Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C@H:7]2[C@@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:9](SC)=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:27][NH:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.CO>ClCCl>[C:21]([O:20][C:18]([N:10]1[C@H:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=[C:9]1[N:28]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:27])=[O:19])([CH3:24])([CH3:23])[CH3:22]
Reactant: CNCc1ccccc1
Reactant: CSC1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Solvent: CO
Solvent: ClCCl
Product: CN(Cc1ccccc1)C1=N[C@@H](c2ccccc2)[C@@H](c2ccccc2)N1C(=O)OC(C)(C)C
Temperature: 95 °C
Yield: 22.9 %

Procedure:
A mixture of intermediate 59 (0.4 g, 0.00109 mol), N-methylbenzylamine (0.42 mL, 0.00326 mol) and MeOH (0.1 mL) is heated at 95° C. for 2 days. The reaction mixture is cooled to RT, dichloromethane is added and the mixture is purified by chromatography on silica gel; gradient elution with heptane:EtOAc (80:20-75:25) gives 110 mg of the product 81. 1H NMR (CDCl3) δ 7.50-7.20 (m, 6H), 7.10-6.90 (m, 7H), 6.90-6.75 (m, 2H), 5.52 (q, 2H), 4.84 (d, 1H), 4.52 (d, 1H), 2.97 (s, 3H), 1.45 (s, 9H); MS: m/z 442 (M++1).
Reaction SMILES: [CH:1]([C@H:3]1[CH2:8][O:7][C@H:6]([CH2:9][OH:10])[CH2:5][O:4]1)=[CH2:2].[H-].[Na+].I[CH3:14]>C1COCC1.O>[CH3:14][O:10][CH2:9][C@@H:6]1[CH2:5][O:4][C@@H:3]([CH:1]=[CH2:2])[CH2:8][O:7]1
Reactant: CI
Reactant: C=C[C@H]1CO[C@H](CO)CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=C[C@H]1CO[C@H](COC)CO1
Temperature: 25 °C
Reaction time: 0.42 h
Yield: 36.5 %

Procedure:
To a solution of ((2R,5S)-5-vinyl-1,4-dioxan-2-yl)methanol (Preparation #17, 0.25 g, 1.734 mmol) in THF (3 mL) was added NaH (41.6 mg, 1.734 mmol) at 0° C. The reaction mixture was slowly warmed to RT and stirred for 25 min. The reaction mixture was cooled to about 0° C. and iodomethane (0.108 mL, 1.734 mmol) was added. Upon completion of addition, the reaction mixture was slowly warmed to RT and stirred for about 2.5 h. The reaction mixture was diluted with water (20 mL) and the product extracted with EtOAc (2×10 mL). The organic layer dried over sodium sulfate and concentrated under reduced pressure. The crude material obtained was purified by column chromatography eluting with 10% EtOAc in hexane to afford (2R,5S)-2-(methoxymethyl)-5-vinyl-1,4-dioxane 0.1 g (36.5%), 1H NMR (400 MHz, CDCl3): δ 5.75-5.67 (m, 1H), 5.36-5.32 (m, 1H), 5.23-5.20 (m, 1H), 4.05-4.00 (m, 1H), 3.87-3.70 (m, 3H), 3.55-3.49 (m, 1H), 3.42-3.35 (m, 6H), ES-MS: m/z 158 (m+H).
Reaction SMILES: Cl.[CH2:2]([N:4]1[CH2:13][CH2:12][C@@:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16](OC)[CH:15]=3)[C@@H:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)[CH2:5]1)[CH3:3].C1(N[N:30]=[C:31]([C:37](=O)[CH3:38])[C:32]([O:34][CH2:35][CH3:36])=[O:33])C=CC=CC=1.C[C:41](O[Na])=[O:42]>C(O)(=O)C.[Zn]>[CH2:2]([N:4]1[CH2:13][CH2:12][C@:11]2([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([O:42][CH3:41])[CH:15]=3)[C@H:6]([CH2:7][C:8]3[C:37]([CH3:38])=[C:31]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[NH:30][C:9]=3[CH2:10]2)[CH2:5]1)[CH3:3]
Reactant: CCOC(=O)C(=NNc1ccccc1)C(C)=O
Reactant: CCN1CC[C@]2(c3cccc(OC)c3)CC(=O)CC[C@H]2C1
Reactant: CC(=O)O[Na]
Agent: Cl
Agent: [Zn]
Solvent: CC(=O)O
Product: CCOC(=O)c1[nH]c2c(c1C)C[C@@H]1CN(CC)CC[C@@]1(c1cccc(OC)c1)C2
Yield: 61.3 %

