Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[N:3]=1.[C:12]([NH:15][NH2:16])(=O)[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.ClC(Cl)(Cl)C#N>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([CH3:11])[C:5]([C:6]2[O:8][C:12]([CH3:13])=[N:15][N:16]=2)=[CH:9][CH:10]=1
Reactant: CC(=O)NN
Reactant: Cc1nc(Cl)ccc1C(=O)O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: N#CC(Cl)(Cl)Cl
Solvent: CC#N
Product: Cc1nnc(-c2ccc(Cl)nc2C)o1
Temperature: 150 °C

Procedure:
6-Chloro-2-methylnicotinic acid (200 mg, 1.2 mmol), acetohydrazide (95 mg, 1.3 mmol), solid supported triphenylphosphine on polystyrene (1.88 mmol/g loading, 1.94 g, 3.5 mmol) were placed in a microwave vial. Dry acetonitrile (16.7 ml) followed by trichloroacetonitrile (0.23 ml, 2.33 mmol) were added and the vial was heated in a microwave at 150° C. for 20 minutes. It was allowed to cool to room temperature, filtered, and the filter cake was washed with acetonitrile. The filtrate was concentrated under reduced pressure to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[N:14]=[N:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:17]=1[NH:27][C:28](=[O:30])[CH3:29].C([O-])(=O)C.[Na+].[CH:36]([NH2:38])=O.C(OC(=O)C)(=O)C>[Cu]I.C(OCCCC)(=O)C>[C:36]([C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]=1[N:14]=[N:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[CH:18][C:17]=1[NH:27][C:28](=[O:30])[CH3:29])#[N:38]
Reactant: NC=O
Reactant: CCN(CC)c1ccc(N=Nc2c(Br)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Agent: [Cu]I
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: CCCCOC(C)=O
Product: CCN(CC)c1ccc(N=Nc2c(C#N)cc([N+](=O)[O-])cc2[N+](=O)[O-])c(NC(C)=O)c1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 88 %

Procedure:
2-Bromo-4,6-dinitro-2'-acetylamino-4'-(N,N-diethylamino) azobenzene (479 parts), copper (I) iodide (19 parts), anhydrous sodium acetate (246 parts), formamide (180 parts), acetic anhydride (408 parts) and n-butyl acetate (2190 parts) are mixed together and heated, with stirring, to 110° C. during 15 minutes. The temperature is maintained at 110° for 30 to 50 minutes, when a solid is suddenly precipitated from the reaction mixture, indicating completion of the reaction. The mixture is allowed to cool to room temperature and the product is collected, washed with ethanol to remove residual n-butyl acetate and dried. 2-Cyano-4,6-dinitro-2'-acetylamino-4'-(N,N-diethylamino)azobenzene is obtained in 88% yield and requires no purification.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].S(=O)(=O)(O)O.[NH2:10][C:11]1[N:20]=[C:19]([NH2:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[Cl:22])[N:12]=1.N>>[NH2:10][C:11]1[N:20]=[C:19]([NH2:21])[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([N+:1]([O-:4])=[O:2])[C:17]=2[Cl:22])[N:12]=1
Reactant: O=[N+]([O-])O
Reactant: Nc1nc(N)c2c(Cl)cccc2n1
Agent: N
Agent: O=S(=O)(O)O
Product: Nc1nc(N)c2c(Cl)c([N+](=O)[O-])ccc2n1
Temperature: -10 °C
Reaction time: 18 h

