Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([CH2:10][CH2:11][CH2:12][NH2:13])[CH:6]=[CH:7][C:8]=1[Cl:9].[Cl:14]C1C=C(Cl)C=CC=1CCC(O)=O>>[ClH:2].[Cl:14][C:6]1[CH:7]=[C:8]([Cl:9])[CH:3]=[CH:4][C:5]=1[CH2:10][CH2:11][CH2:12][NH2:13]
Reactant: NCCCc1ccc(Cl)c(Cl)c1
Reactant: O=C(O)CCc1ccc(Cl)cc1Cl
Agent: Cl
Product: NCCCc1ccc(Cl)cc1Cl

Procedure:
Intermediate 2 was prepared according to the procedures described in Intermediate 1 using 3-(2,4-dichlorophenyl)propanoic acid as the starting material. LC-MS (ESI) m/z 204.0 (M+H)+, RT=1.56 min (Method B).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].O=C1[CH2:13][C@H:12]2[N:14]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C@H]([CH2:10][CH2:11]2)C1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:5]=[C:4]1[CH2:13][CH:12]2[N:14]([C:15]([O:17][C:18]([CH3:20])([CH3:19])[CH3:21])=[O:16])[CH:2]([CH2:10][CH2:11]2)[CH2:3]1
Reactant: [Li]CCCC
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(=O)C2
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=C1CC2CCC(C1)N2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 27 %

Procedure:
To a solution of methyltriphenylphosphonium bromide (2.38 g, 6.6 mmol) in dry THF at 0° C. was added n-BuLi (2.7 mL, 2.5 M) dropwise. After stirring at 0° C. for 30 min, (1R,5S)-tert-butyl 3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylate (500 mg, 2.2 mmol) was added and the mixture was stirred at 0° C. for additional 16 hrs. The reaction was quenched by sat. NH4Cl and extracted with EtOAc (50 mL×3) and purified by SGC (eluting with petroleum ether/ethyl acetate=20/1) to give target compound (130 mg, 27%). 1H NMR (500 MHz, CDCl3) δ4.77 (t, J=4.0 Hz, 2H), 4.21 (br s, 1H), 4.11 (br s, 1H), 2.43-2.33 (m, 2H), 2.01 (s, 1H), 1.98 (s, 1H), 1.79 (d, J=3.0 Hz, 2H), 1.53-1.49 (m, 2H), 1.43 (s, 9H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH2:18].[CH:19]([O-])([O-])[O:20]C(Cl)(Cl)Cl>C1(C)C=CC=CC=1>[N:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[O:11][C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1)=[C:19]=[O:20]
Reactant: Nc1ccccc1Oc1ccc2ccccc2c1
Reactant: [O-]C([O-])OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccccc1Oc1ccc2ccccc2c1

Procedure:
To a solution of the title compound of Step B (7.6 g, 32.3 mmol) in 150 mL of toluene was added trichloromethyl orthoformate (6.40 g, 32.3 mmol) at room temperature. The resultant mixture was then heated at reflux overnight. The reaction mixture was then concentrated under reduced pressure to yield the title compound of Step C as an oil which was then used entirely in Step D.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][CH3:5].[Br:6][C:7]1[CH:12]=[CH:11]C(O)=[CH:9][CH:8]=1>>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:11]=[CH:12][C:7]([Br:6])=[CH:8][CH:9]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCOC
Product: COCOc1ccc(Br)cc1
Yield: 49 %

Procedure:
4-Methoxymethoxy-1-bromobenzene was prepared from formaldehyde dimethyl acetal and 4-bromophenol by the method of Y. P. Yardley and H. Fletcher, Synthesis 1976, p. 244. The boiling point of this derivative is 54°-56° C. at 0.1 hPa, and the yield is 49% of theory.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[N:10][C:11](Cl)=[N:12][CH:13]=1.[CH2:15]([OH:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CN(C)C=O>[CH2:15]([O:22][C:11]1[N:10]=[CH:9][C:8]([Br:7])=[CH:13][N:12]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: OCc1ccccc1
Reactant: Clc1ncc(Br)cn1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1cnc(OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Potassium tert-butoxide (6.96 g) was added to a solution of 5-bromo-2-chloro-pyrimidine (10 g) and benzyl alcohol (6.4 ml) in N,N-dimethylformamide (140 ml) and the mixture was stirred at room temperature for 1.5 hours. Water was added to the mixture and the precipitated solid was collected by filtration, washed with methanol, dried to give the titled compound (10.6 g). MS (m/z): 265/267 [M+H]+.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:10])[CH2:8][OH:9])=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[CH2:19][C:20](Cl)=[O:21]>C1COCC1>[C:4]1([C@H:7]2[NH:10][C:20](=[O:21])[CH2:19][O:9][CH2:8]2)[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: NC(CO)c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1COC[C@@H](c2ccccc2)N1
Reaction time: 1 h