Procedure:
0.8 g (2.47 mmol) of (±)-trans-2-ethyl-4a-(3-methoxyphenyl)-6-oxo-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline hydrochloride and 0.87 g (93.7 mmol) of ethyl 2-phenylhydrazono-3-oxobutyrate [Organic Reactions, R. Adams Ed; Wiley, New York, 10, 32-33, (1951-1959)] were dissolved in a mixture of 3 mi of glacial acetic acid and 0.34 g (4.2 mmol) of CH3COONa. The solution was treated as described in example 1 adding 0.74 g (11.3 mmol) of zinc dust. The residue was purified by flash chromatography (AcOEt/MeOH/conc. NH4OH 94:5:0.5; Rf=0.3), obtaining 0.6 g of the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Mg].[CH2:12]1COC[CH2:13]1.CO[CH2:19][CH2:20][CH2:21][Si@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][CH2:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([C:36]3[CH:41]=[CH:40][C:39](Cl)=[CH:38][CH:37]=3)[CH2:32][CH2:31]2)[CH2:24][CH2:23]1>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)C>[CH2:21]([Si@H:22]1[CH2:27][CH2:26][C@H:25]([CH2:28][CH2:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([C:36]3[CH:41]=[CH:40][C:39]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH3:2])=[CH:6][CH:7]=4)=[CH:38][CH:37]=3)[CH2:32][CH2:31]2)[CH2:24][CH2:23]1)[CH2:20][CH2:19][CH2:12][CH3:13]
Reactant: ClCCOc1ccccc1
Reactant: COCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(Cl)cc3)CC2)CC1
Reactant: C1CCOC1
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Mg]
Solvent: CCOCC
Product: CCCCC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(-c4ccc(OCC)cc4)cc3)CC2)CC1

Procedure:
15.7 g (0.1 mol) of p-chloroethoxybenzene was dripped into a mixture of 2.5 g (0.11 mol) of magnesium and 100 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 100 ml diethyl ether solution of 0.5 g of [1,3-bis(diphenylphosphino)propane]nickel (II) chloride and 31.5 g (0.1 mol) of 4-(trans-4-(2-(trans-4-(3-methoxypropyl)-4-silacyclohexyl)ethyl)cyclohexyl)phenyl chloride. After a conventional after treatment, purification was conducted by means of chromatography to obtain 32.2 g (yield 67.5%) of 4-(trans-4-(2-(trans-4-n-pentyl-4-silacyclohexyl)ethyl)cyclohexyl)-4'-ethoxybiphenyl was obtained.
Reaction SMILES: C[C@]12CC[C@H]3[C@@H](CCC4[C@]3(C)CCC(=O)C=4)[C@@H]1CCC2=O.[C:22]([C:24]1([O:44][C:45](=[O:47])[CH3:46])[CH2:29][CH2:28][C@H:27]2[C@H:30]3[C@H:40]([CH2:41][CH2:42][C@:25]12[CH3:26])[C@:38]1([CH3:39])[C:33](=[CH:34][C:35](=[O:43])[CH2:36][CH2:37]1)[CH2:32][CH2:31]3)#[N:23]>CC(C)(O)C#N>[C:22]([C@@:24]1([O:44][C:45](=[O:47])[CH3:46])[CH2:29][CH2:28][C@H:27]2[C@H:30]3[C@H:40]([CH2:41][CH2:42][C@:25]12[CH3:26])[C@:38]1([CH3:39])[C:33](=[CH:34][C:35](=[O:43])[CH2:36][CH2:37]1)[CH2:32][CH2:31]3)#[N:23]
Reactant: CC(=O)OC1(C#N)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C
Agent: CC(C)(O)C#N
Agent: C[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: CC(=O)O[C@]1(C#N)CC[C@H]2[C@@H]3CCC4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
4-Androsten-3,17-dione (20 g) is dissolved by gentle warming in acetone cyanohydrin (30 ml). The crystals which form after several minutes are filtered, washed with pentane, and then dissolved in a mixture of pyridine (50 ml) and acetic anhydride (50 ml). After 48 hours the volatiles are removed under reduced pressure. The residue is then dissolved in ether and washed successively with 5% hydrochloric acid and aqueous sodium bicarbonate. The organic solution is dried and concentrated to afford a mixture of C-17 epimers of 17-cyano-17-acetoxyandrost-4-ene-3-one. Chromatography affords 17β-cyano-17α-acetoxyandrost-4-ene-3-one.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.ON1C2C=CC=CC=2N=N1.[CH3:25][O:26][C:27]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[C:28]=1[CH2:29][NH2:30]>CN(C=O)C>[CH3:36][O:35][C:31]1[CH:32]=[CH:33][CH:34]=[C:27]([O:26][CH3:25])[C:28]=1[CH2:29][NH:30][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: COc1cccc(OC)c1CN
Reactant: O=C(O)c1ccc2cnccc2n1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(OC)c1CNC(=O)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.6 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2,6-dimethoxybenzylamine (75.0 mg, 0.431 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 100% ethyl acetate) afforded the desired product as a white solid (90.6 mg, 98%): m.p. 169-171° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:9]([OH:11])=[O:10])=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[OH-].[Na+].C1COCC1.CN([CH:22]([SH:24])C)C.[CH3:25][N:26]([CH:28]=O)[CH3:27]>O>[Cl-:1].[C:9]([C:3]1[N:4]=[C:5]([S:24][CH2:22][CH2:28][NH+:26]([CH3:27])[CH3:25])[CH:6]=[CH:7][C:2]=1[Cl:1])([OH:11])=[O:10]
Reactant: CN(C)C=O
Reactant: O=C(O)c1nc(Cl)ccc1Cl
Reactant: CC(S)N(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[NH+](C)CCSc1ccc(Cl)c(C(=O)O)n1
Product: [Cl-]
Yield: 51 %