Procedure:
Nitric acid (90%), 125 mL, was stirred and cooled to -10° C., and 125 mL of 98% sulfuric acid was added dropwise. Upon completion of addition, the reaction mixture temperature was brought to 0° C., and 19.7 grams (0.10 mole) of 2,4-diamino-5-chloroquinazoline (Compound 2, prepared in a manner analogous to that of Step E of Example 1) was added. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred for about 18 hours. The reaction mixture was then poured into 1500 mL of ice. The resultant mixture was made basic with 700 mL of aqueous 30% ammonia, keeping the temperature below 30° C. The mixture was cooled in an ice-bath, and the resultant solid was collected by filtration. The solid was stirred with 1000 mL of tetrahydrofuran and 500 mL of water. The mixture was filtered to remove a solid. The filtrate was diluted with 500 mL of ethyl acetate and then was concentrated under reduced pressure to a solid residue. The two solids were combined, washed with ethyl acetate, and dried, yielding 22.2 grams of 2,4-diamino-5-chloro-6-nitroquinazoline. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: ClCCl.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.[CH3:15][C@@H:16]([C@@H:23]1[C@@:27]2([CH3:43])[CH2:28][CH2:29][C@@H:30]3[C@@:35]4([CH3:41])[CH2:36][CH2:37][C@H:38]([OH:40])[CH2:39][C:34]54[O:42][CH:33]5[CH2:32][C@H:31]3[C@@H:26]2[CH2:25][CH2:24]1)[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21]>CCOCC>[OH:42][CH:33]1[C:34]2[C@:35]([CH3:41])([CH2:36][CH2:37][C:38](=[O:40])[CH:39]=2)[C@@H:30]2[C@H:31]([C@H:26]3[C@:27]([CH3:43])([CH2:28][CH2:29]2)[C@@H:23]([C@H:16]([CH3:15])[CH2:17][CH2:18][CH2:19][CH:20]([CH3:22])[CH3:21])[CH2:24][CH2:25]3)[CH2:32]1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC4OC45C[C@@H](O)CC[C@]5(C)[C@H]3CC[C@]12C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC(O)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 51.7 %

Procedure:
Dichloromethane (50 ml) was added to pyridinium chlorochromate (2.78 g, 12.9 mmol) and molecular shieves (3A) (4.37 g) and the mixture was stirred under a nitrogen atmosphere at room temperature for 15 minutes. To the resulting mixture was added a dichloromethane solution (30 ml) of 5,6-epoxycholesterol (α:β=5:1) (3.323 g, 8.6 mmol) prepared by the method of Fieser and Fieser (L. F. Fieser and H. Fieser, Reagents for Organic Synthesis, Vol. 1: 136, 1967) and the mixture was stirred for 3 hours. Ether (300 ml) was added to the reaction solution and the resulting solution was filtered through silica gel-magnesium sulfate. The organic layer was washed twice with 50 ml of a saturated saline solution and dried. The solvents were distilled off and the residue was purified by column chromatography. 6-Hydroxy-4-cholesten-3-one (α:β=5:1) was obtained as a colorless crystal from the hexane-ethyl acetate (5:1) eluate (yield: 51.7%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([NH:9][NH2:10])=[N:7][CH:6]=[CH:5][N:4]=1.[C:11]([N:16]=[C:17]=[S:18])(=[O:15])[O:12][CH2:13][CH3:14].CO>C(Cl)(Cl)Cl>[Cl:2][C:3]1[C:8]([NH:9][NH:10][C:17]([NH:16][C:11](=[O:15])[O:12][CH2:13][CH3:14])=[S:18])=[N:7][CH:6]=[CH:5][N:4]=1
Reactant: CCOC(=O)N=C=S
Reactant: NNc1nccnc1Cl
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NC(=S)NNc1nccnc1Cl
Yield: 120.9 %