Procedure:
(R)-Phenylglycinol (0.20 g, 1.46 mmol) in dry THF (10 mL) was treated with triethylamine (0.18 g, 1.75 mmol) in one portion at 0°, under an atmosphere of nitrogen. Chloroacetylchloride (0.20 g, 1.75 mmol) was added dropwise over 15 minutes at 0°. The mixture was allowed to reach room temperature over 1 hour then quenched with water (5 mL) and EtOAc (5 mL). The organic layer was washed with brine (10 mL), dried (MgSO4) and evaporated in vacuo to a white solid. NMR shows the precursor to the product (non ring closed). The solid was dissolved in dry THF (5 mL) and 10M NaOH was added slowly at 0°. The suspension was allowed to reach room temperature over 1.5 hours. The suspension was diluted with water (10 mL) and EtOAc (10 mL) and the organic layer was further washed with water (10 mL), then dried (MgSO4) and evaporated in vacuo to a crude yellow solid, which was taken to the next step without any purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>N1C=CC=CC=1>[CH3:23][S:24]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([NH:22][S:24]([CH3:23])(=[O:26])=[O:25])=[CH:20][CH:21]=3)[CH2:12][CH2:13]2)=[CH:6][CH:7]=1)(=[O:26])=[O:25]
Reactant: Nc1ccc(CCN2CCN(c3ccc(N)cc3)CC2)cc1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccc(CCN2CCN(c3ccc(NS(C)(=O)=O)cc3)CC2)cc1
Yield: 72.4 %

Procedure:
1-(4-Aminophenyl)-4-(4-aminophenethyl)piperazine (1.9 g) was dissolved in dry pyridine (15 ml) and methanesulphonyl chloride (1.85 g) was added dropwise with stirring. The mixture was stirred overnight, evaporated to dryness, and the residue triturated with aqueous sodium bicarbonate. The insoluble product was washed with water and digested with ethyl acetate/methanol then cooled and filtered, giving the pure title compound (2.1 g) as a white solid, m.p. 254°-6° (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:4]=1.CC(C)([O-])C.[K+].Cl[CH2:25][CH2:26][C@@H:27]1[CH2:31][C@@H:30]([OH:32])[CH2:29][N:28]1[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C)C(=O)C>[CH2:36]([O:35][C:33]([N:28]1[CH2:29][C@H:30]([OH:32])[CH2:31][C@H:27]1[CH2:26][CH2:25][O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:34])[CH3:37]
Reactant: COc1ccc(O)c(CCc2ccccc2)c1
Reactant: CCOC(=O)N1C[C@H](O)C[C@H]1CCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: CCOC(=O)N1C[C@H](O)C[C@H]1CCOc1ccc(OC)cc1CCc1ccccc1
Yield: 24 %

Procedure:
1130 mg of 4-methoxy-2-(2-phenylethyl)phenol were dissolved in 10 ml of N,N-dimethylacetamide, allowed to react with 610 mg of potassium t-butoxide and 1000 mg of (2S,4R)-2-(2-chloroethyl)-1-ethoxycarbonyl-4-hydroxypyrrolidine and extracted in the same manner as described in step (a) of Example 2. The resulting oily substance was purified by silica gel column chromatography, using a 1:2 by volume mixture of hexane and ethyl acetate as the eluent, to give 448 mg (yield 24%) of the title compound as an oily substance.
Reaction SMILES: [CH3:1][C:2]1[C:7](=[O:8])[CH2:6][CH:5]([C:9]([CH3:11])=[CH2:10])[CH2:4][CH:3]=1.[OH:12]O.[OH-].[Na+]>CO.O>[C:9]([C@@H:5]1[CH2:6][C@@H:7]2[C@@:2]([CH3:1])([O:8]2)[C:3](=[O:12])[CH2:4]1)([CH3:11])=[CH2:10]
Reactant: C=C(C)C1CC=C(C)C(=O)C1
Reactant: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C=C(C)[C@H]1CC(=O)[C@]2(C)O[C@@H]2C1
Reaction time: 5 h

