Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([C@H:12]([CH2:26][CH2:27][CH2:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:13]([CH2:17][CH2:18][O:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14](O)=[O:15])(=[O:11])=[O:10])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:44][NH2:45]>C(Cl)Cl>[OH:44][NH:45][C:14](=[O:15])[CH:13]([CH2:17][CH2:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]([S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)(=[O:11])=[O:10])[CH2:26][CH2:27][CH2:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: COc1ccc(S(=O)(=O)[C@H](CCCCc2ccccc2)[C@H](CCOc2ccccc2)C(=O)O)cc1
Reactant: C[Si](C)(C)ON
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C(CCCCc2ccccc2)C(CCOc2ccccc2)C(=O)NO)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
(±)-(2R*,3R*)-3-(4-Methoxybenzenesulfonyl)-7-phenyl-2-(2-phenoxyethyl)heptanoic acid (0.17 g, 0.34 mmol) is dissolved in CH2Cl2 (1 mL) and cooled to 0° C. A solution of oxalyl chloride in CH2Cl2 (0.5 mL, 1 mmol) is added dropwise, the bath removed and the reaction allowed to warm and stir at 23° C. for 3 hours. The reaction is then concentrated in vacuo and azeotroped with CHCl3. The resulting oil is dissolved in CH2Cl2 (3 mL), cooled to 0° C. and O-(trimethylsilyl)hydroxylamine (0.16 g, 1.7 mmol) is added dropwise. The bath is removed and the reaction is allowed to warm to 20° C. The reaction is then partitioned between CH2Cl2 (20 mL) and 1 N HCl (10 mL). The organic layer is then separated and washed with water (10 mL), dried (MgSO4) and concentrated in vacuo. The product is purified by reverse phase HPLC (65% CH3CN in 0.1% TFA/H2O) to yield (±)-(2R*, R*)-3-(4-methoxybenzenesulfonyl)-7-phenyl-2-(2-phenoxyethyl)heptanoic acid hydroxyamide (0.12 g, 69%): 1H NMR (300 MHz, CDCl3) δ 7.73 (d, J=8.8 Hz, 2H), 7.28-7.14 (m, 5H), 7.08 (d, J=7.0 Hz, 2H), 6.97-6.89 (m, 3H), 6.73 (d, J=8.1 Hz, 2H), 3.89-3.71 (m, 5H), 3.27-3.20 (m, 2H), 2.51 (t, J=7.2 Hz, 2H), 2.45-2.32 (m, 1H), 1.98-1.75 (m, 3H), 1.55-1.38 (m, 3H), 1.35-1.22 (m, 1H); 13C NMR (75.5 MHz, CDCl3) δ 168.74, 164.06, 158.25, 141.93, 130.70, 129.46, 128.88, 128.34, 128.30, 125.78, 121.06, 114.63, 114.36, 66.37, 65.16, 55.67, 38.36, 35.30, 31.00, 30.35, 27.75, 25.34; MS (FAB) m/e 512 (M+H)+ ; Anal. (C28H33NO6S.0.2 H2O) C, H, N.
Reaction SMILES: C(OC[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11]C=1)=[CH2:8])(=O)C.S(=O)(=O)(O)O.C(OCCC(C1C=CC=CC=1)=C)(=[O:22])C.S(=O)(=O)(O)O.[OH-].[Na+].[CH2:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH:7]([CH:9]1[CH2:14][CH:13]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[CH:12]=[CH:11][O:22]1)([CH3:6])[CH3:8]
Reactant: C=C(CCOC(C)=O)c1ccccc1
Reactant: C1CCCCC1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)C1CC(c2ccccc2)C=CO1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 500 ml three neck reaction flask equipped with stirrer, thermometer, reflux condenser and addition funnel is placed 72 gms (1 mole) of isobutyl aldehyde. The isobutyl aldehyde is heated to 66° C. (reflux) and from the additional funnel, over a period of 1 hour, is added a mixture of 204 g (1 mole) of 3-phenyl-3-buten-1-yl acetate and 1 g concentrated sulfuric acid. During addition of the 3-phenyl-3-buten-1-yl acetate/sulfuric acid mixture, the reaction mass temperature increases to 80°-85° C. At the end of the addition of the mixture, the reaction mass is stirred for a period of three hours at 80°-85° C. The reaction mass is then cooled to room temperature and 100 ml of a 10% aqueous sodium hydroxide solution is added thereto with stirring, followed by 100 ml cyclohexane. The resulting mixture is transferred to a separatory funnel and the aqueous layer is removed. The organic layer is then washed with one 100 ml portion of 10% aqueous sodium chloride. The organic layer is then stripped of solvent and rushed over. To the rushed over material 4.5 gms Primol®, 0.5 gms triethanolamine and 0.1 gms of Ionox® is added. The resulting material is then distilled in an 8 plate vigreux column yielding the following fractions:
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:12]=[C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:10]=[CH:9][C:7]=1[NH2:8])([O-])=O.C.[H][H]>CO>[NH2:8][C:7]1[CH:9]=[CH:10][C:11]([O:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:12][C:6]=1[NH2:3]
Reactant: [H][H]
Reactant: Nc1ccc(OCCCCOc2ccccc2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc(OCCCCOc2ccccc2)cc1N