Procedure:
A solution of 2-chloro-3-hydrazinylpyrazine hydrochloride (3.32 g, 18.34 mmol) in anhydrous chloroform was treated with O-ethyl carbonisothiocyanatidate (1.9 mL, 16.11 mmol) at room temperature. Anhydrous methanol (10 mL) was added to the reaction mixture which was then concentrated under reduced pressure to yield ethyl 2-(3-chloropyrazin-2-yl)hydrazinecarbonothioylcarbamate (5.37 g) as an orange solid.
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16](Br)[CH:15]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[Si:23]([O:30][CH2:31][CH2:32][N:33]([CH2:41][C:42]#[CH:43])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:38])[CH3:37])([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].C(N(CC)CC)C>[Cu]I.C(#N)C>[C:1]12([CH2:11][NH:12][C:13]([C:14]3[C:19]([Cl:20])=[CH:18][N:17]=[C:16]([C:43]#[C:42][CH2:41][N:33]([CH2:32][CH2:31][O:30][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:24])[CH3:25])[C:34](=[O:40])[O:35][C:36]([CH3:39])([CH3:37])[CH3:38])[CH:15]=3)=[O:22])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(Br)ncc1Cl
Reactant: C#CCN(CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N(CC#Cc1cc(C(=O)NCC23CC4CC(CC(C4)C2)C3)c(Cl)cn1)CCO[Si](C)(C)C(C)(C)C
Yield: 47.1 %

Procedure:
The sub-titled compound was prepared from N-(1 adamantylmethyl)-2-bromo-5-chloroisonicotinamide (Example 2(i)) (0.37 g), tert-butyl (2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)prop-2-yn-1-ylcarbamate (Example 11(i)) (0.54 g), copper (I) iodide (0.004 g), bis-triphenyphosphine palladium dichloride (0.014 g), triethylamine (6 ml) and anhydrous acetonitrile (6 ml) by the method of Example 2(iii). The crude product was purified by chromatography on silica gel eluting with, iso-hexane:ethyl acetate (8:1 to 4:1) to afford the sub-titled compound (0.28 g) as a yellow gum.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:11][CH2:12][CH3:13])[C:5]1[CH:10]=[CH:9][N:8]=[CH:7][CH:6]=1)[CH3:2].[I:14][CH3:15]>ClCCl>[I-:14].[CH2:12]([O:11][CH:4]([O:3][CH2:1][CH3:2])[C:5]1[CH:6]=[CH:7][N+:8]([CH3:15])=[CH:9][CH:10]=1)[CH3:13]
Reactant: CCOC(OCC)c1ccncc1
Reactant: CI
Solvent: ClCCl
Product: CCOC(OCC)c1cc[n+](C)cc1
Product: [I-]
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.1 %

Procedure:
4-(Diethoxymethyl)pyridine (4.41 g, 24.3 mmol) was dissolved in dichloromethane (90.0 mL). To this, iodomethane (1.82 mL, 29.2 mmol) was added under a nitrogen atmosphere at room temperature and the mixture was stirred at room temperature for 48 hours. The reaction mixture was concentrated, the residue was washed with diisopropyl ether, and thereby 4-(diethoxymethyl)-1-methylpyridinium iodide (7.47 g, yield: 95%) was obtained.
Reaction SMILES: CO[C:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:8]([CH:10]=[CH:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[N:9]=1.[Cl-:22].[NH4+:23]>CO>[ClH:22].[NH:23]=[C:3]1[NH:9][CH:8]([CH:10]=[CH:11][C:12]2[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=2[C:14]([O:16][CH3:17])=[O:15])[CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: [NH4+]
Reactant: COC(=O)c1ccccc1C=CC1CCCCC(OC)=N1
Reactant: [Cl-]
Solvent: CO
Product: COC(=O)c1ccccc1C=CC1CCCCC(=N)N1
Product: Cl

