Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.Cl[C:15]1[C:19]2[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=2[S:17](=[O:26])(=[O:25])[N:16]=1.C(#N)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:15]2[C:19]3[CH:20]=[C:21]([Cl:24])[CH:22]=[CH:23][C:18]=3[S:17](=[O:25])(=[O:26])[N:16]=2)=[N:6][CH:7]=1
Reactant: O=S1(=O)N=C(Cl)c2cc(Cl)ccc21
Reactant: Cc1cc(Br)cnc1CCCCN
Solvent: ClC(Cl)Cl
Solvent: CC#N
Product: Cc1cc(Br)cnc1CCCCNC1=NS(=O)(=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a refluxing solution of 4-(5-bromo-3-methyl-2-pyridinyl)butylamine (300 mg, 1.23 mmol) in chloroform (20 ml, purified as in previous example) was added over 10 minutes a solution of 3,5-dichloro-1,2-benzisothiazole 1,1-dioxide (U.S. Pat. No. 4,490,527) (400 mg, 1.69 mmol) in chloroform (20 ml)/acetonitrile (10 ml). Since a precipitate formed during the addition, another 10 ml of acetonitrile was added to give almost complete solution. Heating at 65°-70° C. was continued for 60 minutes giving a slightly cloudy mixture. Cooling to room temperature, filtration and evaporation of the filtrate in vacuo gave a solid residue. Recrystallization from methanol/methylene chloride/2-propanol gave 0.410 g of the title compound as an off-white solid hydrochloride: m.p. 231°-235° C., IR(KBr) 3005, 2500 (broad), 1620, 1278, 1160 cm-1. 1H NMR (Me2SO-d6) 9.87 (1H, t), 8.68 (1H, s), 8.60 (1H, s), 8.25 (1H, s), 7.90 (2H, m), 3.42 (2H, m), 2.83 (2H, m), 2.37 (3H, s), 1.68 (4H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][CH2:12][NH:11][CH2:10][C@H:9]2[CH2:14][OH:15])=[CH:4][CH:3]=1.[C:16](=[O:19])([O-])[O-:17].[Na+].[Na+].ClCCl>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:16]([O:17][C:5]([CH3:8])([CH3:6])[CH3:4])=[O:19])[CH2:10][C@H:9]2[CH2:14][OH:15])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: OC[C@@H]1CNCC[C@H]1c1ccc(F)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(F)cc2)[C@H](CO)C1
Reaction time: 0.5 h
Yield: 184.7 %

Procedure:
To a mixture of [(3S,4R)-4-(4-fluorophenyl)piperidine-3-yl]methanol (3.0 g, 14 mmol), sodium carbonate (6.1 g, 57 mmol), dichloromethane (40 mL) and water (40 mL) was added di-tert-butyl Bicarbonate (3.8 g, 17 mmol) under ice cooling, followed by stirring at the same temperature for 30 minutes. The reaction mixture was added to a mixed solution of dichloromethane and water, and the organic layer was separated. The organic layer was washed with brine and dried over anhydrous magnesium sulfate, and the solvent was distilled away under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:1) to give the title compound (4.0 g, 90% yield).
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([CH3:11])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:12]1([C:18](Cl)=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:12]1([C:18]([NH:2][CH:3]([C:9]([CH3:11])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCOC(=O)C(N)C(C)=O
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)C1CCCCC1)C(C)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a suspension of 23.6 g of ethyl alpha-aminoacetoacetate hydrochloride in 450 ml of chloroform cooled to 0° C. was added 19.52 ml of cyclohexylcarbonyl chloride. After 20 minutes at 0° C. 36 ml of triethylamine was added dropwise over a period of 30 minutes. The reaction mixture was allowed to warm to room temperature, was washed with water (2×300 ml) and brine (300 ml) and dried over magnesium sulfate. Removal of the solvent in vacuo gave 35.1 g of an oil which on chromatographing on 400 g of silica gel (hexane-ethyl acetate; 7.5:2.5; v:v) gave 13.9 g of product, m.p. 74°-75° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:16][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2[C:4](=O)[CH2:3]1.COC1C=CC(P2(=S)SP(=S)(C3C=CC(OC)=CC=3)[S:28]2)=CC=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH3:1][C:2]1([CH3:18])[CH2:16][C:6]2[N:7]=[C:8]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)[S:9][C:5]=2[C:4](=[S:28])[CH2:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC1(C)CC(=O)c2sc(N3CCOCC3)nc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC1(C)CC(=S)c2sc(N3CCOCC3)nc2C1
Reaction time: 2 h
Yield: 49.6 %