Procedure:
The procedure of the first paragraph of Example 26 is repeated substituting 4-phenxoybutyl bromide for the 3-phenoxypropyl bromide to afford 2-nitro-4-(4-phenoxybutoxy)acetanilide. After treatment at 20°-25° with methanolic-5N aqueous sodium hydroxide, 1.2 g. of the resultant 2-nitro-4-(4-phenoxybutoxy)aniline in a mixture of 20 ml. of methanol and 0.3 g. of 5% palladized charcoal is hydrogenated under ambient conditions. When the theoretical amount of hydrogen has been taken up, the mixture is filtered and the filtrate stripped to afford 1,2-diamino-4-(4-phenoxybutoxy)benzene as a gum.
Reaction SMILES: [OH-].[Li+].[CH3:3][C:4]1[N:5]=[C:6]([CH:22]([CH3:24])[CH3:23])[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:21])([CH3:20])[CH3:19])[C:8]=1[C:9]([O:11]CC)=[O:10].CO.OP(O)(O)=O>C1COCC1>[CH3:3][C:4]1[N:5]=[C:6]([CH:22]([CH3:24])[CH3:23])[N:7]([CH2:14][O:15][CH2:16][CH2:17][Si:18]([CH3:19])([CH3:21])[CH3:20])[C:8]=1[C:9]([OH:11])=[O:10]
Reactant: CCOC(=O)c1c(C)nc(C(C)C)n1COCC[Si](C)(C)C
Agent: O=P(O)(O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(C(C)C)n(COCC[Si](C)(C)C)c1C(=O)O
Temperature: 40 °C
Reaction time: 8 h
Yield: 99.7 %

Procedure:
Lithium hydroxide (2 mL, 2 mmol, 1 M in H2O) was added to a solution of ethyl 4-methyl-2-(1-methylethyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxylate (133 mg, 0.41 mmol) in THF:MeOH (6 mL/2 mL). The reaction mixture was heated at 40° C. and stirred overnight. The mixture was then acidified by H3PO4 (1N), extracted with 10% MeOH in CHCl3 and the organic layer was dried over sodium sulfate. The solvent was evaporated and dried in vacuo to give the title compound (122 mg, >99%) as a yellow gel which was directly used in the next step without purification. LCMS: m/z 299 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH3:11])[C:3]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)=[O:4].[CH2:13]([O:15][C:16](=[O:38])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH:31]=O)=[CH:27][CH:26]=2)=[C:21]([O:33]CCOC)[CH:20]=1)[CH3:14]>C1COCC1>[CH2:13]([O:15][C:16](=[O:38])[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([CH2:31][N:8]3[CH2:9][CH2:10][N:5]([C:3](=[O:4])[C:2]([CH3:12])([CH3:11])[CH3:1])[CH2:6][CH2:7]3)=[CH:27][CH:26]=2)=[C:21]([O:33][CH2:18][CH2:17][CH2:16][O:15][CH3:13])[CH:20]=1)[CH3:14]
Reactant: CC(C)(C)C(=O)N1CCNCC1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(C=O)cc2)c(OCCOC)c1
Solvent: C1CCOC1
Product: CCOC(=O)CCc1ccc(-c2ccc(CN3CCN(C(=O)C(C)(C)C)CC3)cc2)c(OCCCOC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 153.6 %

