Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[C:19]([C:25]([O:27][CH3:28])=[O:26])#[C:20][C:21]([O:23][CH3:24])=[O:22]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:24][O:23][C:21]([C:20]1[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[CH:10]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19]=1[C:25]([O:27][CH3:28])=[O:26])=[O:22]
Reactant: COc1ccccc1NCC(=O)c1ccccc1
Reactant: COC(=O)C#CC(=O)OC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1c(-c2ccccc2)cn(-c2ccccc2OC)c1C(=O)OC

Procedure:
A solution of 7,4 g of 2-(2-methoxyphenyl)amino-1-phenyl-ethan-1-one and 11,3 ml of dimethyl acetylenedicarboxylate in 150 ml of toluene is refluxed for 12 hours and then the solvent is eliminated in vacuo. The residue remaining is taken up in ethyl acetate and washed with water. After the organic phase has been dried the solvent is distilled off in vacuo and the residue remaining is chromatographed on silica gel (n-hexane:ethyl acetate 80:20). 9,4 g of 2,3-di(methoxycarbonyl)-1-(2-methoxyphenyl)-4-phenyl-pyrrole are obtained as a colourless oil.
Reaction SMILES: [N:1]1[C:6]2[S:7][C:8]([CH:10]=O)=[CH:9][C:5]=2[CH:4]=[N:3][CH:2]=1.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:17][NH2:18]>C(Cl)Cl>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:17][N:18]=[CH:10][C:8]1[S:7][C:6]2[N:1]=[CH:2][N:3]=[CH:4][C:5]=2[CH:9]=1
Reactant: O=Cc1cc2cncnc2s1
Reactant: COc1ccc(CN)cc1OC
Solvent: ClCCl
Product: COc1ccc(CN=Cc2cc3cncnc3s2)cc1OC
Yield: 100 %

Procedure:
Thieno[2,3-d]pyrimidine-6-carbaldehyde (intermediate 13) (40 mg), 3,4-dimethoxybenzylamine (0.04 ml) and 4 Å molecular sieves (150 mg) were heated at reflux in DCM (5 ml) for 3 hours under an inert atmosphere. The molecular sieves were removed by filtration and the solvent evaporated to afford the title compound as a pale yellow solid (76 mg, 100%);
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:17]C)[CH:14]=2)[NH:9]1.B(Br)(Br)Br>C(Cl)Cl>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:17])[CH:14]=2)[NH:9]1
Reactant: COc1ccc2c(c1)CC(c1ccccc1N)N2
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Nc1ccccc1C1Cc2cc(O)ccc2N1
Reaction time: 1 h
Yield: 103.2 %

Procedure:
A solution of 5.25 g 2-(2-aminophenyl)-5-methoxy-2,3-dihydro-1H-indole in 115 ml CH2Cl2 was added dropwise to 90.4 ml 1.0M BBr3 in CH2Cl2 at 0° C. The solution was stirred at 0°-5° C. for one hour, and then quenched by dropwise addition of 135 ml water. A total of 400 ml 7.5% NaHCO3 was added dropwise, and the resulting solution was stirred 30 minutes. It was then basified to a pH of ~9 with K2CO3 and extracted with EtOAc. The extracts were washed with saturated NaCl solution, dried (MgSO4), and concentrated to yield 5.10 g solid. Trituration with 5% EtOAc/CH2Cl2 and recrystallization from MeOH/water yielded 1.00 g solid, m.p. 169°-171° C.
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH:6]([F:8])[C:5](=[O:9])[N:4](C(OC(C)(C)C)=O)[C@@:3]1([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[F:24])[CH3:17].[CH3:26][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI.C(O)(C(F)(F)F)=O>O1CCCC1.C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[F:8][C:6]1([CH3:26])[CH2:7][C:2]([F:1])([F:25])[C@:3]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])([CH3:17])[NH:4][C:5]1=[O:9]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)N1C(=O)C(F)CC(F)(F)[C@@]1(C)c1ccccc1F
Agent: [Li+]
Solvent: CI
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(F)CC(F)(F)[C@@](C)(c2ccccc2F)NC1=O
Temperature: -78 °C
Reaction time: 8 h
Yield: 187.8 %

