Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]([CH2:5][CH3:6])[CH:3]=[O:4].[CH:7]([Mg]Cl)=[CH2:8].O>O1CCCC1>[CH3:1][CH:2]([CH2:5][CH3:6])[CH:3]([OH:4])[CH:7]=[CH2:8].[CH2:3]([OH:4])[CH:2]=[CH2:1]
Reactant: C=C[Mg]Cl
Reactant: CCC(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: C=CC(O)C(C)CC
Product: C=CCO
Yield: 122.1 %

Procedure:
215 g (2.5 moles) of 2-methylbutan-1-al are added to a solution of 2.6 moles of vinyl-magnesium chloride in 2 liters of tetrahydrofuran in the course of one hour, whilst cooling with ice. After a reaction time of one hour, the mixture is hydrolyzed with 260 ml of water and the organic phase is isolated. The solvent is distilled off and the reaction product is fractionated, giving 263 g of the allyl alcohol 4-methyl-hex-1-en-3-ol. This corresponds to a yield of 93% of theory, based on 2-methylbutan-1-al employed. B.p. = 75° - 77° C at 50 mm Hg; nD25 = 1.4346.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:5]=[CH:6][CH:7]=1.[C:16]1([P:22](Cl)(Cl)=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([P:22]2(=[O:23])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[CH2:9][N:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cccc(NCc2ccccc2)c1
Reactant: O=P(Cl)(Cl)c1ccccc1
Product: Cc1cccc(N2Cc3ccccc3P2(=O)c2ccccc2)c1

Procedure:
The procedure of Example 1 was employed utilizing N-3-methylphenyl-N-benzylamine and phenyl phosphonic dichloride. The reaction of the dilithio compound and the phenyl phosphonic dichloride was conducted at 0° C. The crude product produced as a result of the chromatographic separation was crystallized from diethyl ether then recrystallized from carbon tetrachloride to yield 1-phenyl-2-(3-methylphenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide as a yellow solid. A second crop was obtained to give a total yield of 1.2 g (12% yield) of 1-phenyl-2-(3-methylphenyl)-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide having a melting point of 190°-192° C. and the following analysis:
Reaction SMILES: [CH3:1][C:2](=[O:7])[CH2:3][C:4](=[O:6])[CH3:5].[H-].[Na+].Cl.[F:11][C:12]([F:39])([F:38])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33](Cl)=[O:34])=[CH:31][CH:30]=1>COCCOC>[F:11][C:12]([F:39])([F:38])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]1[CH:37]=[CH:36][C:32]([C:33]([CH:3]([C:2](=[O:7])[CH3:1])[C:4](=[O:6])[CH3:5])=[O:34])=[CH:31][CH:30]=1
Reactant: CC(=O)CC(C)=O
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(=O)C(C(C)=O)C(=O)c1ccc(NCCCCCCCCCCCCCCCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 28.4 g. of 2,4-pentanedione and 20 ml. of 1,2-dimethoxyethane is added to a suspenison of 13.6 g. of sodium hydride in 220 ml. of 1,2-dimethoxyethane under argon. A solution of 28.7 g. of 4-[15-(trifluoromethyl)pentadecylamino]benzoyl chloride hydrochloride in 1,2-dimethoxyethane is then added. The reaction mixture is stirred at room temperature for 12 hours, cooled, poured on ice-and extracted with ether. The ether solution is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue is then chromatographed over silica gel to yield the product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([CH:9]3[CH2:12][C:11](=O)[CH2:10]3)[S:8][C:4]=2[CH:3]=1.[CH3:16][C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1.N1C=CC=CC=1.B>ClCCl.C(O)C>[Br:1][C:2]1[CH:15]=[CH:14][C:5]2[N:6]=[C:7]([C@H:9]3[CH2:12][C@@H:11]([N:18]4[CH2:19][CH2:20][CH2:21][C@H:17]4[CH3:16])[CH2:10]3)[S:8][C:4]=2[CH:3]=1
