Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I-].[CH3:2][S+](C)C.[H-].[Na+].[C:8]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)(=[O:10])[CH3:9]>CN(C=O)C.CS(C)=O>[CH3:9][C:8]1([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[CH2:2][O:10]1
Reactant: C[S+](C)C
Reactant: CC(=O)c1ccncc1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CC1(c2ccncc2)CO1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Trimethylsulfonium iodide (43.8 g, 210 mmol) was dissolved in 100 mL DMF and NaH (19.8 g, 495 mmol) was added. The reaction mixture was stirred for 5 min. and a solution of 4-acetylpyridine (20 g, 165 mmol) in 20 mL DMSO was added dropwise at RT. After the addition was complete, reaction mixture was stirred at RT for 2 h after which it was poured into ice water. The product was extracted with EtOAc, organic layer was washed with water, dried over sodium sulfate and concentrated under reduced pressure. Yield: 21 g.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:19]([O-])([O-])=O.[K+].[K+].CI>CN(C=O)C>[CH3:19][C:10]([C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)([C:15]([O:17][CH3:18])=[O:16])[C:11]([O:13][CH3:14])=[O:12]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)C(C(=O)OC)c1ccc([N+](=O)[O-])cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C(C)(C(=O)OC)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 66.3 %

Procedure:
To a stirred solution of dimethyl 2-(4-nitrophenyl)malonate (10 g, 39.52 mmol, 1.0 eq) and K2CO3 (10.9 g 79.05 mmol 2.0 eq) in DMF (40 mL), was added methyl iodide (4.94 mL, 79.05 mmol 2.0 eq) at 0° C. and the mixture stirred at RT for 18 h. K2CO3 was filtered out and the filtrate concentrated under vacuum. The residue was diluted with water (80 mL) and extracted with EtOAc (2×80 mL). The organic layer was separated washed with brine solution, dried over anhydrous Na2SO4 and the solvent evaporated to get dimethyl 2-methyl-2-(4-nitrophenyl)malonate (7 g, 66%; TLC system: EtOAc/PE (3:7), Rf: 0.5.)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[CH:16]=[O:17])[C:2]1=2.[CH3:18][Mg]Br.Cl.[OH-].[NH4+]>C1COCC1>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[C:9]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][C:11]=3[CH:16]([OH:17])[CH3:18])[C:2]1=2
Reactant: C[Mg]Br
Reactant: O=Cc1cnccc1-c1cccc2ccsc12
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(O)c1cnccc1-c1cccc2ccsc12
Reaction time: 2 h
Yield: 62 %

Procedure:
Cool a solution of 4-benzo[b]thiophen-7-yl-pyridine-3-carbaldehyde (1.5 g, 6.27 mmol in THF (50 mL) in a 250-mL round bottom flask to 0° C. and add gradually methylmagnesium bromide (2.38 g, 6.90 mmol, 2.30 mL) to the solution. Stir the mixture from 0° C. to RT for 2 h. Hydrolyze the mixture by mixing with 1 N HCl (200 mL). Adjust the pH to 11 with ammonium hydroxide. Extract into chloroform/IPA (3/1, 200 mL). Wash the organic phase with water and saturated aqueous sodium chloride. Dry over sodium sulfate and concentrate in vacuo. Purify by FCC (hexane to 10% ethyl acetate in hexane, then 20% THF in DCM) to give the title compound as a yellow oil (1.00 g, 62%). MS (ES) m/z 256 [M+1]+.
Reaction SMILES: [OH-].[Na+].[C:3]1([P:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]2[CH:15]=[CH:14][C:13]([P:16](=[O:23])([O:20]CC)[O:17]CC)=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O.C1COCC1.Cl>[C:24]1([P:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:10]2[CH:15]=[CH:14][C:13]([P:16](=[O:17])([OH:20])[OH:23])=[CH:12][CH:11]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOP(=O)(OCC)c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=P(O)(O)c1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: 23 °C
Reaction time: 0.33 h