Procedure:
(2R)-Tert-butyl 3,3,5-trifluoro-2-(2-fluorophenyl)-2-methyl-6-oxopiperidine-1-carboxylate (1.30 g, 3.60 mmol) (1:1 mixture of diastereomers) was dissolved in tetrahydrofuran (36 mL) (dried over 4 Å MS) and added to a dry round bottom flask. The solution was cooled to −78° C. using a dry ice/acetone bath. LiHMDS (lithium hexamethyldisilazide) (4.50 mL, 4.50 mmol, 1.0 M in tetrahydrofuran) was added in a dropwise manner and the resulting solution was stirred at stirred at −78° C. for 1 h. Methyl iodide (2.55 g, 1.13 mL, 18 mmol) was added in a dropwise manner and the solution was stirred at −78° C. for 45 min then the cooling was removed and the solution was stirred for another 15 min at room temperature. The solution was re-cooled to −78° C. and quenched with saturated aqueous NH4Cl (25 mL). The cooling bath was removed and the reaction was allowed to warm to room temperature. The two reaction mixtures were combined and ethyl acetate (200 mL) and water (50 mL) were added. The phases were separated and the aqueous layer was extracted with ethyl acetate (2×100 mL). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. All of the thus obtained material was dissolved in 1,2-dichloroethane (85 ml) and the solution was cooled to 0° C. using an ice/water bath. TFA (21 ml, 273 mmol) was added and the cooling bath was allowed to slowly expire overnight, with stirring of the reaction mixture. The reaction was diluted with toluene (50 mL) and concentrated to approximately 25 ml-under vacuum. The residue was diluted with ethyl acetate (150 mL) and washed with saturated aqueous NaHCO3 (50 mL). The phases were separated and the aqueous layer was extracted with ethyl acetate (2×75 mL). The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified using a CombiFlash system (80 g SiO2, gradient elution; heptanes:ethyl acetate 100:0→50:50) to afford (6R)-3,5,5-trifluoro-6-(2-fluorophenyl)-3,6-dimethylpiperidin-2-one (1.86 g, 6.76 mmol, 94% yield) (1:1.8 mixture of diastereomers) LC-MS (m/z) 276.2 (MH+) tR=0.62 minutes (Method B).
Reaction SMILES: C[O:2][C:3]([C:5]1([CH:13]=[N:14][O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6]1)=[O:4].O.[OH-].[Li+].Cl>C1COCC1.O>[CH2:16]([O:15][N:14]=[CH:13][C:5]1([C:3]([OH:4])=[O:2])[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCCCC1CC(C=NOCc2ccccc2)(C(=O)OC)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCC1CC(C=NOCc2ccccc2)(C(=O)O)C1
Temperature: 90 °C

Procedure:
A mixture of 1-(benzyloxyimino-methyl)-3-butyl-cyclobutanecarboxylic acid methyl ester (7.23 g, 23.8 mmol) and lithium hydroxide monohydrate (10 g, 238 mmol) in THF (100 mL) and water (50 mL) was heated at 90° C. for 18 h. The reaction mixture was acidified to pH 3 with 6N aqueous HCl and was extracted with dichloromethane (75 mL×6). The combined organic layers were dried (MgSO4) and were evaporated in vacuo to yield the title compound as a pale yellow oil. (6.33 g, 92%). MH+290.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8]([O:11][CH3:12])([O:9][CH3:10])[CH2:7][CH2:6][NH:5][CH2:4]1.C(Cl)Cl.Cl[C:17]([O:19][CH2:20][CH3:21])=[O:18].C(N(CC)CC)C>>[CH3:1][O:2][CH:3]1[C:8]([O:11][CH3:12])([O:9][CH3:10])[CH2:7][CH2:6][N:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:4]1
Reactant: CCOC(=O)Cl
Reactant: COC1CNCCC1(OC)OC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCC(OC)(OC)C(OC)C1
Reaction time: 8 h

