Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: II.[OH:3][CH2:4]/[CH:5]=[C:6](/[CH2:8][CH2:9]/[CH:10]=[C:11](/[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])\[CH3:12])\[CH3:7].[CH2:19]([Sn:23]([CH2:30][CH2:31][CH2:32][CH3:33])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24]I)[CH2:20][CH2:21][CH3:22]>O1CCCC1>[CH2:30]([Sn:23]([CH2:19][CH2:20][CH2:21][CH3:22])([CH2:26][CH2:27][CH2:28][CH3:29])[CH2:24][O:3][CH2:4][CH:5]=[C:6]([CH3:7])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:12])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[CH2:31][CH2:32][CH3:33]
Reactant: CCCC[Sn](CI)(CCCC)CCCC
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Agent: II
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)COCC=C(C)CCC=C(C)CCC=C(C)C
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 108.3 %

Procedure:
A 1.15 g (10.0 mmol) of 35% KH in mineral oil was washed with three 5 mL portions of dry hexane and suspended in 15 mL of dry tetrahydrofuran (THF) under argon. A solution of 242 mg (0.95 mmol) of iodine in 10 mL of THF was added over 50 minutes and the reaction was allowed to stir for an additional 40 minutes at room temperature to give a white suspension. (E,E)-Farnesol (1.5 g, 6.75 mmol) in 10 mL of THF was added dropwise over 15 minutes, and after 75 minutes, a solution of 2.43 g (5.64 mmol) of tributyl(iodomethyl)tin was added rapidly in 6 mL of THF. The mixture was stirred for three hours and carefully quenched with methanol Upon dilution with diethyl ether, the organic layer was washed with water and brine, dried (MgSO4) and evaporated to give 3.21 g of a pale yellow liquid The crude material was chromatographed on 720 g of silica gel eluted with 0.5:99.5 diethyl ether: petroleum ether, and the impure fractions were further purified on 150 g of silica gel eluted with 0.33:99.67 diethyl ether:petroleum ether to provide a total of 2.09 g (71%) of pure title stannane as a colorless liquid.
Reaction SMILES: C(Cl)Cl.[C:4]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])[CH2:5][CH3:6].[Br:14]Br.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[C:8]1([C:4](=[O:7])[CH:5]([Br:14])[CH3:6])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: BrBr
Reactant: CCC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(Br)C(=O)c1ccccc1
Reaction time: 1 h

Procedure:
To a methylene chloride solution (5 mL) of 4.934 g (36.82 mmol) of propiophenone, a methylene chloride solution (5 mL) of 6.4873 g (1.1 equivalents) of bromine was gradually added at 15° C., followed by 1 hour of stirring. To the resulting solution, 30 mL of a saturated sodium hydrogen carbonate solution and 40 mL of ethyl acetate were added to conduct extraction. The organic layer was washed with 20 mL of a 20 wt % sodium thiosulfate aqueous solution and then with 20 mL of saturated brine, dried over anhydrous magnesium sulfate, and subjected to distillation under a reduced pressure to remove the solvent. 1-Phenyl-2-bromo-1-propanone was obtained as an yellow, oily substance (8.7633 g, crude yield: 92%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([OH:9])[CH2:2]2.[C:10](OC(=O)C)(=[O:12])[CH3:11]>N1C=CC=CC=1>[C:10]([O:9][CH:3]1[CH:4]2[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]2)[CH2:2]1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: OC1CN2CCC1CC2
Solvent: c1ccncc1
Product: CC(=O)OC1CN2CCC1CC2
Reaction time: 4 h
Yield: 62 %

Procedure:
A solution of (RS)-3-quinuclidinol (25 g, 0.2 mmol) in pyridine (100 ml) was treated with acetic anhydride (100 ml), kept at 50° C. for 4 hours and left at room temperature for 15 hours. After removal of the pyridine and excess acetic anhydride under vacuum, the clear light brown oil was then dissolved in water (25 ml) and made slightly alkaline with saturated potassium carbonate. The ester was then extracted with chloroform (5×50 ml) and extracts were dried over K2CO3. After evaporation of the solvent in vacuo the residue was distilled yielding 20.6 g (62%) of (RS)-3-acetoxyquinuclidine as a colorless liquid.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH2:21]([O:2][C:1]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH3:10]
Reactant: Oc1ccccc1O
Reactant: CCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCCCCCCCOc1ccccc1O
Temperature: 60 °C
Yield: 40.9 %