Reactant: O=C1CC(c2nc3ccc(Br)cc3s2)C1
Reactant: C[C@@H]1CCCN1
Agent: B
Solvent: c1ccncc1
Solvent: CCO
Solvent: ClCCl
Product: C[C@@H]1CCCN1[C@H]1C[C@@H](c2nc3ccc(Br)cc3s2)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 7.2 %

Procedure:
The product of Example 1C (500 mg, 1.77 mmole) was dissolved in 6 ml dichloromethane and 4 ml ethanol. 2-(R)-methylpyrrolidine (1.04 g, 4.43 mmole, toluene extract from 50% sodium hydroxide) was added and stirred at room temperature for 30 minutes. Then borane-pyridine (358 μl, 3.54 mmole) was added. The mixture was stirred at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate and extracted with dichloromethane. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product which was purified by column chromatography (0.4% ammonium hydroxide and 4% methanol in dichloromethane) to give 45 mg (9% yield) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 7.98 (d, J=1.83 Hz, 1H) 7.80 (d, J=8.85 Hz, 1H) 7.54 (dd, J=8.54, 1.83 Hz, 1H) 3.54-3.65 (m, 1H) 3.15-3.29 (m, 1H) 3.00-3.13 (m, 1H) 2.73-2.86 (m, 1H) 2.56-2.69 (m, 2H) 2.32-2.57 (m, 3H) 1.92-2.05 (m, 1H) 1.79-1.90 (m, 1H) 1.67-1.78 (m, 1H) 1.46-1.57 (m, 1H) 1.17 (s, 3H). MS: (M+H)+=351/353.
Reaction SMILES: [CH3:1][C@H:2]1[C@@:41]2([OH:43])[O:42][C@H:5]([CH2:6][C@H:7]([O:64][CH3:65])[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][C@@H:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17]([C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24]([CH2:26][C@@H:27]([C@@H:44]([CH2:46][C@H:47]3[CH2:52][C@@H:51]([O:53][CH3:54])[C@H:50]([OH:55])[CH2:49][CH2:48]3)[CH3:45])[O:28][C:29]([C@H:31]3[N:36]([C:37]([C:39]2=[O:40])=[O:38])[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:30])=[O:25])=[O:18])[CH2:4][CH2:3]1.N1C(C)=CC=CC=1C.S(O[CH2:82][CH2:83][O:84][CH2:85][CH3:86])(C(F)(F)F)(=O)=O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:82][CH2:83][O:84][CH2:85][CH2:86][O:55][C@H:50]1[C@H:51]([O:53][CH3:54])[CH2:52][CH:47]([CH2:46][C@H:44]([CH:27]2[O:28][C:29](=[O:30])[C@H:31]3[N:36]([CH2:35][CH2:34][CH2:33][CH2:32]3)[C:37](=[O:38])[C:39](=[O:40])[C@:41]3([OH:43])[O:42][C@@H:5]([CH2:4][CH2:3][C@H:2]3[CH3:1])[CH2:6][C@H:7]([O:64][CH3:65])[C:8]([CH3:63])=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][CH:14]([CH3:62])[CH2:15][C@@H:16]([CH3:61])[C:17](=[O:18])[C@H:19]([O:59][CH3:60])[C@H:20]([OH:58])[C:21]([CH3:57])=[CH:22][C@@H:23]([CH3:56])[C:24](=[O:25])[CH2:26]2)[CH3:45])[CH2:48][CH2:49]1
Reactant: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)C=CC=CC=C1C
Reactant: CCOCCOS(=O)(=O)C(F)(F)F
Agent: CCOCCO[C@@H]1CCC(C[C@@H](C)C2CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)CC(C)/C=C/C=C/C=C(\C)[C@@H](OC)C[C@@H]3CC[C@@H](C)[C@@](O)(O3)C(=O)C(=O)N3CCCC[C@H]3C(=O)O2)C[C@H]1OC
Agent: CO[C@H]1C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N2CCCC[C@H]2C(=O)O[C@H]([C@H](C)C[C@@H]2CC[C@@H](O)[C@H](OC)C2)CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)/C=C/C=C/C=C/1C