Procedure:
3,6-Dichloropyridine-2-carboxylic acid (1.0 g, 5.23 mmol.), sodium hydroxide (1.64 g, 15.7 mmol.), and anhydrous THF (10 mL) were combined before slowly adding the N,N-dimethylaminoethanethiol (1.9 g, 18.3 mmol). After stirring for several hours under nitrogen, two aliquots of DMF (10 mL each) were added. Several hours later, additional DMF (10 mL) and dimethylaminoethanethiol (1.9 g, 18.3 mmol) were added. The reaction was stirred overnight at room temperature. The solution was diluted with water and extracted three times with methylene chloride. The aqueous was acidified to pH 5 and extracted four times with methylene chloride. The aqueous was acidified to pH 1, the solvent was removed, and the residue was recrystallized from hot water. Yellow solid, 0.786 g (51% yield). 1H NMR (300 MHz, CD3OD): δ 2.98 (s, 6H), 3.53 (m, 4H), 7.50 (d, 1H), 7.85 (d, 1H). 13C NMR (75 MHz, CD3OD): δ 24.4, 42.8, 58.2, 125.7, 128.1, 140.0, 147.3, 158.2, 166.0.
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>O1CCCC1.C(OCC)C>[CH2:25]([O:24][C:22](=[O:23])[CH2:21][C:7]([C:8]#[N:9])([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH3:26]
Reactant: N#CCc1ccccc1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCOC(=O)CC(C#N)(CC(=O)OCC)c1ccccc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Combine phenylacetonitrile (5.85 g, 50.0 mmol) and tetrahydrofuran (140 mL). Cool to about 5° C. Add dropwise, a solution of sodium bis(trimethylsilyl)amide (800 mL, 1 M in tetrahydrofuran, 800 mmol). When the addition is complete, warm the reaction mixture to ambient temperature and allow to stir for 1 hour. Transfer the above solution via cannula into a cooled (−8° C.) solution of ethyl bromoacetate (84.5 mL, 762 mmol) in tetrahydrofuran (500 mL) at such a rate that the temperature of the reaction mixture does not rise above about 20° C. Allow to stir at ambient temperature. After 18 hours, dilute with diethyl ether (1.5 L) and extract with saturated aqueous solution of ammonium chloride, then water, and then saturated aqueous solution of sodium chloride. Dry the organic layer over MgSO4, filter, and concentrate in vacuo to obtain a residue. Distill the residue by bulb-to-bulb distillation to give the title compound: bp; 140-150° C. at 0.2 mm Hg.
Reaction SMILES: [Mg].Br[CH:3]([CH2:5][CH2:6][CH3:7])[CH3:4].[CH3:8][C:9](=[CH:12][CH2:13][CH3:14])[CH:10]=[O:11].[Cl-].[NH4+]>CCOCC>[CH3:4][C:3]([CH:10]([OH:11])[CH:9]([CH3:8])[CH2:12][CH2:13][CH3:14])=[CH:5][CH2:6][CH3:7]
Reactant: CCC=C(C)C=O
Reactant: CCCC(C)Br
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: CCC=C(C)C(O)C(C)CCC
Temperature: 10 °C