Procedure:
(R)-Carvone was epoxidized according to a modification of the method of E. Klein and G. Ohloff (Tetrahedron, 1963, 11, 1091-1099). Thus H2O2 (31%, 95 mL, 836 mmol, 1.3 equivalents) was added to a solution of (L)-carvone (100 mL, 640 mmol) in 650 mL of methanol at <5° C. After cooling to <0° C., 6N NaOH (10.5 mL, 63 mmol, 0.1 equivalents) was added. The reaction temperature was maintained at <5° C. After 5 hours, the reaction was diluted with 650 mL water, then quenched with 0.5 N KH2PO4 (250 mL) and 325 mL of 1 molal Na2SO3, keeping the temperature at <25° C. The reaction was extracted with 2×750 mL tert-butyl methyl ether. The combined tert-butyl methyl ether extracts were washed with 500 mL each of 20% aqueous NaCl then 10% then 25% to provide a clear organic layer which was dried over MgSO4, then filtered and concentrated, then chased with 100 mL of methanol. The resulting solution assayed (GC) at 101.3 g (96%) of the titled compound, which contained 5% of the minor isomer. 1H NMR (400 MHz, CDCl3) δ ppm 1.40 (s, 3 H) 1.70 (s, 3 H) 1.89 (ddd, J=14.75, 11.11, 1.17 Hz, 1 H) 2.02 (dd, J=17.56, 11.66 Hz, 1 H) 2.31 -2.41 (m, 1 H) 2.58 (ddd, J=17.56, 4.67, 1.37 Hz, 1 H) 2.65-2.76 (m, 1 H) 3.44 (dd, J=3.09, 1.03 Hz, 1 H) 4.70 (d, J=0.69 Hz, 1 H) 4.75-4.80 (m, 1 H).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH2:3][CH2:4][C:5]1[O:6][C:7]2[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[CH:10][C:8]=2[CH:9]=1.[BH4-].[Na+]>[Pd].ClCCl.O>[NH2:14][C:11]1[CH:12]=[CH:13][C:7]2[O:6][C:5]([CH2:4][CH2:3][C:2]([F:18])([F:1])[F:17])=[CH:9][C:8]=2[CH:10]=1
Reactant: O=[N+]([O-])c1ccc2oc(CCC(F)(F)F)cc2c1
Agent: [Pd]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Nc1ccc2oc(CCC(F)(F)F)cc2c1
Reaction time: 5 h

Procedure:
A mixture of 2.4 g (9.2 mmol) of 2-(3,3,3-trifluoropropyl)-5-nitrobenzofuran, 0.65 g (17 mmol) of sodium borohydride, 45 mg of Adogen® 464 (methyl trialkylammonium chloride) and 0.38 g of 5% palladium on carbon containing 50% of water in 95 ml of dichloromethane and 48 ml of water is stirred for 5 hours, then it is filtered on silica and the silica is rinsed with ethanol. The filtrate is then concentrated under reduced pressure and coevaporated with toluene. By chromatography of the residue on a silica column using a 0-30% mixture of ethyl acetate in cyclohexane, 2.0 g of product are obtained. Melting point: 74° C.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][CH2:5]O.[CH3:8][N:9]([CH3:13])[C:10]([NH2:12])=[S:11]>Br>[CH3:8][N:9]([CH3:13])[C:10](=[NH:12])[S:11][CH2:5][CH2:4][CH2:3][N:2]([CH3:7])[CH3:1]
Reactant: CN(C)CCCO
Reactant: CN(C)C(N)=S
Agent: Br
Product: CN(C)CCCSC(=N)N(C)C

Procedure:
A mixture of 3-dimethylaminopropanol (10.3 g), N,N1 -dimethylthiourea (10.4 g) and aqueous hydrobromic acid (48%, 60 ml) was boiled under reflux for 18 hours and evaporated to dryness. The residue was recrystallised from ethanol to give the dihydrobromide of the title compound m.p. 173°-174°.
Reaction SMILES: [CH:1]([CH2:3][SiH:4](Cl)Cl)=[CH2:2].[C:7]([OH:15])(=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CCCCCC>[CH:1]([CH2:3][SiH:4]([O:15][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[O:14][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[CH2:2]
Reactant: C=CC[SiH](Cl)Cl
Reactant: O=C(O)c1ccccc1
Solvent: CCCCCC
Product: C=CC[SiH](OC(=O)c1ccccc1)OC(=O)c1ccccc1

