Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16](F)[CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].BrC1C=CC(C([Cl:29])=O)=C(Cl)C=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][C:15]=2[Cl:29])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)c(F)c2)C1
Reactant: O=C(Cl)c1ccc(Br)cc1Cl
Product: CC(C)(C)OC(=O)N1CCOC(c2ccc(N)cc2Cl)C1

Procedure:
In analogy to (RS)-2-(4-Amino-3-fluoro-phenyl)-morpholine-4-carboxylic acid tert-butyl ester (Example 1, steps a-g) using 4-bromo-2-chlorobenzoyl chloride (CAS 21900-55-0) instead of 4-bromo-3-fluorobenzoyl chloride.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH:24]1([NH2:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([NH:30][C:19](=[O:21])[C:18]2[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]3[C:4]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)=[N:5][O:6][C:2]=3[CH3:1])=[N:16][CH:17]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: NC1CCCCC1
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCCC2)cn1
Yield: 100 %

Procedure:
As described for example 8b, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid (100 mg, 0.32 mmol) was converted, using cyclohexylamine instead of methylamine, to the title compound (126 mg, 100%) which was obtained as a white solid. MS: m/e=392.3 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:7]=12.[CH2:18]([OH:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:2]1[N:3]=[N:4][CH:5]=[C:6]2[C:10]([CH3:11])=[C:9]([CH3:12])[N:8]([CH2:13][CH:14]=[C:15]([CH3:17])[CH3:16])[C:7]=12)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(C)=CCn1c(C)c(C)c2cnnc(Cl)c21
Reactant: OCc1ccccc1
Product: CC(C)=CCn1c(C)c(C)c2cnnc(OCc3ccccc3)c21

Procedure:
The title compound was prepared as a white powder in -6.2% yeild in a similar procedure to that described in Example 1 by using 7-chloro-2,3-dimethyl-1-(3-methyl-2-butenyl)pyrrolo[2,3-d]pyridazine and benzyl alcohol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5](N2C3C(=CC=CC=3)C=C2)=[CH:4][CH:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22]([CH2:26][N:27]3[CH2:32][CH2:31][CH:30]([C:33]4[CH:34]=[C:35]([NH:39][C:40](=[O:44])[CH:41]([CH3:43])[CH3:42])[CH:36]=[CH:37][CH:38]=4)[CH2:29][CH2:28]3)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.IC1C=CC=C(C)C=1>>[CH3:43][CH:41]([CH3:42])[C:40]([NH:39][C:35]1[CH:36]=[CH:37][CH:38]=[C:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH2:26][C:22]3[CH:21]=[C:20]4[C:25](=[CH:24][CH:23]=3)[N:17]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[CH:18]=[CH:19]4)[CH2:28][CH2:29]2)[CH:34]=1)=[O:44]
Reactant: Cc1ccc(-n2ccc3ccccc32)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc4[nH]ccc4c3)CC2)c1
Agent: Cc1cccc(I)c1
Product: Cc1cccc(-n2ccc3cc(CN4CCC(c5cccc(NC(=O)C(C)C)c5)CC4)ccc32)c1
Yield: 60 %

Procedure:
According to the procedure used for the synthesis of 1-(4-methylphenyl)1H-indole, N-{3-[1-(1H-indol-5-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide (37.5 mg, 0.100 mmol) and 1-iodo-3-methylbenzene (43.6 mg, 0.200 mmol) gave the desired product (28 mg, 60%). 1H NMR (400 MHz, CDCl3) δ 7.68-6.60 (m, 14H), 3.66 (s, 2H), 3.16-2.96 (m, 2H), 2.59-2.44 (m, 2H), 2.44 (s, 3H), 2.18-2.01 (m, 2H), 1.91-1.68 (m, 4H), 1.24 (d, 6H, J=6.8 Hz); ESMS m/e: 466.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]([C:18]([OH:20])=[O:19])=[N:10]2)=[CH:5][CH:4]=1.[CH:21](N(C(C)C)CC)(C)[CH3:22].C(O)C>S(Cl)(Cl)=O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)c1cc(C(=O)O)nn1-c1ccc(OC)cc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)c1cc(C(=O)OC)n(-c2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.9 %