Procedure:
28.3 g (1.18 g atoms) of magnesium in 200 ml of ether are placed in an apparatus which is customary for Grignard reactions. While stirring and under a protective gas atmosphere (nitrogen) there are subsequently added dropwise 178.1 g (1.18 mol) of 2-bromopentane in 500 ml of absolute ether so that, after initiation of the reaction, the ether constantly boils slightly. After completing the addition, the mixture is held at reflux temperature for a further 30 minutes, then cooled to 10° C. and a solution of 96.1 g (0.98 mol) of 2-methyl-2-pentenal in 300 ml of ether is added dropwise during 30 minutes so that the reaction temperature during the addition lies between 10° and 20° C. In order to complete the reaction, the mixture is refluxed for 1 hour, then the Grignard complex is decomposed with saturated ammonium chloride solution and ice, the supernatant ethereal solution is washed with saturated sodium chloride solution and subsequently dried. After evaporating the solvent, there remain behind 176 g of crude product, which are fractionally distilled. There are thus obtained 119 g (71.4%) of olfactorily good 4,6-dimethyl-3-nonen-5-ol of boiling point 92° C./12 mm Hg.
Reaction SMILES: [C-:1]#[N:2].[K+].Br[CH2:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][CH2:11][N:12]2[S:15]([C:18]2[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[CH:20][C:19]=2[CH3:27])(=[O:17])=[O:16])=[CH:8][CH:7]=1>CO.O.C(OCC)(=O)C>[CH3:26][O:25][C:21]1[CH:22]=[C:23]([CH3:24])[C:18]([S:15]([N:12]2[C:13]3[C:9](=[CH:8][CH:7]=[C:6]([CH2:5][C:1]#[N:2])[CH:14]=3)[CH2:10][CH2:11]2)(=[O:17])=[O:16])=[C:19]([CH3:27])[CH:20]=1
Reactant: [C-]#N
Reactant: COc1cc(C)c(S(=O)(=O)N2CCc3ccc(CBr)cc32)c(C)c1
Agent: [K+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1cc(C)c(S(=O)(=O)N2CCc3ccc(CC#N)cc32)c(C)c1

Procedure:
Potassium cyanide (0.133 g, 0.0020 mol) was added to a solution of 6-(bromomethyl)-1-(4-methoxy-2,6-dimethylphenylsulfonyl)indoline (0.7 g, 0.0017 mol) in methanol (14 ml) and water (2 ml), and the resulting reaction mixture was refluxed for 4 h. The mixture was then diluted with ethyl acetate (400 ml) and washed with saturated sodium chloride solution (2×), water (2×), saturated iron sulfate solution and finally with saturated sodium chloride solution. It was then dried (Na2SO4), filtered and concentrated in vacuo. The resulting crude product was used directly in the following stage. Yield: 0.6 g (99%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][C@H:15]([CH3:18])[N:14]3[C:19](OC(C)(C)C)=[O:20])=[N:10][CH:9]=2)=[CH:4][CH:3]=1.Cl.[CH3:27][O:28][C:29]([NH:31][C@@H:32]([CH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1)C(O)=O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][C@H:15]([CH3:18])[N:14]3[C:19](=[O:20])[C@@H:32]([NH:31][C:29](=[O:30])[O:28][CH3:27])[CH:36]3[CH2:41][CH2:40][O:39][CH2:38][CH2:37]3)=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: COC(=O)N[C@H](C(=O)O)C1CCOCC1
Reactant: C[C@H]1CC[C@@H](c2ncc(-c3ccc(Br)cc3)[nH]2)N1C(=O)OC(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1c1ncc(-c2ccc(Br)cc2)[nH]1)C1CCOCC1
Temperature: 40 °C
Reaction time: 1 h
Yield: 98.8 %

Procedure:
To a solution of (2S,5S)-tert-butyl 2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-5-methylpyrrolidine-1-carboxylate (0.50 g, 1.23 mmol) in a mixture of CH2CL2 (10 mL) and methanol (1.0 mL) was added HCl (4M in dioxane, 6.00 mL, 24 mmol). The solution was stirred at 40° C. for 1 h, cooled to room temperature and concentrated to dryness. The crude solid was suspended in CH2CL2 (10 mL), followed by the addition of (S)-2-(methoxycarbonylamino)-2-(tetrahydro-2H-pyran-4-yl)acetic acid (0.298 g, 1.37 mmol), HATU (0.562 g, 1.48 mmol) and DIPEA (0.60 mL, 3.44 mmol). The resulting solution was stirred at room temperature for 18 h. The solution was diluted with CH2CL2 and washed with a mixture of sodium bicarbonate (aqueous, sat) and brine. The aqueous layer was back-extracted with CH2CL2. The combined organic layers were dried over Na2SO4 and concentrated to provide a crude oil. Purification by column chromatography (SiO2, 10-100% EtOAc (10% MeOH)/Hexanes) provided methyl (S)-2-((2S,5S)-2-(5-(4-bromophenyl)-1H-imidazol-2-yl)-5-methylpyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate (0.614 g, 99%). MS (ESI) m/z 505.844 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH3:10].C1C(=O)N([Br:18])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:18][CH2:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[Cl:1]
Reactant: COc1ccc(Cl)c(C)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COc1ccc(Cl)c(CBr)c1
Temperature: 25 °C

Procedure:
To a solution of the 1-chloro-4-methoxy-2-methylbenzene (2.0 g, 12.77 mmol) in anhydrous carbon tetrachloride (50 mL), NBS (2.29 g, 12.98 mmol) and benzoyl peroxide (0.154 g, 0.64 mmol) was added. The reaction mixture was heated to reflux overnight. Then, the reaction mixture was cooled to room temperature and filtered. The filtrate was evaporated to provide crude 2-(bromomethyl)-1-chloro-4-methoxybenzene, which was used for the next step without any further purification; 1H NMR (400 MHz, DMSO-d6): δ 3.74 (s, 3H), 4.66 (s, 2H), 7.01 (d, J=8.9 Hz, 1H), 7.19 (s, 1H), 7.38 (d, J=8.9 Hz, 1H).
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)=[O:19])=[CH:14][CH:13]=1.N1C=CC=CC=1>ClCCl>[CH3:27][O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([C:15]2[CH:16]=[CH:17][C:12]([NH:11][S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)(=[O:9])=[O:8])=[CH:13][CH:14]=2)=[O:19])=[CH:21][CH:22]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: COc1ccc(C(=O)c2ccc(N)cc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(C(=O)c2ccc(NS(=O)(=O)c3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 66.4 %

Procedure:
Benzenesulfonyl chloride (0.26 mL, 2.03 mmol) was slowly added to an ice-cooled solution of (4-amino-phenyl)-(4-methoxy-phenyl)-methanone (178) (0.42 g, 1.85 mmol) and pyridine (0.16 mL, 2.03 mmol) in dry dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 20 h then partitioned between EtOAc and water. The layers were separated and the aqueous layer was extracted with EtOAc. The organic extracts were combined, washed with brine, dried over Na2SO4, filtered, and concentrated to give a solid. The solid was recrystallized from hot dichloromethane and methanol to give 0.451 g (66%) of the title compound 182. 1H NMR (400 MHz, DMSO-d6): δ 3.82 (s, 3 H), 7.03 (d, J=8.8 Hz, 2 H), 7.22 (d, J=8.6 Hz, 2 H), 7.57-7.65 (m, 7 H), 7.84 (d, J=7.3 Hz, 2 H), 10.87 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH:11][C:12](=[O:17])[C:13]([F:16])([F:15])[F:14])=[CH:6][CH:5]=1)([O-])=O.C(OCC)(=O)C.[H][H]>C(O)C.[Pt]=O>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][NH:11][C:12](=[O:17])[C:13]([F:14])([F:15])[F:16])=[CH:8][CH:9]=1
Reactant: O=C(NNc1ccc([N+](=O)[O-])cc1)C(F)(F)F
Reactant: [H][H]
Agent: O=[Pt]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(NNC(=O)C(F)(F)F)cc1

Procedure:
2-(4-Nitrophenyl)-1-trifluoroacetylhydrazine (2.5 g, 0.01 mole) and platinum oxide (84%, catalytic amount) were mixed in ethanol (100 ml) and ethyl acetate (100 ml) in a Parr shaker bottle. The reaction mixture was hydrogenated at room temperature until hydrogen uptake ceased. The reaction mixture was filtered and the solvent was evaporated from the filtrate leaving a brown semisolid. Yield 2.0 g (91%), no m.p. was taken on this material. Spectral data verified its structure.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:7]([O:15][CH2:16][CH2:17][OH:18])[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:5]1.CN(C=O)C.Br[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>O>[CH2:31]([O:18][CH2:17][CH2:16][O:15][C:7]1[C:6]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:5][N:4]([CH3:3])[C:8]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCBr
Reactant: Cn1nc(-c2ccccc2)c(OCCO)c1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCOCCOc1c(-c2ccccc2)nn(C)c1-c1ccccc1

Procedure:
Sodium hydride (0.89 g, 57%, 0.02 mole) is added to a solution of 2-[(1-methyl-3,5-diphenyl-4-pyrazolyl)oxy]ethanol (5.9 g, 0.02 mole) and dry DMF (50 ml). The reaction mixture is stirred and heated to 80°-90°C. The stirred mixture is allowed to cool. This mixture is added to a solution of 1-bromoheptane (9 g, 0.05 mole) and dry FMD (75 ml). After heating at 80°-90°C for 4 hours, the stirred reaction mixture is poured into water.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:73]=[CH:72][C:67]([C:68]([O:70][CH3:71])=[O:69])=[CH:66][C:65]=1[O:74][CH3:75]>>[CH3:71][O:70][C:68](=[O:69])[C:67]1[CH:72]=[CH:73][C:64]([NH:63][C:30]([C@@H:20]2[NH:19][C@@H:18]([CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C@:17]3([C:12]4[C:13](=[CH:14][C:9]([Br:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[C@H:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[C:65]([O:74][CH3:75])[CH:66]=1
Reactant: COC(=O)c1ccc(N)c(OC)c1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Br)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@@]3(C(=O)Nc4cc(Br)ccc43)[C@H]2c2cccc(Cl)c2F)c(OC)c1
Yield: 47.3 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 92 (0.4 g, 0.66 mmol) was reacted with diisopropylethylamine (0.43 g, 3.3 mmol), diphenylphosphinic chloride (0.31 g, 1.3 mmol), then reacted with methyl 4-amino-3-methoxybenzoate (Ark Pharm) (0.18 g, 0.99 mmol) to give rac-4-{[(2′S,3′R,4′S,5′R)-6-bromo-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carbonyl]-amino}-3-methoxy-benzoic acid methyl ester as a white solid (Yield 0.21 g, 48%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:22]C)[N:12]2[CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].Br[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29]>>[NH2:24][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:22])[N:12]2[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:17]1
Reactant: CC(C)CCBr
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCCNC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCCN(CCC(C)C)C3)c2n1

Procedure:
Prepared similarly to Example 24 from 2-(butyloxy)-8-(methyloxy)-9-(3-piperidinylmethyl)-9H-purin-6-amine and 1-bromo-3-methylbutane.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P([N:31]=[N+:32]=[N-:33])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH2:12][N:31]=[N+:32]=[N-:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1cccc(OCc2ccccc2)c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: [N-]=[N+]=NCc1cccc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 3-benzyloxybenzyl alcohol (5.0 g, 23.3 mmol) and diphenylphosphoryl azide (7.7 g, 28.0 mmol) in dry toluene (40 mL) at 0° C., was added 1,8-diazabicyclo[5.4.0]undec-7-ene (3.9 g, 25.6 mmol). The resulting mixture was allowed to warm to ambient temperature, and stirred under argon for 18 hrs, then washed with water (2×15 mL), then 5% hydrochloric acid (15 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with hexane −4% ethyl acetate to yield the product as a colorless oil.