Procedure:
0.40 g (10.0 mmol) of NaOH in 7 ml of water are added dropwise at 23° C. to a solution of 2.00 g (5.0 mmol) of diethyl 4-diphenylphosphinophenylphosphonate in 7 ml of THF. After refluxing for 6 hours, the mixture is diluted with a further 7 ml of THF, 4.0 ml of 2N hydrochloric acid are added dropwise at 23° C. and the mixture is stirred for 20 min at 23° C. After phase separation, the aqueous phase is extracted twice, each time with 25 ml of dichloromethane, and the combined organic phases are washed with 25 ml of water. After drying over Na2SO4, complete evaporation on a rotary evaporator and drying under reduced pressure, 1.54 g of 4-diphenylphosphinophenylphosphonic acid (90% of theory) are obtained in the form of a pale yellow solid having an m.p. of 87° C.
Reaction SMILES: C(OC([NH:11][C@@H:12]1[CH2:27][N:16]2[C:17](=[O:26])[C:18]([OH:25])=[C:19]([C:21]([O:23]C)=O)[N:20]=[C:15]2[CH2:14][CH2:13]1)=O)C1C=CC=CC=1.CO.[F:30][C:31]1[CH:38]=[CH:37][C:34]([CH2:35][NH2:36])=[CH:33][CH:32]=1>>[NH2:11][C@@H:12]1[CH2:27][N:16]2[C:17](=[O:26])[C:18]([OH:25])=[C:19]([C:21]([NH:36][CH2:35][C:34]3[CH:37]=[CH:38][C:31]([F:30])=[CH:32][CH:33]=3)=[O:23])[N:20]=[C:15]2[CH2:14][CH2:13]1
Reactant: COC(=O)c1nc2n(c(=O)c1O)C[C@@H](NC(=O)OCc1ccccc1)CC2
Reactant: NCc1ccc(F)cc1
Solvent: CO
Product: N[C@H]1CCc2nc(C(=O)NCc3ccc(F)cc3)c(O)c(=O)n2C1

Procedure:
The product from Step 2 was dissolved in MeOH (6 mmol), p-fluorobenzylamine (2.0 eq) was added and the mixture was stirred at reflux for 6 hours. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate. The organic phase was washed with 1N HCl, brine, dried over Na2SO4, filtered and concentrated to dryness under vacuum. To the resulting crude MeOH was added (20 ml/mmol) and the mixture was hydrogenated at atm pressure on 10% (w/w) Pd/C over night. After filtration of the catalyst, solvent was evaporated to give a crude that was purified by preparative RP-HPLC (Symmetry Column C18, 5 μm, 19×100 mm, gradient of CH3CN/H2O+0.01% TFA).
Reaction SMILES: [Mg].[CH2:2](Br)[CH3:3].[Cl:5][C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:10].[Cl-].[NH4+]>O1CCCC1.CCOCC>[Cl:5][C:6]1[CH:7]=[C:8]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)([OH:10])[CH2:2][CH3:3])[CH:25]=[CH:26][CH:27]=1
Reactant: CCBr
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1cccc(Cl)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC(O)(c1ccc(OCc2ccccc2)cc1)c1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
To a Grignard reactant prepared from 7.2 g. of magnesium turnings and 32.6 g. of ethyl bromide in 120 ml. of dry ether a solution of 24 g. of 3-chloro-4'-benzyloxy-benzophenone in 120 ml. of tetrahydrofurane is added dropwise, with stirring at 0° to 5° C. The reaction mixture is then slightly boiled for 30 minutes, and the Grignard complex is decomposed with a saturated aqueous solution of ammonium chloride under cooling. The aqueous phase is extracted with ether, the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure. Crystallization of the residue from a mixture of ethyl acetate and n-hexane yields 16.2 g. of the named compound, melting at 52°-53° C.
Reaction SMILES: [CH:1]([C:4]1[S:13][C:12]2[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=[C:7]([NH2:18])[C:6]=2[N:5]=1)([CH3:3])[CH3:2].[CH2:19]([C@H:26]1[CH2:31]N[CH2:29][CH2:28][NH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH2:19]([C@@H:26]1[NH:27][CH2:28][CH2:29][N:18]([C:7]2[C:6]3[N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[S:13][C:12]=3[NH:11][C:10]3[CH:14]=[CH:15][CH:16]=[CH:17][C:9]=3[N:8]=2)[CH2:31]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: c1ccc(C[C@H]2CNCCN2)cc1
Reactant: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N
Product: CC(C)c1nc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](Cc2ccccc2)C1
Yield: 25.3 %