Procedure:
A mixture of catechol (11 g, 100 mmole), bromododecane (32.4 g, 130 mmoles) and potassium carbonate (18.2 g, 130 mmole) in dry DMF (100 ml) was stirred and heated at 60° C. for 48 h. The mixture was poured into water (500 ml) and extracted with diethyl ether (3×100 ml). The combined ether extracts were washed with saturated sodium chloride solution (2×100 ml) and dried with anhydrous magnesium sulphate. The ether was removed to give a solid. Distillation at reduced pressure gave 2-dodecyloxyphenol (11.4 g, 41%), b.p. 175° C./0.5 mmHg, (Found C, 77.80; H, 10.80; C18H30O2 requires C,77.65; H, 10.86; MS (CI) m/e 296 (M+ +NH4+), δH (200 MHz, CDCl3) 0.90(t, 3H), 1.28(br s, 18H), 1.82(q, 2H), 4.04(t, 2H), 5.70(s, 1H) and 6.85(m, 4H) and Catechol bis-decyl ether (11.2 g, 25%), b.p. 225° C./0.5 mmHg, m.p. 46° C. (Lit. 46° C.)5.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[CH:5]=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([CH2:8][N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[N:7]=1
Reactant: O=Cc1cccc(Br)n1
Reactant: C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: Brc1cccc(CN2CCCCC2)n1
Reaction time: 20 h

Procedure:
To a stirred solution of 6-bromo-2-pyridine carboxaldehyde (5.05 g, 27 mmol) in anhydrous CH2Cl2 (200 mL) at RT, under N2, piperidine (2.95 mL, 29 mmol) was added, followed by NaBH(OAc)3 (11.51 g, 54 mmol) and AcOH (6.2 mL, 108 mmol) 30 min later. After 20 h, a 2M solution of Na2CO3(aq) (20 mL) was added. The mixture was vigorously stirred for an additional 30 min, washed successively with a saturated solution of NaHCO3(aq) until the pH of the aqueous layer reached 7 (2×100 mL), H2O (100 mL) and brine (100 mL). The organic layer was separated, dried over MgSO4, filtered and concentrated under reduced pressure to yield the title compound as a yellow oil. This was used crude in the next step. MS m/z: 255 (M+H), 257 (M+3).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]([C:14]2[N:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)[C:17]([CH:26]=O)=[N:16][CH:15]=2)([CH3:13])[CH3:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:28][C:29]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:30]=1[NH2:31].CC1C=CC(S(O)(=O)=O)=CC=1.[BH4-].[Na+]>C1COCC1>[Cl:28][C:29]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:30]=1[NH:31][CH2:26][C:17]1[N:18]([C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:14]([C:11]([C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)([CH3:12])[CH3:13])=[CH:15][N:16]=1
Reactant: Nc1c(F)cccc1Cl
Reactant: COc1ccc(C(C)(C)c2cnc(C=O)n2-c2ccc(F)cc2)cc1OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(C(C)(C)c2cnc(CNc3c(F)cccc3Cl)n2-c2ccc(F)cc2)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 41.4 %