Solvent: Cc1cccc(C)n1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOCCO[C@@H]1CCC(C[C@@H](C)C2CC(=O)[C@H](C)C=C(C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)CC(C)C=CC=CC=C(C)[C@@H](OC)C[C@@H]3CC[C@@H](C)[C@@](O)(O3)C(=O)C(=O)N3CCCC[C@H]3C(=O)O2)C[C@H]1OC
Reaction time: 1.5 h

Procedure:
To a stirred solution of 1 g rapamycin, and 7.66 g 2,6-lutidine in 14.65 mL toluene held at 60° C. was added 5.81 g 2-ethoxyethanol triflate. Stirring was continued for 90 minutes after which 50 mL ethyl acetate was added to the reaction and the solution was washed with 50 mL 1M HCl. The organic material was washed with D.I. water until pH of wash solution was neutral and the organic solution was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, 200–400 mesh (40:60 hexane-ethyl acetate (v/v) to give 210 mg 42-O-(2-ethoxyethyl) rapamycin. TLC Rf=0.41 using 40:60 hexane-ethyl acetate (v/v). MS (ESI) m/z 1008.5 C55H87NNaO14. A mass spectrum of the title compound is shown in FIG. 1.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[OH:10][CH:11]([CH3:27])[CH:12]([NH:17][CH2:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:13]([O:15][CH3:16])=[O:14].FC(F)(F)S(O[Si:34]([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35])(=O)=O.C(OCC)C>C(Cl)Cl>[Si:34]([O:10][CH:11]([CH3:27])[CH:12]([NH:17][CH2:18][C:19](=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:13]([O:15][CH3:16])=[O:14])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: COC(=O)C(NCC(=O)c1ccccc1)C(C)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: ClCCl
Product: COC(=O)C(NCC(=O)c1ccccc1)C(C)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Diisopropylethylamine (3.1 ml) is added to a solution of methyl (2RS,3RS)-3-hydroxy-2-(2-oxo-2-phenylethyl)aminobutyrate (3.70 g, Reference compound No. 46-10) in methylene chloride (35 ml). The mixture is cooled with ice, and tert-butyldimethylsilyl trifluoromethanesulfonate (4.06 ml) is added to the mixture. Then, the temperature is raised to room temperature, and the whole is stirred overnight. Diethyl ether is added to the reaction mixture, and the whole is washed with a saturated aqueous sodium hydrogencarbonate solution and saturated brine successively, and the organic layer is dried over anhydrous magnesium sulfate. The organic layer is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled reference compound (4.21 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O:20][CH3:21])(=[O:19])[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[NH2:14].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:1]1([CH2:7][CH2:8][CH2:9][NH:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[C:11]([O:20][CH3:21])=[O:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrCCCc1ccccc1
Reactant: COC(=O)c1ccccc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COC(=O)c1ccccc1NCCCc1ccccc1
Reaction time: 60 h

Procedure:
A mixture of 14 g of 3-phenylpropyl bromide, 7.5 g of methyl anthranilate and 18 g of finely ground anhydrous potassium carbonate in 40 ml of anhydrous dioxane is boiled under a reflux condenser with a protective atmosphere of argon gas for about 60 hours, with magnetic stirring. After the solvent has been removed by distillation, 200 ml of methylene chloride and 100 ml of water are added, the organic phase is separated off and dried over magnesium sulfate, and the solvent is driven off. Column chromatography of the residue on silica gel (mobile phase toluene/methanol=10:1) provides methyl 2-(3-phenylpropylamino)benzoate as a viscous yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[O:15][CH2:16][CH2:17][CH2:18][OH:19])(=[O:10])=[O:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.CS(C)=O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH3:25])=[C:6]([S:8]([O:11][C:12]2[CH:13]=[C:14]([CH:20]=[C:21]([CH3:23])[CH:22]=2)[O:15][CH2:16][CH2:17][CH:18]=[O:19])(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(OCCCO)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(Cl)cc1S(=O)(=O)Oc1cc(C)cc(OCCC=O)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
To a cooled (0° C.) solution of 3-[3-(5-chloro-2-methoxyphenylsulfonyloxy)-5-methylphenoxy]propanol (3.32 g, 8.58 mmol), N,N-diisopropylethylamine (3.14 mL, 18.0 mmol), and anhydrous dimethyl sulfoxide (1.83 mL, 25.7 mmol) in anhydrous dichloromethane (20 mL) under nitrogen was added sulfur trioxide pyridine complex (2.73 g, 17.1 mmol) portionwise over 23 minutes. The solution was stirred at 0° C. for 1 hour then quenched with 5% w/v aqueous citric acid (200 mL, 48 mmol). The mixture was extracted with diethyl ether (250 mL). The aqueous layer was extracted with diethyl ether (2×100 mL), and the combined organic extracts were washed with pH 7 buffer (100 mL) and brine (100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated. Crude product was purified by flash column chromatography through silica gel (50% to 70% diethyl ether in hexane) to give the title compound as a gold oil (2.34 g, 71%). 1H-NMR (300 MHz, CDCl3) δ 9.81 (t, 1 H, J=1.5 Hz), 7.79 (d, 1 H, J=2.7 Hz), 7.54 (dd, 1 H, J=2.7, 8.9 Hz), 7.01 (d, 1 H, J=8.9 Hz), 6.54-6.60 (m, 1 H), 6.52-6.53 (m, 1 H), 6.43-6.44 (m, 1 H), 4.19 (t, 2 H, J=6.1 Hz), 3.99 (s, 3 H), 2.85 (td, 2 H, J=1.5, 6.1 Hz), 2.25 (d, 3 H, J=0.5 Hz). Mass spectrum (MALDI-TOF, α-cyano4- hydroxycinnamic acid matrix) calcd. for C17H17ClO6S: 407.0 (M+Na). Found: 407.0.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:16]([F:19])([F:18])[F:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13]([OH:15])=O)[CH:7]=[CH:6]2)#[N:2].[F:20][C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[C:23]([NH:25][NH2:26])=O>>[F:20][C:21]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][C:22]=1[C:23]1[O:15][C:13]([CH2:12][N:8]2[C:9]3[C:5](=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=3)[CH:6]=[CH:7]2)=[N:26][N:25]=1
Reactant: N#Cc1ccc2c(ccn2CC(=O)O)c1C(F)(F)F
Reactant: NNC(=O)c1cc(F)ccc1F
Product: N#Cc1ccc2c(ccn2Cc2nnc(-c3cc(F)ccc3F)o2)c1C(F)(F)F

Procedure:
Synthesized as described in Example 35C from [5-cyano-4-(trifluoromethyl)-1H-indol-1-yl]acetic acid and 2,5-difluorobenzohydrazide: MS (ES) m/z 405 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([OH:19])=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=2)[CH:6]=[C:7]([F:9])[CH:8]=1.[N:20]([O-])=O.[Na+].[CH3:24][C:25]1([CH3:41])[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([N:34]3[C:38](=[O:39])[CH2:37][C:36]([CH3:40])=[N:35]3)[CH:32]=2)[CH2:27][CH2:26]1.C(=O)(O)[O-].[Na+]>Cl>[CH3:24][C:25]1([CH3:41])[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([N:34]3[C:38](=[O:39])[C:37](=[N:20][NH:2][C:3]4[C:4]([OH:19])=[C:5]([C:10]5[CH:15]=[CH:14][CH:13]=[C:12]([C:16]([OH:18])=[O:17])[CH:11]=5)[CH:6]=[C:7]([F:9])[CH:8]=4)[C:36]([CH3:40])=[N:35]3)[CH:32]=2)[CH2:27][CH2:26]1
Reactant: CC1=NN(c2ccc3c(c2)C(C)(C)CC3)C(=O)C1
Reactant: O=N[O-]
Reactant: Nc1cc(F)cc(-c2cccc(C(=O)O)c2)c1O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CC1=NN(c2ccc3c(c2)C(C)(C)CC3)C(=O)C1=NNc1cc(F)cc(-c2cccc(C(=O)O)c2)c1O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.5 %

Procedure:
3′-Amino-5′-fluoro-2′-hydroxy-biphenyl-3-carboxylic acid hydrochloride 2f (200 mg, 0.71 mmol) was dissolved in 2.4 mL of hydrochloric acid (1 N) upon cooling by an ice-water bath, followed by dropwise addition of 1 mL of aqueous sodium nitrite (54 mg, 0.78 mmol). After the mixture was stirred for 20 minutes, 2-(3,3-dimethyl-indan-5-yl)-5-methyl-2,4-dihydro-pyrazol-3-one 8i (153 mg, 0.64 mmol) was added. The mixture was adjusted to pH 8-9 by batch addition of aqueous sodium bicarbonate (889 mg, 10.6 mmol). The generated bubbles were quenched with 2 mL of ethanol. The reaction mixture was warmed up to room temperature and reacted overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filter cake was dissolved in 20 mL of water. After mixing well, the mixture was adjusted to pH 3˜4 with concentrated hydrochloric acid, filtered and dried. The crude product was purified by HPLC to obtain the title compound 3′-{N′-[1-(3,3-dimethyl-indan-5-yl)-3-methyl-5-oxo-1,5-dihydro-pyrazol-4-ylidene]-hydrazino}-5′-fluoro-2′-hydroxy-biphenyl-3-carboxylic acid 17 (120 mg, yield 38.0%) as a red solid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][SH:3].C[O-].[Na+].Cl[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][C:13]#[N:14].O>CO.CN(C=O)C>[NH2:14][C:13]1[CH:12]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[S:3][C:2]=1[C:1]([O:5][CH3:6])=[O:4]
Reactant: N#CC=C(Cl)c1ccccc1
Reactant: COC(=O)CS
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: COC(=O)c1sc(-c2ccccc2)cc1N
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
To a solution of methyl thioglycolate (1 g, 9.43 mmol) in methanol (5 mL) was added a solution of sodium methoxide (0.5 g, 9.43 mmol) in methanol (5 mL) and stirred for 0.5 h. To the above mixture, a solution of 3-chloro-3-phenylprop-2-enenitrile (1.22 g, 7.5 mmol) in DMF (3.5 mL) was added dropwise for 10 min at rt and stirred the mixture at 60° C. for 2 h. Then, a solution of sodium methoxide (1 g, 18.6 mmol) in methanol (10 mL) was added dropwise at rt and stirring was continued for 2 h at 60° C. The mixture was allowed to rt and poured into cold water and stirred for 15 min. The solution was extracted with chloroform (3×100 mL) and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent. The residue was chromatographed over silica gel using hexane-ethyl acetate (92:8) as eluent to give the product as a pale yellow color solid (1.1 g, 50%), mp 130-132° C. 1H NMR (400 MHz, DMSO-d6): δ 7.62-7.65 (2H, m), 7.38-7.48 (3H, m), 7.00 (1H, s), 4.29 (2H, br s), 3.74 (3H, s); LC-MS (positive ion mode): m/z 234 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:4]=1.[C-:13]#[N:14].[Na+]>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.C1C=CC=CC=1.O>[CH3:10][O:9][C:7](=[O:8])[C:6]1[CH:11]=[CH:12][C:3]([CH2:2][C:13]#[N:14])=[CH:4][CH:5]=1