Procedure:
705 g (5 moles) of vinylmethyldichlorosilane and 1000 ml of hexane are placed in the apparatus of Example 1. The reaction with 1245 g of benzoic acid (=10.2 moles) is performed as described under Example 1; the distillation of the raw product is performed in the same manner. At a pressure of 0.5 mbar and a head temperature of 141° C., 1295 g (4.15 moles) of a colorless liquid is distilled off. The yield amounts to 83%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:26][CH2:25][C:20]5(OCC[O:21]5)[CH2:19][CH:18]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:26][CH2:25][C:20](=[O:21])[CH2:19][CH:18]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCC4(CC3)OCCO4)cc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCC(=O)CC3)cc12
Reaction time: 8 h

Procedure:
To a suspension of Example 83A (370 mg, 0.970 mmol) in 15 mL dichloromethane was added excess trifluoroacetic acid. The reaction was held at room temperature overnight. The volatiles were removed in vacuo, and the residue was dissolved in 30 mL ethyl acetate. The mixture was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated to give the title compound. MS (ESI+) m/z 338.2 (M+H)+.
Reaction SMILES: CI.[Cl:3][C:4]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:5]=1[CH2:6][C:7]1[NH:12][C:11](=[O:13])[C:10]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[C:9]([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[N:8]=1.[C:32](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:3][C:4]1[CH:30]=[CH:29][CH:28]=[C:27]([Cl:31])[C:5]=1[CH2:6][C:7]1[N:12]([CH3:32])[C:11](=[O:13])[C:10]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[C:9]([C:21]2[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=2)[N:8]=1
Reactant: O=C([O-])[O-]
Reactant: O=c1[nH]c(Cc2c(Cl)cccc2Cl)nc(-c2ccncc2)c1-c1ccc(F)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1c(Cc2c(Cl)cccc2Cl)nc(-c2ccncc2)c(-c2ccc(F)cc2)c1=O
Reaction time: 2 h

Procedure:
Methyl iodide (41 ml, 0.65 mmol) was added to a stirring mixture of 2-(2,6-dichlorobenzyl)-5-(4-fluorophenyl)-6-(4-pyridyl)-4(3H)-pyrimidinone (280 mg, 0.61 mmol) and potassium carbonate (181 mg, 1.30 mmol) in N,N-dimethylformamide (2 ml). Stirring was continued for 2 h, followed by evaporation and flash chromatography of the resulting product on a column of silica gel (hexane-acetone=3:1) to yield the title compound as a white solid. MS (m/z): 440.2 (M+H)+; C23H16Cl2FN3O requir. 440.3.
Reaction SMILES: [C:1]([C:5]1[O:6][C:7]([C:10]2[C:14]([C:15]#[CH:16])=[C:13]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:12]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:11]=2)=[N:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:32][Si]([N-][Si](C)(C)C)(C)C.[Li+].IC>O1CCCC1>[C:1]([C:5]1[O:6][C:7]([C:10]2[C:14]([C:15]#[C:16][CH3:32])=[C:13]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)[N:12]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=3[Cl:31])[N:11]=2)=[N:8][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: C#Cc1c(-c2nnc(C(C)(C)C)o2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Product: CC#Cc1c(-c2nnc(C(C)(C)C)o2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Temperature: 78 °C
Reaction time: 0.17 h
Yield: 12.7 %

Procedure:
To a solution of 2-tert-butyl-5-(5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-ethynyl-1H-pyrazol-3-yl)-1,3,4-oxadiazole (100 mg, 0.21 mmol) in tetrahydrofuran (15 ml) at 78° C., lithium bis(trimethylsilyl)amide (0.23 ml, 1.0 M solution in tetrahydrofuran, 0.23 mmol) was added slowly not to warm up the reaction solution. After stirring at 78° C. for 10 minutes, iodomethane (0.04 ml, 0.7 mmol) was added quickly. The resulting solution was stirred for 20 minutes, and then it was warmed up to room temperature slowly. After quenching with saturated ammonium solution, the organic layer was separated with ethyl acetate. The organic solution was evaporated in reduced pressure and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1 to hexane/ethyl acetate=5/1) to produce title compound (13 mg, 13% yield) as light yellow solid.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][CH:6]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:7]([OH:9])=[O:8].[CH:20](O)([CH3:22])[CH3:21]>>[CH:20]([O:8][C:7](=[O:9])[CH:6]([NH2:5])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([CH3:22])[CH3:21]
Reactant: CC(C)O
Reactant: CCCCCCCCCCC(N)C(=O)O
Solvent: O=S(Cl)Cl
Product: CCCCCCCCCCC(N)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 ml of isopropanol is stirred at 0° C. under argon and mixed drop by drop with 3.12 ml (41.6 mmol) of thionyl chloride. 30 minutes later, 7.40 g (34.4 mmol) of α-aminolauric acid is added in portions, stirred for one hour at room temperature and the batch then is allowed to reflux for two hours. After cooling off to room temperature, the batch is completely concentrated by evaporation, the residue is taken up in tert-butyl methyl ether and shaken out from aqueous sodium carbonate solution. The organic phase is dried on magnesium sulfate, filtered and concentrated by evaporation.
Reaction SMILES: [Br:1][C:2]1[C:6]([C:7]([F:10])([F:9])[F:8])=[N:5][N:4]([CH3:11])[C:3]=1[C:12]1[CH:13]=[C:14]([NH2:20])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>C(Cl)Cl>[Br:1][C:2]1[C:6]([C:7]([F:10])([F:8])[F:9])=[N:5][N:4]([CH3:11])[C:3]=1[C:12]1[CH:13]=[C:14]([NH:20][C:29]([NH:28][C:25]2[CH:26]=[CH:27][C:22]([F:21])=[CH:23][CH:24]=2)=[O:30])[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: COc1ccc(N)cc1-c1c(Br)c(C(F)(F)F)nn1C
Reactant: O=C=Nc1ccc(F)cc1
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1c(Br)c(C(F)(F)F)nn1C
Yield: 62.5 %

Procedure:
3-(4-Bromo-2-methyl-5-trifluoromethyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.03 g, 0.08 mmol) was treated with 4-fluorophenyl isocyanate (0.01 g, 8.99 μL, 0.08 mmol, 1.1 equiv.) in CH2Cl2 (2.0 mL), in a similar manner as described in Example 1.102, to afford Compound 39 (0.03 g, 0.05 mmol, 64% yield) as a white solid: LCMS m/z (%)=487 (M+H79Br, 100), 489 (M+H81Br, 93). 1H NMR (400 MHz, MeOH-d4) δ: 7.58 (dd, J=10.0, 2.0 Hz, 1H), 7.42 (dd, J=4.0 Hz, 2H), 7.38 (dd, J=10.0, 2.0 Hz, 1H), 7.16 (d, J=12.0 Hz, 1H), 7.03 (dd, J=12.0, 8.0 Hz, 2H), 3.84 (s, 3H), 3.75 (s, 3H).
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]([NH:10][NH:11][C:12]([N:14]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][C:16]2[CH:25]=[CH:26][C:27]([NH2:29])=[CH:28][C:15]1=2)=[O:13])=[O:9])(=[O:5])=[O:4])[CH3:2].[CH3:30][S:31](Cl)(=[O:33])=[O:32]>N1C=CC=CC=1>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]([NH:10][NH:11][C:12]([N:14]1[CH2:20][C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[O:17][C:16]2[CH:25]=[CH:26][C:27]([NH:29][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:28][C:15]1=2)=[O:13])=[O:9])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(N)cc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CCS(=O)(=O)CCC(=O)NNC(=O)N1Cc2ccccc2Oc2ccc(NS(C)(=O)=O)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of the title compound of Example 13 (1.0 g) in pyridine (15 mL) under nitrogen at approximately 5° C. (ice water bath) was added dropwise via syringe methanesulfonyl chloride (0.28 mL). The ice bath was removed, and the reaction was stirred at ambient temperature for 2 hours. The reaction was then evaporated under vacuum, and the residue was treated with 1 M HCl. The insoluble product was collected by filtration, washed twice with 1 M HCl, and then with water. The solid was suspended in methanol, heated to reflux on a steam bath, cooled to room temperature, and the product was collected by filtration. Recrystallization from acetonitrile yielded the title compound as a pinkish solid. Mp: 211°-212° C.
Reaction SMILES: C([NH:8][C:9]1[C:10](=[CH:21][C:22]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:24]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])(OC(C)(C)C)=O.Cl.C(OCC)(=O)C.CO.C([Cl:45])(=O)C>C(OCC)(=O)C>[ClH:45].[CH2:26]([O:25][C:22]1[CH:21]=[C:10]([C:11]([O:13][CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[C:9]([NH2:8])=[CH:24][CH:23]=1)[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: Nc1ccc(OCc2ccccc2)cc1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 21 h
Yield: 86 %

