Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:38]=[C:11]3[N:12]=[C:13]([CH3:37])[C:14]([C@H:27]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])=[C:15]([N:16]4[CH2:21][CH2:20][C:19](/[CH:23]=[CH:24]/[CH:25]=[CH2:26])([CH3:22])[CH2:18][CH2:17]4)[N:10]3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Cl:39][C:40]1[CH:41]=[CH:42][C:43]([OH:49])=[C:44](B(O)O)[CH:45]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:23](/[C:19]1([CH3:22])[CH2:18][CH2:17][N:16]([C:15]2[N:10]3[N:9]=[C:8]([C:4]4[CH:3]=[C:2]([C:42]5[CH:41]=[C:40]([Cl:39])[CH:45]=[CH:44][C:43]=5[OH:49])[CH:7]=[CH:6][CH:5]=4)[CH:38]=[C:11]3[N:12]=[C:13]([CH3:37])[C:14]=2[C@H:27]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[CH2:21][CH2:20]1)=[CH:24]\[CH:25]=[CH2:26]
Reactant: OB(O)c1cc(Cl)ccc1O
Reactant: C=C/C=C/C1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(Br)c4)nn23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: C=C/C=C/C1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)nc3cc(-c4cccc(-c5cc(Cl)ccc5O)c4)nn23)CC1
Temperature: 90 °C
Yield: 73.9 %

Procedure:
To a microwave tube was added (S,E)-methyl 2-(2-(3-bromophenyl)-7-(4-(buta-1,3-dien-1-yl)-4-methylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (100 mg, 0.172 mmol), (5-chloro-2-hydroxyphenyl)boronic acid (44.5 mg, 0.258 mmol), and 2.0 M aqueous K2CO3 (0.086 mL, 0.172 mmol) in dioxane (2 mL) and water (0.5 mL). The reaction was sparged with nitrogen for 1 minutes, treated Pd(PPh3)4 (19.87 mg, 0.017 mmol) then sparged for 1 min. The reaction tube was sealed and then heated at 90° C. in a microwave tube for 1 h. LCMS analysis showed 40% completion. Additional 10 mg of Pd(PPh3)4 added and heated at 90° C. for another 2 h. The reaction was concentrated, diluted with water (15 mL) and extracted wtih EtOAc. The EtOAc layer was washed with brine, then dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by biotage (0%-40% EtOAc in hexanes) to isolate 80 mg (74%) of the product as off-white foam. 1H NMR (500 MHz, CDCl3) δ 8.09 (br. s., 1H), 8.06 (d, J=7.9 Hz, 1H), 7.60 (t, J=7.5 Hz, 1H), 7.50-7.45 (m, 1H), 7.34 (d, J=2.5 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 6.85 (s, 1H), 6.39 (dt, J=16.9, 10.2 Hz, 1H), 6.17 (dd, J=15.4, 10.4 Hz, 1H), 6.07 (s, 1H), 5.88 (d, J=15.3 Hz, 1H), 5.33 (br. s., 1H), 5.19 (d, J=17.2 Hz, 1H), 5.04 (d, J=9.6 Hz, 1H), 4.50-2.50 (m, 4 H), 3.75 (s, 3H), 2.64 (s, 3H), 1.93 (d, J=12.9 Hz, 1H), 1.87-1.73 (m, 2H), 1.67 (br. s., 1H), 1.29-1.24 (m, 12H). LCMS (M+1)=629.08.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[C:24]([C:34](=[O:37])[NH:35][CH3:36])[C:23]=3[CH:38]=2)[C:17]=1[CH3:18])[C:12](O)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1[C:45]1([NH2:48])[CH2:47][CH2:46]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]([O:8][C:9]1[C:17]([CH3:18])=[C:16]([C:19]2[CH:20]=[CH:21][C:22]3[O:26][C:25]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)=[C:24]([C:34]([NH:35][CH3:36])=[O:37])[C:23]=3[CH:38]=2)[CH:15]=[C:11]([C:12](=[O:13])[NH:48][C:45]2([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][N:39]=3)[CH2:47][CH2:46]2)[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1(c2ccccn2)CC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)cc(OCc4ccccc4)c3C)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ccccn5)CC4)cc(OCc4ccccc4)c3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 3-(benzyloxy)-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.2 g, 0.40 mmol, 1 eq), 1-(pyridin-2-yl)cyclopropanamine (0.064 g, 0.47 mmol, 1.2 eq) (60% purity), HOBT (0.68 g, 0.012 mmol, 1.7 eq), EDC.HCl (0.064 g, 0.72 mmol, 1.8 eq) in DCM at ambient temperature under nitrogen was added Diisopropylethylamine (0.26 g, 2.0 mmol, 5.0 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was further purified by column chromatography (neutral alumina) using 0.5% Methanol/DCM and preparative HPLC. Yield: 0.17 g (70%). 1H NMR (400 MHz, DMSO-d6): δ 1.26-1.27 (m, 2H), 1.54-1.56 (m, 2H), 2.18 (s, 3H), 2.81-2.82 (s, 3H), 5.26 (s, 2H) 7.13-7.15 (q, 1H, J=4.4 Hz), 7.30-7.43 (m, 6H), 7.58 (d, 4H), 7.65-7.69 (t, 2H, J=3.9 Hz), 7.74-7.79 (d, 1H, J=8.0 Hz), 7.97-8.01 (m, 2H), 8.43-8.48 (dd, 2H, J=4.89 Hz), 9.186 (s, 1H). LCMS: (ES+) m/z=626 (M+H) Ascentis Express C18 (5.0×2.1-2.7 μm) Mphase A: 2% MeCN-98% H2O-10 mM NH4COOH Mphase B: 98% MeCN-2% H2O-10 mM NH4COOH
Reaction SMILES: [C:1]1(=[O:7])[O:6][CH:4]([CH3:5])CO1.[NH:8](CCO)[CH2:9][CH2:10][OH:11]>>[OH:11][CH2:10][CH2:9][N:8]1[CH2:5][CH2:4][O:6][C:1]1=[O:7]
Reactant: OCCNCCO
Reactant: CC1COC(=O)O1
Product: O=C1OCCN1CCO
Temperature: 120 °C

Procedure:
5.1 mol of propylene carbonate were provided as an initial charge at 23° C. under a nitrogen atmosphere. 5 mol of diethanolamine were added over 30 to 120 minutes with stirring, and the temperature of the reaction mixture rose. On completion of the addition the mixture was heated to 120° C. in the course of 10 to 120 minutes and left to stir at 120° C. for 2 hours. Then a 10 to 20 mbar vacuum was applied, the temperature was raised from 120° C. to 160° C. and propylene glycol was distilled off. The N-(2-hydroxyethyl)oxazolidin-2-one obtained almost quantitatively as undistilled bottom product comprised 96 to 98% by weight of product of value and had a Hazen color number in the range from 0 to 15.
Reaction SMILES: Br[C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[F:20][C:21]([F:34])([F:33])[C:22](B1OC(C)(C)C(C)(C)O1)=[CH2:23].C(=O)([O-])[O-].[Na+].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:20][C:21]([F:34])([F:33])[C:22]([C:2]1[C:12]2[O:11][CH2:10][CH2:9][N:8]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)=[CH2:23]
Reactant: C=C(B1OC(C)(C)C(C)(C)O1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)cccc2C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: C=C(c1cccc2c1OCCN(C(=O)OC(C)(C)C)C2)C(F)(F)F
Temperature: 85 °C
Reaction time: 12 h
Yield: 87.4 %

Procedure:
A mixture of tert-butyl 9-bromo-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (328 mg, 1.00 mmol), 1-(trifluoromethyl)vinylboronic acid pinacol ester (222 mg, 1.00 mmol), saturated aqueous sodium carbonate solution (6 ml) and tetrakis(triphenylphosphine)palladium(0) (32.6 mg, 0.0282 mmol) in dimethoxyethane (10 ml) was stirred at 85° C. for 12 hr under a nitrogen atmosphere. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the desired product (300 mg, 87.5%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]=[O:21])=[CH:15][C:14]=2[CH3:22])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8].[CH2:23](O)[CH2:24][OH:25].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:3]([NH:9][CH2:10][CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][CH:20]3[O:25][CH2:24][CH2:23][O:21]3)=[CH:15][C:14]=2[CH3:22])=[N:4][CH:5]=[N:6][C:7]=1[CH3:8]
Reactant: Cc1cc(CC=O)ccc1OCCNc1ncnc(C)c1Cl
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(CC2OCCO2)ccc1OCCNc1ncnc(C)c1Cl
Yield: 69.4 %

Procedure:
10.0 g of 5-chloro-4-[2-(4-formylmethyl-2-methylphenoxy)ethylamino]-6-methylpyrimidine and 3.0 g of ethylene glycol were dissolved in 300 ml of toluene. A small amount of p-toluenesulfonic acid was added to the solution, and the reaction vessel was equipped with a device for quantitatively determining water. The mixture was then heated under reflux for 8 hours. At the end of this time, the reaction mixture was washed with water and dried over anhydrous sodium sulfate. Toluene was removed by distillation under reduced pressure and the oily product thus obtained was subjected to column chromatography (Wakogel C-200, eluted with a 2:1 by volume mixture of toluene and ethyl acetate) to isolate the product and give 7.9 g of the title compound as a colorless oily liquid, n23.4 =1.5730.
Reaction SMILES: [Cl-].[C:2]([O:13][CH3:14])(=[O:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([O-:9])=O)=[CH:5][CH:4]=1.[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.C(N(CC)CC)C>ClCCl>[N:15]1([C:7]([C:6]2[CH:5]=[CH:4][C:3]([C:2]([O:13][CH3:14])=[O:12])=[CH:11][CH:10]=2)=[O:9])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: COC(=O)c1ccc(C(=O)[O-])cc1
Reactant: C1CCNC1
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(C(=O)N2CCCC2)cc1

Procedure:
29.0 g (0.146 mol) of monomethyl terephthalate chloride was reacted with 14.2 g (200 mmol) of pyrrolidine and 21.0 g (208 mmol) of triethylamine in 350 ml of dichloromethane. After the treatment in an ordinary manner, methyl 4-(1-pyrrolidylcarbonyl)benzoate was obtained. 29.0 g of the ester was hydrolyzed with 12.0 g of sodium hydroxide in a mixed solvent comprising 70 ml of water, 70 ml of methanol and 70 ml of tetrahydrofuran. After the completion of the reaction, the solvent was evaporated. 1 N hydrochloric acid was added to the residue and the obtained mixture was treated with dichloromethane as the extraction solvent in an ordinary manner to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=O)[CH2:3]1.Cl.[NH2:11][OH:12].C(=O)([O-])[O-].[Na+].[Na+]>C(O)C.O>[CH3:1][C:2]1([CH3:9])[CH2:7][CH2:6][CH2:5][C:4](=[N:11][OH:12])[CH2:3]1
Reactant: NO
Reactant: CC1(C)CCCC(=O)C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CC1(C)CCCC(=NO)C1

Procedure:
To a mixture of 3,3-dimethylcyclohexanone (4.0 g, 0.032 mol) and hydroxylamine hydrochloride (2.9 g, 0.041 mol) in ethanol (20 mL) was added dropwise a solution of sodium carbonate (4.3 g, 0.041 mol) in water (25 mL). The mixture was heated at reflux for 3 hours. The mixture was concentrated in vacuo to remove the ethanol and the aqueous residue was extracted with ethyl acetate. The organic phase was dried (MgSO4), filtered and concentrated in vacuo to give 3,3-dimethylcyclohexanone oxime as a yellow oil. This material was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]([CH2:13][CH:14]=O)[C:4](=[O:16])[CH:3]=1.[C:17]([O:21][C:22](=[O:41])[N:23]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[CH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:17]([O:21][C:22](=[O:41])[N:23]([CH2:30][C:31]1[CH:40]=[CH:39][C:34]2[O:35][CH2:36][CH2:37][O:38][C:33]=2[CH:32]=1)[CH:24]1[CH2:29][CH2:28][N:27]([CH2:14][CH2:13][N:5]2[C:6]3[C:11](=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=3)[C:2]([Cl:1])=[CH:3][C:4]2=[O:16])[CH2:26][CH2:25]1)([CH3:20])([CH3:18])[CH3:19]
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: O=CCn1c(=O)cc(Cl)c2ccc(Cl)cc21
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)cc(Cl)c3ccc(Cl)cc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.7 %

Procedure:
To 3 mL of a chloroform solution containing 69 mg of (4,7-dichloro-2-oxoquinolin-1(2H)-yl)acetaldehyde, 94 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 24 mg of acetic acid were added, and stirred at room temperature for 2 hours. To the reaction mixture, 86 mg of sodium triacetoxyborohydride was added, and stirred for 2.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60N, eluent; ethyl acetate], to give 109 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4,7-dichloro-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][CH2:10][O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([NH:18][S:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])=[CH:24][CH:23]=3)(=[O:21])=[O:20])[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)=[N:6][CH:7]=1.[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.Cl>N1C=CC=CC=1.C(Cl)Cl>[C:28]([C:25]1[CH:26]=[CH:27][C:22]([S:19]([NH:18][C:14]2[N:15]=[CH:16][N:17]=[C:12]([O:11][CH2:10][CH2:9][O:8][C:5]3[N:6]=[CH:7][C:2]([NH:1][C:39](=[O:46])[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:3][CH:4]=3)[C:13]=2[C:32]2[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(N)cn2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(-c2c(NS(=O)(=O)c3ccc(C(C)(C)C)cc3)ncnc2OCCOc2ccc(NC(=O)c3ccccc3)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
To a solution of N-{6-{2-(5-aminopyridin-2-yloxy)ethoxy}-5-(4-methylphenyl)pyrimidin-4-yl}-4-tert-butylbenzenesulfonamide (150 mg) in pyridine (2 ml) is added a solution of benzoyl chloride (43 mg) in methylene chloride (0.4 ml), and the mixture is stirred at room temperature for two hours. To the reaction solution is added 10% hydrochloric acid, and the mixture is extracted with ethyl acetate. The ethyl acetate layer is washed, dried and evaporated to remove the solvent. The residue is recrystallized from ethyl acetate/n-hexane to give N-(6-[2-{6-(4-tert-butylphenylsulfonylamino)-5-(4-methylphenyl)pyrimidin-4-yloxy}ethoxy]pyridin-3-yl)benzamide (161 mg) as crystals.
Reaction SMILES: [SH:1][CH:2]([CH3:6])[CH2:3][CH2:4][OH:5].[CH3:7][C:8]1C=CC(S(O)(=O)=O)=C[CH:13]=1.C(=O)CCC>C(Cl)Cl>[CH2:8]([CH:13]1[S:1][CH:2]([CH3:6])[CH2:3][CH2:4][O:5]1)[CH3:7]
Reactant: CC(S)CCO
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCC=O
Solvent: ClCCl
Product: CCC1OCCC(C)S1
Temperature: 25 °C

Procedure:
A solution of 3-mercapto-1-butanol (106 g, 1 mol, synthesized as above) and PTSA (paratoluenesulfonic acid monohydrate, 38 g, 0.2 mol, commercially available from Sigma-Aldrich, Inc.) in 400 mL of CH2Cl2 (dichloromethane) were cooled with an ice bath. Butyraldehyde (106 mL, 1.2 mol, commercially available from Sigma-Aldrich, Inc.) was added drop wise to the solution, and the reaction mixture was stirred with cooling for half an hour and at room temperature for another 1 hour. The reaction mixture was washed twice with saturated sodium bicarbonate solution and once with brine. The organic phase was then dried with anhydrous magnesium sulfate. The solvent was removed with a rotary evaporator and the crude product was distilled under vacuum to provide 2-ethyl-4-methyl-1,3-oxathiane (98 g), which had a boiling point of 80° C. at a pressure of 10.4 mmHg.
Reaction SMILES: [OH:1][CH:2]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1)[CH2:3][C:4]#[C:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].CCN(CC)CC.[H][H]>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].C1COCC1>[OH:1][CH:2]([CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:16][CH:15]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10]
Reactant: [H][H]
Reactant: CCCCCc1ccc(OCC(O)CC#CCCCC(=O)O)cc1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCc1ccc(OCC(O)CCCCCCC(=O)O)cc1

Procedure:
A mixture of 3.5 g of 8-hydroxy-9-(4-pentylphenoxy)-5-nonynoic acid, 0.3 g of Lindlar's catalyst, 2.5 ml of Et3N and 80 ml of THF was hydrogenated under 1 atm of hydrogen until the uptake hydrogen ceased. The solvent and catalyst were removed. The crude product was recrystallized in toluene to yield the title compound, mp 105.0°-105.5°. CI-MS (high resolution) (M+1=337.2298).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12](Cl)[N:11]=2)=[CH:6][CH:5]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>C(O)C.O>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:15]([Cl:16])=[CH:14][N:13]=[C:12]([NH:22][CH:19]3[CH2:21][CH2:20]3)[N:11]=2)=[CH:6][CH:5]=1
Reactant: NC1CC1
Reactant: COC(=O)c1ccc(-c2nc(Cl)ncc2Cl)cc1
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccc(-c2nc(NC3CC3)ncc2Cl)cc1
Temperature: 80 °C
Yield: 100 %

Procedure:
4-(2,5-Dichloropyrimidin-4-yl)-benzoic acid methyl ester (85 mg, 0.30 mmol) was dissolved in ethanol with 0.2 mL cyclopropylamine and the reaction mixture heated to 80° C. overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to afford 4-(5-chloro-2-cyclopropylaminopyrimidin-4-yl)-benzoic acid methyl ester as a solid, 90 mg, 0.30 mmol, 100% yield. LCMS: ES+=304.1.
Reaction SMILES: C(N(CC)CC)C.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18]([OH:20])=O.C1(P([N:35]=[N+:36]=[N-:37])(C2C=CC=CC=2)=O)C=CC=CC=1>O1CCCC1>[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[CH:10][C:9]=1[C:18]([N:35]=[N+:36]=[N-:37])=[O:20]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: [N-]=[N+]=NC(=O)c1ccc2ccccc2n1
Temperature: -10 °C
Reaction time: 0.17 h
Yield: 263.9 %

Procedure:
47 ml (0.34 mol) of triethylamine are added to a stirred suspension, cooled to -10° C., of 30.0 g (0.17 mol) of quinoline-2-carboxylic acid in 385 ml of anhydrous tetrahydrofuran, and the mixture is stirred at -10° C. for 10 minutes, whereupon a clear solution forms. 73.0 ml (0.34 mol) of diphenylphosphoryl azide are then added dropwise and the reaction mixture is left to stand in a refrigerator at 0° C. for 20 hours. Thereafter, the mixture is stirred into 350 ml of ice-cold dilute NaHCO3 solution. The precipitate formed is separated off by filtration, washed with water and dried in air. 88.9 g (86%) of the title compound are obtained as a pale solid.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CON(C)[C:39]([C:41]1[S:42][CH:43]=[CH:44][N:45]=1)=[O:40].C1COCC1>CC(OC)(C)C>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([F:34])[C:23]([F:35])=[C:22]([C:39]([C:41]2[S:42][CH:43]=[CH:44][N:45]=2)=[O:40])[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2F)C[C@@H](C)O1
Reactant: CON(C)C(=O)c1nccs1
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(C(=O)c3nccs3)c(F)c2F)C[C@@H](C)O1

Procedure:
Starting materials (2R,6R)-4-(6-((tert-butyldiphenylsilyloxy)methyl)-2,3-difluorophenyl)-2,6-dimethylmorpholine (Intermediate 43) and N-methoxy-N-methylthiazole-2-carboxamide (MTBE was used as solvent instead of THF).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[C:39](Cl)(=[O:46])[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39](=[O:46])[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CCc1ccc(C(=N)NC(=O)c3ccccc3)cc1)n2C)c1ccccn1
Yield: 79 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[2-(4-amidinophenyl)ethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and benzoyl chloride. Yield: 79% of theory, C35H34N6O4 (602.7); Rf value: 0.52 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=603; (M+Na)+=625.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[NH:9][CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:4][CH:3]=1.[CH3:24][N:25]=[C:26]=[O:27]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:18]2[CH2:23][CH2:22][N:21]([C:26]([NH:25][CH3:24])=[O:27])[CH2:20][CH2:19]2)[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:26]([NH:25][CH3:24])=[O:27])=[CH:6][CH:7]=1
Reactant: CN=C=O
Reactant: Fc1ccc(C(NCCc2ccccc2)C2CCNCC2)cc1
Solvent: ClCCl
Product: CNC(=O)N1CCC(C(c2ccc(F)cc2)N(CCc2ccccc2)C(=O)NC)CC1
Yield: 79.1 %

Procedure:
A solution of 2.25 g (0.0072 mol) of α-(4-fluorophenyl)-N-(2-phenylethyl)-4-piperidinemethanamine and 2.50 g (0.044 mol) of methyl isocyanate in 200 mL of methylene chloride was stirred at room temperature overnight. The solvent was removed in vacuo to give a solid. This was triturated with anhydrous ether, and the solid was collected to give 2.43 g (79.1%) of white solid, mp 186°-188° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][C:7]([OH:9])=O.[N+]([O-])(O)=O.[O:18]([CH2:22][CH2:23][NH2:24])[N+:19]([O-:21])=[O:20].C(OC(C)C)(C)C>>[O:18]([CH2:22][CH2:23][NH:24][C:7](=[O:9])[CH2:6][O:5][C:4]1[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=1[O:2][CH3:1])[N+:19]([O-:21])=[O:20]
Reactant: COc1ccccc1OCC(=O)O
Reactant: NCCO[N+](=O)[O-]
Solvent: CC(C)OC(C)C
Solvent: O=[N+]([O-])O
Product: COc1ccccc1OCC(=O)NCCO[N+](=O)[O-]
Yield: 28.2 %

Procedure:
Following a similar treatment to that in Example 2 and using 0.77 g of 2-methoxyphenoxyacetic acid and 0.60 g of nitroxyethylamine nitrate, 0.27 g of the title compound was obtained as colorless needles (solvent for recrystallization; diisopropyl ether).