Reactant: COC(=O)c1ccc(CBr)cc1
Reactant: [C-]#N
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: COC(=O)c1ccc(CC#N)cc1
Yield: 60.1 %

Procedure:
A mixture of methyl 4-(bromomethyl)benzoate (10.09 g, 44.05 mmol), sodium cyanide (6.42 g, 131 mmol) and cetyltrimethylammonium bromide (1.59 g, 4.36 mmol) in benzene/water (2:1, 187.5 mL) was heated at reflux for 5 h then extracted with CH2Cl2 3×50 mL). The organic extracts were dried (MgSO4), filtered and concentrated under reduced pressure. Purification of the crude material by chromatography on silica gel (35% EtOAc/hexanes) gave 4-cyanomethyl-benzoic acid methyl ester as a colourless solid (4.64 g, 60%). 1H NMR (CDCl3) δ 3.82 (s, 2H), 3.93 (s, 3H), 7.42 (d, 2H, J=9 Hz), 8.06 (d, 2H, J=9 Hz).
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][NH:17][CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1.[C:26]([N:30]=[C:31]=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-]>>[F:25][C:3]([F:2])([F:24])[C:4]1[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:5]=1[CH:6]([O:14][CH:15]1[CH2:18][N:17]([C:31]([NH:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[CH2:16]1)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=1
Reactant: CC(C)(C)N=C=O
Reactant: Fc1ccc(C(OC2CNC2)c2ccc(Cl)cc2)c(C(F)(F)F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Product: CC(C)(C)NC(=O)N1CC(OC(c2ccc(Cl)cc2)c2ccc(F)cc2C(F)(F)F)C1

Procedure:
This material was prepared from 3-[2-(trifluoromethyl)-4-fluoro-4′-chlorobenzhydryloxy]azetidine hydrochloride (125) (0.25 mmol), tert-butyl isocyanate (0.25 mmol) and MP-carbonate (2.62 mmol/g, 0.76 mmol) using the procedure described for compound (10) (72.4 mg, 63%).
Reaction SMILES: C([Li])CCC.[N:6]1([C:11]2[CH:32]=[CH:31][C:14]([CH2:15][C:16]3[C:17]([O:29][CH3:30])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22](Br)=[CH:21][C:20]=4[CH3:28])=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1.[CH3:33][N:34]1[C:38]([C:39]([C:41]2[N:45]([CH3:46])[CH:44]=[N:43][CH:42]=2)=[O:40])=[CH:37][N:36]=[CH:35]1.[NH4+].[Cl-]>C1COCC1.O.CCOC(C)=O>[N:6]1([C:11]2[CH:32]=[CH:31][C:14]([CH2:15][C:16]3[C:17]([O:29][CH3:30])=[N:18][C:19]4[C:24]([C:25]=3[Cl:26])=[CH:23][C:22]([C:39]([C:38]3[N:34]([CH3:33])[CH:35]=[N:36][CH:37]=3)([C:41]3[N:45]([CH3:46])[CH:44]=[N:43][CH:42]=3)[OH:40])=[CH:21][C:20]=4[CH3:28])=[CH:13][CH:12]=2)[CH:10]=[CH:9][CH:8]=[N:7]1
Reactant: COc1nc2c(C)cc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cn1cncc1C(=O)c1cncn1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: COc1nc2c(C)cc(C(O)(c3cncn3C)c3cncn3C)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