Procedure:
A solution of 1-[(4-methoxy)phenyl]-5-(methoxycarbonyl)pyrazole -3-carboxylic acid (7.50 g, 27.1 mmol) in 50 mL of thionyl chloride was stirred at 80° C. for 1 h. The volatiles were then removed and the residue was azeotroped with 20 mL of toluene and dried in vacuo. The residue was dissolved in 100 mL of tetrahydrofuran and then there was added diisopropylethylamine (11.8 mL, 67.9 mmol) and absolute ethanol (3.2 mL, 54.3 mmol). The reaction mixture was allowed to stir at ambient temperature for 24 h. The volatiles were removed and the residue was dissolved in ethyl acetate. This solution was filtered through a pad of silica gel and was concentrated in vacuo to afford 3.7 g (45%) of the title compound which was used without purification. LRMS (DCI): 305.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[O:26]C(=O)O[C:23]2=O)=[CH:18][CH:17]=1.C[O-].[Na+].CO>C1COCC1>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([OH:26])[C:23]2[N:6]=[C:4]([OH:5])[C:3]3[C:2](=[CH:10][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:8][CH:7]=3)[N:1]=2)=[CH:18][CH:17]=1
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1N
Reactant: O=C1OC(=O)C(c2ccc(F)cc2)O1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Oc1nc(C(O)c2ccc(F)cc2)nc2cc(C(F)(F)F)ccc12
Temperature: 50 °C

Procedure:
To 2-amino-4-(trifluoromethyl)benzamide (840 mg, 4.16 mmol), in THF (15 mL) was added 5-(4-fluorophenyl)-1,3-dioxolane-2,4-dione from Example 16 (1225 mg, 6.24 mmol) and the mixture was heated at 50° C. for 4 h. The solvent was evaporated and the crude 2-(2-(4-fluorophenyl)-2-hydroxyacetamido)-4-(trifluoromethyl)benzamide was dissolved in MeOH (10 mL), added 0.5 M sodium methoxide in MeOH (2.5 mL, 1.25 mmol) and the reaction mixture was heated at 50° C. for 1 h. The solvent was evaporated and then 1N hydrochloric acid was added. The mixture was extracted with EtOAc and the organic phase was dried over sodium sulfate and concentrated in vacuo to afford crude 2-((4-fluorophenyl)(hydroxy)methyl)-7-(trifluoromethyl)quinazolin-4-ol, which was used in next reaction without purification. LC-MS (ESI) m/z 339 (M+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[N:9].[CH2:10]1[CH2:20][C:18](=O)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11]1.B(F)(F)F.CCOCC>>[NH2:1][C:2]1[C:3]2[C:8]3[N:9]=[C:17]4[C:12]([CH:11]=[CH:10][CH:20]=[CH:18]4)=[CH:13][C:14]=3[CH2:15][CH2:16][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: N#Cc1ccccc1N
Reactant: O=C1CCCc2ccccc21
Agent: FB(F)F
Solvent: CCOCC
Product: Nc1cccc2c1-c1nc3ccccc3cc1CC2

Procedure:
2-amino-1-cyano-benzene (2.0 g, 16.9 mmol), α-tetralone (3, 4-dihydro-[2H]-naphthalene-1-one) (Aldrich Chemicals) (2.7 g, 18.5 mmol) and boron trifluoride diethyl etherate (1M, 2.3 ml, 18.8 mmol) were treated according to the general procedure described herein to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:37]=[C:38]([F:40])[CH:39]=1)[CH2:5][C@H:6]([NH:20][C:21](C1C=C(C)N=C(N(CCC)CCC)N=1)=[O:22])[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[CH:12]=1.[CH2:41]([C:45]1[N:49]2[CH:50]=[C:51](C(O)=O)[CH:52]=[CH:53][C:48]2=[N:47][CH:46]=1)[CH2:42][CH2:43][CH3:44]>>[CH2:41]([C:45]1[N:49]2[CH:50]=[C:51]([C:21]([NH:20][C@@H:6]([CH2:5][C:4]3[CH:3]=[C:2]([F:1])[CH:39]=[C:38]([F:40])[CH:37]=3)[C@H:7]([OH:19])[CH2:8][NH:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH3:18])[CH:12]=3)=[O:22])[CH:52]=[CH:53][C:48]2=[N:47][CH:46]=1)[CH2:42][CH2:43][CH3:44]
Reactant: CCCCc1cnc2ccc(C(=O)O)cn12
Reactant: CCCN(CCC)c1nc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)n1
Product: CCCCc1cnc2ccc(C(=O)N[C@@H](Cc3cc(F)cc(F)c3)[C@H](O)CNCc3cccc(CC)c3)cn12

Procedure:
In the same manner as for N-{(1S,2R)-1-(3,5-difluorobenzyl)-3-[(3-ethylbenzyl)amino]-2-hydroxypropyl}-2-(dipropylamino)-6-methylpyrimidine-4-carboxamide {Example S-SP-235}, Step 3, 3-butylimidazo[1,2-a]pyridine-6-carboxylic acid (0.16 g) was converted to 0.30 g of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:25]1([C:31]2[N:32]=[CH:33][N:34]([CH2:36][CH2:37][CH2:38][NH2:39])[CH:35]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([C:31]2[N:32]=[CH:33][N:34]([CH2:36][CH2:37][CH2:38][NH:39][C:10]([C:2]3[NH:1][C:9]4[C:4]([CH:3]=3)=[CH:5][CH:6]=[CH:7][CH:8]=4)=[O:12])[CH:35]=2)[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1cc2ccccc2[nH]1
Reactant: NCCCn1cnc(-c2ccccc2)c1
Agent: O=C(n1ccnc1)n1ccnc1
Product: O=C(NCCCn1cnc(-c2ccccc2)c1)c1cc2ccccc2[nH]1

Procedure:
The compound of this Example is obtained when indole-2-carboxylic acid is reacted with 1,1'-carbonyldiimidazole and 4-phenyl-1H-imidazole-1-propanamine by the procedure of Example 33.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)[C:10](=[O:19])[CH:9]=2)[CH:7]=1.[NH2:22][C:23]1[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:20]#[N:21])=[C:6]([C:8]2[CH:13]=[CH:12][N:11]([CH:14]([CH3:18])[C:15]([NH:22][C:23]3[CH:35]=[CH:34][C:26]([C:27]([O:29][C:30]([CH3:31])([CH3:32])[CH3:33])=[O:28])=[CH:25][CH:24]=3)=[O:17])[C:10](=[O:19])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Reactant: CC(C(=O)O)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O
Product: CC(C(=O)Nc1ccc(C(=O)OC(C)(C)C)cc1)n1ccc(-c2cc(Cl)ccc2C#N)cc1=O

Procedure:
76 mg (purity 83%, 0.21 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-2-oxopyridin-1(2H)-yl]propanoic acid (racemate) and 1.1 eq. of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 43 mg (43% of theory)
Reaction SMILES: [C:1]1([C@:7]([C:10]([OH:12])=[O:11])([CH3:9])[NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].C[NH+](C)C.[C:18]([O:22][C:23](=O)[O:24]C(C)(C)C)([CH3:21])([CH3:20])[CH3:19]>C(#N)C>[C:18]([O:22][C:23]([NH:8][C@@:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([C:10]([OH:12])=[O:11])[CH3:9])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: C[C@@](N)(C(=O)O)c1ccccc1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Agent: C[NH+](C)C
Agent: [OH-]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@](C)(C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 500 mg of 2-phenyl-D-alanine (3.02 mmol) and trimethylammonium hydroxide (aqueous solution 10%, 2.8 mL, 3.02 mmol) in 15 mL of acetonitrile, diterbutylcarbonate (1.047 g, 4.8 mmol) was added and the mixture was stirred at room temperature for 2 days. The solvent was then removed under vacuo, the residue was dissolved in water and washed with diethylether. The aqueous layer was acidified to pH=3-4 with citric acid and the product was extracted with ethyl acetate (3×20 mL). The combined organic phase was washed with water, dried over Na2SO4 and evaporated. The title product was recovered as white solid (630 mg, yield 78%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:23]1[CH:24]=[CH:25][C:26]([N+:38]([O-:40])=[O:39])=[C:27]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH:28]=1.[H-].[Na+]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([O:21][C:23]3[CH:24]=[CH:25][C:26]([N+:38]([O-:40])=[O:39])=[C:27]([N:29]([CH3:37])[C:30](=[O:36])[O:31][C:32]([CH3:33])([CH3:34])[CH3:35])[CH:28]=3)=[CH:19][CH:20]=2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Oc1ccc(-c2ccc(OCc3ccccc3)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccc(OCc4ccccc4)cc3)cc2)ccc1[N+](=O)[O-]
Yield: 69.9 %

Procedure:
In a similar manner to that described in Reference Example 6, a reaction was carried out using 4′-benzyloxybiphenyl-4-ol (11.07 g), t-butyl N-(5-chloro-2-nitrophenyl)-N-methylcarbamate (11.5 g), sodium hydride (55 wt. %, 2.2 g) and anhydrous N,N-dimethylformamide/anhydrous tetrahydrofuran/anhydrous toluene=1/1/1 (360 ml) and the reaction mixture was purified to give the title compound (14.75 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.C([Li])CCC.[CH2:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)[CH3:17].[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH2:22][C:21]1[CH:24]=[CH:25][C:18]([CH2:16][CH3:17])=[CH:19][CH:20]=1
Reactant: CCc1ccc(CBr)cc1
Reactant: COc1cccc(OC)c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCc1ccc(Cc2c(OC)cccc2OC)cc1
Reaction time: 1.5 h
Yield: 49.7 %

Procedure:
To a mixture of 1,3-dimethoxybenzene (6.9 g, 50 mmol) and tetrahydrofuran (70 mL), n-butyllithium (1.57 M in hexane, 35 mL) was added in ice and stirred for 1.5 hours. Subsequently, 4-ethylbenzyl bromide (10 g, 50 mmol) was added in ice and stirred for an additional 3.5 hours. After addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate, and the organic phase was washed with saturated aqueous sodium chloride and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5–85:15) to give 1,3-dimethoxy-2-(4-ethylbenzyl)benzene (6.37 g, 49%, mp 62.5–66.5° C.) as a light-yellow powder.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[N:8]1[C:12]2=[C:13]3[S:19][CH:18]=[CH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]=[C:9]1[CH2:20]Cl.[CH3:22][S:23]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:25])=[O:24].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[N:8]1[C:12]2=[C:13]3[S:19][CH:18]=[CH:17][C:14]3=[N:15][CH:16]=[C:11]2[N:10]=[C:9]1[CH2:20][N:26]([S:23]([CH3:22])(=[O:24])=[O:25])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30]
Reactant: ClCc1nc2cnc3ccsc3c2n1[C@H]1CC2CCC1C2
Reactant: CC(C)(C)OC(=O)NS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1nc2cnc3ccsc3c2n1[C@H]1CC2CCC1C2)S(C)(=O)=O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[(2S)-bicyclo[2.2.1]hept-2-yl]-2-(chloromethyl)-1H-imidazo[4,5-d]thieno[3,2-b]pyridine (0.10 g, 0.31 mmol) dissolved in N,N-dimethylformamide (1 mL) was added tert-butyl (methylsulfonyl)carbamate (0.092 g, 0.47 mmol) and potassium carbonate (0.087 g, 0.63 mmol). The mixture was stirred at 50° C. overnight, then diluted with water and extracted with EtOAc. The combined organic layers were dried over MgSO4 and concentrated to give crude tert-butyl ({1-[(2S)-bicyclo[2.2. l]hept-2-yl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-2-yl}methyl)(methylsulfonyl)carbamate. LCMS calculated for C22H29N4O4S2 (M+H)+: m/z=477.2. Found: 477.1. The crude intermediate was treated with trifluoroacetic acid (0.5 mL, 6 mmol) in methylene chloride (0.5 mL) at room temperature for 30 min, then the solvent was removed in vacuo. The residue was re-dissolved in MeOH and purified on prep-LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (30 mg, 25%). LCMS calculated for C17H21N4O2S2 (M+H)+: m/z=377.1. Found: 377.0.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][NH:6][CH2:7]2.C[O:13][C:14](=O)[C:15]([F:18])([F:17])[F:16].CN(C=O)C>ClCCl>[OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][N:6]([C:14](=[O:13])[C:15]([F:18])([F:17])[F:16])[CH2:7]2
Reactant: Oc1cccc2c1CCNC2
Reactant: COC(=O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(N1CCc2c(O)cccc2C1)C(F)(F)F
Temperature: 25 °C

Procedure:
2.35 g (15.9 mmol) 5-hydroxy-1,2,3,4-tetrahydroisoquinoline, 1.92 mL (19.0 mmol) methyltrifluoroacetate and 15 mL DMF were mixed and stirred for over night at room temperature. The reaction mixture was diluted with dichloromethane, washed with water containing one drop of dil. hydrochloric acid and with aqueous sodium chloride. After drying over Na2SO4 and evaporation to dryness, the product was purified by silicagel chromatography (system C). Yield quantitative. 1H NMR (CDCl3, 400 MHz): 8.15 (1H, bd), 7.06 (1H, t, 8.1 Hz), 6.6-6.9 (2H, m), 4.75 (2H, ss), 3.86 (2H, m), 2.90 (2H, m).
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:17])[NH:4][CH:5]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2C)[CH:7]=1.COC1C(OC)=CC(CCC2C=CC=CC=2)=CN=1>>[OH:1][C:2]1[C:3](=[O:17])[NH:4][CH:5]=[C:6]([CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:7]=1
Reactant: Cc1ccccc1CCc1c[nH]c(=O)c(O)c1
Agent: COc1cc(CCc2ccccc2)cnc1OC
Product: O=c1[nH]cc(CCc2ccccc2)cc1O
Yield: 16 %

Procedure:
Prepared as described for 3-Hydroxy-5-(2-methylphenethyl)pyridin-2(1H)-one (Example 26) from 2,3-dimethoxy-5-(2-phenylethyl)pyridine (Intermediate 6). Purification by column chromatography (C18-SiO2; 5-95% methanol in water with 0.01% formic acid) gave 3-hydroxy-5-(2-phenylethyl)pyridin-2(1H)-one as a purple solid (10 mg, 16%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([NH:19][C:4]2[CH:5]=[N:6][C:7]([O:8][C:9]3[N:10]=[CH:11][C:12]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][CH:13]=4)=[C:2]([Cl:1])[CH:3]=2)(=[O:29])=[O:28])=[CH:23][CH:22]=1
Reactant: Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Product: O=S(=O)(Nc1cnc(Oc2cc3ccccc3cn2)c(Cl)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared by reacting 5-chloro-6-(isoquinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 2) and 4-chlorobenzene-1-sulfonyl chloride. 1H NMR (DMSO-d6) δ: 7.56-7.62 (m, 2H), 7.63-7.68 (m, 2H), 7.72-7.81 (m, 5H), 7.92 (d, 1H), 8.10 (d, 1H), 9.06 (s, 1H), 10.75 (s, 1H); MS (ES): 444.0 (M−1).
Reaction SMILES: [CH:1]1([N:4]2[C:11](=[O:12])[CH2:10][CH2:9][NH:8][C:7]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:6]=3[CH2:5]2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:26][C:27]1[O:31][N:30]=[C:29]([C:32](Cl)=[O:33])[CH:28]=1>ClC(Cl)C>[CH:1]1([N:4]2[C:11](=[O:12])[CH2:10][CH2:9][N:8]([C:32]([C:29]3[CH:28]=[C:27]([CH3:26])[O:31][N:30]=3)=[O:33])[C:7]3[CH:13]=[CH:14][C:15]([O:17][CH3:18])=[CH:16][C:6]=3[CH2:5]2)[CH2:2][CH2:3]1
Reactant: COc1ccc2c(c1)CN(C1CC1)C(=O)CCN2
Reactant: Cc1cc(C(=O)Cl)no1
Solvent: CC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)CN(C1CC1)C(=O)CCN2C(=O)c1cc(C)on1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.5 %