Procedure:
To a solution of 2,2-dimethyl-1-piperazin-1-yl-propan-1-one (37.45 mg, 0.22 mmol) in THF (2 mL) concentrated acetic acid (63 μL, 1.1 mmol), Ethyl-3-[4′-Formyl-2-(2-methoxy-ethoxy)-biphenyl-4-yl]-propionate (74 mg, 0.2 mmol) dissolved in THF (1 mL) and cyanoborhydride resin (123 mg, 0.3 mmol) was added. The reaction was shaken in a closed-vessel under argon at r.t. overnight. The mixture was filtered and dried under reduced pressure. The residue was redissolved in ethyl acetate (20 mL) and washed with an aqueous sodium hydrogen carbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered and dried under reduced pressure to give 80.6 mg of the titled compound.
Reaction SMILES: [C:1]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:11][N:10]([C:12](=[O:29])[C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C@H:9]([C:30]([O:32]C)=[O:31])[CH2:8]2)=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[C:1]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH:2]=[CH:3][C:4]([C@@:7]2([S:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:11][N:10]([C:12](=[O:29])[C@@H:13]([NH:21][C:22]([O:24][C:25]([CH3:27])([CH3:28])[CH3:26])=[O:23])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH:19]=[CH2:20])[C@H:9]([C:30]([OH:32])=[O:31])[CH2:8]2)=[CH:5][CH:6]=1
Reactant: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](SCCCC)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=CCCCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N1C[C@](SCCCC)(c2ccc(-c3ccccc3)cc2)C[C@H]1C(=O)O
Reaction time: 3 h
Yield: 88 %

Procedure:
To a solution of (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)non-8-enoyl)-4-(butylthio)pyrrolidine-2-carboxylate (135 mg, 0.217 mmol) in THF (1.5 mL) and methanol (1.500 mL) was added pre-made solution of lithium hydroxide monohydrate (18.19 mg, 0.433 mmol) in water (1.5 mL). The resulting cloudy solution was stirred at room for 3 hours. Quenched with 5% citric acid, extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, filtered, concentrated to afford the desired product (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)non-8-enoyl)-4-(butylthio)pyrrolidine-2-carboxylic acid (129 mg, 0.191 mmol, 88% yield) as a white foam. LC-MS (retention time: 3.67 min, method C), MS m/z 609 (M+H).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][O:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([CH:16]=O)=[CH:12][CH:11]=1.CCCCCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:16]([C:13]1[CH:14]=[CH:15][C:10]([C:9]([O:8][CH3:7])=[O:18])=[CH:11][CH:12]=1)=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)c1ccc(C=O)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C=Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.2 %

Procedure:
To a slurry of methyltriphenylphosphonium bromide (10.88 g, 30.46 mmol, 1 eq.) and potassium tert-butoxide (31 mL, 1 M solution in THF, 30.46 mmol, 1 eq.) in THF is added methyl-4-formylbenzoate (5.0 g, 30.46 mmol, 1 eq.). The bright yellow reaction mixture is stirred at room temperature for 5 hrs. Hexane is added and after stirring for 10 minutes, the mixture is filtered and washed twice with hexanes. Solvent is removed in vacuum and the crude oily residue is purified by silica gel chromatography (0-14% ethyl acetate/hexanes) to give 3.76 g of a white oily solid, methyl 4-vinylbenzoate (23.21 mmol, 76.2% yield). 1H NMR (300 MHz, CDCl3): δ 7.99 (2H, d, J=9 Hz), 7.45 (2H, d, J=9 Hz), 6.76 (1H, dd, J=17, 11 Hz), 5.86 (1H, d, J=17 Hz), 5.37 (1H, d, J=11 Hz), 3.91 (3H, s).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([C:9]2[O:13][C:12]([CH3:14])=[N:11][C:10]=2[CH3:15])([OH:8])[CH3:7])=[CH:2]1.[H-].[Na+].CI.[C:20](=O)([O-])O.[Na+]>CN(C)C=O>[CH3:20][O:8][C:6]([C:9]1[O:13][C:12]([CH3:14])=[N:11][C:10]=1[CH3:15])([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)[CH3:7]
Reactant: O=C([O-])O
Reactant: Cc1nc(C)c(C(C)(O)c2ccoc2)o1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(C)(c1ccoc1)c1oc(C)nc1C
Reaction time: 0.33 h

Procedure:
1-(3-Furyl)-1-(2,4-dimethyl-5-oxazolyl)ethanol (2 g) in dry N,N-dimethylformamide (15 ml) was added to a stirred suspension of sodium hydride (80%, 300 mg) in dry N,N-dimethylformamide (10 ml) at 0° C. After 20 minutes, methyl iodide (1.5 g) was added dropwise. The mixture was allowed to warm to room temperature and after 30 minutes aqueous sodium hydrogen carbonate was added.
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11](=[O:21])[C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[O:19][CH3:20])=[N:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CN(C)C=O.[CH3:27][C:28](C)([O-])[CH3:29].[K+].C(Br)C=C>O1CCCC1>[CH2:29]([N:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:9]/[C:8]/1=[N:10]\[C:11](=[O:21])[C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=1[O:19][CH3:20])[CH:28]=[CH2:27]
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C(C)(C)C)s1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: C=CCBr
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C=CCn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(Cl)ccc1OC
Temperature: 65 °C
Reaction time: 1 h

Procedure:
To a solution of Example 244A (410 mg, 1.3 mmol) in 5 mL of tetrahydrofuran:N,N-dimethylformamide (4/1) at 0° C. was added potassium tert-butoxide (230 mg, 1.9 mmol). The reaction mixture was stirred for 1 hour then allyl bromide (0.16 mL, 1.9 mmol) was added. The mixture was warmed to 65° C. and stirred overnight. The mixture was cooled to ambient temperature, concentrated, diluted with CH2Cl2 and washed with water and brine. The organic layer was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by chromatography (20-50% ethyl acetate/hexane gradient) afforded the title compound. 1H NMR (CDCl3, 300 MHz) δ ppm 1.34 (s, 9H), 3.90 (s, 3H), 4.78-4.85 (m, 3H), 522-5.36 (m, 2H), 5.90-6.09 (m, J=17.0, 10.17 Hz, 1H), 6.62 (s, 1H), 6.90 (d, J=9.2 Hz, 1H), 7.32 (dd, J=8.8, 3.1 Hz, 1H), 8.00 (d, J=2.7 Hz, 1H); MS (DCI/NH3) m/z 365 (M+H)+.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:10]=[CH:9][O:8][N:7]=1)=[O:5].[CH:12]([Mg]Br)=[CH2:13]>O1CCCC1>[O:8]1[CH:9]=[CH:10][C:6]([C:4](=[O:5])[CH:12]=[CH2:13])=[N:7]1
Reactant: CON(C)C(=O)c1ccon1
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(=O)c1ccon1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
The product of step (a) (0.66 g) was dissolved in dry tetrahydrofuran (20 ml), under a nitrogen atmosphere and cooled to −30° C. A solution of vinyl magnesium bromide (1M, 6 ml) was added dropwise over 5 minutes and the reaction mixture was allowed to warm to 0° C. and stirred at this temperature for 2 h. The mixture was then poured into ice-cold 2N hydrochloric acid (50 ml) and extracted into ethyl acetate. The extract was washed with water, brine, dried over magnesium sulphate and evaporated to give a dark oil (0.4 g).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:18]I>CN(C)C=O>[CH3:18][N:13]1[CH2:14][CH2:15][N:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)[CH2:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reaction time: 0.5 h
Yield: 90.4 %

Procedure:
1.04 g (5.0 mmol) of N-(4-nitrophenyl)piperazine was dissolved in 5 ml of dimethylformamide. Sodium hydride (0.24 g, 6.0 mmol) was added to the reaction mixture in three portions under nitrogen atmosphere and cooling over a period of 10 min. After 30 min of stirring, 0.31 ml (6.0 mmol) of methyl iodide was added dropwise to the reaction mixture at 0° C. Stirring was continued for 1 h at room temperature, the reaction mixture was then evaporated to dryness, and purified by silica gel chromatography (methylene chloride:methanol:triethylamine 94:5:1) to yield 1.0 g (90%) of 1-methyl-4-(4-nitrophenyl)piperazine.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][Cl:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:18]([C:21]1[C:22]([CH3:30])=[N:23][C:24]([O:28][CH3:29])=[N:25][C:26]=1[CH3:27])=[C:19]=S.C(=O)([O-])O.[Na+].Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>O1CCCC1.O>[Cl:12][C:11]1[C:2]2[N:1]=[C:19]([NH:18][C:21]3[C:26]([CH3:27])=[N:25][C:24]([O:28][CH3:29])=[N:23][C:22]=3[CH3:30])[N:13]([CH2:14][CH2:15][CH2:16][Cl:17])[C:3]=2[C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=1
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCCl
Reactant: COc1nc(C)c(N=C=S)c(C)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c2nc(Nc3c(C)nc(OC)nc3C)n(CCCCl)c12
Temperature: 60 °C
Reaction time: 36 h
Yield: 74.4 %

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-chloropropyl)amino]benzoate (500 mg, 1.80 mmol), 5-isothiocyanato-2-methoxy-4,6-dimethylpyrimidine (527 mg, 2.70 mmol) and sodium hydrogen carbonate (454 mg, 5.40 mmol) in tetrahydrofuran (1 mL) was stirred at 60° C. for 36 h. After tetrahydrofuran (4 mL), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (345 mg, 1.80 mmol) and triethylamine (0.251 mL, 1.80 mmol) were added to the mixture at room temperature, the resultant mixture was stirred at 50° C. for 40 min and poured into water (50 mL). The precipitate was collected by filtration and washed with water and diethyl ether to afford the title compound as a colorless solid (589 mg, 1.34 mmol, 74%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1)([CH3:3])=[CH2:2].CN1C=CN=C1.[N+](=[CH:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[N-]>C1(C)C=CC=CC=1>[CH3:3][C:1]1([C:4]2[CH:9]=[CH:8][C:7]([C:10]([F:11])([F:13])[F:12])=[CH:6][CH:5]=2)[CH2:2][CH:22]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: C=C(C)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: Cn1ccnc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CC1(C)c1ccc(C(F)(F)F)cc1
Yield: 82 %

Procedure:
To a toluene (50 ml) solution of 1-isopropenyl-4-(trifluoromethyl)benzene (4.93 g, 26.5 mmol) [Tetrahedron (2003), 59(17), 2999-3002], Co(TPP) (534 g, 0.795 mmol) and 1-methyl-1H-imidazole (6.53 g, 79.5 mmol), ethyl diazoacetate (4.23 g, 37.0 mmol) was added. Then the reaction and the following work-up were carried out according to the procedure described in Example 2H. The crude residue was applied to a silica gel chromatography column and eluted with a volume mixture of hexane and EtOAc (20/1) to afford 5.92 g (82% yield, trans) of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[CH:5]=[CH:6][C:7]=1[C:8](=[O:13])N(OC)C.[H-].[H-].[H-].[H-].[Li+].[Al+3].CCOC(C)=O.CCCCCCC>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([C@@H:14]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[CH:5]=[CH:6][C:7]=1[CH:8]=[O:13]
Reactant: CON(C)C(=O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1F
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)c1ccc(C=O)c(F)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 79 %

Procedure:
To a cooled (0° C.) solution of (S)-tert-butyl 1-(3-fluoro-4-(methoxy(methyl)carbamoyl)phenyl)ethylcarbamate (1.175 g, 3.6 mmol) in THF (36 mL) was added a solution of LAH in THF (1.0 M, 18 mL, 18 mmol) and the resulting mixture was stirred at 0° C. for 20 min. The reaction mixture was quenched by addition of a saturated Na2SO4 solution until gas evolution ceased. The reaction mixture was extracted with EtOAc (2×100 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/heptane 12 to 100%) provided (S)-tert-butyl 1-(3-fluoro-4-formylphenyl)ethylcarbamate as a white solid (760 mg, 79% yield).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[CH:2]1.[Cl:6][C:7]([Cl:11])([Cl:10])[CH:8]=[O:9]>CCCCCCC>[Cl:6][C:7]([Cl:11])([Cl:10])[CH:8]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[OH:9]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: c1ccsc1
Solvent: CCCCCCC
Product: OC(c1cccs1)C(Cl)(Cl)Cl
Yield: 20 %

Procedure:
Thiophene (4.2 g, 50 mmol) and trichloroacetaldehyde (7.35 g, 50 mmol) were dissolved in n-heptane (25 ml). The solution was heated under reflux for 3.5 hr. under a Soxleht apparatus in which Amberlyst 15 (4.2 g) had been placed. After cooling, the n-heptane solution was concentrated, and the residue was purified by distillation to give 2.32 g of α-trichloromethyl-2-thiophenemethanol boiling at 98°-100° C./1.0 mmHg.
Reaction SMILES: [CH:1]1([CH2:4][O:5][CH2:6][CH:7]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8]2)[CH2:3][CH2:2]1.Cl>C(O)(C)C>[CH:1]1([CH2:4][O:5][CH2:6][CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH2:2][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(COCC2CC2)C1
Agent: Cl
Solvent: CC(C)O
Product: C1CC(COCC2CC2)CN1
Yield: 64.5 %

Procedure:
tert-Butyl 3-[(cyclopropylmethoxy)methyl]pyrrolidine-1-carboxylate (Preparation 66, 50 g, 0.2 mol, 1 eq) was dissolved in isopropanol (200 mL) and treated with concentrated hydrogen chloride solution (28 mL, 0.3 mol, 1.5 eq). The mixture was refluxed for 1 h and evaporated. The residue was dissolved in water and washed with ether (2×100 mL). The aqueous fraction was made alkaline with potassium carbonate to pH 12-13 and extracted with chloroform. The extract was dried over sodium sulfate and evaporated to give title compound (20 g, 0.129 mol, 65%).
Reaction SMILES: Cl.[F:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CCN(C(C)C)C(C)C.[C:20](Cl)([Cl:22])=[O:21]>ClCCl>[F:2][CH2:3][C:4]1([OH:10])[CH2:9][CH2:8][N:7]([C:20]([Cl:22])=[O:21])[CH2:6][CH2:5]1
Reactant: OC1(CF)CCNCC1
Reactant: O=C(Cl)Cl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Cl)N1CCC(O)(CF)CC1
Reaction time: 0.25 h
Yield: 37 %

Procedure:
4-(Fluoromethyl)piperidin-4-ol hydrochloride (233 mg, 1.37 mmol) was suspended in dichloromethane (3 mL) followed by addition of DIPEA (0.6 mL, 3.4 mmol) and the slurry obtained added in portions over several minutes to a solution of phosgene (20W % in toluene, 0.75 mL) diluted into dichloromethane (5 mL) and the mixture was allowed to stir at this temperature for 15 minutes. The mixture was then concentrated and the residue partitioned with ethyl acetate and water. The organic solution was washed 0.5M hydrochloric acid, brine then dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (3:1 ethyl ether:hexanes) to give 4-(fluoromethyl)-4-hydroxypiperidine-1-carbonyl chloride (100 mg, 37% yield) as a colorless amorphous residue. GC-MS (EI) for C7H11FNO2Cl: 196 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[N:3]=1.[CH2:16]([CH:18]1[O:20][CH2:19]1)Cl.C(=O)([O-])[O-].[K+].[K+]>>[CH3:8][C:6]1[CH:7]=[C:2]([CH3:1])[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH:18]3[O:20][CH2:19]3)=[CH:11][CH:10]=2)[N:5]=1
Reactant: Cc1cc(C)nc(-c2ccc(O)cc2)n1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1cc(C)nc(-c2ccc(OCC3CO3)cc2)n1

Procedure:
4,6-dimethyl-2-(4-hydroxyphenyl)-pyrimidine is reacted with epichlorohydrin in the presence of potassium carbonate analogously to Example 5b). After working up, 4,6-dimethyl-2-[4-(2,3-epoxypropoxy)-phenyl]-pyrimidine is obtained which, after recrystallisation from isopropanol, has a melting point of 88°-90°.