Procedure:
By using a similar method of the method of Example 460, using 2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(1.44 g, 5.5 mmol) and (S)-2-benzyl-piperazine (0.983 g, 5.5 mmol) to give 0.580 g of the title compound as a yellow solid: mass spectrum (ion spray): m/z=418 (M+1); Analysis for C24H27N5S(0.2 H2O): calcd: C, 68.44; H, 6.56; N, 16.63; found: C, 68.63; H, 6.43; N, 16.74.
Reaction SMILES: [C:1]([Si:5]([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[O:6][CH2:7][CH:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=2)=[CH:12][CH:11]=1)[OH:9])([CH3:4])([CH3:3])[CH3:2].[CH3:38][O:39][C:40](=[O:59])[C@@H:41]([NH:51][C:52]([O:54][C:55]([CH3:58])([CH3:57])[CH3:56])=[O:53])[CH2:42][C:43]1[CH:48]=[CH:47][C:46](O)=[C:45]([Br:50])[CH:44]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[CH3:38][O:39][C:40](=[O:59])[C@@H:41]([NH:51][C:52]([O:54][C:55]([CH3:57])([CH3:56])[CH3:58])=[O:53])[CH2:42][C:43]1[CH:48]=[CH:47][C:46]([O:9][CH:8]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=3)=[CH:14][CH:15]=2)[CH2:7][O:6][Si:5]([C:1]([CH3:4])([CH3:2])[CH3:3])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[C:45]([Br:50])[CH:44]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)c(Br)c1)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](OCC(O)c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)(c1ccccc1)c1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(OC(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2ccc(OCc3ccc(Cl)c(Cl)c3)cc2)c(Br)c1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-(tert-Butyl-diphenyl-silanyloxy)-1-[4-(3,4-dichloro-benzyloxy)-phenyl]-ethanol (11.0 g), (S)-3-(3-bromo-4-hydroxy-phenyl)-2-tert-butoxycarbonylamino-propionic acid methyl ester (7.46 g), and triphenylphosphine (7.87 g) were dissolved in 75.0 mL of anhydrous DCM and the mixture cooled to 0° C. DIAD (5.85 mL) was added drop wise to the reaction mixture. After 1 h, the cooling bath was removed and the reaction stirred overnight. Concentration gave a dark orange oil which was purified by silica gel chromatography (ethyl acetate/hexanes) to obtain the desired product. LCMS: 910.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19][CH3:20])=[O:18]>CN(C)C=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:13][CH2:14][CH2:15][C:16]([CH3:22])([CH3:21])[C:17]([O:19][CH3:20])=[O:18])=[CH:3][CH:4]=1)=[O:7]
Reactant: O=Cc1ccc(O)cc1
Reactant: COC(=O)C(C)(C)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)CCCOc1ccc(C=O)cc1
Temperature: 65 °C
Reaction time: 0.75 h

Procedure:
A solution of 48.9 g (0.4 mol) of 4-hydroxybenzaldehyde in 600 ml of dimethylformamide was stirred under a nitrogen atmosphere. Sodium hydride (31.2 g; 0.44 mol) was added to the stirring solution over 45 minutes. The temperature of the reaction mixture was maintained at 35°-40° during the addition, and stirring was continued for an additional 45 minutes at room temperature. Methyl 5-bromo-2,2-dimethylpentanoate (98.1 g; 0.44 mol), was added dropwise over 20 minutes. The reaction temperature was maintained at 40° during the addition. After addition was complete, the temperature was raised to 65° C. and stirring was continued at 65° C. for 31/2 hours. After standing overnight, the dimethylformamide was removed on a rotary evaporator and the residue was taken up in water and ether. The aqueous layer was extracted a second time with ether and the combined extracts were washed, dried, and concentrated under reduced pressure. The residue was triturated two times with n-heptane. The heptane insoluble oil was distilled via a short path apparatus to give methyl 5-[4-formylphenoxy)-2,2-dimethyl-pentanoate: bp 143°-144° C. at 0.03 mm of Hg; yield 39.4 g (37%). Additional analytically pure product was obtained from the heptane extract: 32.3 g (31%). Anal. Calcd. for C15H20O4 :
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=[O:13])[CH:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][Li].[Cl-].[NH4+]>>[CH3:14][CH:8]1[CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1
Reactant: O=C1C=CC(c2ccccc2)CC1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Product: CC1CC(=O)CCC1c1ccccc1