Procedure:
To a stirred solution of Example 48 (0.266 g, 1 mmol) in THF (10 mL) at r.t. was added 2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide (0.808 g, 2 mmol). The reaction mixture was stirred for 2 h and then poured into saturated NaHCO3 solution (50 ml) and extracted with DCM (2×50 mL). The combined organic fractions were dried over MgSO4, filtered and the solvent removed by evaporation in vacuo to give the title compound (0.14 g, 50%) as a solid. δH (DMSO-d6) 3.72-3.60 (8H, m), 2.74 (2H, s), 2.61 (2H, s), 1.02 (6H, s). LCMS (ES+) 283.0 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[Ca+2].I(Cl)(=O)=O.[I:10](Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1.C1(C)C=CC=CC=1.[CH3:32][C:33]1[C:38]([CH3:39])=[CH:37][C:36]([CH3:40])=[C:35]([CH2:41][C:42]([CH3:44])=[CH2:43])[C:34]=1[OH:45]>CO>[I:10][CH2:43][C:42]1([CH3:44])[CH2:41][C:35]2[C:36]([CH3:40])=[CH:37][C:38]([CH3:39])=[C:33]([CH3:32])[C:34]=2[O:45]1
Reactant: O=I(=O)Cl
Reactant: C=C(C)Cc1c(C)cc(C)c(C)c1O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1cc(C)c2c(c1C)OC(C)(CI)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 183.4 %

Procedure:
Calcium carbonate (1.37 g, 13.7 mmol) and benzyltrimethylammonium dichloroiodate (4.04 g, 11.6 mmol) were sequentially added to a solution of toluene (20 mL)/methanol (10 mL) containing 2,3,5-trimethyl-6-(2-methylprop-2-en-1-yl)phenol (1.00 g, 5.26 mmol) synthesized in Reference Example 2 under ice-cooling condition, and the mixture was stirred at 0° C. for 30 minutes. After that, the reaction solution was concentrated under reduced pressure, and water and ethyl acetate were added to the residue to separate an organic layer. The organic layer was washed with 10% sodium sulfite aqueous solution and saturated saline, and dried using anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was purified by silica gel chromatography (hexane-ethyl acetate 100:0-95:5) to give 3.05 g of the title compound (yield: 92%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]([C:24]1[N:25]=[C:26]([CH3:29])[S:27][CH:28]=1)[C:20]([O:22][CH3:23])=[O:21]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]([C:24]2[N:25]=[C:26]([CH3:29])[S:27][CH:28]=2)[C:20]([O:22][CH3:23])=[O:21])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: COC(=O)C(N)c1csc(C)n1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Product: COC(=O)C(NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)c1csc(C)n1

Procedure:
Following General Procedure C and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and methyl 2-amino-2-(2-methylthiazol-4-yl)acetate (prepared from N-Boc-2-amino-2-(2-methylthiazol-4-yl)acetic acid [CAS 105381-90-6] using General Procedure H above), the title compound was prepared as a solid. The product was purified by tituration using Et2O/hexanes.
Reaction SMILES: C[O:2][C:3]1[CH2:21][CH2:20][C@@:19]2(C)[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:18]2[CH2:17][CH2:16][C@@:15]2([CH3:23])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2C=C)[CH:4]=1.O.O.C(O)(=O)C(O)=O>CC(C)=O>[CH3:23][C@:15]12[CH2:16][CH2:17][C@H:18]3[C@@H:8]([CH2:7][CH2:6][C:5]4[CH2:4][C:3](=[O:2])[CH2:21][CH2:20][C:19]=43)[C@@H:9]1[CH2:10][CH:11]=[CH:12]2
Reactant: C=C[C@H]1CC[C@H]2[C@@H]3CC=C4C=C(OC)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C(O)C(=O)O
Solvent: CC(C)=O
Solvent: O
Product: C[C@@]12C=CC[C@H]1[C@@H]1CCC3=C(CCC(=O)C3)[C@H]1CC2
Reaction time: 6 h
Yield: 75.5 %

