Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:26]([OH:28])=O)[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.O[N:30]=[C:31]([C:33]1[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][CH:34]=1)[NH2:32]>>[CH3:39][C:36]1[CH:37]=[CH:38][C:33]([C:31]2[N:32]=[C:26]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:25])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[O:28][N:30]=2)=[CH:34][CH:35]=1
Reactant: O=C(O)C1CC(c2ccc(OC(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: Cc1ccc(C(N)=NO)cc1
Product: Cc1ccc(-c2noc(C3CC(c4ccc(OC(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)n2)cc1

Procedure:
80 mg (0.20 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethoxy)phenyl]piperidine-3-carboxylic acid (Example 44A) and 33 mg (0.22 mmol, 1.1 eq.) of N′-hydroxy-4-methylbenzenecarboximidamide were reacted according to the General Method 1. Yield: 68 mg (66% of theory)
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][CH:8]=O)[C:4](=[O:10])O1.[NH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)CCl>[OH:6][C@@H:5]1[CH2:7][CH2:8][N:12]([CH:13]2[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]2)[C:4]1=[O:10]
Reactant: CC1(C)OC(=O)[C@@H](CC=O)O1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CC[C@@H](O)C2=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.4 %

Procedure:
(R)-2-(2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetaldehyde (16 g, 101 mmol) was dissolved in ClCH2CH2Cl (500 mL) and tert-butyl 4-aminopiperidine-1-carboxylate (40.5 g, 202 mmol) and acetic acid (6.94 mL, 121 mmol) were added and stirred at ambient temperature for 15 minutes. NaBH(OAc)3 (64.3 g, 304 mmol) was added in 3 portions and the reaction stirred at ambient temperature overnight. The reaction was carefully quenched with saturated aqueous NaHCO3. The reaction was partitioned between aqueous NaHCO3 and CH2Cl2, extracted, washed with 10% citric acid, brine, dried over Na2SO4, filtered and concentrated. The solids were purified over silica gel (5 to 10% methanol in EtOAc) to afford (R)-tert-butyl 4-(3-hydroxy-2-oxopyrrolidin-1-yl)piperidine-1-carboxylate (20.5 g, 72.1 mmol, 71.3% yield) as a white solid.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=[C:11]2[C:19]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:37])([CH:34]([CH3:36])[CH3:35])[CH3:33])=[CH:28][CH:27]=2)=[CH:20][CH:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>C(O)C.O1CCCC1.ClCCl>[CH:21]1([CH:20]=[C:19]([C:26]2[CH:27]=[CH:28][C:29]([C:32]([OH:37])([CH:34]([CH3:35])[CH3:36])[CH3:33])=[CH:30][CH:31]=2)[C:11]2[NH:10][C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[CH:12]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: CC(C)C(C)(O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3n2S(=O)(=O)c2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)C(C)(O)c1ccc(C(=CC2CCCC2)c2cc3cccnc3[nH]2)cc1
Yield: 78.5 %

Procedure:
A mixture of 2-{4-[1-(1-benzenesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)-2-cyclopentyl-vinyl]-phenyl}-3-methyl-butan-2-ol (90 mg, 0.17 mmol) in ethanol (4 mL), tetrahydrofuran (6 mL) and an aqueous sodium hydroxide solution (10%, 2 mL) was heated at 50° C. for 36 h. The mixture was diluted with dichloromethane (50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 2-{4-[2-cyclopentyl-1-(1H-pyrrolo[2,3-b]pyridin-2-yl)-vinyl]-phenyl}-3-methyl-butan-2-ol (50 mg, 76%) which was used in the next step without further purification: LC/MS m/e calcd for C25H30N2O [M+H]+ 375.53, observed 375.1.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[CH:27]=[C:26]([C:28]5[O:29][C:30]([C:33]67OCC(C)(C[O:38]6)C[O:34]7)=[CH:31][CH:32]=5)[N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:42]>C1COCC1.O>[ClH:42].[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[C:19]4[CH:27]=[C:26]([C:28]5[O:29][C:30]([C:33]([OH:38])=[O:34])=[CH:31][CH:32]=5)[N:25]=[CH:24][C:20]=4[N:21]=[CH:22][N:23]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC12COC(c3ccc(-c4cc5c(Nc6ccc7c(cnn7Cc7ccccc7)c6)ncnc5cn4)o3)(OC1)OC2
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2cc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3cn2)o1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(1-Benzylindazol-5-yl)-(6-[5-(4-methyl-2,6,7-trioxa-bicyclo[2.2.2]oct-1-yl)-furan-2-yl]-pyrido-[3,4-d]pyrimidin-4-yl)-amine (0.445 g, 0.81 mmol) was suspended in a mixture of THF (15 ml) and dilute HCl (15 ml) and stirred at room temperature for 18 hours. The mixture was diluted with water to preciptate the intermediate (partial hydrolysis) which was collected by filtration and washed with water. This solid was suspended in a mixture of THF (10 ml) and NaOH (1M, 10 ml) and stirred at room temperature for 18 hours. The THF was removed in vacuo and the residue was acidified to pH1 with dilute HCl to give the product as an orange solid, which was collected by filtration (0.322 g, 0.645 mmol, 79%); δH [2H6]DMSO 10.63 (1H,s), 9.19 (1H,s), 8.89 (1H,s), 8.64 (1H,s), 8.17-8.22 (2H,m), 7.67-7.80 (2H,m), 7.46 (1H,s), 7.23-7.39 (6H,m), 5.70 (2H,s); m/z (M+1+) 463.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[K+].C(O)C.[CH2:22](Cl)[CH:23]=[CH2:24].[C:26](=[S:28])=[S:27]>>[CH2:22]([S:28][C:26]([N:2]1[CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:12][C:13]=2[CH2:1]1)=[S:27])[CH:23]=[CH2:24]
Reactant: C=CCCl
Reactant: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C=CCSC(=S)N1Cc2[nH]c3ccccc3c2CC1C(=O)O
Yield: 59 %

Procedure:
In the same manner as described in Example 6, (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (3.24 g), KOH (1.75 g), 50% ethanol (60 ml), carbon disulfide (1.8 ml) and allyl chloride (2.3 g) are reacted and treated. The product is crystallized from chloroform to give the title compound (3.0 g, 59%), m.p. 161°-162° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]=[CH:7][C:6]([C:14]#[N:15])=[C:5]2[NH:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[C:19]([Cl:24])[CH:18]=1.[CH3:25][O:26][CH2:27][C@@H:28]1[CH2:32][CH2:31][CH2:30][NH:29]1>>[ClH:24].[ClH:24].[Cl:24][C:19]1[CH:18]=[C:17]([NH:16][C:5]2[C:4]3[C:9](=[CH:10][C:11]([O:12][CH3:13])=[C:2]([NH:1][C:11](=[O:12])[CH:2]=[CH:3][CH2:4][N:29]4[CH2:30][CH2:31][CH2:32][C@H:28]4[CH2:27][O:26][CH3:25])[CH:3]=3)[N:8]=[CH:7][C:6]=2[C:14]#[N:15])[CH:22]=[CH:21][C:20]=1[F:23]
Reactant: COc1cc2ncc(C#N)c(Nc3ccc(F)c(Cl)c3)c2cc1N
Reactant: COC[C@@H]1CCCN1
Product: COC[C@@H]1CCCN1CC=CC(=O)Nc1cc2c(Nc3ccc(F)c(Cl)c3)c(C#N)cnc2cc1OC
Product: Cl
Yield: 215.4 %

Procedure:
By using the method of Example 89, 1.2 g (3.5 mmol) of 6-amino-4-(3-chloro-4-fluoro-phenylamino)-7-methoxy-quinoline-3-carbonitrile and 2.4 g (21 mmol) of (S)-(+)-2-(methoxymethy) pyrrolidine were converted to 1.5 g the title compound, obtained as a yellow powder: mass spectrum (electrospray, m/e): M+H 524.0, (M+2H)+2 262.4. This reaction can also be done with (R)-(−)-2-(methoxymethy) pyrrolidine or racemic 2-(methoxymethy) pyrrolidine giving the R-entaniomer or the racemate, respectively.
Reaction SMILES: [CH2:1]([NH:8][C:9]([NH:11][CH2:12]C1C=CC=CC=1)=[O:10])C1C=CC=CC=1.[C:19](NC)([NH:21]C)=O.C(O[C:29](=[O:31])[CH3:30])(=O)C.C(O)(=O)C>>[C:19]([CH2:30][C:29]([N:11]([CH3:12])[C:9]([NH:8][CH3:1])=[O:10])=[O:31])#[N:21]
Reactant: CC(=O)OC(C)=O
Reactant: CNC(=O)NC
Reactant: O=C(NCc1ccccc1)NCc1ccccc1
Solvent: CC(=O)O
Product: CNC(=O)N(C)C(=O)CC#N
Yield: 90 %

Procedure:
Cyanoacetyldimethylurea is prepared in analogy to Example 1. Instead of dibenzylurea, dimethylurea is employed. The product is worked up by stripping off the acetic anhydride/acetic acid mixture on a rotary evaporator under reduced pressure. The residue obtained in this way is recrystallized from water.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:26])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:15][CH2:14]1.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:19]([N:16]1[CH2:17][CH2:18][CH:13]([CH:12]=[O:11])[CH2:14][CH2:15]1)(=[O:26])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(c1ccccc1)N1CCC(CO)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=CC1CCN(C(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 0.1 %

Procedure:
To 1.99 g of dimethyl sulfoxide in 45 mL methylene chloride at −78° C. was added 2.16 g of oxalyl chloride. After 10 min, 1865 g of 4-hydroxymethyl-N-benzoylpiperidine (Step B) in 15 mL of methylene chloride was added at −78° C. and stirred for 30 min. DIEA (5.49 mL) was added and this mixture was stirred for an additional 30 min. at −78° C. and then warmed to room temperature and stirred another 30 min. The reaction was quenched with 50 mL water and extracted with 3×50 mL methylene chloride. The combined organic layers were dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed with 2:1 hexane:ethyl acetate followed by 1:1 hexane:ethyl acetate to give 1.445 g of the title compound.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH:9]1([C:15]([O:17][CH3:18])=[O:16])[CH2:14][CH2:13][CH2:12][CH:11]=[CH:10]1.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+].C1COCC1.[OH2:36]>>[Br:8][CH:10]1[C:11](=[O:36])[CH2:12][CH2:13][CH2:14][CH:9]1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C1C=CCCC1
Reactant: O
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)C1CCCC(=O)C1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., NBS (9.08 g, 51.0 mmol) was added to a soln. of methyl cyclohex-2-enecarboxylate (5.96 g, 42.5 mmol) [Bioorg. Med. Chem. 1999, 7, 1505-1511] in THF/H2O (500 mL, 9:1). The mixture was allowed to warm to RT and stirred for 2 h. Subsequently, aq. sat. Na2S2O3 and aq. sat. NaHCO3 were added and the mixture was conc. in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[N:9]=[CH:10]/[CH:11]=[C:12]2[C:17](=[O:18])[O:16]C(C)(C)[O:14][C:13]2=O)=[CH:4][CH:3]=1.C[O-].[Na+].Cl.C(Cl)Cl>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]([C:17]([OH:16])=[O:18])=[CH:11][CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC1(C)OC(=O)C(=C/C=N/Nc2ccc(F)cc2)C(=O)O1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: O=C(O)c1ccnn(-c2ccc(F)cc2)c1=O
Yield: 87.5 %

Procedure:
A mixture of (E)-5-(2-(2-(4-fluorophenyl)hydrazono)ethylidene)-2,2-dimethyl-1,3-dioxane-4,6-dione (0.60 g, 2.05 mmol) and NaOMe (0.133 g, 2.46 mmol) in MeOH (10 mL) was heated under reflux for 15 hours. The salt was treated with cold 1 N HCl solution, extrated with CH2Cl2, dried over MgSO4, and concentrated to afford 0.42 g (87%) of the desired product. 1H NMR (400 MHz, CDCl3) δ 13.57 (br s, 1H), 8.29 (m, 2H), 7.63 (m, 2H), 7.24 (m, 2H); 19F NMR (376 MHz, CDCl3) δ −110.7. LRMS (ESI pos) m/e 235.1 (M+1).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][C:5]([Cl:8])=[CH:6][N:7]=1.N1C=CC=CC=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=1)=[O:17]>C(Cl)Cl>[Cl:8][C:5]1[S:4][C:3]([NH:2][C:16](=[O:17])[O:18][C:19]2[CH:20]=[CH:21][C:22]([N+:25]([O-:27])=[O:26])=[CH:23][CH:24]=2)=[N:7][CH:6]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Nc1ncc(Cl)s1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ncc(Cl)s1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.4 %

Procedure:
2-Amino-5-chlorothiazole hydrochloride (1.00 g, 5.80 mmol) was dissolved in methylene chloride (50 mL), and the obtained solution was then washed with a saturated aqueous solution of sodium hydrogen carbonate. The resulting solution was dried over anhydrous sodium sulfate and was then filtered. After that, pyridine (0.47 mL, 5.80 mmol) and 4-nitrophenyl chloroformate (1.18 g, 5.80 mmol) were added to the filtrate, and the obtained mixture was then stirred at room temperature for 3 hours. Thereafter, a solid was collected by filtration, was then washed with methylene chloride, and was then dried to obtain 4-nitrophenyl (5-chlorothiazol-2-yl)carbamate (980 mg, 56%) in the form of a white solid. t-Butyl 5-bromospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate (65.1 mg, 0.184 mmol) synthesized by a method described in the known method (International Publication WO2009/089454) or a method similar thereto was dissolved in N,N′-dimethylformamide (2 mL). Thereafter, 4-nitrophenyl (5-chlorothiazol-2-yl)carbamate (55.2 mg, 0.184 mmol) and triethylamine (13 μL, 0.092 mmol) were added to the above obtained solution, and the obtained mixture was then stirred at 50° C. for 3 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain the captioned compound (60.0 mg, 64%) in the form of a white solid.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])([CH3:5])([CH3:4])[CH3:3].[H-].[Na+].Br[CH2:15][C:16]1[CH:40]=[CH:39][C:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:25]([C:35]([F:38])([F:37])[F:36])[CH:24]=3)[S:22][C:18]=2[CH:17]=1>CN(C=O)C.CCOC(C)=O>[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH:10][CH2:15][C:16]1[CH:40]=[CH:39][C:19]2[N:20]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[C:25]([C:35]([F:36])([F:37])[F:38])[CH:24]=3)[S:22][C:18]=2[CH:17]=1)([CH3:5])([CH3:4])[CH3:3]
Reactant: FC(F)(F)c1cc(-c2nc3ccc(CBr)cc3s2)ccc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)CCN
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CCNCc1ccc2nc(-c3ccc(-c4ccccc4)c(C(F)(F)F)c3)sc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.8 %

Procedure:
To a solution of β-alanine tert-butyl ester hydrochloride (47 mg, 1.1 eq.) in DMF (2 ml) is added NaH (60% in mineral oil) (28 mg, 3 eq.) at room temperature. The mixture is stirred at room temperature for 15 minutes before a solution of 6-bromomethyl-2-(2-trifluoromethyl-biphenyl-4-yl)benzothiazole (105 mg, 0.234 mmol) in DMF (1 ml) is added. The mixture is stirred at room temperature overnight, diluted with EtOAc, washed with 10% Na2S2O3, brine, dried over MgSO4, filtered and concentrated. Column chromatography (CH2Cl2/CH3OH, 95/5) gave 31 mg (26%) of 3-{[2-(2-trifluoromethyl-biphenyl-4-yl)-benzothiazol-6-ylmethyl]-amino}-propionic acid tert-butyl ester.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7](S)[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)=[O:15]>>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([CH2:13][C:14]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:15])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(S)c1
Reactant: COc1ccc(C(=O)CBr)cc1
Product: COc1ccc(C(=O)Cc2cccc(OC(C)C)c2)cc1

Procedure:
3-Isopropoxythiophenol and 2-bromo-4'-methoxyacetophenone were converted to the title compound by the procedure of Preparation 1.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:8])[CH2:6][CH3:7].[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16][C:15]2([CH3:25])[CH3:24]>C(Cl)Cl>[CH3:10][O:11][C:12]1[C:21]([C:5](=[O:8])[CH2:6][CH3:7])=[CH:20][C:19]2[C:18]([CH3:23])([CH3:22])[CH2:17][CH2:16][C:15]([CH3:25])([CH3:24])[C:14]=2[CH:13]=1
Reactant: CCC(=O)Cl
Reactant: COc1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCC(=O)c1cc2c(cc1OC)C(C)(C)CCC2(C)C

Procedure:
Following General Procedure A and using AlCl3 (3.7 g, 27.5 mmol), CH2Cl2 (40 mL), propionyl chloride (2.4 mL, 27.5 mmol), and 6-methoxy-1,1,4,4-tetramethyl-1,2,3,4-tetrahydro-naphthalene (Intermediate 2, 5.0 g, 22.9 mmol) in CH2Cl2 (10 mL) at ambient temperature for 1.5 h followed by recrystallization from Et2O, the title compound was obtained as a white solid (5.4 g, 86%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[C:5]([NH2:10])[CH:4]=1.[C:13](N1C=CN=C1)(N1C=CN=C1)=[O:14]>C1COCC1>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:8]=[CH:7][C:6]2[NH:9][C:13](=[O:14])[NH:10][C:5]=2[CH:4]=1
Reactant: Nc1ccc(C(F)(F)F)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=c1[nH]c2ccc(C(F)(F)F)cc2[nH]1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 4-trifluoromethyl-1,2-phenylenediamine (8.8 g, 50 mmol, Lancaster) and 1,1′-carbonyldiimidazole (9.0 g, 55 mmol, Aldrich) in THF (50 mL) was stirred at room temperature for 16 h. The solvent was removed in vacuo and the residue was purified by silica gel chromatography, eluting with EtOAc to give the title compound. MS (ESI, pos. ion) m/z: 203 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].[Cl:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[N:50]=[C:51]=[O:52]>CN(C=O)C>[Cl:43][C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[NH:50][C:51]([N:27]1[C:17]2[N:18]=[C:19]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[N:20]=[C:15]([C:12]3[CH:11]=[N:10][C:9]([N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=4)[CH2:30][C:31]4[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=4)=[N:14][CH:13]=3)[C:16]=2[CH2:29][CH2:28]1)=[O:52]
Reactant: O=C=Nc1ccccc1Cl
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4C(=O)Nc3ccccc3Cl)cn2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 112.1 %

Procedure:
To a DMF solution (2 ml) of ice-cooled bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (80.0 mg, 0.148 mmol), 60% oily NaH (18 mg) was added, followed by stirring at room temperature for 15 minutes. To the reaction mixture, 2-chlorophenylisocyanate (53.4 μl, 0.445 mmol) was added, followed by further stirring for 1 hour. The reaction mixture was ice-cooled, and quenched with water (1 ml). This was diluted with dichloromethane (10 ml), and washed with water (10 ml×2). After the organic layer was dried over sodium sulfate, the sodium sulfate was filtered off, and the filtrate was concentrated under reduced pressure, to obtain a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid (2-chloro-phenyl)-amide as a brown solid (115 mg), and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-217) as a colorless powder (39.2 mg, 58%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=O)=[CH:4][CH:3]=1.[S-:17][C:18]#[N:19].[NH4+:20]>C(O)CC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:19]=[C:18]([SH:17])[NH:20][C:9]=2[C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1
Reactant: [NH4+]
Reactant: O=C(c1cccs1)C(O)c1ccc(F)cc1
Reactant: N#C[S-]
Solvent: CCCO
Product: Fc1ccc(-c2nc(S)[nH]c2-c2cccs2)cc1

Procedure:
Alternatively, reaction of 63.4 g (0.27 mole) of 2-(4-fluorophenyl)-2-hydroxy-1-(2-thienyl)ethanone with 29.0 g (0.38 mole) of ammonium thiocyanate in 1-propanol gave 71.6 g of 4-(4-fluorophenyl)-5-(2-thienyl)-1H-2-imidazolethiol, m.p. 275°-277° (Recrystallized from 1-butanol).
Reaction SMILES: F[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].C([O-])([O-])=O.[K+].[K+].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][NH2:25])[CH:19]=1.[CH3:26][S-:27].[Na+]>CS(C)=O>[CH3:26][S:27][C:6]1[CH:5]=[CH:4][C:3]([N+:9]([O-:11])=[O:10])=[C:2]([CH:7]=1)[NH:25][CH2:24][C:20]1[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=1
Reactant: NCc1cccnc1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: C[S-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1ccc([N+](=O)[O-])c(NCc2cccnc2)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 2,4-difluoro-1-nitrobenzene (2 g, 0.012 mol) in DMSO (60 ml) was added K2CO3 (5.2 g, 0.037 mol). Then pyridin-3-ylmethanamine (1.05 g, 0.013 mol) was added drop wise and the resulting solution was continued to stir at room temperature for 6 h. After complete conversion of 2,4-difluoro-1-nitrobenzene monitored by MS sodium thio-methoxide (1.2 g, 0.013 mol) was added and heated at 60° C. for the next 12 h. The reaction was diluted with ice cold water and extracted with ethyl acetate (3×100 ml). The combined organic layers were washed with brine dried over Na2SO4 and concentrated under vacuum to afford the crude compound which was purified by chromatography to obtain title compound 5-(methyl-thio)-2-nitro-N-(pyridin-3-ylmethyl)aniline as a yellow solid. 1H NMR (400 MHz, CDCl3), δ: 8.65 (s, 1H), 8.58 (s, 2H), 8.11-8.09 (d, J=9.2 Hz, 1H), 7.69-7.67 (d, J=7.6 Hz, 1H), 7.33-7.29 (m, 1H), 6.54-6.51 (dd, J=7.2 Hz, J=1.6 Hz, 1H), 6.43 (s, 1H), 4.58-4.57 (d, J=5.6 Hz, 2H), 2.48 (s, 3H). MS (M+1): 276.
Reaction SMILES: [NH:1]([C:43](OC(C)(C)C)=[O:44])[C@H:2]([C:12]([N:14]1[CH2:42][CH2:41][CH2:40][C@@H:15]1[C:16]([NH:18][C@H:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+:26]([O-:28])=[O:27])=[O:17])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[NH:50]([C:59]([O:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)=[O:60])[C@H:51](C(O)=O)[CH2:52][C:53](=[O:55])[NH2:54].C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>Cl.CCOC(C)=O>[NH:50]([C:59]([O:61][CH2:62][C:63]1[CH:64]=[CH:65][CH:66]=[CH:67][CH:68]=1)=[O:60])[C@H:51]([C:43]([NH:1][C@H:2]([C:12]([N:14]1[CH2:42][CH2:41][CH2:40][C@@H:15]1[C:16]([NH:18][C@H:19]([C:30]([O:32][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:31])[CH2:20][CH2:21][CH2:22][NH:23][C:24](=[NH:29])[NH:25][N+:26]([O-:28])=[O:27])=[O:17])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:44])[CH2:52][C:53](=[O:55])[NH2:54]
Reactant: NC(=O)C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)N[C@@H](CCCNC(=N)N[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Product: N=C(NCCC[C@H](NC(=O)[C@H]1CCCN1C(=O)[C@H](COCc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)N[N+](=O)[O-]

Procedure:
The desired compound was prepared from 3.0 g of Boc-Ser(Bzl)-D-Pro-Arg(NO2)-OBzl, 10 ml of 4N HCl-AcOEt, 1.2 g of Z-Asn-OH, 0.9 g of HOBt and 0.95 g of DCC in the same manner as in Example 7-(3).