Procedure:
The intermediate 3-methyl-4-phenylcyclohexanone is prepared, first by the reaction of 4-phenylcyclohexanone with phenylselenenyl chloride and aqueous 30% hydrogen peroxide, yielding 4-phenyl-2-cyclohexenone, and then the reaction of the cyclohexenone with 1.4M methyllithium and aqueous ammonium chloride, affording 3-methyl-4-phenylcyclohexanone. The cyclohexanone is then reacted with cyanoguanidine as previously described. Example 15 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27](I)[CH:28]=5)[N:23]=[CH:22][N:21]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:31]([N:34]1[CH:38]=[CH:37][N:36]=[CH:35]1)[C:32]#[CH:33].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>CCN(CC)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[C:27]([C:33]#[C:32][CH2:31][N:34]6[CH:38]=[CH:37][N:36]=[CH:35]6)[CH:28]=5)[N:23]=[CH:22][N:21]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Nc3ncnc4ccc(I)cc34)ccc21
Reactant: C#CCn1ccnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1)n1ccc2cc(Nc3ncnc4ccc(C#CCn5ccnc5)cc34)ccc21
Temperature: 80 °C
Yield: 51 %

Procedure:
Quinazoline 14 (150 mg, 0.28 mmol), 1-N-2-propynylimidazole (200 mg, 1.89 mmol), Pd(OAc)2 (4 mg, 0.016 mmol) and PPh3 (9 mg, 0.033 mmol) were mixed in NEt3 (1.25 mL) and DMF (0.5 mL). The mixture was heated at 80° C under N2 for 16 hours. Upon cooling the black suspension was concentrated under reduced pressure and the residue dissolved in MeOH. Silica gel (1 g) was added and the methanol removed in vacuo. The resulting silica gel was placed atop a silica gel (40g) column which was then eluted with 200 mL 50:1 CH2Cl2:MeOH, the 300 mL 25:1 CH2Cl2 to provide alkyne 15 (72 mg, 51%) as a yellow foam. 1H NMR (CDCl3; 400 MHz): δ: 8.95 (br, 1H, NH), 8.63 (s, 1H), 8.62 (s, 1H), 8.24 (s, 1H), 7.96 (d, 1H, J=1.7 Hz), 7.84 (m, 3H), 7.71 (m, 2H), 7.51 (m, 3H), 7.41 (m, 2H), 7.14 (s, 1H), 7.10 (s, 1H), 6.55 (d, 1H, J=3.5 Hz), 5.01 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:15]=[C:16](/[CH:21]=[CH:22]/[S:23](Cl)(=[O:25])=[O:24])[CH:17]=[CH:18][C:19]=1[Cl:20]>>[Cl:13][C:14]1[CH:15]=[C:16](/[CH:21]=[CH:22]/[S:23]([NH:1][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[S:9]([NH2:12])(=[O:10])=[O:11])(=[O:25])=[O:24])[CH:17]=[CH:18][C:19]=1[Cl:20]
Reactant: O=S(=O)(Cl)/C=C/c1ccc(Cl)c(Cl)c1
Reactant: Cc1ccc(S(N)(=O)=O)c(N)c1
Product: Cc1ccc(S(N)(=O)=O)c(NS(=O)(=O)/C=C/c2ccc(Cl)c(Cl)c2)c1
Yield: 54 %

Procedure:
The title compound was synthesized as described for Example 194 a) in 54% yield, starting from 2-amino-4-methylbenzenesulfonamide and (E)-2-(3,4-dichlorophenyl)ethenesulfonyl chloride (1.5 equiv.). Purification by column chromatography, using chloroform/methanol (95:5) as the eluent.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1.C([Li])CCC.[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]=[O:18]>O1CCCC1.CCCCCC>[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH:17]([OH:18])[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1Br
Reactant: Clc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1ccc(Cl)cc1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.9 %