Procedure:
The title product of Example 80 in MeOH is reacted with ammonium chloride by the method of Example 5 to generate the title material.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=12.C(N(CC)CC)C.[CH:18]1([C:21](Cl)=[O:22])[CH2:20][CH2:19]1.O>CCOC(C)=O.C([O-])(O)=O.[Na+]>[N:4]1[N:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]2=[C:2]([NH:1][C:21]([CH:18]2[CH2:20][CH2:19]2)=[O:22])[CH:3]=1
Reactant: Nc1cnn2ccccc12
Reactant: O=C(Cl)C1CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1cnn2ccccc12)C1CC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 3-aminopyrazolo[1,5-a]pyridine (0.74 g, 5.55 mmol) and triethylamine (1.0 ml, 6.95 mmol) in EtOAc (15.0 mL) was added cyclopropanecarbonyl chloride (0.63 mL, 6.95 mmol). The resulting mixture was stirred at room temperature for 48 h and diluted with saturated NaHCO3 solution. More EtOAc and H2O were added and separated. The EtOAc solution was concentrated in vacuo to dryness. The residue was recrystalized from EtOAc to give 0.86 g (77%) of light brown solid as the title compound: mp 159–162° C.; IR (diffuse reflectance) 3207, 3085, 3073, 3044, 2998, 1645, 1596, 1477, 1401, 1356, 1330, 1218, 950, 738, 727 cm−1; MS (EI) m/z 201 (M+); Anal. Calcd for C11H11N3O: C, 65.66; H, 5.51; N, 20.88. Found: C, 65.52; H, 5.48; N, 20.82.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].Br[CH2:15][CH2:16][CH3:17].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([O:13][CH2:15][CH2:16][CH3:17])[CH:4]=1
Reactant: CCCBr
Reactant: COC(=O)c1ccc(OC)cc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOCC
Product: CCCOc1cc(OC)ccc1C(=O)OC

Procedure:
A stirred mixture of methyl 4-methoxysalicylate (25 g), bromopropane (15.6 ml), potassium iodide (2.82 g) and anhydrous potassium carbonate (27.53 g) was heated under reflux for 48 hours. The cooled reaction mixture was filtered and the filtrate was evaporated under reduced pressure to yield an oil which was dissolved in diethyl ether (200 ml). The ethereal solution was extracted with aqueous sodium hydroxide to remove unreacted starting material and the organic phase was then washed with water and brine, dried (magnesium sulphate) and evaporated under reduced pressure to yield methyl 4-methoxy-2-propoxybenzoate, 22.45 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2].[OH:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=1.C(=O)([O-])[O-].[K+].[K+].N1C=CC=CC=1>[Cu](I)I.C(N(CC)CC)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:17])[NH:7][C@H:8]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:18][C:19]2[CH:24]=[N:23][C:22]([CH3:25])=[CH:21][CH:20]=2)[CH:11]=1)[CH3:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(O)cn1
Reactant: C[C@H](NC(=O)OC(C)(C)C)c1cccc(Br)c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: Cc1ccc(Oc2cccc([C@H](C)NC(=O)OC(C)(C)C)c2)cn1
Temperature: 145 °C
Yield: 0 %

Procedure:
A mixture of (S)-[1-(3-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (10 g, 33.3 mol), 5-hydroxy-2-methylpyridine (4 g, 36.7 mol), copper iodide (6.3 g, 33.3 mol), potassium carbonate (9.2 g, 66.7 mol) and pyridine (33 mL) in sealed tube was heated at 145° C. for six days. The reaction was cooled down to room temperature and filtered, the filtrate was washed with H2O and extracted with CH2Cl2 three times, and the combined organic layers were dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 30:20:1/Hexane:EtOAc:triethylamine to give the title product (3.8 g, 33% yield) as sticky yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[CH:4][N:3]=1.O.[NH2:10][NH2:11]>CC(O)C>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([NH:10][NH2:11])[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: NN
Solvent: CC(C)O
Solvent: O
Product: NNc1cc(Cl)ncn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.9 %