Procedure:
A solution of 5-(2-(3,4-dimethoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole-2-carbaldehyde (280 mg, 0.76 mmol), 2-chloro-6-fluoroaniline (332 mg, 2.28 mmol), TsOH (72 mg, 0.38 mmol) in THF (8 mL) was heated at reflux for 15 h over molecular sieves (4A). The solution was cooled to 0° C., and NaBH4 (57 mg, 1.5 2 mmol) was added in several portions. The resulting mixture was stirring for 1 h, and filtered through Celite™ to remove molecular sieves. The filtrate was quenched with H2O (5 mL), 2N NaOH (5 mL) and extracted with DCM (2×10 mL). The organic layers were dried over MgSO4 and concentrated to give a residue, which was purified by flash chromatography to provide the title compound as a white solid (157 mg, 0.315 mmol, 42%). 1H NMR (400 MHz, CDCl3) δ1.49 (s, 6H), 3.72 (s, 3H), 3.85 (s, 3H), 4.13 (d, 2H), 4.65 (br, 1H), 6.45 (dd, 1H), 6.48 (m, 2H), 6.51 (d, 1H), 6.60 (m, 1H), 6.64 (d, 1H), 6.76 (dd, 1H), 6.80 (t, 2H), 7.00 (dt, 1H), 7.13 (s, 1H). MS (EI) m/z 498 [M+H]+.
Reaction SMILES: C(OC([NH:8][CH:9]([C:11]1[C:12]([O:33][CH3:34])=[C:13]([CH:19]2[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:20]2)[C:14]([CH3:18])=[C:15]([Cl:17])[CH:16]=1)[CH3:10])=O)(C)(C)C.[ClH:35].O1CCOCC1>C(Cl)Cl>[NH2:8][CH:9]([C:11]1[C:12]([O:33][CH3:34])=[C:13]([CH:19]2[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[O:24])[CH2:20]2)[C:14]([CH3:18])=[C:15]([Cl:17])[CH:16]=1)[CH3:10].[ClH:35]
Reactant: COc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1c(C(C)N)cc(Cl)c(C)c1C1CN(C(=O)OCc2ccccc2)C1

Procedure:
Benzyl 3-(3-{1-[(tert-butoxycarbonyl)amino]ethyl}-5-chloro-2-methoxy-6-methylphenyl)azetidine-1-carboxylate (0.45 g, 0.92 mmol, from Example 170, Step 3, chiral intermediate) and was treated with 4.0 M HCl in dioxane (2 mL, 8 mmol) in methylene chloride (6 mL) at room temperature for 2 hours. The reaction mixture was then stripped to dryness to give benzyl 3-{3-[1-aminoethyl]-5-chloro-2-methoxy-6-methylphenyl}azetidine-1-carboxylate as a HCl salt. LCMS calculated for C21H26ClN2O3 (M+H)+: m/z=389.2. found: 389.1. A mixture of the above HCl salt, 6-bromo-9H-purine (0.20 g, 1.0 mmol) and DIPEA (0.80 mL, 4.6 mmol) in ethanol (9 mL) was heated at 100° C. overnight. The mixture was concentrated and purified on silica gel (eluting with 0 to 5% MeOH in dichloromethane) to give the desired product (0.25 g, 55% in 2 steps). LCMS calculated for C26H28ClN6O3 (M+H)+: m/z=507.2. found: 507.1.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[C:25]3[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1)#[N:2].BrN1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([C:16]2[C:25]3[CH2:24][CH2:23][CH:22]=[CH:21][C:20]=3[CH:19]=[CH:18][CH:17]=2)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(N(C(=O)C(F)(F)F)c2cccc3c2CCCC3)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1ccc(N(C(=O)C(F)(F)F)c2cccc3c2CCC=C3)cc1