Procedure:
A solution of 23.0 g (120 mmole) of 4-bromochlorobenzene in 150 ml of dry tetrahydrofuran was cooled to -78° C. under nitrogen and 78 ml (120 mmole) of 1.55 M n-butyllithium in hexane was added dropwise at a rate to maintain temperature below -60° C. After stirring an additional 15 minutes, 14.0 ml (120 mmole) of 2-bromo-benzaldehyde was added and the reaction was stirred for 15 minutes. The reaction was quenched at -78° C. with saturated aqueous ammonium chloride and allowed to warm to room temperature. The reaction solution was diluted with 300 ml of diethyl ether and washed with three 75 ml portions of 1.0 M sodium bisulfite, followed by 50 ml of 1.0 M sodium hydroxide, 100 ml of water, and 50 ml of saturated sodium chloride. After drying over magnesium sulfate, the solvent was removed to give 35.3 g (99%) of crude 2-bromo-α-(4-chlorophenyl)benzyl alcohol as a pale yellow oil.
Reaction SMILES: [N:1]1([C:7]2[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]3[NH:11][C:12]([C:14]([F:17])([F:16])[F:15])=[N:13][C:9]=3[CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[C:33]=1[CH3:42]>CN(C)C=O>[CH3:42][C:33]1[C:34]([C:38]([F:39])([F:40])[F:41])=[CH:35][CH:36]=[CH:37][C:32]=1[CH2:31][N:13]1[C:9]2[CH:8]=[C:7]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:19]=[C:18]([C:20]([O:22][CH3:23])=[O:21])[C:10]=2[N:11]=[C:12]1[C:14]([F:17])([F:15])[F:16]
Reactant: COC(=O)c1cc(N2CCOCC2)cc2nc(C(F)(F)F)[nH]c12
Reactant: Cc1c(CBr)cccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)cc2c1nc(C(F)(F)F)n2Cc1cccc(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 24.12 %

Procedure:
A suspension of methyl 5-(4-morpholinyl)-2-(trifluoromethyl)-1H-benzimidazole-7-carboxylate, prepared as described in Example 45 (1.5 g, 4.56 mmol) and potassium carbonate (1.889 g, 13.67 mmol) in N,N-Dimethylformamide (DMF) (10 mL) was stirred at rt for 15 min. 1-(Bromomethyl)-2-methyl-3-(trifluoromethyl)benzene (1.729 g, 6.83 mmol) was added in and the resulting reaction mixture was stirred for 3 h at 80° C. The mixture was then cooled to room temperature and poured into ice/water. The precipitate was collected by filtration, washed with water, then hexanes (turned into a gum on the filter paper—some material was lost). The crude material was purified on a silica gel column (ISCO, eluting with 0-5% MeOH in DCM) to give the desired product (580 mg, 1.099 mmol, 24.12% yield) (several mixed fractions obtained were discarded). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.65 (d, J=2.53 Hz, 1H), 7.61 (d, J=7.83 Hz, 1H), 7.37 (d, J=2.27 Hz, 1H), 7.23 (t, J=7.96 Hz, 1H), 6.29 (d, J=7.58 Hz, 1H), 5.76 (s, 2H), 3.93 (s, 3H), 3.70-3.78 (m, 4H), 3.12-3.22 (m, 4H), 2.53 (s, 3H). MS (ES+) m/e 502 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O:11][C:12](=O)[CH2:13][C:14](=O)[CH2:15][Cl:16])C.S(=O)(=O)(O)O>O>[Cl:16][CH2:15][C:14]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([CH3:1])[CH:7]=2)[O:8][C:12](=[O:11])[CH:13]=1
Reactant: CCOC(=O)CC(=O)CCl
Reactant: Cc1ccc(O)cc1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ccc2oc(=O)cc(CCl)c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
To a mixture of 4-methylphenol (21.6 g, 200 mmol) and 4-chloro-3-oxo-butyric acid ethyl ester (32.9 g, 200 mmol) is added dropwise during 30 min. at 0° C. a mixture of concentrated sulfuric acid (180 mL) and water (60 mL). The resulting clear solution is stirred for 18 h at room temperature, during which time a white precipitate is formed. The reaction mixture is poured over crushed ice (1 kg) and the formed precipitate is collected, washed with water and dried in vacuo at 50° C. to yield the title compound as a white powder (35.8 g, 172 mmol, 86%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.45 (s, 1H), 7.40 (d, J=8.6 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.58 (s, 1H), 4.69 (s, 1H), 2.46 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]CC)=[O:6].[CH3:13][C:14]([CH3:18])=[CH:15][CH2:16]Br.C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH3:13][C:14]([CH3:18])=[CH:15][CH2:16][O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)c1cccc(O)c1
Reactant: CC(C)=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)=CCOc1cccc(C(=O)O)c1

Procedure:
The reaction of ethyl 3-hydroxybenzoate and 3,3-dimethylallyl bromide in 2-butanone in the presence of potassium carbonate was performed as described in Example 2 to give 3-(3-Methyl-but-2-enyloxy)-benzoic acid as white powder. 1H-NMR (400 MHz, d6-DMSO): 12.97 (br, —CO2H); 7.48 (m, 1 arom.H); 7.42 (m, 1 arom.H); 7.41 (m, 1 arom.H); 7.15 (m, 1 arom.H); 5.40 (m, CH═C(CH3)2); 4.54 (d-like, CH2CH═C(CH3)2); 1.69, 1.63 (2s, CH═C(CH3)2). 13C-NMR (100 MHz, d6-DMSO): 167.16 (C═O); 158.38; 137.32; 132.24; 129.59; 121.43; 119.68; 119.48; 114.67; 64.46; 25.40; 18.00.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:9]=[N:10][C:11]([S:14]([CH3:17])(=O)=O)=[N:12][CH:13]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24]C(S)=[CH:22][CH:21]=1>C(C(C)=O)C>[Cl:7][C:8]1[CH:9]=[N:10][C:11]([S:14][C:17]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[N:12][CH:13]=1
Reactant: CS(=O)(=O)c1ncc(Cl)cn1
Reactant: COc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1ccc(Sc2ncc(Cl)cn2)cc1
Yield: 96.7 %

Procedure:
Potassium carbonate (5.8 g) was added to a solution of 5-chloro-2-methylsulphonylpyrimidine (6.7 g) and 4-methoxythiophenol (5.0 g) in methyl ethyl ketone (50 ml) and the mixture was stirred and boiled under reflux for 3 hours. The solvent was evaporated under reduced pressure and the residue partitioned between chloroform and 5% sodium hydroxide aqueous solution. The chloroform extracts were dried (Mg SO4) and evaporated under reduced pressure to give 5-chloro-2-(4-methoxyphenylthio)pyrimidine (8.5 g) as a colourless solid, m.p. 75° C.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[NH2:24][C:25]1[S:26][CH:27]=[C:28]([CH3:30])[N:29]=1>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:6][CH2:5][C:4]([C:1]([NH:24][C:25]4[S:26][CH:27]=[C:28]([CH3:30])[N:29]=4)=[O:3])([CH2:9][CH2:8]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: Cc1csc(N)n1
Product: Cc1csc(NC(=O)C23CCC(NCC(=O)N4C[C@@H](F)C[C@H]4C#N)(CC2)CC3)n1
Yield: 17.7 %

Procedure:
In a similar manner to Example 63, (2S,4S)-1-[[N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 2-amino-4-methylthiazole (38.8 mg) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(4-methylthiazol-2-yl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (11.5 mg).
Reaction SMILES: C([O:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6]1)(=O)C.C(O)C.[OH-].[K+]>O>[OH:4][C@H:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6]1
Reactant: CC(=O)O[C@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(OCc1ccccc1)N1CC[C@H](O)C1
Reaction time: 0.25 h

Procedure:
To a 20-L, three neck round bottom flask containing 427 g (1.62 mol) of benzyl (3S)-3-acetoxypyrrolidine-1-carboxylate was added 4 L of absolute ethanol followed by 101 g (1.57 mol) of potassium hydroxide in about 400 mL of water. After about 15 min, the reaction mixture was poured into 8 L of water and extracted with 8 L of ethyl acetate. The aqueous layer was then extracted with an additional 4 L of ethyl acetate. The combined organics were washed with saturated aqueous brine, dried over magnesium sulfate and concentrated to a thick oil and solids.