Procedure:
The title compound was prepared by taking 3,4,4-trimethoxypiperidine (150 mg, 0.00086 mol) in Methylene chloride (10 mL, 0.2 mol) and adding Ethyl chloroformate (0.098 mL, 0.0010 mol) and Triethylamine (0.24 mL, 0.0017 mol). The reaction was stirred overnight and then quenched with NaHCO3. The crude was obtained by evaporating the organic layer and was taken to the next step as-is (210 mg, 99%). MS calculated for C11H21NO5: (M+H) 248; found 248.1.
Reaction SMILES: [ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][C:14]([O:16][CH3:17])=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=3)[C:12]2=[O:29])=[CH:7][CH:6]=1)(=[NH:4])[NH2:3].[CH:30]1(O)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>C(Cl)Cl>[ClH:1].[C:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][C:14]([O:16][CH3:17])=[C:13]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([O:28][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]4)=[O:27])=[CH:20][CH:19]=3)[C:12]2=[O:29])=[CH:7][CH:6]=1)(=[NH:3])[NH2:4]
Reactant: OC1CCCCC1
Reactant: COC1=C(c2ccc(CCC(=O)O)cc2)C(=O)N(c2ccc(C(=N)N)cc2)C1
Agent: Cl
Solvent: ClCCl
Product: COC1=C(c2ccc(CCC(=O)OC3CCCCC3)cc2)C(=O)N(c2ccc(C(=N)N)cc2)C1
Temperature: 40 °C

Procedure:
Prepared by passing dry hydrogen chloride through a solution of 1-(4-amidinophenyl)-3-[4-(2-carboxy-ethyl)phenyl]-4-methoxy-3-pyrrolin-2-one and an excess of cyclohexanol in methylene chloride for one hour and subsequently heating to 40° C. for one hour.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:7][CH2:8][CH2:9][C:10]3[CH:16]=[C:15]([C:17]4[N:18]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=5[F:29])[N:19]=[CH:20][N:21]=4)[S:14][C:11]=3[C:12]=2[N:13]=1)#[N:2].OO.C(=O)([O-])[O-:33].[K+].[K+]>O.CS(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:7][CH2:8][CH2:9][C:10]3[CH:16]=[C:15]([C:17]4[N:18]([C:22]5[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:23]=5[F:29])[N:19]=[CH:20][N:21]=4)[S:14][C:11]=3[C:12]=2[N:13]=1)(=[O:33])[NH2:2]
Reactant: O=C([O-])[O-]
Reactant: N#Cc1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Agent: OO
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: NC(=O)c1ccc2c(n1)-c1sc(-c3ncnn3-c3ccc(F)cc3F)cc1CCO2
Yield: 38 %

Procedure:
Following the procedure to prepare 379, compound 366, hydrogen peroxide, potassium carbonate in water and DMSO were reacted to give 432. Yield 38% MS: (ESI+)=426.1
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:4]=1[CH2:5][C:6]1[CH2:10][CH:9]=[CH:8][CH:7]=1.C([Li:25])CCC>CCCCCC>[F:1][C:2]([F:19])([F:20])[C:3]1[CH:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:12]=[CH:11][C:4]=1[CH2:5][C:6]1([Li:25])[CH:10]=[CH:9][CH:8]=[CH:7]1
Reactant: [Li]CCCC
Reactant: FC(F)(F)c1ccc(CC2=CC=CC2)c(C(F)(F)F)c1
Solvent: CCCCCC
Product: [Li]C1(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)C=CC=C1
Yield: 85 %

Procedure:
3.5 g of 2,4-bistrifluoromethylbenzylcyclopentadiene and 30 ml of hexane are charged, in an argon atmosphere, into a tailed test-tube equipped with magnetic stirring. 6 ml of a 2.5 M solution of butyllithium in hexane are then added. There is an immediate reaction with the development of heat and the formation of a yellow precipitate which is washed several times with hexane by decanting and finally dried. 3.0 g of the desired salt are obtained with a yield of 85%.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:13][O:14][CH3:15])[CH:12]=1)[C:6]([O:8]C)=[O:7])#[N:2].[OH-].[Li+]>O1CCCC1>[C:1]([C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([CH2:13][O:14][CH3:15])[CH:12]=1)[C:6]([OH:8])=[O:7])#[N:2]
Reactant: COCc1cc(C#N)cc(C(=O)OC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COCc1cc(C#N)cc(C(=O)O)c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 101.1 %

Procedure:
A solution of methyl 3-cyano-5-(methoxymethyl)benzoate (184 mg, 0.75 mmol) in tetrahydrofuran (2.1 mL) was treated with 0.5 N lithium hydroxide (1.8 mL, 0.90 mmol). The reaction was stirred at 70° C. for 30 minutes and then after cooling the solvent was removed in vacuo. The residue was dissolved in a small amount of water and then acidified with 2 N hydrogen chloride until pH˜2–3. Following extraction of the aqueous layer with ethyl acetate, the organic layer washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford 145 mg (quantitative) of 3-cyano-5-(methoxymethyl)benzoic acid.
Reaction SMILES: [OH:1][CH:2]([CH:6]([S:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([OH:5])=[O:4].[C:33]1([C:39]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[N+]=[N-])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1(C)C=CC=CC=1>[OH:1][CH:2]([CH:6]([S:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]([O:5][CH:39]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:4]
Reactant: O=C(O)CCSC(c1ccccc1CCCCCCCCc1ccccc1)C(O)C(=O)O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(O)CCSC(c1ccccc1CCCCCCCCc1ccccc1)C(O)C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 45 °C

Procedure:
A partially dissolved mixture of 2-hydroxy-3-[(2-carboxyethyl)thio]-3-[2-(8-phenyloctyl)phenyl]propanoic acid prepared as in Example 20(c) (2.3 g, 5 mmol) in 25 ml of toluene was heated in an oil bath at 45° C. and stirred under argon while a solution of diphenyldiazomethane (1.02 g, 5.26 mmol) in 25 ml of toluene was added dropwise over a period of 20 minutes. The solvent was evaporated and the residue was flash chromatographed on silica gel (30% EtOAc/hexane, 1% HCO2H) to give the product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH:18]([C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1)=[CH2:19]>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:19][CH2:18][C:20]3[CH:21]=[N:22][CH:23]=[N:24][CH:25]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1cncnc1
Agent: [K+]
Agent: [OH-]
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2cncnc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.5 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.15 g, 0.68 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.19 g, 3.4 mmol) and allowed to stir for 10 min at RT. 5-vinyl pyrimidine (0.177 g, 1.7 mmol) was added and stirred for further 5 h at 60 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.030 g, 14% yield). 8-Chloro-2-methyl-5-(2-pyrimidin-5-yl-ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.025 g, 0.076 mmol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.0096 g, 0.076 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.025 g, 78% yield).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[C:8]([CH3:11])[C:7]([OH:12])=[CH:6][C:3]=1[CH:4]=[O:5].[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[OH:1][C:2]1[C:9]([CH3:10])=[C:8]([CH3:11])[C:7]([O:12][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Cc1c(O)cc(C=O)c(O)c1C
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Product: Cc1c(OC2CCCCO2)cc(C=O)c(O)c1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.8 %

Procedure:
2,5-Dihydroxy-3,4-dimethyl-benzaldehyde (2.0 g) was dissolved in dichloromethane (50 mL) and 3,4-dihydro-2H-pyran (1.5 g) was added followed by addition of p-toluenesulfonic acid monohydrate (200 mg). The solution was stirred at room temperature for 1 hour and quenched by adding sodium bicarbonate solution (1 mL). Then the dichloromethane solution was dried over MgSO4 and concentrated. The residue was purified by silica gel column eluting with hexane and ethyl acetate (8:2) to give 1.5 g of 2-hydroxy-3,4-dimethyl-5-(tetrahydro-pyran-2-yloxy)-benzaldehyde product.
Reaction SMILES: [CH3:1][C:2]([NH:7][C:8]([C:10]1[CH:34]=[CH:33][C:13]2[N:14]([CH3:32])[C:15]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:31])([F:30])[F:29])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9])([CH3:6])[C:3]([OH:5])=O.[CH3:35][NH:36][CH3:37].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:35][N:36]([CH3:37])[C:3]([C:2]([NH:7][C:8]([C:10]1[CH:34]=[CH:33][C:13]2[N:14]([CH3:32])[C:15]([NH:17][C:18]3[S:19][C:20]4[CH:26]=[C:25]([O:27][C:28]([F:29])([F:31])[F:30])[CH:24]=[CH:23][C:21]=4[N:22]=3)=[N:16][C:12]=2[CH:11]=1)=[O:9])([CH3:6])[CH3:1])=[O:5]
Reactant: CNC
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)NC(C)(C)C(=O)O)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)C(C)(C)NC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Temperature: 0 °C

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (1-dimethylcarbamoyl-1-methyl-ethyl)-amide (47 mg) was prepared by following General Procedure F using 2-methyl-2-{[1-methyl-2-(6-trifluoromethoxy-benzo-thiazol-2-ylamino)-1H-benzimidazole-5-carbonyl]-amino}-propionic acid (49 mg), dimethyl amine (0.3 ml, 1.0 M solution in THF), HBTU (38 mg), and DIEA (0.1 ml), with a minor modification of General Procedure F where DIEA was slowly added to the reaction mixture at last while stirring at 0° C. LC/MS: m/z 522. 1H NMR (DMSO-d6, 400 MHz): δ 8.54 (s, 1H), 8.09 (s, 1H), 7.92 (s, 1H), 7.78 (d, 1H), 7.64 (br, 1H), 7.47 (d, 1H), 7.36 (d, 1H), 3.67 (s, 3H), 2.87 (d, 6H), and 1.49 (s, 6H), —NH proton signals was not observed.
Reaction SMILES: C([Li])CCC.[CH2:6]([C:8]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1)([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[C:13]([CH3:19])[CH:12]=1)[CH2:9][CH3:10])[CH3:7].[C:28]1(=[O:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.[Cl-].[NH4+]>O1CCCC1>[CH2:6]([C:8]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[C:18][C:28]2([OH:35])[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[C:13]([CH3:19])[CH:12]=1)([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[C:22]([CH3:27])[CH:21]=1)[CH2:9][CH3:10])[CH3:7]
Reactant: O=C1CCCCCC1
Reactant: C#Cc1ccc(C(CC)(CC)c2ccc(O)c(C)c2)cc1C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc(C#CC2(O)CCCCCC2)c(C)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.9 %

Procedure:
n-Butyllithium (1.59 M solution in hexane, 5.4 mL, 8.59 mmol) was added to a solution of 4-[1-ethyl-1-(4-ethynyl-3-methyl-phenyl)-propyl]-2-methyl-phenol (Example 1-(3); 1.00 g, 3.42 mmol) in tetrahydrofuran (15 mL) in a nitrogen atmosphere at 0° C., and the mixture was stirred for 15 minutes. Then, cycloheptanone (0.81 mL, 6.87 mmol) was added to the reaction mixture, which was stirred at 0° C. for one hour, heated to room temperature and further stirred for one hour. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=90:10 to 50:50) to give the target compound as a colorless oil (829 mg, 60%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Li])CCC.[CH3:17][Si:18](Cl)([CH3:20])[CH3:19]>CCCCCC.O1CCCC1>[CH3:17][Si:18]([CH3:20])([CH3:19])[CH:6]1[C:5]2[N:4]=[CH:3][C:2]([CH3:1])=[CH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cnc2c(c1)CCCC2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cnc2c(c1)CCCC2[Si](C)(C)C
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A mixture of 5,6,7,8-tetrahydro-3-methylquinoline (29.4 g, 0.2 M) and tetrahydrofuran (THF) (50 ml) was added to a mixture of a 1.55 molar solution of butyl lithium in hexane (129 ml, 0.2 M) and THF (50 ml), maintained below 10°. After 0.5 hour the mixture was blown over by inert gas onto a mixture of trimethylsilyl chloride (50 ml, 0.4 M) in the THF (100 ml), maintained below 10°. After 0.5 hour, the mixture was evaporated and the residue extracted with hexane. The hexane extracts were evaporated with the residue distilled to give the title compound (40 g, 91%) b.p. 118°-124°/5 mbar. (Found: C70.9; H,9.65; N,6.4% C13H21NSi requires: C,71.2; H,9.6; N6.4%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]([CH3:21])([CH3:20])[CH2:9][C:10]1[C:18]2[C:13](=[C:14]([OH:19])[CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31](Cl)=[N:30][CH:29]=1.O>CN(C)C=O>[CH3:25][O:26][C:27](=[O:35])[C:28]1[CH:33]=[CH:32][C:31]([O:19][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]3[C:13]=2[NH:12][CH:11]=[C:10]3[CH2:9][C:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:22])([CH3:21])[CH3:20])=[N:30][CH:29]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CC(C)(Cc1c[nH]c2c(O)cccc12)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(Oc2cccc3c(CC(C)(C)NC(=O)OC(C)(C)C)c[nH]c23)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.9 %

Procedure:
To a solution of [2-(7-hydroxy-1H-indol-3-yl)-1,1-dimethyl-ethyl]-carbamic acid tert-butyl ester (104 mg, 0.342 mmol) in dimethylformamide (10 mL) is added sodium hydride (10 mg, 0.410 mmol). The mixture is stirred at ambient temperature for 30 minutes under nitrogen. 6-Chloro-nicotinic acid methyl ester (99 mg, 0.581 mmol) is added and the mixture is heated in an oil bath to eighty degrees Celsius for 15 hours, under nitrogen. The mixture is then heated an additional 5 hours at eighty-five degrees Celsius. Water (100 ml) is added to quench the reaction and the mixture is extracted three times with 50 mL of ethyl acetate. The organic layers are combined and washed twice with 50 mL of 1.00 N sodium hydroxide. The organic layer is dried with sodium sulfate, filtered and the solvent evaporated. The residue is dissolved in dichloromethane and purified using silica gel chromatography (6% 2M ammonia in methanol, 94% dichloromethane used as mobile phase) to give 87 mg (58%) of 6-[3-(2-tert-butoxycarbonylamino-2-methyl-propyl)-1H-indol-7-yloxy]-nicotinic acid methyl ester. FDMS m/e=440 (M++1).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:6](=[S:13])[NH:5][C:4](=[O:14])[C:3]=1[N:15]=O.N.O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>C(O)(=O)C>[NH2:15][C:3]1[C:4](=[O:14])[NH:5][C:6](=[S:13])[N:7]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:2]=1[NH2:1]
Reactant: CCCCCn1c(N)c(N=O)c(=O)[nH]c1=S
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCCCn1c(N)c(N)c(=O)[nH]c1=S
Temperature: 75 °C
Reaction time: 0.08 h
Yield: 74.7 %

Procedure:
To a mixture of 6-amino-1-pentyl-5-nitroso-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (6.4 g, 0.0264 mol), aqueous ammonia (60 mL, 0.60 mol) and water (60 mL) at 75° C. was added sodium dithionite (9.0 g, 0.050 mol) in small portions. After the addition was complete, the color of the solution changed from red to pale yellow. After stirring at 75° C. for another 5 mins, a precipitate was formed. Stirring was continued at room temperature for 1.5 h. The solution was then neutralized with 10% acetic acid (150 mL). The solid was filtered and washed with water to yield the product (4.5 g, 86.1%). LCMS calculated for C9H17N4OS: (M+H) 229.1; found 229.1.