Procedure:
A solution of N-(4-cyanophenyl)-N-(5,6,7,8-tetrahydro-1-naphthyl)-2,2,2-trifluoroacetamide (10.7 g, 31.1 mmol), N-bromosuccinimide (6.6 g, 37 mmol), and AIBN (200 mg, 1.2 mmol) in CCl4 (300 ml) was stirred at reflux under nitrogen for 1 hour. After cooling the solution was filtered, concentrated in vacuo to a volume of ~ 25 ml, and applied to a column of silica gel. Elution with ethyl acetate:hexane (1:10) gave a mixture of benzylic bromides (10.7 g). A solution of the bromides and Li2CO3 (5.0 g, 68 mmol) in DMF (50 ml) was stirred at 110-120° C. under nitrogen for 3 hours and then overnight at room temperature. The solution was concentrated in vacuo and the residue taken up in methylene chloride (150 ml) and washed with water (50 ml). The aqueous phase was separated, extracted with more methylene chloride (100 ml), and the combined organic solutions were then washed with a small volume of water, dried (K2CO3) and concentrated in vacuo. The residue was purified by chromatography on silica gel eluting with ethyl acetate:hexane (1:13) to give N-(4-cyanophenyl)-N-(7,8-dihydro-1-naphthyl)-2,2,2-trifluoroacetamide and the corresponding 5,6,-dihydroisomer in a 3:1 ratio as determined by NMR (4.3 g). 1H NMR (DMSO-d6, 200 MHz) δ: 2.10-2.46 (m, 3H, CH2), 2.63-2.89 (m, 1H, CH2), 6.03-6.22 (m, 1H, CH), 6.41 (dt, J=10,2 Hz, 0.25H, CH), 6.48 (dt, J =10,2 Hz, 0.75H, CH), 7.08-7.33 (m, 3H, Ar), 7.41 (d, J=9 Hz, 2H, Ar), 7.64 (d, J=9 Hz, 2H, Ar). Anal. Calculated for C19H13F3N2O: C, 66.67; H, 3.83; N, 8.18. Found: C, 66.55; H, 3.86; N, 8.10.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=O.[N:13]1([C:19]2[N:20]=[N:21][N:22]([CH2:24][C:25]([NH:27][NH2:28])=[O:26])[N:23]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>C(O)(=O)C>[I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[N:28][NH:27][C:25](=[O:26])[CH2:24][N:22]1[N:21]=[N:20][C:19]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[N:23]1
Reactant: NNC(=O)Cn1nnc(N2CCOCC2)n1
Reactant: O=C1Nc2ccc(I)cc2C1=O
Solvent: CC(=O)O
Product: O=C(Cn1nnc(N2CCOCC2)n1)NN=C1C(=O)Nc2ccc(I)cc21
Temperature: 100 °C
Yield: 76 %

Procedure:
Following the general method as outlined in Example 1, into a suspension of 5-iodo-1H-indole-2,3-dione in acetic acid was added 2-[5-(4-morpholinyl)-2H-tetrazol-2-yl]acetohydrazide. After stirring at 100° C. the reaction mixture was cooled to rt and a yellow solid precipitated out. Filtration on a fritté, washing with AcOH, water and drying under vacuo at 60° C. overnight gave 73 mg of the title compound (76%) as a yellow powder in 86.7% purity by HPLC (Rt: 3.84, gradient of 8 min, MaxPlot detection between 230 and 400 nm).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([I:14])=[CH:11][CH:12]=3)[C:7](=[O:15])[C:6]([C:16]([O:18]CC)=O)=[CH:5]2)[CH2:3][CH2:2]1.[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1.ClCCl.Cl>CO>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH:27][C:16]([C:6]2[C:7](=[O:15])[C:8]3[C:13](=[CH:12][CH:11]=[C:10]([I:14])[CH:9]=3)[N:4]([CH:1]3[CH2:2][CH2:3]3)[CH:5]=2)=[O:18])=[CH:24][CH:23]=1
Reactant: NCc1ccc(Cl)cc1
Reactant: CCOC(=O)c1cn(C2CC2)c2ccc(I)cc2c1=O
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: O=C(NCc1ccc(Cl)cc1)c1cn(C2CC2)c2ccc(I)cc2c1=O
Temperature: 180 °C

Procedure:
To a flask containing ethyl 1-cyclopropyl-6-iodo-4-oxo-1,4-dihydro-3-quinolinecarboxylate from Preparation No. 19 (0.19 g) is added p-chlorobenzylamine (1.0 mL). The reaction is tightly capped and heated to 180° C. for 1 hour. The reaction is cooled to room temperature and partioned between dichloromethane containing methanol and dilute hydrochloric acid. The aqueous layer is extracted with dichloromethane and the combined organic layers are washed with brine, dried and concentarted under reduced pressure. The residue is adsorbed onto silica and chromatographed on silica eluting with 2% to 6% methanol in dichloromethane. The product containing fractions are evaporated to give 0.10 g of the title compound as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]Cl)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[C:13](O)(=O)[CH3:14]>C(OCC)C>[N+:10]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[S:8][C:14]1[CH:13]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=1[N+:10]([O-:12])=[O:11])([O-:12])=[O:11]
Reactant: CC(=O)O
Reactant: O=[N+]([O-])c1cc(Cl)ccc1SCl
Solvent: CCOCC
Product: O=[N+]([O-])c1cc(Cl)ccc1Sc1ccc(Cl)cc1[N+](=O)[O-]