Procedure:
A mixture of 4,6-dichloro-pyrimidine (18.68 g, 125 mmol), hydrazine monohydrate (18.28 mL, 376 mmol), and 2-propanol (300 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated, triturated with water, and filtered. The solid was washed with water, air-dried to give (6-chloro-pyrimidin-4-yl)-hydrazine (16.97 g, Yield 94%): 1H NMR 400 MHz (d6-DMSO) δ 8.83 (s, 1H), 8.17 (s, 1H), 6.76 (s, 1H), 4.50 (s, 2H); MS m/z 145.02 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([O:14]C)=[O:13])=[N:10][CH:11]=1)[C:2]#[C:3][CH3:4].[OH-].[Li+].CCOC(C)=O.Cl>C1COCC1.O>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=[O:13])=[N:10][CH:11]=1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCOc1ccc(C(=O)OC)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC#CCOc1ccc(C(=O)O)nc1
Reaction time: 72 h
Yield: 45.4 %

Procedure:
To a solution of methyl 5-(but-2-ynyloxy)picolinate (Intermediate 18, 1.42 g, 6.92 mmol) in THF (15 mL) was added lithium hydroxide (0.871 g, 20.76 mmol) dissolved in water (5 mL) to the reaction mixture at r.t. After 3 days of stirring was the reaction mixture partioned between water and EtOAc. The water was made acidic with aq. solution of HCl (2M) and extracted with EtOAc. The organic phase was dried over MgSO4 and concentrated to give 0.60 g (45% yield) of the title compound: 1H NMR (500 MHz, CD3OD) δ ppm 1.84 (t, 3 H), 4.87 (q, 2 H), 7.57 (dd, 1H), 8.14 (d, 1 H), 8.34 (d, 1 H); MS (ES+) m/z 192 [M+H]+.
Reaction SMILES: [H-].[Na+].[C:3]([O:6][C@@H:7]1[C@@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:12]([O:18][C:19](=[O:21])[CH3:20])[C@@H:11]([C:22]([O:24][CH3:25])=[O:23])[O:10][CH:8]1[OH:9])(=[O:5])[CH3:4].[Cl:26][C:27]([Cl:31])([Cl:30])[C:28]#[N:29]>ClCCl>[Cl:26][C:27]([Cl:31])([Cl:30])[C:28]([O:9][C@H:8]1[O:10][C@H:11]([C:22]([O:24][CH3:25])=[O:23])[C@@H:12]([O:18][C:19](=[O:21])[CH3:20])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:7]1[O:6][C:3](=[O:5])[CH3:4])=[NH:29]
Reactant: COC(=O)[C@H]1OC(O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: N#CC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)[C@H]1O[C@H](OC(=N)C(Cl)(Cl)Cl)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
60% Oily sodium hydride (0.366 g) was added to an ice-cooled solution of methyl 2,3,4-tri-O-acetyl-D-glucopyranuronate (3.96 g), trichloroacetonitrile (12 ml) and dichloromethane (100 ml), and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was subjected to short column (70 φ×50 mm) chromatography on silica gel and eluted with ethyl acetate/hexane (1:1). The eluate was concentrated under reduced pressure to obtain the desired compound (4.37 g) as crystals (mp: 108° C.).
Reaction SMILES: C([Li])CCC.CCCCCC.[CH3:12][N:13]1[CH:17]=[CH:16][CH:15]=[N:14]1.[CH3:18][C:19]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][C:20]=1[O:21][CH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1COCC1.Cl>[CH3:12][N:13]1[C:17]([C:25]([C:24]2[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=2[CH2:22][O:21][C:20]2[CH:32]=[C:33]([CH3:36])[CH:34]=[CH:35][C:19]=2[CH3:18])=[O:26])=[CH:16][CH:15]=[N:14]1
Reactant: Cc1ccc(C)c(OCc2ccccc2C(=O)Cl)c1
Reactant: Cn1cccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1ccc(C)c(OCc2ccccc2C(=O)c2ccnn2C)c1
Temperature: -70 °C
Reaction time: 1 h
Yield: 15.6 %