Procedure:
To a solution of 5-cyclopropyl-8-methoxy-2,3,5,6-tetrahydrobenzo[b][1,5]diazocin-4(1H)-one (50.0 mg, 0.203 mmol) from Example 1 in dichloroethane (2.0 ml) was added triethylamine (0.057 ml, 0.406 mmol) and 5-methylisoxazole-3-carbonyl chloride (32.5 mg, 0.223 mmol). The reaction mixture was stirred at room temperature overnight and then quenched with saturated aqueous sodium bicarbonate, followed by extraction with dichloromethane. The combined organic phases were dried over sodium sulfate, filtered and concentrated. Preparative thin layer chromatography (ethyl acetate/methanol:98/2) of the crude residue gave the desired compound (53 mg, 74%).
Reaction SMILES: C(N(CC)CC)C.ClC(OCC)=O.[OH:14][CH:15]([C:21]1[CH:26]=[CH:25][C:24]([N:27]2[C:31](=[O:32])[CH2:30][CH2:29][C@@H:28]2[CH2:33][CH2:34][CH2:35][C:36]2[S:40][C:39]([C:41]([OH:43])=[O:42])=[CH:38][CH:37]=2)=[CH:23][CH:22]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].O[CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1>>[N:47]1([CH2:46][CH2:45][O:42][C:41]([C:39]2[S:40][C:36]([CH2:35][CH2:34][CH2:33][C@H:28]3[CH2:29][CH2:30][C:31](=[O:32])[N:27]3[C:24]3[CH:23]=[CH:22][C:21]([CH:15]([OH:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:26][CH:25]=3)=[CH:37][CH:38]=2)=[O:43])[CH2:52][CH2:51][O:50][CH2:49][CH2:48]1
Reactant: CCCCCC(O)c1ccc(N2C(=O)CC[C@@H]2CCCc2ccc(C(=O)O)s2)cc1
Reactant: OCCN1CCOCC1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Product: CCCCCC(O)c1ccc(N2C(=O)CC[C@@H]2CCCc2ccc(C(=O)OCCN3CCOCC3)s2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
Triethylamine (17.5 μL, 0.13 mmol) and ethyl chloroformate (6 μL, 0.063 mmol) were added sequentially to a solution of 5-(3-{(S)-1-[4-(1-hydroxyhexyl)-phenyl]-5-oxo-pyrrolidin-2-yl}-propyl)-thiophene-2-carboxylic acid (derived from the faster eluting [HPLC] ester diastereomer, see U.S. Ser. No. 10/599,046 or U.S. 60/777,506, 18 mg, 0.042 mmol) in CH2Cl2 (0.6 mL) at 0° C. The mixture was allowed to warm to room temperature. After 30 min at room temperature, 4-(2-hydroxyethyl)morpholine (51 μL, 0.42 mmol) was added. After stirring overnight at room temperature, the reaction mixture was concentrated under a stream of nitrogen. The residue was diluted with EtOAc (20 mL) and washed with H2O (2×5 mL) and brine (5 mL). The organic phase was dried (Na2SO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (CH2Cl2→10% MeOH/CH2Cl2, gradient) afforded 8.5 mg (37%) of the title compound (2).
Reaction SMILES: [Na].[C:2]1([S:8]([C:11]2[C:12]([CH2:28][CH3:29])=[N:13][N:14]3[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:18][C:17](Cl)=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([OH:33])[CH2:31][OH:32]>>[C:2]1([S:8]([C:11]2[C:12]([CH2:28][CH3:29])=[N:13][N:14]3[C:19]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[CH:18][C:17]([O:32][CH2:31][CH2:30][OH:33])=[N:16][C:15]=23)(=[O:10])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCCO
Reactant: CCc1nn2c(N3CCN(C)CC3)cc(Cl)nc2c1S(=O)(=O)c1ccccc1
Agent: [Na]
Product: CCc1nn2c(N3CCN(C)CC3)cc(OCCO)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
0.274 g (12 mmol) of sodium was added to 40 ml of ethylene glycol and this solution was treated with 0.50 g (1.2 mmol) of 3-benzenesulphonyl-5-chloro-2-ethyl-7-(4-methyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidine and subsequently stirred at 80° for 1 hr. After cooling to RT the reaction solution was poured on to 70 ml of ice-water and extracted three times with 50 ml of AcOEt. The combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 9:1) of the residue and crystallization from EtOH yielded 0.24 g (44%) of 2-[3-benzenesulphonyl-2-ethyl-7-(4-methyl-piperazin-1-yl)-pyrazolo[1,5-a]pyrimidin-5-yl-oxy]-ethanol as colorless crystals, m.p. 153-154°.