Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]12([C:11]3[CH:21]=[CH:20][C:14]([O:15][CH2:16][C:17](O)=[O:18])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:22]([O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[CH:27]=1)[CH3:23].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:22]([O:24][C:25](=[O:33])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH:32][C:17](=[O:18])[CH2:16][O:15][C:14]2[CH:13]=[CH:12][C:11]([C:1]34[CH2:10][CH:5]5[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]5)[CH2:8]3)[CH2:2]4)=[CH:21][CH:20]=2)[CH:27]=1)[CH3:23]
Reactant: O=C(O)COc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: CCOC(=O)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cccc(NC(=O)COc2ccc(C34CC5CC(CC(C5)C3)C4)cc2)c1
Reaction time: 8 h
Yield: 89.7 %

Procedure:
To a mixture of [4-(1-adamantyl)phenoxy]acetic acid (143.2 mg, 0.5 mmol), 3-aminobenzoic acid ethyl ester (123.9 mg, 0.5 mmol), N-(3-dimethylaminopropyl)-N′-ethyl carbodiimide HCl (EDC) (143.8 mg, 0.75 mmol) and 1-hydroxybenzotriazole (HOBt) (101.4 mg, 0.75 mmol) in DMF (6 mL) was added N,N-diisopropylethylamine, redistilled (DIPEA) (97.0 mg, 0.13 mL, 0.75 mmol). The mixture wag stirred overnight, and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl acetate:MeOH=6:3:1) to give 3-[2-(4-adamantan-1-yl-phenoxy)-acetylamino]-benzoic acid ethyl ester as a white solid (194.4 mg, 89.7% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH:7]=[C:6]2[CH2:15][C:16]1[NH:24][C:23]2[C:22](=[O:25])[N:21]([CH3:26])[C:20](=[O:27])[N:19]([CH2:28][CH:29]([CH3:32])[CH2:30][OH:31])[C:18]=2[N:17]=1.[C:33](Cl)(=[O:35])[CH3:34]>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH:9]=[N:8][CH:7]=[C:6]2[CH2:15][C:16]1[NH:24][C:23]2[C:22](=[O:25])[N:21]([CH3:26])[C:20](=[O:27])[N:19]([CH2:28][CH:29]([CH3:32])[CH2:30][O:31][C:33](=[O:35])[CH3:34])[C:18]=2[N:17]=1
Reactant: COc1cc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)CO)c2cc1OC
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: COc1cc2cncc(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)COC(C)=O)c2cc1OC
Temperature: 50 °C

Procedure:
A suspension of the product of Example 68, 8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-(3-hydroxy-2-methyl-propyl)-1-methyl-3,7-dihydro-purine-2,6-dione (63 mg, 0.144 mmol) and acetyl chloride (18 ml, 0.25 mmol) in pyridine (1 ml) is heated at 50° C. for 18 hours. After evaporation, flash chromatography (19:1 dichloromethane-methanol elution) affords acetic acid 3-[8-(6,7-dimethoxy-isoquinolin-4-ylmethyl)-1-methyl-2,6dioxo-1,2,6,7-tetrahydro-purin-3-yl]-2-methyl-propyl ester, [MH]+ 482.
Reaction SMILES: [C:1]([NH:4][C@@H:5]([C:10]([OH:12])=[O:11])[C:6]([SH:9])([CH3:8])[CH3:7])(=[O:3])[CH3:2].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.Cl>CCOCC>[C:1]([N:4]1[C@@H:5]([C:10]([OH:12])=[O:11])[C:6]([CH3:7])([CH3:8])[S:9][C@@H:18]1[C:17]1[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)N[C@@H](C(=O)O)C(C)(C)S
Reactant: O=Cc1ccc(F)cc1
Agent: Cl
Solvent: CCOCC
Product: CC(=O)N1[C@@H](c2ccc(F)cc2)SC(C)(C)[C@@H]1C(=O)O
Reaction time: 0.5 h

Procedure:
A solution containing 5.74 g (30 mmoles) of N-acetyl-D-penicillamine and 3.2 ml of 4-fluorobenzaldehyde in 20 ml of ether saturated with gaseous hydrogen chloride is stirred. After 5 to 6 minutes an oil separates which becomes crystalline after 30 minutes on rubbing. The precipitate is filtered out and washed with ether to give the title acid in a yield of 7.81 g (87.1%) which can be recrystallized from ethyl acetate, m.p. 144°-146° C., [α]D20 =+206.9°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14](=[O:25])OC2C=CC([N+]([O-])=O)=CC=2)[CH2:7]1.[NH2:30][CH2:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([NH2:38])=[O:37])=[CH:34][CH:33]=1>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14]([NH:30][CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:36]([NH2:38])=[O:37])=[CH:39][CH:40]=2)=[O:25])[CH2:7]1
Reactant: O=C(NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCc1ccc(C(N)=O)cc1
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(CNC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)cc1
Yield: 103.4 %

Procedure:
Example 54 was prepared in an analogous manner to Example 43 from Intermediate 13 (0.079 g) and 4-aminomethylbenzamide (0.032 g) using N,N-dimethylformamide as solvent to yield the title compound (0.0837 g).
Reaction SMILES: [I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH3:9].[CH:10](=O)[C:11]1[O:15][CH:14]=[CH:13][CH:12]=1.C(O)C.[OH-].[K+]>O>[I-:1].[CH3:2][NH+:3]1[CH:7]=[CH:6][N:5]([CH3:8])[CH:4]1[CH:9]=[CH:10][C:11]1[O:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=Cc1ccco1
Reactant: CC1N(C)C=C[NH+]1C
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN1C=C[NH+](C)C1C=Cc1ccco1

Procedure:
A mixture of 5.0 g of 1,2,3-trimethyl-1H-imidazolium iodide, 2.5 ml of furfural, 20 ml of ethanol and 1 g of potassium hydroxide is refluxed for 10 minutes. The mixture is cooled, water is added, and the resulting solid is filtered off and crystallized from ethanol to yield 5.0 g of the title compound, melting point 299°-300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:5]([N:7]1[CH2:12][CH2:11][CH2:10][C:9]([C:13]2[CH:17]=[CH:16]SC=2)=[N:8]1)=[O:6].ClC1C=C(C=CC=1Cl)[C:26](N1CCCC(C2SC=CC=2)=N1)=[S:27].ClC1C=C(C=CC=1Cl)C(N1CCCC(C2C=CSC=2)=N1)=S>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][C:20]=1[Cl:21])[C:5]([N:7]1[CH2:12][CH2:11][CH2:10][C:9]([C:13]2[S:27][CH:26]=[CH:16][CH:17]=2)=[N:8]1)=[O:6]
Reactant: S=C(c1ccc(Cl)c(Cl)c1)N1CCCC(c2cccs2)=N1
Reactant: O=C(c1ccc(Cl)c(Cl)c1)N1CCCC(c2ccsc2)=N1
Agent: S=C(c1ccc(Cl)c(Cl)c1)N1CCCC(c2ccsc2)=N1
Product: O=C(c1ccc(Cl)c(Cl)c1)N1CCCC(c2cccs2)=N1

Procedure:
1-(3,4-dichlorobenzoyl)-3-(thien-3-yl)-1,4,5,6-tetrahydropyridazine; 1-(3,4-dichlorothiobenzoyl)-3-(thien-2-yl)-1,4,5,6-tetrahydropyridazine and 1-(3,4-dichlorothiobenzoyl)-3-(thien-3-yl)-1,4,5,6-tetrahydropyridazine.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=4)=[CH:15][C:8]=23)=[CH:4][CH:3]=1.O.O.[Sn](Cl)Cl>CCO.Cl>[Cl:1][C:2]1[CH:26]=[CH:25][C:5]([O:6][C:7]2[CH:12]=[N:11][CH:10]=[C:9]3[S:13][C:14]([C:16]4[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=4)=[CH:15][C:8]=23)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc3c(Oc4ccc(Cl)cc4)cncc3s2)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(-c2cc3c(Oc4ccc(Cl)cc4)cncc3s2)cc1
Reaction time: 22 h
Yield: 66.7 %

Procedure:
To a suspension of Example 272A (0.13 g, 0.34 mmol) in EtOH (3.5 mL), a solution of tin(II) chloride dihydrate (0.31 g, 1.36 mmol) in conc. HCl (0.68 mL) was slowly added. The reaction was stirred for 22 hours and partitioned between dichloromethane (75 mL) and 1 N NaOH (75 mL). The organic layer was washed with 1 N NaOH (1×50 mL), brine (1×50 mL), partially dried (Na2SO4), and concentrated to a colored solid (0.13 g). The desired product was crystallized from acetonitrile to yield colored crystals (0.08 g, 68%).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH:31]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)([CH3:33])[CH3:32]>CN1C(=O)CCC1>[CH:31]([N:34]1[CH2:39][CH2:38][N:37]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:16])([CH3:17])[C:10]=3[CH:18]=2)[CH2:36][CH2:35]1)([CH3:33])[CH3:32]
Reactant: CC(C)N1CCNCC1
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Solvent: CN1CCCC1=O
Product: CC(C)N1CCN(c2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Temperature: 120 °C
Reaction time: 3 h

Procedure:
Trifluoro-methane sulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 40 mg, 0.0921 mmol) was dissolved in NMP (1 ml) and added with 1-isopropylpiperazine (236 mg, 20 eq.). The mixture was stirred at 120° C. for 3 hours. After cooling to room temperature, purification was carried out by HPLC to obtain the target compound (white powder, 12.8 mg, 34%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20](O)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OC(N=NC(OC(C)C)=O)=O)(C)C.C1(C)C=CC=CC=1>O1CCCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([O:1][C:2]2[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=2)[CH:5]=[O:6])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(Oc2cccc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
3-Hydroxybenzaldehyde (0.98 g), 1-t-butoxycarbonyl-4-hydroxypiperidine (2.41 g) and triphenylphosphine (3.15 g) were suspended in tetrahydrofuran (10 mL). To the mixture was added dropwise 40% azodicarboxylic acid diisopropyl ester-toluene solution (6.1 mL) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/3) to give the title compound (0.74 g).
Reaction SMILES: [H-].[Na+].[CH:3]1([CH:6]([OH:33])[C:7]2[N:11]([CH3:12])[C:10]3[CH:13]=[C:14]([N:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[CH:19][C:18]4=[O:32])[CH:15]=[CH:16][C:9]=3[N:8]=2)[CH2:5][CH2:4]1.IC.[CH3:36]N(C=O)C>C1COCC1>[CH:3]1([CH:6]([O:33][CH3:36])[C:7]2[N:11]([CH3:12])[C:10]3[CH:13]=[C:14]([N:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][C:25]5[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=5)=[CH:19][C:18]4=[O:32])[CH:15]=[CH:16][C:9]=3[N:8]=2)[CH2:5][CH2:4]1
Reactant: CN(C)C=O
Reactant: Cn1c(C(O)C2CC2)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc21
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: COC(c1nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cc2n1C)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
NaH (40% oil dispersion, 5.2 mg) was added to a solution of 1-(2-(cyclopropyl(hydroxy)methyl)-1-methyl-1H-benzimidazol-6-yl)-4-((4-fluorobenzyl)oxy)pyridin-2(1H)-one (30 mg) and iodomethane (0.013 ml) in THF (2 ml)-DMF (1 ml) at room temperature. The mixture was stirred at room temperature for 30 min. The mixture was quenched with water and extracted with EtOAc twice. The organic layer was separated, washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting solid was washed with Et2O to give the title compound (23.6 mg) as a white solid.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][OH:11])[CH3:8])([CH3:4])[CH3:3].[S:13](Cl)([CH3:16])(=[O:15])=[O:14]>N1C=CC=CC=1.C(Cl)Cl>[C:2]([O:5][C:6]([N:7]([CH3:8])[CH2:9][CH2:10][O:11][S:13]([CH3:16])(=[O:15])=[O:14])=[O:12])([CH3:1])([CH3:3])[CH3:4]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(CCOS(C)(=O)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(2-Hydroxyethyl)methylcarbamic acid 1,1-dimethylethyl ester (350 mg, 2.0 mmol) was dissolved in pyridine (2 ml). Mesyl chloride (0.229 ml, 2.1 mmol) was added at room temperature, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with methylene chloride, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution, dried over MgSO4 and concentrated under reduced pressure to give methanesulfonic acid 2-(tert-butoxycarbonyl-methyl-amino)-ethyl ester. This was used in the next reaction without complete purification.
Reaction SMILES: [C:1](Cl)([CH3:3])=[O:2].Cl.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][N:17]([C:20]2[CH:21]=[CH:22][C:23]3[C:24]4[CH2:33][CH2:32][NH:31][CH2:30][CH2:29][C:25]=4[NH:26][C:27]=3[CH:28]=2)[C:16](=[O:34])[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([N:31]1[CH2:32][CH2:33][C:24]2[C:23]3[CH:22]=[CH:21][C:20]([N:17]4[CH:18]=[CH:19][C:14]([O:13][CH2:6][C:7]5[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=5)=[CH:15][C:16]4=[O:34])=[CH:28][C:27]=3[NH:26][C:25]=2[CH2:29][CH2:30]1)(=[O:2])[CH3:3]
Reactant: O=c1cc(OCc2ccccc2)ccn1-c1ccc2c3c([nH]c2c1)CCNCC3
Reactant: CC(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2[nH]c3cc(-n4ccc(OCc5ccccc5)cc4=O)ccc3c2CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.8 %

Procedure:
AcCl (0.03 mL, 0.4 mmol) was added to a solution of 4-(benzyloxy)-1-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-8-yl)pyridin-2(1H)-one hydrochloride (102 mg, 0.242 mmol), DMAP (6 mg, 0.05 mmol) and Et3N (0.10 mL, 0.73 mmol) in CH2Cl2 (10 mL) under N2, and the resulting solution was stirred at 25° C. for 4 h. The solution was concentrated under reduced pressure. Flash chromatography on silica gel (Et2O/(8:1.9:0.1 Et2O/MeOH/NH4OH) afforded 35 mg (34%) of the title compound as an off-white solid: mp 250-254° C.; 1H NMR (500 MHz, DMSO-d6) δ 10.99 (s, 1H), 7.54 (d, J=7.5 Hz, 1H), 7.49-7.35 (m, 6H), 7.19 (dd, J=2.5, 2.5 Hz, 1H), 6.88-6.83 (m, 1H), 6.07 (dd, J=8.0, 2.5 Hz, 1H), 5.95 (d, J=2.5, 1H), 5.14 (s, 2H), 3.76-3.65 (m, 4H), 3.06-3.02 (m, 1H), 2.97-2.91 (m, 2H), 2.87-2.82 (m, 1H), 2.12 (s, 3H); ESI MS m/z 428 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[C:16]([NH:19][NH2:20])(=[O:18])[CH3:17]>S(Cl)(Cl)=O.C(Cl)(Cl)Cl>[C:16]([NH:19][NH:20][C:13]([C:11]1[O:12][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)=[O:15])(=[O:18])[CH3:17]
Reactant: CC(=O)NN
Reactant: O=C(O)c1ccc(-c2ccc(Cl)cc2)o1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: CC(=O)NNC(=O)c1ccc(-c2ccc(Cl)cc2)o1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A mixture of 111.5 g (0.5 mole) of 5-(p-chlorophenyl)furoic acid in 500 ml of thionyl chloride was heated at reflux for 1-11/4 hr. After slight cooling, the reaction mixture was filtered and the filtrate was concentrated in a water bath at reduced pressure to a creamy solid. The solid was dissolved in 400 ml of chloroform. To this chloroform solution under stirring at room temperature was added a suspension of 74 g (1 mole) of acetyl hydrazine in 900 ml of chloroform. Addition was completed in about 20 min. White creamy solid separated fairly readily while the temperature rose to about 45°. The mixture was allowed to stir at ambient temperature overnight.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([NH2:16])([CH2:9]3)[CH2:7]1)[CH2:13]2)=[O:5].C(N(CC)CC)C.Cl.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31](Cl)=[O:32].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:2][O:3][C:4]([C:6]12[CH2:15][CH:10]3[CH2:11][CH:12]([CH2:14][C:8]([NH:16][C:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=4)=[O:32])([CH2:9]3)[CH2:7]1)[CH2:13]2)=[O:5]
Reactant: O=C(Cl)c1ccccn1
Reactant: COC(=O)C12CC3CC(CC(N)(C3)C1)C2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C12CC3CC(CC(NC(=O)c4ccccn4)(C3)C1)C2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.9 %

Procedure:
To a round bottom flask was added 3-amino-adamantane-1-carboxylic acid methyl ester hydrochloride (20.0 g, 81.4 mmol) and methylene chloride (500 mL) and the solution was cooled at 0° C. To this solution was then added triethylamine (57 mL, 0.41 mol) followed by picolinoyl chloride hydrochloride (15.2 g, 85.4 mmol; TCI America, Wellesley Hills, Mass., USA) and the reaction was stirred at 0° C. for 30 minutes, then at room temperature for 6 hours. To the reaction was added saturated aqueous sodium bicarbonate (500 mL) and the biphasic mixture was stirred vigorously for a few minutes, then transferred to a 2-L separatory funnel. The mixture was extracted, the layers separated and the aqueous layer was extracted again with methylene chloride (2×200 mL). The combined organic layers were washed with brine (300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 24.8 g (97%) of the title compound, 3-[(pyridine-2-carbonyl)-amino]-adamantane-1-carboxylic acid methyl ester, as a pale brown solid. 1H NMR (400 MHz, CDCl3) δ 8.54-8.49 (m, 1H), 8.16 (dt, J=7.8, 1.0 Hz, 1H), 7.96 (br s, 1H), 7.83 (td, J=7.8, 1.8 Hz, 1H), 7.40 (ddd, J=7.6, 4.8, 1.3 Hz, 1H), 3.66 (s, 3H), 2.34-2.30 (m, 2H), 2.29-2.23 (m, 2H), 2.17-2.13 (m, 4H), 1.97-1.80 (m, 4H), 1.78-1.62 (m, 2H). ESI-MS m/z: 315.0 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:7]=1)=[O:4].[CH3:25][C:26]1[CH:27]=[C:28]([N:32]=[C:33]=[O:34])[CH:29]=[CH:30][CH:31]=1>>[CH2:15]([O:14][C:12]([C:8]1[CH:7]=[C:6]([N:5]([CH2:17][C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[C:3](=[O:4])[CH2:2][NH:1][C:33]([NH:32][C:28]2[CH:29]=[CH:30][CH:31]=[C:26]([CH3:25])[CH:27]=2)=[O:34])[CH:11]=[CH:10][CH:9]=1)=[O:13])[CH3:16]
Reactant: Cc1cccc(N=C=O)c1
Reactant: CCOC(=O)c1cccc(N(CC(=O)OC(C)(C)C)C(=O)CN)c1
Product: CCOC(=O)c1cccc(N(CC(=O)OC(C)(C)C)C(=O)CNC(=O)Nc2cccc(C)c2)c1
Yield: 18.5 %

Procedure:
Using a procedure similar to that described in Example 1, but starting with tert-butyl 2-[2-amino-N-(3-ethoxycarbonylphenyl)acetamido]acetate (3.3 g) and 3-methylphenyl isocyanate (1.3 g), and after recrystallisation in diisopropyl ether, tert-butyl 2-{N-(3-ethoxycarbonylphenyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (0.85 g), m.p. 71° C., is obtained.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[NH2:16][C:17]1[CH:21]=[CH:20][S:19][C:18]=1[C:22]([O:24][CH3:25])=[O:23].N1C=CC=CC=1>ClCCl>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([S:12]([NH:16][C:17]3[CH:21]=[CH:20][S:19][C:18]=3[C:22]([O:24][CH3:25])=[O:23])(=[O:14])=[O:13])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: COC(=O)c1sccc1N
Reactant: O=S(=O)(Cl)c1ccc(-n2cccn2)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1sccc1NS(=O)(=O)c1ccc(-n2cccn2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 65.4 %

Procedure:
To a solution of 4-(1H-pyrazol-1-yl)benzene-1-sulfonyl chloride (0.5 g; 2.0 mmol) in dichloromethane (4.5 mL) at room temperature, was added methyl 3-aminothiophene-2-carboxylate (0.27 g; 1.7 mmol) followed by pyridine (0.27 g; 3.4 mmol) and then stirred at room temperature under a nitrogen atmosphere for 24 hours. The reaction mixture was concentrated under reduced pressure and then taken up in ethyl acetate (50 mL) and washed with water. The aqueous layer separated and extracted with ethyl acetate (2×50 mL). The combined organic phases were successively washed with water and aqueous saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The crude residue was recrystallized from ethyl acetate/hexanes (1:9, v/v) to yield the title product as a tan/yellow solid (404 mg).
Reaction SMILES: C(O[C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]([OH:18])=[O:17])=[O:10])C1C=CC=CC=1.[C:19]([C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:43])[C:31]2[CH:36]=[CH:35][C:34]([CH:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[CH:33][CH:32]=2)[CH:26]=[CH:27][CH:28]=1)([CH3:22])([CH3:21])[CH3:20].C(C1C=C(NC(C2C=CC(N3CCN(C([C@H]4CCC[C@@H]4C(O)=O)=O)CC3)=NC=2)=O)C=CC=1)(C)(C)C>>[C:19]([C:23]1[CH:24]=[C:25]([NH:29][C:30]([C:31]2[CH:32]=[CH:33][C:34]([CH:37]3[CH2:38][CH2:39][N:40]([C:9]([C@@H:11]4[CH2:15][CH2:14][CH2:13][C@H:12]4[C:16]([OH:18])=[O:17])=[O:10])[CH2:41][CH2:42]3)=[CH:35][CH:36]=2)=[O:43])[CH:26]=[CH:27][CH:28]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: O=C(O)[C@H]1CCC[C@@H]1C(=O)OCc1ccccc1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(C(=O)[C@H]4CCC[C@@H]4C(=O)O)CC3)nc2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCN(C(=O)[C@@H]4CCC[C@H]4C(=O)O)CC3)cc2)c1

Procedure:
(1R,2R)-2-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidine-1-carbonyl}-cyclopentanecarboxylic acid was synthesized from (1S,2S)-cyclopentane-1,2-dicarboxylic acid monobenzyl ester and N-(3-tert-butyl-phenyl)-4-piperidin-4-yl-benzamide in a manner similar to the one described in the synthesis of (1S,2S)-2-{4-[5-(3-tert-butyl-phenylcarbamoyl)-pyridin-2-yl]-piperazine-1-carbonyl}-cyclopentane-carboxylic acid above. LCMS calcd for C29H36N2O4 (m/e) 476, obsd 477 (M+H).
Reaction SMILES: CON(C)[C:4]([C:6]1[S:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[CH:7]=1)=[O:5].[CH3:16][Mg+].[Br-].[NH4+].[Cl-]>C1COCC1>[S:14]1[C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[CH:7]=[C:6]1[C:4](=[O:5])[CH3:16]
Reactant: C[Mg+]
Reactant: CON(C)C(=O)c1cc2cnccc2s1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1cc2cnccc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of N-methoxy-N-methylthieno[3,2-c]pyridine-2-carboxamide (D′-2) (11.1 g, 50 mmol) in anhydrous THF (150 mL) was added MeMgBr (3M in ethyl ether, 25 mL, 75 mmol) at 0° C. under N2. The reaction mixture was allowed to warm to the ambient temperature and stirred overnight. Saturated aqueous NH4Cl solution was added to quench the reaction. The resulting mixture was then extracted with EtOAc. The combined organic layers were dried over Na2SO4, filtered, and concentrated to afford the title compound. MS (m/z): 178 (M+1)+.
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:7])[CH2:6][CH2:5][CH2:4]1.Cl[C:9]1[N:14]=[CH:13][N:12]=[C:11]([N:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:10]=1>CN(C=O)C>[CH:3]1([O:7][C:9]2[N:14]=[CH:13][N:12]=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[CH:10]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: OC1CCC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)ncn2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2cc(OC3CCC3)ncn2)CC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 469 mg, 11.7 mmol) in DMF (15 mL) was added cyclobutanol (0.92 ml, 11.7 mmol) at 0° C. After stirring at 0° C. for 30 min, a solution of tert-butyl 4-(6-chloropyrimidin-4-yl)piperazine-1-carboxylate (700 mg, 2.34 mmol) in DMF (0.5 mL) was slowly added, and the mixture was stirred at rt for 12 h. Then, the mixture was poured onto water, and the aqueous layer was extracted with EtOAc (twice). The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/EtOAc (5:1-3:1) to give 687 mg (88% yield) of the title compound as a white solid.