Procedure:
Dichloroethane (20 ml), thionyl chloride (1.31 g, 0.011 mol) and N,N-dimethylformamide (0.1 ml) were added to 2-(2,5-dimethylphenoxymethyl)benzoic acid (2.56 g, 0.01 mol), and the mixture was stirred under reflux for 2 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure to give crude 2-(2,5-dimethylphenoxymethyl)benzoyl chloride. 1.6M n-butyllithium/n-hexane solution (6.25 ml, 0.01 mol) was added to a mixture of 1-methylpyrazole (0.99 g, 0.012 mol) and THF (10 ml) at −70 to −60° C. over 15 minutes, and then the mixture was stirred at −70° C. to room temperature for 1 hour. The reaction mixture was cooled to −70° C., and a solution of the crude 2-(2,5-dimethylphenoxymethyl)benzoyl chloride in THF (10 ml) was added, and the mixture was stirred at −70° C. for 1 hour. After completion of the reaction, iN hydrochloric acid (100 ml) was added, and the mixture was extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to give 2-(2,5-dimethylphenoxymethyl)phenyl 1-methylpyrazol-5-yl ketone (0.50 g, 15.6%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([CH3:13])[CH:12]=1)[O:5][CH2:6][C:7]([OH:9])=[O:8].[Cl:14][S:15](O)(=[O:17])=[O:16].O.C1COCC1>C(Cl)Cl>[Cl:14][S:15]([C:12]1[C:11]([CH3:13])=[CH:10][C:4]([O:5][CH2:6][C:7]([OH:9])=[O:8])=[CH:3][C:2]=1[CH3:1])(=[O:17])=[O:16]
Reactant: Cc1cc(C)cc(OCC(=O)O)c1
Reactant: O=S(=O)(O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: Cc1cc(OCC(=O)O)cc(C)c1S(=O)(=O)Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
Referring to FIG. 37, to a solution of 2-(3,5-dimethylphenoxy)acetic acid (13 g, 72 mmol) in DCM (130 mL) was added dropwise a solution of ClSO3H (19.2 g, 166 mmol) in DCM (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 0.5 h. Water (100 mL) and THF (30 mL) were added and the resulting mixture was stirred for 5 min The two layers were separated and the organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give product as a white solid (6 g, 30% yield); 1H NMR (CDCl3, 300 MHz): δ 6.79 (s, 2H), 4.79 (s, 2H), 2.77 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1([C:8]2[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=2)[CH:7]2[CH:3]1[CH2:4][NH:5][CH2:6]2.Cl.C(=O)([O-])O.[Na+].BrC1C=CC(S(O[CH2:36][CH2:37][C@@H:38]([CH:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]2)[OH:39])(=O)=O)=CC=1.C(OCC)C>CN(C)C=O.O>[NH3:5].[CH:40]1([CH:38]([OH:39])[CH2:37][CH2:36][N:5]2[CH2:6][CH:7]3[CH:3]([C:2]3([C:8]3[CH:9]=[C:10]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH:11]=[CH:12][CH:13]=3)[CH3:1])[CH2:4]2)[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1
Reactant: O=S(=O)(OCC[C@H](O)C1CCCCC1)c1ccc(Br)cc1
Reactant: CC1(c2cccc(NS(C)(=O)=O)c2)C2CNCC21
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(CCC(O)C3CCCCC3)CC21
Product: N
Temperature: 50 °C
Reaction time: 0.08 h
Yield: 25 %

Procedure:
To a solution of hydrochloride salt N-[3-(6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenyl]methanesulfonamide (Preparation 53, 200 mg, 0.66 mmol) in N,N-dimethylformamide (8 ml) was added sodium hydrogen carbonate (3 g, 36 mmol) and (S)-3-cyclohexyl-3-hydroxypropyl 4-bromobenzenesulfonate (J. A. Werner et al, J. Org. Chem., 1996, 61, 587) (0.08 ml, 0.89 mmol) and the reaction mixture was heated at 50° C. for 20 h. After cooling, diethyl ether (15 ml) and water (15 ml) were added and the reaction mixture was stirred vigorously for 5 min. The phases were separated and the aqueous layer was further extracted with diethyl ether (2×15 ml). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residual oil was purified by flash column chromatography using a Sep-Pak™ cartridge packed with silica gel (10 g) eluting with dichloromethane:ethanol:0.88 ammonia solution (200:8:1) to afford the title compound as an oil (90 mg, 25%).
Reaction SMILES: CN1CCCCC1.[CH:8]([O:11][C:12]([NH:14][C@H:15]([C:19]([OH:21])=O)[CH:16]([CH3:18])[CH3:17])=[O:13])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.[Cl:30][C:31]1[C:32]([O:39][CH2:40][CH:41]([NH2:43])[CH3:42])=[N:33][CH:34]=[N:35][C:36]=1[CH2:37][CH3:38]>C(Cl)Cl.O>[Cl:30][C:31]1[C:32]([O:39][CH2:40][CH:41]([NH:43][C:19](=[O:21])[C@H:15]([CH:16]([CH3:17])[CH3:18])[NH:14][C:12]([O:11][CH:8]([CH3:9])[CH3:10])=[O:13])[CH3:42])=[N:33][CH:34]=[N:35][C:36]=1[CH2:37][CH3:38]
Reactant: CCc1ncnc(OCC(C)N)c1Cl
Reactant: CC(C)OC(=O)N[C@H](C(=O)O)C(C)C
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCCCC1
Solvent: O
Solvent: ClCCl
Product: CCc1ncnc(OCC(C)NC(=O)[C@@H](NC(=O)OC(C)C)C(C)C)c1Cl
Temperature: -20 °C
Reaction time: 1 h
Yield: 43.6 %

Procedure:
0.34 g of N-methylpiperidine was added to a solution containing 0.7 g of N-isopropoxycarbonyl-L-valine dissolved in 50 ml of methylene chloride, at -20° C. After the mixture was stirred for 10 minutes at the same temperature, 0.47 g of isobutyl chloroformate was added to the mixture, and stirred for 1 hour at -20° C. 0.74 g of 1-(5-chloro-6-ethyl-4-pyrimidinyloxy)-2-propylamine was added to this mixture at -60° C., and then the reaction mixture was allowed to sit and warm naturally to room temperature while being stirred, and was stirred for 20 hours at room temperature. Water was subsequently added to the reaction mixture. After the methylene chloride layer was washed successively with a 5% aqueous solution of sodium bicarbonate and water, the organic layer was dried over anhydrous magnesium sulfate and the methylene chloride was removed under reduced pressure. The obtained crude crystal was purified by column chromatography on silica gel, thus obtaining 0.6 g of the desired product in the form of a white prism-shaped crystal (yield: 43%).
Reaction SMILES: CN(C)CCC[C:6]1[CH:14]=[C:13]([N:15]([CH3:17])[CH3:16])[CH:12]=[CH:11][C:7]=1[C:8]([NH2:10])=[O:9].[CH2:19]([Br:31])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CC(CC)=O>[Br-:31].[CH2:19]([N+:15]([CH2:13][CH2:12][CH2:11][NH:10][C:8](=[O:9])[C:7]1[CH:6]=[CH:14][C:13]([N:15]([CH3:16])[CH3:17])=[CH:12][CH:11]=1)([CH3:17])[CH3:16])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CN(C)CCCc1cc(N(C)C)ccc1C(N)=O
Reactant: CCCCCCCCCCCCBr
Solvent: CCC(C)=O
Product: CCCCCCCCCCCC[N+](C)(C)CCCNC(=O)c1ccc(N(C)C)cc1
Product: [Br-]
Temperature: 70 °C

Procedure:
13.2 g of N- (3-dimethylaminopropyl-p-dimethylaminobenzamide (0.05 mole) from Example 1 and 12.5 g of dodecylbromide (0.05 mole) were dissolved in 30 ml of methylethylketone and maintained at 70° C. for 8 hours. After cooling to ambient temperature the crystalline product (24 g, 93.5% of theoretical) was filtered and recovered.