Procedure:
N-Boc-5-benzyloxyanthranilic acid, benzyl ester (70 g, 161 mmol) was added to a 1.4 M HCl/ethyl acetate solution (prepared by the addition of methanol to acetyl chloride and subsequent dilution with ethyl acetate). The reaction mixture was stirred at room temperature for 21 hours. After cooling to 0° C., the reaction was gently stirred for an additional 2 hours. The crystalline product was filtered off and washed with 50 ml of cold ethyl acetate. Trace solvents were removed under high vacuum to yield 5-benzyloxyanthranilic acid, benzyl ester, hydrochloride (53.4 g, 86% yield).
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH2:6])([CH3:5])[CH3:4].[C:7](#N)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>C(=S)=S>[CH3:4][C:3]1([CH3:5])[CH2:2][NH:1][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[N:6]1
Reactant: CCCCCC#N
Reactant: CC(C)(N)CN
Solvent: S=C=S
Product: CCCCCC1=NC(C)(C)CN1
Yield: 73.3 %

Procedure:
8.41 g (95.4 mmoles) of 1,2-diamino-2-methylpropane, 7.4 g (76.16 mmoles) of hexanenitrile and 0.4 ml of carbon disulfide were heated at 125° C. for 24 hours and then worked up as under Example 23. Distillation at 105°-107° C./0.5 mm gave 9.4 g (73.4%) of product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([OH:13])=[O:12].S(=O)(=O)(O)O.[CH2:19](O)[CH3:20]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11]([O:13][CH2:19][CH3:20])=[O:12]
Reactant: COc1ccccc1CCC(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCc1ccccc1OC
Temperature: 25 °C

Procedure:
A solution of 25.0 g (139.0 mmol) 3-(2-methoxyphenyl)propionic acid in 250 mL ethanol is treated at 0° C. with 5.0 mL concentrated sulfuric acid. The reaction mixture is heated to reflux for 2 hr. The reaction mixture is cooled to room temperature and volatiles removed by rotary evaporation. The residue is diluted with 250 mL dichloromethane, washed with 200 mL water, 200 mL sat. NaHCO3, and 200 mL brine. The resulting organic layer is dried over anhydrous Na2SO4 and the solvent removed in vacuo to yield ethyl 3-(2-methoxyphenyl)propanoate, 28 g, as a tan oil.
Reaction SMILES: [C:1]([C:4]1[N:8]([CH3:9])[N:7]=[C:6]([O:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH:5]=1)(O)=O.CCN=C=NCCCN(C)C.[CH2:28]([N:31]1[C:38]([NH2:39])=[C:37]([NH2:40])[C:35](=[O:36])[N:34]([CH2:41][CH:42]=[CH2:43])[C:32]1=[O:33])[CH:29]=[CH2:30]>CO>[CH2:41]([N:34]1[C:35](=[O:36])[C:37]2[NH:40][C:1]([C:4]3[N:8]([CH3:9])[N:7]=[C:6]([O:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=3)=[N:39][C:38]=2[N:31]([CH2:28][CH:29]=[CH2:30])[C:32]1=[O:33])[CH:42]=[CH2:43]
Reactant: CCOC(=O)COc1cc(C(=O)O)n(C)n1
Reactant: C=CCn1c(N)c(N)c(=O)n(CC=C)c1=O
Agent: CCN=C=NCCCN(C)C
Solvent: CO
Product: C=CCn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CC=C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (5-carboxy-1-methylpyrazol-3-yl)oxyacetate (0.5 mmol) and EDCI (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-diallyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-diallyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid.