Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][C:6]1[CH:7]=[N:8][C:9]([OH:12])=[N:10][CH:11]=1.[CH3:17][N:18]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:19](Cl)=[O:20].N12CCN(CC1)CC2.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][C:15]=1[Cl:16])[O:5][C:6]1[CH:11]=[N:10][C:9]([O:12][C:19](=[O:20])[N:18]([CH3:17])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N:8][CH:7]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: Oc1ncc(Oc2ccc(Cl)c(Cl)c2)cn1
Agent: C1CN2CCN1CC2
Solvent: O
Solvent: CN(C)C=O
Product: CN(C(=O)Oc1ncc(Oc2ccc(Cl)c(Cl)c2)cn1)c1ccccc1
Yield: 65.3 %

Procedure:
A solution of 5-(3,4-dichloro-phenoxy)-pyrimidin-2-ol (0.51 g, 2.00 mmol), N-methyl-N-phenylcarbamoyl chloride (0.34 g, 2.00 mmol) and 1,4-diazabicyclo[2.2.2]octane (0.22 g, 2.00 mmol) in dimethylformamide (15 ml) was stirred at room temperature for 1 hour. Water was added and the precipitates were collected by suction. The solids were dissolved in dichloromethane and the solution was dried over sodium sulphate, filtered and evaporated in vacuo. The residue was crystallised from ethyl acetate:heptane yielding the title compound (0.51 g, 65% yield) as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][CH3:22])[C:6]2[S:10][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:20]=1.O.O.Cl[Sn]Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:21][CH3:22])[C:6]2[S:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)=[N:8][C:7]=2[CH:20]=1
Reactant: COc1cc(OC)c2sc(-c3ccc([N+](=O)[O-])cc3)nc2c1
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: COc1cc(OC)c2sc(-c3ccc(N)cc3)nc2c1

Procedure:
To a stirred solution of 3,5-dimethoxybenzenamine (16c, 4g, 26.1 mmol) in pyridine as solvent and base to this 4-nitrobenzoyl chloride (17, 5.3 g, 28.7 mmol) is added slowly and reflux for 2h, after completion of the reaction, reaction mixture is poured in water, filter and washed with dil HCl and dried to afford compound N-(3,5-dimethoxyphenyl)-4-nitrobenzamide (18c). To a stirred solution of amide (18c, 5g, 16.5 mmol) taken in toluene add lawessons reagent (4.6 g, 11.5 mmol) and refluxed at 110° C. for 7h. After completion of the reaction toluene is evaporated under vacuum and water is added and extracted into chloroform and finally purified by column chromatography to afford pure compound N-(3,5-dimethoxyphenyl)-4-nitrobenzothioamide (19c). Treating the thioamide product (19c, 3g, 9.4 mmol) with potassium ferricyanide (4 eq) in aqueous sodium hydroxide (8 eq) solution at 90° C. for 2h cyclization takes place to obtain the 5,7-dimethoxy-2-(4-nitrophenyl)benzo[d]thiazole (20c) solid is precipitated from the reaction mixture filtered and washed with water and dried to afforded product 20c. Reduction of the nitro compound (20c, 500 mg, 1.5 mmol) is proceeded with SnCl2.2H2O in ethanol and reflux at 80° C. for 2h, after completion of reaction ethanol is evaporated under vacuum and to this saturated sodium bicarbonate solution is added to quench the excess stannous chloride and filtered in celite bed and purified in silica column (60-120) to afforded pure compound (21c). The compound 4-(5,7-dimethoxybenzo[d]thiazol-2-yl)benzenamine (21c, 200 mg, 0.698 mmol) on reaction with 3,4,5-trimethoxybenzaldehyde (22f, 137 mg, 1 eq) in ethanol using catalytic amount of acetic acid and refluxed for 2h after completion reaction mixture is cooled to 0° C. solid is precipitated from the reaction mixture it is filtered and washed with ethanol to gave the enamine product and immediately proceeded for the next reaction by using (p-tolylsulfonyl) methyl isocyanide (tosmic) (1.5 eq), and potassium carbonate (2 eq) as base, in 10 mL of methanol and 5 mL of DME was heated under reflux for 12 h after completion of reaction as monitored by TLC. It was cooled to room temperature (27° C.); the solution was concentrated in vacuo and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with EtOAc and Hexane to gave compound 6f as a yellow solid (53%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:20]([CH3:38])=[C:21]([NH:25][C:26](=[O:37])[C:27]5[CH:32]=[CH:31][C:30]([C:33]([CH3:36])([CH3:35])[CH3:34])=[CH:29][CH:28]=5)[CH:22]=[CH:23][CH:24]=4)[C:13]=3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.[Br:47]C(Cl)(Cl)C(Cl)(Cl)Br>C1COCC1>[C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:20]([CH3:38])=[C:21]([NH:25][C:26](=[O:37])[C:27]5[CH:28]=[CH:29][C:30]([C:33]([CH3:34])([CH3:35])[CH3:36])=[CH:31][CH:32]=5)[CH:22]=[CH:23][CH:24]=4)[C:13]=3[CH:12]=[C:11]2[Br:47])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2c1ccn2S(=O)(=O)c1ccccc1
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1c(NC(=O)c2ccc(C(C)(C)C)cc2)cccc1-c1ncnc2c1cc(Br)n2S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
To a solution of Intermediate 52 (4.26 g, 8.12 mmol) in THF (150 ml) at −78° C. was added LDA (1.5 M in THF, 16.24 ml, 24.36 mmol) slowly. The resulting mixture was stirred for 1.5 hrs at −78° C. before adding a solution of 1,2-dibromo-tetrachloroethane (3.97 g, 12.18 mmol) in THF (1 ml). Stirring was continued at −78° C. for 2 hrs, then the reaction mixture was quenched by addition of sat. aqueous NH4Cl solution and warmed up to r.t. The mixture was extracted with EtOAc and the organic layer was dried, filtered, and evaporated to dryness. Purification by flash chromatography (silica gel, cyclohexane/EtOAc gradient) yielded Intermediate 53.
Reaction SMILES: [CH:1]12[O:6][CH:2]1[CH2:3][CH2:4][CH2:5]2.[NH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>[OH-].[Na+].CCOC(C)=O>[OH:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1
Reactant: C1CC2OC2C1
Reactant: NCCc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Oc1ccc(CCNC2CCCC2O)cc1
Reaction time: 6 h

Procedure:
Stir a mixture of cyclopentene oxide (482.0 mg, 5.73 mmol) and tyramine (943.2 mg, 6.88 mmol) in 1.0 N NaOH (20 mL) at room temperature for 64 hours, at 45-55° C. for 6 hours, and at 100° C. for 18 hours. Quench the reaction with saturated aqueous NH4Cl (40 mL) and take it up in EtOAc (50 mL). Separate the layers after shaking. Wash the organic layer with H2O and brine (50 mL each). Back-extract the aqueous layers with CH2Cl2, EtOAc and CH2Cl2 (50 mL each). Adjust the pH of the combined aqueous layers to alkaline and concentrate. Suspend the residue in 10:40:50 2.0 M NH3 in MeOH/CH2Cl2/EtOAc and decant off the supernatant. Dissolve the residual solid in H2O and extract it with 10:40:50 2.0 M NH3 in MeOH/CH2Cl2/EtOAc (100 mL) and 10:90 2.0 M NH3 in MeOH/CH2Cl2. Combine all the organic layers and concentrate. Dissolve the residue in a small amount of MeOH and purify by flash chromatography, eluting with 10:40:50 2.0 M NH3 in MeOH/CH2CL2/EtOAc to afford the title compound as a 1:3 cis/trans isomeric mixture (566 mg, 45%): MS ES+ 222.0 (M+H)+, HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 5-95% over 19 min], tR=4.72 min, 76% and 6.52 min, 24%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([C:8]([OH:10])=O)[NH:5][C:6]=1[CH3:7].[NH2:13][C@@H:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][C@@H:15]1[O:25][CH2:26][CH3:27].C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.CCN=C=NCCCN(C)C.Cl>ClCCl>[Cl:1][C:2]1[C:3]([C:11]#[N:12])=[C:4]([C:8]([NH:13][C@@H:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][C@@H:15]2[O:25][CH2:26][CH3:27])=[O:10])[NH:5][C:6]=1[CH3:7]
Reactant: CCOC(=O)N1CC[C@@H](N)[C@@H](OCC)C1
Reactant: Cc1[nH]c(C(=O)O)c(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)N1CC[C@@H](NC(=O)c2[nH]c(C)c(Cl)c2C#N)[C@@H](OCC)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
To a solution of 4-chloro-3-cyano-5-methyl-1H-pyrrole-2-carboxylic acid (Intermediate 16, 1.01 g, 5.55 mmol) and ethyl (3S,4R)-4-amino-3-ethoxypiperidine-1-carboxylate (Intermediate 24, 1.2 g, 5.55 mmol) in dichloromethane (480 mL) were added HOBt (850 mg, 5.55 mmol) and N-methyl morpholine (1.82 mL, 16.66 mmol). The reaction mixture was stirred for 1 h at room temperature and EDC HCl (1.9 g, 9.99 mmol) was added. The resulting reaction mixture was stirred at room temperature overnight. The reaction mixture was quenched with 2N hydrochloric acid (120 mL). The organic layer was washed with sodium bicarbonate (150 mL), water (150 mL) and brine, dried over anhydrous sodium sulphate, filtered, concentrated under vacuum. Purification by flash column chromatography (silica, 35% ethylacetate in pet ether) afforded ethyl (3S,4R)-4-{[(4-chloro-3-cyano-5-methyl-1H-pyrrol-2-yl)carbonyl]amino}-3-ethoxypiperidine-1-carboxylate 1.5 g (71%) as solid.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[S:3]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[C:10]([CH:17]([OH:20])[CH2:18][OH:19])[CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:5])=[O:4].N1C=CN=C1.[Si:28](Cl)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29].O>CN(C=O)C>[F:22][C:2]([F:1])([F:21])[S:3]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[C:10]([CH:17]([OH:20])[CH2:18][O:19][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[CH:11]=[CH:12][CH:13]=2)[N:8]=1)(=[O:5])=[O:4]
Reactant: O=S(=O)(Oc1ccc2cccc(C(O)CO)c2n1)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCC(O)c1cccc2ccc(OS(=O)(=O)C(F)(F)F)nc12
Yield: 87.3 %

Procedure:
A solution of 12 g (35 mmol) of 2-trifluoromethanesulfonyloxy-8-(1,2-dihydroxyethyl)quinoline, of 5.33 g (78.3 mmol) of imidazole and of 5.63 g of tert-butyldimethylsilyl chloride in 280 ml of DMF is stirred at ambient temperature for 16 h. 800 ml of water are added and extraction is carried out with ethyl acetate (3×250 ml). The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under vacuum. The residue is purified by silica chromatographic column (eluent: cyclohexane/ethyl acetate 8/2) to provide 13.8 g of 2-trifluoromethanesulfonyloxy-8-(1-hydroxy-2-tert-butyldimethylsilyloxyethyl)quinoline in the form of a yellow oil. (Yield: 91%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:6][C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]2=[O:25])=[C:4]([F:26])[CH:3]=1.S(=O)(=O)(O)O.[N+:32]([O-])([OH:34])=[O:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([F:26])[C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[NH:16][C:15]2=[O:25])=[C:6]([N+:32]([O-:34])=[O:33])[C:7]=1[NH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)Nc1cc(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c(F)cc1Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)Nc1c(Cl)cc(F)c(-n2c(=O)cc(C(F)(F)F)[nH]c2=O)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-(4Chloro-5-ethoxycarbonylamino-2-fluorophenyl)-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (XLVII) (1.0 g) was stirred with sulfuric acid (2 ml) at 0° C., then a mixture of nitric acid (1 ml) and sulfuric acid (1 ml) was dropwise added. After stirring at room temperature for 3 hr, it was poured into ice water (50 ml) and yellow crystals formed immediately which was filtered, washed with water and dried in fume hood overnight (0.5 g).
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:14]1[CH:19]=[C:18]([C:20]2[CH:21]=[C:22]([CH3:26])[CH:23]=[CH:24][CH:25]=2)[CH:17]=[CH:16][N:15]=1
Reactant: NO
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(-c2cccc(C)c2)ccn1
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cccc(-c2ccnc(N(CCCCCCC(=O)NO)c3ccccn3)c2)c1
Reaction time: 24 h
Yield: 62 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to II (31 mg, 0.074 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 24 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:4 to 100:7) to furnish III as a colourless oil (18 mg, 62%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)(=O)C>[C:12]([NH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(C(=O)O)cc1N
Solvent: CC(=O)O
Product: CC(=O)Nc1cc(C(=O)O)ccc1C
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
A mixture of 3-amino-4-methylbenzoic acid (13) (27.23 g, 180.2 mmol) and acetic acid (190 mL) is heated to 60° C., and acetic anhydride (120 mL, 1300 mmol) is introduced to the reaction mixture over about 0.25 hours. The reaction mixture is then heated to reflux and stirred for about 30 minutes. The mixture is then cooled to room temperature, and the solid obtained is filtered, washed with water (100 mL), and dried to provide 3-(Acetylamino)-4-methylbenzoic Acid (14) as a light pink colored solid (26.37 g, 76% Yield).
Reaction SMILES: [N:1]1([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]2=[O:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([C:9]1([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:7]([N:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:8]1=[O:16])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C1Cc2ccccc2N1N1CCCCC1
Reactant: ClCc1ccccc1
Product: O=C1N(N2CCCCC2)c2ccccc2C1(Cc1ccccc1)Cc1ccccc1

Procedure:
By substituting 1,3-dihydro-1-(1-piperidinyl)-2H-indol-2-one and benzyl chloride in Example 8, the desired product was obtained; m.p. 94°-96° C. (hexane). Anal. (C27H28N2O): C,H,N.
Reaction SMILES: C(=O)(OC(C)(C)C)N.[CH3:9][O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([C:19]2([NH:22][C:23]([CH:25]3[N:32](C(OC(C)(C)C)=O)[CH2:31][CH2:30][C:27]4([CH2:29][CH2:28]4)[CH2:26]3)=[O:24])[CH2:21][CH2:20]2)=[CH:15][CH:14]=1)=[O:12]>>[CH2:28]1[C:27]2([CH2:30][CH2:31][NH:32][CH:25]([C:23]([NH:22][C:19]3([C:16]4[CH:17]=[CH:18][C:13]([C:11]([O:10][CH3:9])=[O:12])=[CH:14][CH:15]=4)[CH2:20][CH2:21]3)=[O:24])[CH2:26]2)[CH2:29]1
Reactant: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3C(=O)OC(C)(C)C)CC4)CC2)cc1
Agent: CC(C)(C)OC(N)=O
Product: COC(=O)c1ccc(C2(NC(=O)C3CC4(CCN3)CC4)CC2)cc1
Yield: 103.5 %

Procedure:
The title compound (D88) (230 mg) was prepared according to the general procedure for t-Butyl carbamate (Boc) cleavage starting from tert-butyl 5-((1-(4-(methoxycarbonyl)phenyl)cyclopropyl)carbamoyl)-6-azaspiro[2.5]octane-6-carboxylate (racemic mixture) (D54) (290 mg).
Reaction SMILES: CC1SC(C([O-])=S)=CC=1.[NH2:10][C:11](=[S:22])[C:12]1[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=1[CH3:17].Br[CH2:24][C:25]([C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=1)=O>CC(C)=O>[CH3:34][O:33][C:30]1[CH:31]=[CH:32][C:27]([C:25]2[N:10]=[C:11]([C:12]3[CH:13]=[C:14]([C:18]([O:20][CH3:21])=[S:19])[S:15][C:16]=3[CH3:17])[S:22][CH:24]=2)=[CH:28][CH:29]=1
Reactant: COc1ccc(C(=O)CBr)cc1
Reactant: COC(=S)c1cc(C(N)=S)c(C)s1
Agent: Cc1ccc(C([O-])=S)s1
Solvent: CC(C)=O
Product: COC(=S)c1cc(-c2nc(-c3ccc(OC)cc3)cs2)c(C)s1
Yield: 104.3 %

Procedure:
Methyl 4-]4-(4-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate: 30 mg (0.122 mmol) of methyl 4-(aminothioxomethyl)-5-methylthiothiophene-2-carboxylate (Maybridge Chemical Co. LTD., Cornwall, U.K.) was dissolved in 1.2 mL of reagent grade acetone. 2-bromo-4′-methoxy acetophenone (0.146 mmol; 28 mg; Aldrich Chemical Co.) was added and the solution was allowed to reflux for 3 h. The solution was allowed to cool and a solid was filtered and washed with methanol and dried in vacuo to afford 46 mg (90% yield) of methyl 4-[4-(4-methoxyphenyl)(1,3-thiazol-2-yl)]-5-methylthiothiophene-2-carboxylate.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([CH:11]=O)[N:2]=1.[NH:13]1[CH:17]=[CH:16][N:15]=[C:14]1[NH:18][C:19]([C:21]1[C:29]2[NH:28][C:27]([NH2:30])=[N:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)=[O:20].[BH4-].[Na+]>ClCCCl.CC(O[Ti](OC(C)C)(OC(C)C)OC(C)C)C>[NH:15]1[CH:16]=[CH:17][N:13]=[C:14]1[NH:18][C:19]([C:21]1[C:29]2[N:28]=[C:27]([NH:30][CH2:11][C:3]3[N:2]=[CH:1][C:10]4[C:5]([CH:4]=3)=[CH:6][CH:7]=[CH:8][CH:9]=4)[NH:26][C:25]=2[CH:24]=[CH:23][CH:22]=1)=[O:20]
Reactant: Nc1nc2cccc(C(=O)Nc3ncc[nH]3)c2[nH]1
Reactant: O=Cc1cc2ccccc2cn1
Agent: CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(Nc1ncc[nH]1)c1cccc2[nH]c(NCc3cc4ccccc4cn3)nc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 7.3 %

Procedure:
To a solution of 150 mg (0.95 mmol) of isoquinoline-3-carbaldehyde in dry DCE (1 mL) was added 60 mg (0.25 mmol) of 2-amino-3H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide (intermediate B), and Ti(OiPr)4 (3 mL). The mixture was sonicated for 30 min then stirred at room temperature for 6 h. NaBH4 (0.5 g) was added, and the mixture was stirring for 12 h. The reaction was quenched by addition of methanol (2 mL). After usual workup, the residue was purified by column chromatography eluting with DCM then EtOAc/methanol (v/v=100:5) to give 7 mg (7%) of 2-[(isoquinolin-3-ylmethyl)-amino]-1H-benzoimidazole-4-carboxylic acid (1H-imidazol-2-yl)-amide. LCMS: 384 (M+1)+. 1H NMR (DMSO-d6, 400 MHz): δ 12.58 (s, 1H), 11.8 (s, 1H), 11.6 (s, 1H), 9.07 (s, 1H), 8.69 (s, 1H), 8.22 (t, 1H), 7.96 (d, 1H), 7.91 (d, 1H), 7.67 (m, 2H), 7.53 (t, 1H), 7.36 (d, 1H), 7.02 (t, 1H), 6.90 (s, 1H), 6.85 (s, 1H), 4.78 (d, 2H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:22](N1C=CN=C1)([N:24]1C=CN=C1)=O.CN>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([C@@H:17]([CH3:21])[C:18]([NH:24][CH3:22])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[C@@H](C(=O)O)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Agent: CN
Solvent: C1CCOC1
Product: CNC(=O)[C@H](C)n1c(-c2ccc(Cl)cc2)nc2cccnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.5 %

Procedure:
A solution of (S)-2-(4-chlorophenyl)-α-methyl-3H-imidazo [4,5-b]pyridine-3-acetic acid (3.0 g, 0.00995 mole), 1,1'-carbonyldiimidazole (1.61 g, 0.00995 mole) and dry tetrahydrofuran (60 ml) was stirred at room temperature for 1.75 hours with a stream of nitrogen bubbling through it. A solution of methylamine in tetrahydrofuran (20 ml of a 3.03M solution, 0.060 mole) was added and the reaction mixture was stirred at room temperature overnight under nitrogen. The solvents were removed under reduced pressure and the resulting solid was triturated in water, collected by filtration, rinsed twice with water, twice with 5% potassium hydroxide solution, and twice again with water. The solid was dissolved in hot isopropyl alcohol and filtered hot. Upon cooling to room temperature, solid precipitated which was collected by filtration and dried under high vacuum at 50° C. overnight to give 0.86 g (28%) of title compound, mp 218°-220° C.
Reaction SMILES: C[O:2][C:3]([C:5]([C@H:24]1[CH2:27][C@@H:26]([C:28]([O:30]C)=[O:29])[CH2:25]1)([CH2:9][C:10]1[C:11]2[C:16]([CH:17]=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)C(O)=O)=[O:4].C([N:34](CC)CC)C.C1C=CC(OP(OC2C=CC=CC=2)(N=[N+]=[N-])=O)=CC=1>C1(C)C=CC=CC=1>[NH2:34][C:5]([C@H:24]1[CH2:27][C@@H:26]([C:28]([OH:30])=[O:29])[CH2:25]1)([CH2:9][C:10]1[C:11]2[C:16]([CH:17]=[C:18]3[C:23]=1[CH:22]=[CH:21][CH:20]=[CH:19]3)=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]([OH:2])=[O:4]
Reactant: COC(=O)C(Cc1c2ccccc2cc2ccccc12)(C(=O)O)[C@H]1C[C@@H](C(=O)OC)C1
Reactant: CCN(CC)CC
Agent: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: Cc1ccccc1
Product: NC(Cc1c2ccccc2cc2ccccc12)(C(=O)O)[C@H]1C[C@@H](C(=O)O)C1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
A mixture of cis-2-methoxycarbonyl-2-(3-methoxycarbonylcyclobutyl)-3-(9-anthracenyl)propanoic acid (0.15 g, 0.36 mmol), dry triethylamine (37 mg, 0.37 mmol) and diphenylphosphonic azide (103 mg, 0.37 mmol) in dry toluene (5 ml) was heated with stirring at 100° C. under a nitrogen atmosphere for 5 hours. Work up and chromatography eluting with hexane-diethyl ether (17:8) as described in Example 16 (v) gave the title compound as a white solid.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.C[Si](Cl)(C)C.[CH3:22][CH:23]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:24][C:25](Cl)=[O:26].N>N1C=CC=CC=1>[CH3:22][CH:23]([CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:24][C:25]([NH:14][C:13]1[CH:15]=[CH:16][N:9]([C@@H:1]2[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]2)[C:10](=[O:11])[N:12]=1)=[O:26]
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Reactant: CC(CC(=O)Cl)CC(C)(C)C
Agent: C[Si](C)(C)Cl
Agent: N
Solvent: c1ccncc1
Product: CC(CC(=O)Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1)CC(C)(C)C
Yield: 127.9 %

Procedure:
Suspending 2′-Deoxycytidine (2.3 g, 10.0 mmol) in dry pyridine, followed by concentration under reduced pressure was repeated 3 times to perform dehydrative azeotropic distillation, the concentrate was suspended again in dry pyridine (60 ml), and trimethylsilyl chloride (6.4 ml, 50 mmol) was added dropwise over 5 min. To the reaction mixture was added 3,5,5-trimethyl-1-hexanoyl chloride (9.5 ml, 50.0 mmol) over 5 min. After completion of the reaction, under ice-cooling, aqueous ammonia (25 ml) was added and the mixture was reacted for 20 min. The reaction mixture was concentrated under reduced pressure. Water (150 ml) was added to the concentrate, and the mixture was extracted 3 times with ethyl acetate (100 ml). The organic layer was concentrated and the obtained oil was purified by silica gel column chromatography to give the title compound (4.7 g).
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[NH2:9][C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=2[Cl:23])[N:13]=[C:12]([C:24]#[N:25])[CH:11]=1>C(#N)C.ClCCl>[NH2:9][C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][C:16]=2[Cl:23])[N:13]=[C:12]([C:24]#[N:25])[C:11]=1[I:1]
Reactant: O=C1CCC(=O)N1I
Reactant: N#Cc1cc(N)n(-c2c(Cl)cc(Cl)cc2Cl)n1
Solvent: CC#N
Solvent: ClCCl
Product: N#Cc1nn(-c2c(Cl)cc(Cl)cc2Cl)c(N)c1I

Procedure:
N-Iodosuccinimide (17.67 g) was added portionwise to a stirred solution of 5-amino-3-cyano-1-(2,4,6-trichlorophenyl)pyrazole (U.S. Pat. No. 5,232,940; 22.5 g) in acetonitrile (300 ml) and the resulting mixture stirred at room temperature for 1 hour, then evaporated under reduced pressure. The residue was partially purified by chromatography on silica gel (800 g), using an elution gradient of dichloromethane:ethyl acetate (100:0 to 0:100), to produce a pale brown solid which was further purified as follows. Trituration with hexane (25 ml ) provided a residue which was dissolved in dichloromethane (500 ml). This solution was washed with water (500 ml), the aqueous washing back-washed with ethyl acetate (500 ml) and the combined organic solutions dried (Na2SO4) and evaporated under reduced pressure to furnish the title compound as a pale brown solid. δ(DMSOd6): 6.28 (br.s,2H), 7.98 (s,2H). MS (thermospray): M/Z [M+H] 413.0; C10H4Cl3IN4+H requires 412.9.