57 g, 18.98 mmol) and K2CO3 (1.3 g, 9.5 mmol) followed by Pd(PPh3)4 (0.219 g, 0.189 mmol). The resultant reaction mixture was heated at 150° C. in a microwave for 30 min and then was concentrated under reduced pressure. Purification by column chromatography (SiO2, 15% EtOAc in petroleum ether) afforded the title compound as a solid (200 mg, 13%): mp 174-176° C.; 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.94 (m, 4H), 7.29 (d, J=8.4 Hz, 2H), 6.72 (d, J=8.4 Hz, 2H), 6.61 (m, 1H), 5.61 (d, J=17.6 Hz, 1H), 5.05 (d, J=11.2 Hz, 1H); ESIMS m/z 263.18 ([M−H]−).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH:27]=2)=[N:4][C:5]2[N:6]([N:9]=[CH:10][C:11]=2[C:12]2[CH:13]=[N:14][C:15]3[C:20]([CH:21]=2)=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]=1[NH2:8].C(N(CC)C(C)C)(C)C.Br[CH2:38][C:39]([O:41]C(C)(C)C)=[O:40]>CN(C=O)C>[NH2:8][C:7]1[N:6]2[N:9]=[CH:10][C:11]([C:12]3[CH:13]=[N:14][C:15]4[C:20]([CH:21]=3)=[CH:19][CH:18]=[CH:17][CH:16]=4)=[C:5]2[N:4]=[C:3]([C:22]2[CH2:23][CH2:24][N:25]([CH2:38][C:39]([OH:41])=[O:40])[CH2:26][CH:27]=2)[C:2]=1[Br:1]
Reactant: Nc1c(Br)c(C2=CCNCC2)nc2c(-c3cnc4ccccc4c3)cnn12
Reactant: CC(C)(C)OC(=O)CBr
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Nc1c(Br)c(C2=CCN(CC(=O)O)CC2)nc2c(-c3cnc4ccccc4c3)cnn12
Temperature: 50 °C
Reaction time: 18 h

Procedure:
6-Bromo-3-(quinolin-3-yl)-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-7-amine (0.035 mmol) was charged to a 20 mL scintillation vial. Then DMF (1 ml), N,N-diisopropylethylamine (0.14 mmol, 25 μL), and tert-butyl 2-bromoacetate (0.035 mmol, 5.2 μL) were added, respectively. The resulting reaction mixture was stirred at 50° C. 18 hours. After 18 hours, the reaction was concentrated in vacuo and treated with 1 mL TFA. This reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and purified via reverse-phase preparatory HPLC to yield 2-(4-(7-amino-6-bromo-3-(quinolin-3-yl)pyrazolo[1,5-a]pyrimidin-5-yl)-5,6-dihydropyridin-1(2H)-yl)acetic acid as yellow solid. (m+H=479.17, retention time=2.09 min)