Procedure:
To 1.37 g of 3-butenyltributyltin was added 0.89 g. of 4-chloro-2-nitrobenzene sulfenyl chloride dissolved in 20 ml. glacial acetic acid at steam bath temperature. The mixture was then heated on a steam bath for 30 minutes and poured into an ice water bath. The product was taken up in diethyl ether, washed twice with 50 ml. portions of water, twice with 50 ml. portions of saturated sodium bicarbonate and an additional time with 50 ml. of water. The resulting ether layer was separated, dried over magnesium sulfate and filtered. The solvent was removed on a rotary evaporator and the concentrate analyzed by proton nmr. The product proved to be cyclopropylcarbinyl 2-nitro-4-chlorophenyl sulfide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].I[CH2:17][CH3:18]>CN(C=O)C>[CH2:17]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1)[CH3:18]
Reactant: OCCC1CCNCC1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN1CCC(CCO)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirring solution of 2-(4-piperidinyl)ethanol (1 g, 7.74 mmol) and potassium carbonate (2.67 g, 19.35 mmol) in dry DMF (10 ml) was added iodoethane (0.687 ml, 8.51 mmol). The reaction mixture was allowed to stir at room temperature for 18 hours. The solvent was partially removed in vacuo and the residue partitioned between water (20 ml) and ethyl acetate (20 ml). The aqueous was washed with further ethyl acetate and the combined organics dried (hydrophobic frit) and concentrated in vacuo to give the title compound as a mixture with residual DMF as a clear oil, 1.55 g
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[N:14]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:15]=[C:16](Br)[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li]C(C)(C)C.[C:32](=[O:34])=[O:33]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[N:14]([CH2:19][O:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])[CH:15]=[C:16]([C:32]([OH:34])=[O:33])[N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc(Br)cn1COCC[Si](C)(C)C
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC1c1nc(C(=O)O)cn1COCC[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.1 %

Procedure:
2-[4-Bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (1.0 g, 2.2 mmol) in THF (10 mL) was cooled to −78° C. and treated with t-BuLi (1.7 M in pentane, 2.7 mL, 4.6 mmol). The reaction mixture was stirred for 1 hour and treated with solid CO2 (500 mg). The mixture was warmed to ambient temperature and mixture was concentrated. The solution was dried over MgSO4 and subjected to a 120 g SiO2 COMBIFLASH column (0-100% EtOAc-hexanes followed by 0-20% MeOH-EtOAc gradient) to afford 2-(1-tert-butoxycarbonyl-pyrrolidin-2-yl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carboxylic acid (200 mg, 22%): MS (ESI) m/z 412 [M+H]+.
Reaction SMILES: C[C:2]1([C:18]([O-])=[O:19])[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[CH2:4][CH2:3]1.CC(C[AlH]CC(C)C)C.CO.[Cl-].[Na+]>C1(C)C=CC=CC=1>[CH:18]([CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:9])[CH2:4][CH2:3]1)=[O:19]
Reactant: CC1(C(=O)[O-])CCN(C(=O)OCc2ccccc2)CC1
Agent: CC(C)C[AlH]CC(C)C
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: O=CC1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 1 h

Procedure:
A solution of 1-benzyl 4-methylpiperidine-1,4-dicarboxylate (10 g) in toluene (100 ml) under nitrogen was cooled to −78° C. DIBAL-H (60.9 ml) was then added dropwise at −78° C., and the mixture was stirred for one hour at that temperature (TLC monitoring). Because the reaction was incomplete, a further 0.2 eq. of DIBAL-H were added and stirring was carried out for a further 30 minutes (TLC monitoring: some starting material and the corresponding alcohol were detectable). Methanol (40 ml) followed by saturated sodium chloride solution (40 ml) were added slowly to the reaction mixture at −78° C. The mixture was filtered over Celite and the solvent was removed in vacuo. The residue was extracted with ethyl acetate (3×75 ml), dried (Na2SO4) and concentrated in vacuo. The crude product so obtained was purified by column chromatography (silica gel, 20% ethyl acetate/hexane). Yield: 4.3 g (49%)
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C[O-].[Na+].Cl.[NH2:14][OH:15]>CO>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4](=[N:14][OH:15])[NH2:5]
Reactant: N#Cc1ccccc1N
Reactant: NO
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: NC(=NO)c1ccccc1N

Procedure:
A suspension of 2-aminobenzonitrile (10 g, 0.084 mol), sodium methoxide (4.65 g, 0.084 mol) and hydroxylamine hydrochloride (5.88 g, 0.048 mol) in methanol was heated under reflux for 18 hours. The mixture was concentrated to an oil which was partitioned between ethyl acetate and 10% sodium hydroxide solution. The basic phase was separated and extracted three times with ethyl acetate. The combined organic solution was washed three times with saturated brine and dried over magnesium sulphate. Evaporation of the solvent gave the product as an oil which was purified by flash column chromatography on silica gel, eluting with dichloromethane/ethanol as eluant to afford the product as an oil (7.3 g), MS (+FAB) 152 ([M+H]+), 1H NMR (CDCl3) 7.3-6.7 (4H, m), 5.1-4.7 (4H, br, s).
Reaction SMILES: [CH:1]1([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][CH:18]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>CCCCCC>[CH:18]1([N:17]([CH2:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][N:8]([CH:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)=[O:34])[CH:11]=2)[C:33]([NH:32][C:29]2[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=2)=[O:34])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: c1cc(CNC2CCCCCC2)cc(CNC2CCCCCC2)c1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: CCCCCC
Product: O=C(Nc1ccc(F)cc1)N(Cc1cccc(CN(C(=O)Nc2ccc(F)cc2)C2CCCCCC2)c1)C1CCCCCC1
Reaction time: 2 h
Yield: 81.8 %

Procedure:
To a solution of 0.5 g N,N'-dicycloheptyl-m-xylylenediamine in 50 ml n-hexane, was added dropwise with stirring 5 ml of a n-hexane solution containing 0.46 g 4-fluorophenyl isocyanate under ice cooling, and stirring was continued at room temperature for two hours. The solid which separated out was collected by filtration, washed with n-hexane and recrystallized from methanol, giving 0.75 g of 1,3-bis[[1-cycloheptyl-3-(p-fluorophenyl)ureido]methyl]benzene.
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:5]=2[S:4][C:3]=1[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]([F:28])([F:27])[F:26].[C:29](=[O:31])=[O:30]>C1COCC1>[CH3:12][N:8]1[C:9](=[O:11])[C:10]2[C:2]([C:29]([OH:31])=[O:30])=[C:3]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])[S:4][C:5]=2[N:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]1=[O:13]
Reactant: O=C=O
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(Br)c(Cc3ccccc3C(F)(F)F)sc21
Solvent: C1CCOC1
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C(=O)O)c(Cc3ccccc3C(F)(F)F)sc21

Procedure:
To a solution of 5-bromo-3-methyl-1-(2-methylpropyl)-6-[[2-(trifluoromethyl)phenyl]methyl]-thieno[2,3-d]pyrimidine-2,4(1H,3H)-dione (WO 0183489) in THF (60 ml) was added isopropylmagnesiumcholride (2M solution in THF, 3.35 ml) dropwise at 0° C. under nitrogen. After 5 min the mixture was treated with a stream of carbon dioxide for 10 min. The reaction mixture was quenched with water, acidified 2N HCl and extracted into ethyl acetate (×3). The combined organic extracts were washed with dilute HCl, brine, dried (MgSO4) and concentrated in vacuo to give the subtitle compound as a yellow solid (2.48 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[F:9])[NH2:5].[C:10](Cl)(Cl)=[O:11]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:5]=[C:10]=[O:11])[CH:6]=[CH:7][C:8]=1[F:9]
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(F)c(Cl)c1
Temperature: 110 °C

Procedure:
At -10° to 0° C. and while stirring, a solution of 156 parts by weight of 3-chloro-4-fluoroaniline (J. Chem. Soc., 1928, 423) is metered into a solution of 250 parts by weight of phosgene in 1,000 parts by weight of toluene. The mixture is slowly heated to 110° C. (internal temperature), at which temperature it becomes clear.