n-Butyllithium (1.6 M in hexane; 0.5 mL, 0.718 mmol) was added dropwise to a suspension of the 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-4-chloro-2-methoxy-8-methylquinoline (0.29 g, 0.653 mmol, Intermediate 19: step b) in dry THF (4 mL) over a 2 minute period at −78° C. A heterogeneous mixture of bis(1-methyl-1H-imidazol-5-yl)methanone (0.14 g, 0.653 mmol, Intermediate 39: step b) in THF (3 mL) was added as a slurry and stirring was continued at −78° C. for 5 minutes. The resulting homogeneous mixture was warmed up to 0° C. and stirred for 10 minutes. The mixture was warmed to room temperature and saturated aqueous NH4Cl was added followed by EtOAc. H2O was added and layers were separated. The aqueous layer was again extracted with EtOAc and the combined organic extracts washed with brine, dried over Na2SO4, filtered, evaporated to dryness. The crude product was purified by chromatography (10% MeOH in CH2Cl2; gradient) to provide the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.95-8.04 (m, 1H), 7.79-7.89 (m, 1H), 7.65-7.71 (m, 1H), 7.50-7.60 (m, 2H), 7.34-7.45 (m, 5H), 7.32 (s, 1H), 6.36-6.52 (m, 2H), 4.31 (s, 2H), 4.10 (s, 3H), 3.53 (s, 6H), 2.62 (s, 3H). mass calcd. C30H28ClN7O2, 554.05; m/z found, 554.2
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[CH2:8]([OH:12])[CH2:9][CH:10]=[CH2:11]>>[CH2:8]([O:12][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH:1]1[OH:7])[CH2:9][CH:10]=[CH2:11]
Reactant: C=CCCO
Reactant: C1CCC2OC2C1
Product: C=CCCOC1CCCCC1O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of cyclohexene oxide (3-1) (10.0 g, 102 mmol) in 3-buten-1-ol (17.4 mL, 204 mmol) cooled to 0° C. was added FeCl3 (1.65 g, 10.2 mol) The mixture was removed from the ice bath and stirred at rt for 1 hr. The reaction was quenched with water and extracted ether. The combined organics were washed with brine, dried, filtered, and concentrated. The residue was purified by column chromatography to give the title compound. 1H NMR (400 MHz, CDCl3) δ 5.77-5.88 (m, 1H), 5.00-5.15 (m, 2H), 3.69-3.76 (m, 1H), 3.39-3.44 (m, 2H), 2.98-3.05 (m, 1H), 2.74 (s, 1H), 2.30-2.39 (m, 2H), 1.94-2.11 (m, 3H), 1.61-1.79 (m, 3H), 1.06-1.37 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]([CH3:20])(O)[CH3:18])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C(N(CC)CC)C.[C:30](Cl)(=[O:40])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39].[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46]>C(Cl)(Cl)Cl.C(O)C>[C:42]([OH:49])(=[O:48])/[CH:43]=[CH:44]/[C:45]([OH:47])=[O:46].[C:30]([O:40][CH2:18][CH:17]([CH3:20])[CH2:16][CH2:15][N:12]1[CH2:13][CH2:14][CH:9]([C:6]2[C:5]3[CH:21]=[CH:22][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)[CH2:10][CH2:11]1)(=[O:46])[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]
Reactant: CCCCCCCCCC(=O)Cl
Reactant: CC(C)(O)CCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCC(=O)OCC(C)CCN1CCC(c2noc3cc(F)ccc23)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of 4-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]-2-methyl-2-butanol (4.68 g, 15.3 mmol) and triethylamine (2.23 g, 22.3 mmol) in chloroform (20 ml) was added decanoyl chloride (3.5 g, 18.4 mmol, 1.2 eq) dropwise at 0° C. The reaction was stirred at ambient temperature for 4 hours. The solvent was removed. The residue was purified by flash chromatography over a silica gel column (SiO2, 65 g, eluted with DCM, 1 l, 1% CH3OH in DCM, 1 l). The product thus purified weighed 5.7 g (80%) as an oil. This oily product was converted to the fumarate salt in ethanol with fumaric acid (1.51 g, 1.0 eq) to yield 3.34 g, m.p.=133°-134° C.