Procedure:
Estra-2,5(10), 16-triene-3-methyl ether (2) (646.3 mg, 2.390 mmole), dissolved in 50 ml of acetone was hydrolyzed for 6 h at room temperature using oxalic acid dihydrate (0.84 g, 6.7 mmole). The reaction mixture was quenched with 25 ml of saturated sodium bicarbonate and then extracted twice with 25 ml portions of ethyl acetate. The combined organic extracts were washed twice with 25 ml of brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from hexane to give product (462.5 mg, 1.804 mmole, 75%), m.p. 112-116 C.
Reaction SMILES: [NH:1]([C:11]([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH2:6].[C:28]1([C:34]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)O)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.S(=O)(=O)(O)O.C(OC(=O)C)(=O)C>C(O)(=O)C>[NH:1]([C:11]([O:13][CH2:14][CH:15]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]2[C:16]1=[CH:17][CH:18]=[CH:19][CH:20]=2)=[O:12])[C@H:2]([C:8]([OH:10])=[O:9])[CH2:3][CH2:4][C:5](=[O:7])[NH:6][C:34]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: NC(=O)CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: OC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: O=C(CC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O)NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.17 h

Procedure:
A mixture of 7.4 g of Fmoc-Gln-OH (20 mmol) and 10.4 g of triphenylmethanol (40 mmol) in 300 ml of acetic acid is stirred at 100° for 10 minutes. After the addition of 0.1 ml of concentrated sulfuric acid the whole is stirred at 100° for a further 15 minutes, a clear yellow solution forming. This is concentrated by evaporation under reduced pressure at 60°, and the residue is dried under reduced pressure for 10 minutes. The solid residue is dissolved in 60 ml of acetic acid at 60°, left at 60° for 20 minutes, then 2 ml of acetic anhydride (20 mmol) are added and after 1 hour at 60° the whole is concentrated by evaporation under reduced pressure. The oily residue is dried for 10 minutes at 60°, then dissolved in 100 ml of acetic acid and introduced dropwise into 500 ml of ice-cold water. The precipitate is isolated by filtration, washed well with water and dissolved in ethyl acetate; the aqueous phase is separated off and the organic phase is washed with a saturated aqueous sodium chloride solution. After drying over sodium sulfate, the organic solution is concentrated to dryness by evaporation, the residue is dissolved in 50 ml of 1,2-dichloroethane and applied to 100 g of silica gel; elution is carried out with 1,2-dichloroethane and with 1,2-dichloroethane containing 2%, then 4%, methanol. The fractions containing the Fmoc-Gln(Trt)-OH are concentrated by evaporation under reduced pressure, and the product is crystallised from a mixture of ethyl acetate and diisopropyl ether, m.p. from 125°.
Reaction SMILES: Cl.[CH:2]1([N:5]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:6](=[O:18])[C:7]2[CH:12]=[CH:11][C:10]([C:13]3[O:17][CH:16]=[N:15][CH:14]=3)=[CH:9][CH:8]=2)[CH2:4][CH2:3]1.[CH3:25][O:26][C:27]([C:29]1[CH:30]=[N:31][C:32](Cl)=[N:33][CH:34]=1)=[O:28]>CN1CCCC1=O>[CH3:25][O:26][C:27]([C:29]1[CH:30]=[N:31][C:32]([N:22]2[CH2:23][CH2:24][CH:19]([N:5]([CH:2]3[CH2:4][CH2:3]3)[C:6](=[O:18])[C:7]3[CH:8]=[CH:9][C:10]([C:13]4[O:17][CH:16]=[N:15][CH:14]=4)=[CH:11][CH:12]=3)[CH2:20][CH2:21]2)=[N:33][CH:34]=1)=[O:28]
Reactant: O=C(c1ccc(-c2cnco2)cc1)N(C1CCNCC1)C1CC1
Reactant: COC(=O)c1cnc(Cl)nc1
Agent: Cl
Solvent: CN1CCCC1=O
Product: COC(=O)c1cnc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)nc1

Procedure:
The title compound is prepared from N-cyclopropyl-4-oxazol-5-yl-N-piperidin-4-yl-benzamide hydrochloride and 2-chloro-pyrimidine-5-carboxylic acid methyl ester following a procedure analogous to that described in Example 19 using N-methylpyrrolidinone as solvent. LC (method 16): tR=0.48 min; Mass spectrum (ESI+): m/z=448 [M+H]+.
Reaction SMILES: [N:1]1[C:2](=[O:10])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.[CH3:11][N:12]([CH3:25])[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=O)=[CH:15][CH:14]=1>N1CCCCC1.C(O)C>[CH3:11][N:12]([CH3:25])[C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH:23]=[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]2=[O:10])=[CH:15][CH:14]=1
Reactant: O=C1C=c2ccccc2=N1
Reactant: CN(C)c1ccc(C=O)c2ccccc12
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)c1ccc(C=C2C(=O)Nc3ccccc32)c2ccccc12
Temperature: 25 °C

Procedure:
A mixture of 1.33 g of indole-2-one (10 mmol), 1.99 g of 4-dimethylamino-1-naphthaldehyde (10 mmol) and 3 drops of piperidine are refluxed in 40 ml of ethanol for 5 hours. The desired product precipitates as an orange solid during the reaction. After cooling to room temperature, the product is filtered off, washed with ethanol and dried in vacuo. Yield 2.67 g (85%).
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[NH:18])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23]([N:27]=[C:28]=[O:29])[CH:24]=[CH:25][CH:26]=1>>[CH2:6]([N:13]1[CH2:17][CH2:16][CH2:15][C:14]1=[N:18][C:28]([NH:27][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:20]([F:19])([F:30])[F:31])[CH:22]=1)=[O:29])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Reactant: N=C1CCCN1Cc1ccccc1
Agent: F[B-](F)(F)F
Product: O=C(N=C1CCCN1Cc1ccccc1)Nc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The fluoroborate salt of 1-benzyl-2-iminopyrrolidine (6.55 g.; 0.025 mole) is converted to free base (4.36 g.; 0.025 mole) in the usual manner. After drying over K2CO3, the benzene solution is filtered through diatomaceous earth and 4.68 g. (0.025 mole) of m-trifluoromethylphenylisocyanate is added. The reaction mixture is stirred at room temperature for 1 hour and then evaporated to dryness in vacuo to give an oily residue of 1-(1-benzyl-2-pyrrolidylidene)-3-(m-trifluoromethylphenyl)urea which is dissolved in ether and converted to the hydrochloride salt. Recrystallizations from acetone-ether yields the pure product, 1-(1-benzyl-2-pyrrolidylidene)-3-(m-trifluoromethylphenyl)urea HCl, m.p. = 164°-165° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>CCO.[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: COc1cc([N+](=O)[O-])ccc1N1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: COc1cc(N)ccc1N1CCOCC1
Temperature: 20 °C
Reaction time: 12 h

Procedure:
To a solution of 4-(2-methoxy-4-nitro-phenyl)-morpholine (Step A, 1.0 g, 4.2 mmol) in EtOH (25 mL) at 20° C. was added Pd/C (100 mg). The flask was capped with a rubber septum and H2 pressure applied through a balloon/needle. The reaction was stirred at 20° C. for 12 h, filtered through sand/Celite® and concentrated. Purification by chromatography of the crude mixture (97:3 CH2Cl2:MeOH) afforded 3-methoxy-4-morpholin-4-yl-phenylamine as a purple solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.[F:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[C:10]([O:17][CH3:18])[C:9]=1F.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:9]2[C:10]([O:17][CH3:18])=[CH:11][C:12]([N+:14]([O-:16])=[O:15])=[CH:13][C:8]=2[F:7])[CH:6]=1
Reactant: COc1cc([N+](=O)[O-])cc(F)c1F
Reactant: Clc1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: COc1cc([N+](=O)[O-])cc(F)c1-n1cnc(Cl)c1
Temperature: 80 °C
Yield: 22.1 %

Procedure:
Step M (5): A mixture of 4-chloro-1H-imidazole (102 mg, 1.00 mmol), 1,2-difluoro-3-methoxy-5-nitrobenzene (200 mg, 1.00 mmol), and cesium carbonate (325 mg, 1 mmol) in acetonitrile (6 mL) was heated at 80° C. for 12 h. The reaction mixture was quenched with 1 N HCl. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (20% EtOAc/hexane) to afford 4-chloro-1-(2-fluoro-6-methoxy-4-nitrophenyl)-1H-imidazole (60 mg, 22% yield).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([NH2:9])=[C:4]([CH3:10])[N:3]=1.Cl.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH:13]1[C:18](O)=[O:19].CCN(C(C)C)C(C)C>CS(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([CH3:10])[C:5]2[NH:9][C:18](=[O:19])[CH:13]3[CH2:14][O:15][CH2:16][CH2:17][N:12]3[C:6]=2[N:7]=1
Reactant: Cc1nc(Cl)nc(Cl)c1N
Reactant: O=C(O)C1COCCN1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: Cc1nc(Cl)nc2c1NC(=O)C1COCCN21
Temperature: 100 °C
Yield: 4.1 %

Procedure:
A round-bottom flask was charged with crude 2,4-dichloro-6-methylpyrimidin-5-amine (6.644 g, 37.3 mmol), morpholine-3-carboxylic acid hydrochloride (7.51 g, 44.8 mmol), DIPEA (26.1 mL, 149 mmol) and DMSO (49.0 mL). The flask was heated overnight at 100° C. The mixture was subsequently cooled to room temperature and then poured into ice. The solution was stirred while slowly warmed to room temperature. The mixture was subsequently filtered, and the filtrate was purified by preparatory HPLC using a gradient of 15-40% CH3CN (with 0.035% TFA) in H2O (with 0.05% TFA). The fractions were collected and concentrated in vacuo to give the title compound as a white solid (387 mg, 4.1%). 1H NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3 H), 2.54 (s, 1 H), 2.87-2.99 (m, 1 H), 3.43-3.52 (m, 1 H), 3.91 (dd, J=11.72, 3.42 Hz, 1 H), 4.10-4.22 (m, 2 H), 4.29 (dd, J=10.74, 3.91 Hz, 1 H), 10.51 (s, 1 H). ESI-MS m/z [M+H]+ calc'd for C10H11ClN4O2, 255.06; found 255.5.
Reaction SMILES: [CH:1]([NH:4][C:5]([C@H:7]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[CH:19]=[C:18]([S:20]([CH3:23])(=[O:22])=[O:21])[CH:17]=[CH:16][C:15]=2[N+:24]([O-])=O)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].C([O-])=O.[NH4+].C(Cl)Cl>CO.[Pd]>[NH2:24][C:15]1[CH:16]=[CH:17][C:18]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:19][C:14]=1[NH:13][C@@H:10]1[CH2:9][CH2:8][C@H:7]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:12][CH2:11]1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(S(C)(=O)=O)ccc2[N+](=O)[O-])CC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: ClCCl
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(S(C)(=O)=O)ccc2N)CC1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
To a solution of cis-N-Isopropyl-4-(5-(methylsulfonyl)-2-nitrophenylamino)cyclohexanecarboxamide (0.120 g, 0.313 mmol) in MeOH (1.2 mL) was added 5% Pd/C (0.067 g, 0.031 mmol) and ammonium formate (0.154 mL, 3.13 mmol) (exotherm). The reaction mixture was stirred at 20° C. for 1 hour and then the mixture was filtered through a pad of Celite® brand filter aid, washing with MeOH. The filtrate was concentrated under vacuum, and the remaining residue was dissolved in DCM then washed with water. The organic layer was concentrated under vacuum. The residue was purified by flash chromatography, eluting with 0-80% 90:10:1 DCM/MeOH/NH4OH:DCM to afford cis-4-(2-amino-5-(methylsulfonyl) phenylamino)-N-isopropylcyclohexanecarboxamide as a pale yellow oil (0.107 g, 97% yield). MS (ESI pos. ion) m/z: 354.2 [M+H].
Reaction SMILES: [CH2:1]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.Br[CH2:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1/[CH:31]=[CH:32]/[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34].O>C1COCC1>[CH2:1]([N:8]([C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])[C@@H:31]1[C:25]2[C:24](=[CH:29][C:28]([CH3:30])=[CH:27][CH:26]=2)[CH2:23][C@H:32]1[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](NCc1ccccc1)c1ccccc1
Reactant: Cc1ccc(/C=C/C(=O)OC(C)(C)C)c(CBr)c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)C[C@@H](C(=O)OC(C)(C)C)[C@@H]2N(Cc1ccccc1)[C@H](C)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.5 ml of (1R)—N-benzyl-1-phenylethanamine in 40 ml of THF was added 4.35 ml of n-butyllithium (1.62 M hexane solution) at −78° C., followed by stirring for 30 minutes. At the same temperature, a solution of 1.00 g of tert-butyl (2E)-3-[2-(bromomethyl)-4-methylphenyl]acrylate in 5 ml of THF was added thereto, followed by stirring for 1.5 hours. To the reaction mixture was added water, followed by warming to room temperature. The solvent was evaporated under reduced pressure and ethyl acetate was then added thereto to carry out a layer separation operation. The organic layer was washed with a 1 M aqueous citric acid solution, water, and saturated brine in this order, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 1.17 g of tert-butyl (1S,2R)-1-{benzyl[(1R)-1-phenylethyl]amino}-5-methylindane-2-carboxylate. Further, the present Preparation Example is in accordance with the method described in a reference (Synlett, 1999, No. 12, 1919-1920 by D. A. Price).
Reaction SMILES: [I:1][C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[CH:7][N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11].[Br:21]Br.OS([O-])=O.[Na+]>CC([O-])=O.[Na+]>[I:1][C:2]1[N:3]=[C:4]([NH2:20])[C:5]2[N:6]=[C:7]([Br:21])[N:8]([C:18]=2[N:19]=1)[C@@H:9]1[O:17][C@H:14]([CH2:15][OH:16])[C@@H:12]([OH:13])[C@H:10]1[OH:11]
Reactant: Nc1nc(I)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: O=S([O-])O
Agent: [Na+]
Product: Nc1nc(I)nc2c1nc(Br)n2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Iodoadenosine (1, 2.93 g, 7.45 mmol) was dissolved in NaOAc buffer (1.0 M, pH 4, 50 ml) at 50° C. The solution was cooled to room temperature and bromine (0.46 mL, 8.94 mmol) was added. After stirring overnight at room temperature, adding NaHSO3 destroyed the excess of bromine and the pH of the solution was adjusted to 7 with NaOH solution (5 M). The reaction mixture was kept at 4° C. for 5 hr and the precipitate was filtered. The white solid was washed with water and dried. Yield 2.43 mg (5.14 mmol, 69%), Rƒ 0.69 (10% MeOH in EtOAc); 1H NMR (DMSO-d6) δ 7.91 (s, 2H, NH2), 5.77 (d, 1H, J=6.52 Hz, H-1′), 5.47 (d, 1H, J=5.84 Hz, OH-2′), 5.24 (d, 1H, J=4.80 Hz, OH-5′), 5.03–4.84 (m, 2H, OH-3′, H-2′), 4.20–4.09 (m, 1H, H-3′), 3.97–3.88 (m, 1H, H-4′), 3.71–3.42 (m, 2H, H-5′) ppm.
Reaction SMILES: [CH3:1]O.S(Cl)(Cl)=O.[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19]([CH3:20])=[CH:18][C:17](=[O:21])[C:16]([C:22]([OH:24])=[O:23])=[N:15]2)=[CH:10][CH:9]=1>O>[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:19]([CH3:20])=[CH:18][C:17](=[O:21])[C:16]([C:22]([O:24][CH3:1])=[O:23])=[N:15]2)=[CH:10][CH:9]=1
Reactant: CO
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(Cl)cc1
Solvent: O=S(Cl)Cl
Solvent: O
Product: COC(=O)c1nn(-c2ccc(Cl)cc2)c(C)cc1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 100 ml of methanol, cooled to -5° C., there is added dropwise 11.9 g (0.1 mol) of thionyl chloride. Upon completion of the addition 13.23 g (0.05 mol) of 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic Acid (see Example 12) is added. The suspension formed is vacuum filtered after stirring at room temperature for 3 hrs. to afford the product, mp 183°-193° C. decomp. Treatment of the product with water affords the Methyl 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylate.