Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:23]=[C:22](Br)[CH:21]=[CH:20][C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[Li]CCCC.[Mg+2].[Br-].[Br-].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([C:48]([C:50]2[C:51]3[CH:61]=[CH:60][C:59]([O:62][CH2:63][C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)=[CH:58][C:52]=3[S:53][C:54]=2N(C)C)=[O:49])[CH:38]=[CH:39][C:40]=1[CH2:41][N:42]1[CH2:47][CH2:46]O[CH2:44][CH2:43]1>C1COCC1>[CH3:33][O:34][C:35]1[CH:36]=[C:37]([C:48]([C:50]2[C:51]3[CH:61]=[CH:60][C:59]([O:62][CH2:63][C:64]4[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=4)=[CH:58][C:52]=3[S:53][C:54]=2[C:22]2[CH:21]=[CH:20][C:11]([O:12][CH2:13][CH2:14][N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[C:10]([CH2:9][O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH:23]=2)=[O:49])[CH:38]=[CH:39][C:40]=1[CH2:41][N:42]1[CH2:43][CH2:44][CH2:46][CH2:47]1
Reactant: COc1cc(C(=O)c2c(N(C)C)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCOCC1
Reactant: CC(C)(C)[Si](C)(C)OCc1cc(Br)ccc1OCCN1CCCC1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Mg+2]
Solvent: C1CCOC1
Product: COc1cc(C(=O)c2c(-c3ccc(OCCN4CCCC4)c(CO[Si](C)(C)C(C)(C)C)c3)sc3cc(OCc4ccccc4)ccc23)ccc1CN1CCCC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 11.1 %

Procedure:
To a solution of (142 mg, 0.343 mmol) 1-[2-(2-t-butyldimethylsilyloxymethyl-4-bromophenoxy)ethyl]pyrrolidine (Part B) in 15 mL of freshly distilled THF cooled to −78° C. was added 0.24 mL of n-BuLi. The solution was stirred at −78° C. for 1 h 20 min. To the solution was added 1.0 mL of freshly prepared MgBr2 (prepared by reacting 54 mL of dibromoethane with 13 mg of etched magnesium ribbon in 1.0 mL of THF) via cannula at −78° C. and stirred for 10 min. The ice bath was removed and the solution was stirred at room temperature for 30 min. The Grignard reagent was then added dropwise via a cannula to (177 mg, 0.343 mmol) 6-benzyloxy-2-(dimethylamino)benzo[b]thiophen-3-yl 3-methoxy-4-[(4-morpholinyl)methyl]phenyl ketone (Example 49, Part C) dissolved in 1.0 mL of THF at room temperature. The reaction was stirred for 5.5 h. The reaction was quenched by adding 4 mL of satd. NH4Cl solution. The mixture was then extracted with EtOAc (2×40 mL). The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. Purification by flash chromatography (silica gel, 46:46:8 CHCl3-Hexanes-2 M NH3 in MeOH) afforded 30.8 mg (0.0381 mmol, 11%) of a yellow foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13](=[O:17])[CH:14]=[N+]=[N-])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([OH:21])(=[O:20])[CH3:19]>>[C:18]([O:21][CH2:14][C:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:17])(=[O:20])[CH3:19]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)C=[N+]=[N-]
Reactant: CC(=O)O
Product: CC(=O)OCC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 100 °C

Procedure:
(S)-1-(tert-Butoxycarbonyl)-2-(diazoacetyl)pyrrolidine (16.2 g) was dissolved in acetic acid and the mixture was heated at 100° C. for 10 minutes. The reaction mixture was allowed to cool and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with an aqueous solution of sodium bicarbonate and water in order, dried over anhydrous sodium sulfate, and concentrated to give the title compound (8.9 g).
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH2:23](Br)[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: BrCCc1ccccc1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCCN(CCc2ccccc2)C1

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)piperidine (0.3 g), phenethyl bromide (0.2 g), anhydrous potassium carbonate (0.3 g) and acetonitrile (10 ml) was heated under reflux for 7 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a colourless solid which was recrystallised from aqueous ethanol to give the title compound, yield, 0.17 g, m.p. 175°-1780° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1([C:12]([F:29])([F:28])[C:13]2[N:18]=[CH:17][C:16]([O:19][C:20]3[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=3)=[CH:15][CH:14]=2)[CH2:11][O:10]1.[N-:30]=[N+:31]=[N-:32].[Na+].C([O-])(O)=O.[Na+]>CN(C=O)C>[N:30]([CH2:11][C:9]([C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])([OH:10])[C:12]([C:13]1[N:18]=[CH:17][C:16]([O:19][C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)=[CH:15][CH:14]=1)([F:29])[F:28])=[N+:31]=[N-:32]
Reactant: N#Cc1ccc(Oc2ccc(C(F)(F)C3(c4ccc(F)cc4F)CO3)nc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(C(F)(F)C(O)(CN=[N+]=[N-])c3ccc(F)cc3F)nc2)cc1
Yield: 86.5 %

Procedure:
A solution of 4-((6-((2-(2,4-difluorophenyl)oxiran-2-yl)difluoromethyl)pyridin-3-yl)oxy)benzonitrile (3.5 g, 8.74 mmol) and sodium azide (1.705 g, 26.2 mmol) in DMF (43.7 mL) was heated at 50° C. for 17 h. The reaction was poured into sat. aq. NaHCO3, and the mixture was extracted with Et2O (3×). The combined organic phases were washed with brine, dried (MgSO4) and concentrated to give the title compound as a brown oil (3.353 g, 69%).
Reaction SMILES: COC1C=CC(C[NH:8][C:9]2[C:14]([C:15]3[N:16]=[C:17]4[N:21]([CH:22]=3)[C:20]([CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:19][S:18]4)=[CH:13][CH:12]=[CH:11][N:10]=2)=CC=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[N:24]1([CH2:23][C:20]2[N:21]3[CH:22]=[C:15]([C:14]4[C:9]([NH2:8])=[N:10][CH:11]=[CH:12][CH:13]=4)[N:16]=[C:17]3[S:18][CH:19]=2)[CH2:25][CH2:26][O:27][CH2:28][CH2:29]1
Reactant: COc1ccc(CNc2ncccc2-c2cn3c(CN4CCOCC4)csc3n2)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Nc1ncccc1-c1cn2c(CN3CCOCC3)csc2n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(4-Methoxy-benzyl)-[3-(3-morpholin-4-ylmethyl-imidazo[2,1-b]thiazol-6-yl)-pyridin-2-yl]-amine (100 mg, 0.23 mmol) was mixed with 2 mL of CH2Cl2 along with triethylsilane (0.11 mL, 2 eq). Trifluoroacetic acid (1 mL) was added and the reaction mixture was stirred at room temperature for 18 hours. The following day, the reaction mixture was concentrated. The resulting residue was triturated with Et2O to afford essentially quantitative yield of 3-(3-morpholin-4-ylmethyl-imidazo[2,1-b]thiazol-6-yl)-pyridin-2-ylamine as the TFA salt.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][CH:6]=1.[F:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.ClCCl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:10][O:9][C:7]([C:4]1[S:3][C:2]([C:15]2[CH:16]=[CH:17][C:12]([F:11])=[CH:13][CH:14]=2)=[CH:6][CH:5]=1)=[O:8]
Reactant: OB(O)c1ccc(F)cc1
Reactant: COC(=O)c1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccc(F)cc2)s1
Temperature: 80 °C
Reaction time: 6 h
Yield: 97.8 %

Procedure:
To a suspension of 2-bromo-5-methoxycarbonylthiophene (1.11 g), 4-fluorophenylboronic acid (0.91 g) and tetrakis(triphenylphosphine)palladium (289 mg) in 1,2-dimethoxyethane (10 ml) was added aqueous solution of sodium carbonate (2M, 6.5 ml) followed by stirring at 80° C. for 6 hours. The mixture was diluted with dichloromethane and washed with water and brine. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by a silica gel column chromatography eluting with 30% dichloromethane in n-hexane to give 2-methoxycarbonyl-5-(4-fluorophenyl)thiophene (1.16 g, 98.3%).
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[N:7](C(OC(C)(C)C)=O)[C:8]2[C:13]([CH:14]=1)=[C:12]([OH:15])[CH:11]=[CH:10][CH:9]=2)=[O:5].[Cl:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26](Cl)[N:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([O:15][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([Cl:23])[N:25]=1)[CH:11]=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: Clc1cccc(Cl)n1
Reactant: CCOC(=O)c1cc2c(O)cccc2n1C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc2c(Oc3cccc(Cl)n3)cccc2[nH]1
Temperature: 160 °C

Procedure:
159 (500 mg, 1.6 mmol), 2,6-Dichloro-pyridine (360 mg, 24 mmol) are dissolved in 15 ml of dimethylformamide. After addition of potassium carbonate (340 mg, 24 mmol) and a catalytic amount Cu-powder the mixture is heated to 160° C. for 3 hours. The reaction mixture is cooled to room temperature, diluted with ethyl acetate and washed with water. The organic layers are dried over sodium sulphate and evaporated. The crude product is solved in dichloromethane and after evaporation crystallized with cyclohexane.
Reaction SMILES: CO[C:3](=[O:18])[CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[CH3:19][O:20][CH2:21][CH2:22][NH2:23]>C(O)C>[CH3:19][O:20][CH2:21][CH2:22][NH:23][C:3](=[O:18])[CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: COCCN
Reactant: COC(=O)CCCNC(=O)OCc1ccccc1
Solvent: CCO
Product: COCCNC(=O)CCCNC(=O)OCc1ccccc1

Procedure:
5.02 g of 4-benzyloxycarbonylaminobutyric acid methyl ester are stirred under reflux in 35 ml of ethanol with 15 ml of 2-methoxyethylamine for 5 days. The reaction mixture is concentrated by evaporation and the residue is purified by means of FC (240 g of silica gel, dichloromethane/methanol=95:5). The title compound is obtained: Rf (dichloromethane/methanol=95:5)=0.33.
Reaction SMILES: C(OC([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:10][C@H:9]1[CH3:19])=O)(C)(C)C.Cl>ClCCl.C(OCC)C>[CH3:19][C@@H:9]1[CH2:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:12][NH:8]1
Reactant: C[C@@H]1C[C@@H](c2ccccc2)CN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: C[C@@H]1C[C@@H](c2ccccc2)CN1
Temperature: 25 °C
Reaction time: 16 h
Yield: 101.4 %

Procedure:
1.68 g of (2R,4S)-2-Methyl-4-phenyl-pyrrolidine-1-carboxylic acid tert-butyl ester (6.42 mmol) were dissolved in 40 ml dichloromethane and 19.2 ml (38.56 mmol) 2N HCl in diethylether dropwise added. After stirring at room temperature for 16 h, the solvents were evaporated, the residue was dissolved in water, the pH was adjusted to pH 9 with aqueous sodium hydroxide, and the aqueous phase was extracted three times with ethyl acetate. The organic phases were combined, dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure to yield 1.05 g of product.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].C(N(CC)CC)C.[CH3:15][C:16]1([CH3:30])[C:20]([CH3:22])([CH3:21])[O:19][B:18]([C:23]2[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=2)[O:17]1>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:7])[S:3](=[O:5])(=[O:4])[NH:27][C:26]1[CH:25]=[CH:24][C:23]([B:18]2[O:19][C:20]([CH3:22])([CH3:21])[C:16]([CH3:30])([CH3:15])[O:17]2)=[CH:29][CH:28]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CN(C)S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C)S(=O)(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
Dimethylsulfamoyl chloride (492 mg) and triethylamine (0.95 mL) were added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (500 mg) in chloroform (5 mL), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:0→2:1) to give the title compound as a pale orange powder (427 mg).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([OH:21])=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:34][C:35]([CH3:39])([CH3:38])[CH2:36]O.O>CN(C)C=O>[C:1]1([C:7]2[O:8][C:9]3[C:17]([CH2:18][C:19]([O:21][CH2:34][C:35]([CH3:39])([CH3:38])[CH3:36])=[O:20])=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CC(C)(C)CO
Reactant: O=C(O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)COC(=O)Cc1cccc2c(=O)cc(C3=CCCCC3)oc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
[2-(1-Cyclohexenyl)-4-oxo-4H-[1]-benzopyran-8-yl]acetic acid (2.84 g) was dissolved in dimethylformamide (30 ml) and carbodiimidazole (1.78 g) was added to the solution. After stirring at room temperature for 2 hours, 2,2-dimethyl-propanol (0.88 g) was added. After stirring at 60° C. for 4 hours, water was added and the mixture was extracted with ethyl acetate. The extracted layer was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography to obtain the title compound (0.82 g), yield 23%, m.p. 138°-139° C. (recrystallized from hexane-ethyl acetate).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[CH3:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)=[N:4][N:3]=[N:2]1.[C:43](=O)(O)[O-].[Na+].S(OC)(OC)(=O)=O>CC(C)=O>[CH3:43][N:3]1[NH:2][N:1]=[C:5]([C:6]2[CH:7]=[C:8]([NH:12][C:13]([CH:15]3[CH:19]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:21]=4[CH3:27])[C:18]([C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[F:37])([C:28]#[N:29])[CH:17]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[NH:16]3)=[O:14])[CH:9]=[CH:10][CH:11]=2)[NH:4]1
Reactant: Cc1c(Cl)cccc1C1C(C(=O)Nc2cccc(-c3nnn[nH]3)c2)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: Cc1c(Cl)cccc1C1C(C(=O)Nc2cccc(C3=NNN(C)N3)c2)NC(CC(C)(C)C)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 24.3 %

Procedure:
To a stirred solution of rac (2R,3R,4R,5S)-4-(4-Chloro-2-fluoro-phenyl)-3-(3-chloro-2-methyl-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid [3-(1H-tetrazol-5-yl)-phenyl]-amide (44 mg, 0.172 mmol) in acetone (5 mL), sodium bicarbonate (84 mg, 1 mmol) and dimethyl sulfate (30 uL, 0.22 mmol) was added and the mixture was stirred at rt for 5 hrs. The solvent was removed and the residue was suspended in 3 mL of methylene chloride. The mixture was filtered and the filtrate was loaded on a silica gel column. Eluting with 35-70% EtOAc/Hexanes on an ISCO machine gave the desired product (26 mg) and the other regioisomer (12 mg).
Reaction SMILES: [Cl:1][C:2]1[NH:3][CH:4](Cl)[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1.Cl.[OH-:22].[Na+]>>[Cl:1][C:2]1[NH:3][C:4](=[O:22])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[CH:7]=[N:8][C:9]=2[N:10]=1
Reactant: [OH-]
Reactant: COc1ccc(Cn2cnc3c2C(Cl)NC(Cl)=N3)cc1
Agent: Cl
Agent: [Na+]
Product: COc1ccc(Cn2cnc3nc(Cl)[nH]c(=O)c32)cc1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
To the 2,6-dichloro-7-(4-methoxybenzyl)-6,7-dihydro-1H-purine 6 (10 g, 32.46 mmol) was added NaOH (1 M, 100 ml). The reaction was stirred at 90° C. for 90 minutes. The reaction mixture was cooled to room temperature and then was neutralized by HCl (2 M) to pH 7. The desired product was precipitated out and was collected by filtration. The solid was air dried and placed in oven over night at 80° C. to afford 2-chloro-7-(4-methoxybenzyl)-1H-purin-6(7H)-one 7.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:13])=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.[CH2:14]([C@H:16]1[O:18][CH2:17]1)[Cl:15]>CCO.O>[Cl:15][CH2:14][CH:16]([OH:18])[CH2:17][NH:1][C:2]1[C:3]([F:13])=[CH:4][C:5]2[S:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1
Reactant: ClC[C@@H]1CO1
Reactant: Nc1cc2c(cc1F)SCC(=O)N2
Solvent: O
Solvent: CCO
Product: O=C1CSc2cc(F)c(NCC(O)CCl)cc2N1
Yield: 57.1 %

Procedure:
A solution of 6-amino-7-fluoro-4H-benzo[1,4]thiazin-3-one (1 g, 5 mmol, Bioscience, Biotechnology, and Biochemistry 1994, 58, 788) and (S)-epichlorohydrin (0.467 g, 5 mmol) in EtOH/H2O (9:1, 20 mL) was heated at 80° C. for 3 d. The volatiles were removed under reduced pressure and the residue was crystallized from MeOH to give a brown solid (0.83 g, 57%).
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([NH2:23])[C:17]3[N:22]=[N:21][NH:20][C:18]=3[N:19]=2)=[N:6]1.[CH3:28]CN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.IC>CN(C)C=O>[F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[C:16]([NH2:23])[C:17]3[C:18](=[N:20][N:21]([CH3:28])[N:22]=3)[N:19]=2)=[N:6]1
Reactant: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Reactant: Nc1nc(-c2nn(Cc3ccccc3F)c3ncccc23)nc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1nc2nc(-c3nn(Cc4ccccc4F)c4ncccc34)nc(N)c2n1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
250 mg (0.692 mmol) of the compound from example 53 and 190 mg (0.692 mmol) of BEMP were initially charged in 12 ml of dimethylformamide, and a solution of 98 mg (0.692 mmol) of iodomethane in 3 ml of dimethylformamide was added dropwise at 0° C. within 10 min. The mixture was stirred at 0° C. for 20 min. Subsequently, the reaction solution was concentrated under reduced pressure and the residue was purified by means of preparative HPLC (eluent: methanol/aqueous 0.1% ammonia solution=65:35). The residue was stirred with acetonitrile and filtered with suction, and the solids were dried under high vacuum. 50 mg (19% of theory) of the title compound and 78 mg (30% of theory) of example 54 were obtained.
Reaction SMILES: [CH:1]([C:4]1[CH2:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].N1C[CH2:12][CH2:11][CH2:10]1>CC(C)=O>[CH:1]([C:4]1[CH:8]=[CH:7][C:6](=[C:11]([CH3:12])[CH3:10])[CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)C1=CC=CC1
Reactant: C1CCNC1
Solvent: CC(C)=O
Product: CC(C)=C1C=CC(C(C)C)=C1

Procedure:
Therefore, 1,3-diisopropylcyclopentadiene was selected as the starting point for the synthesis. Unfortunately, the reported syntheses of 1,3-diisopropylcyclopentadiene gave low yields since the final step was always separation of the 1,3 product from the 1,2 product. A more selective method was found by extension of work by Nile in which he prepared a number of 1,3 disubstituted cyclopentadienes using a fulvene route. Using this method, reaction of isopropylcyclopentadiene with acetone catalyzed by pyrrolidine gave the 3-isopropyl-6,6-dimethylfulvene. Subsequent reduction of the fulvene with LAH and hydrolysis provided 1,3-diisopropylcyclopentadiene, "iPr2Cp." ##STR10##
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH3:21])([CH3:20])[C:17](=[O:22])[CH:16]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C(=O)N([Br:30])C(=O)C1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:19][C:18]([CH3:20])([CH3:21])[C:17](=[O:22])[C:16]=2[Br:30])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(c2ccc(OCc3ccccc3)cc2)=CC1=O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(c2ccc(OCc3ccccc3)cc2)=C(Br)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 107.2 %

Procedure:
To a room temperature solution of 5-(4-(benzyloxy)phenyl)-2,2-dimethylfuran-3(2H)-one (1.5 g, 0.005 mol) in CHCl3 (50 mL), NBS (1.37 g, 0.007 mol) was added portionwise. The reaction mixture was stirred for 2 h at RT and then concentrated in vacuo to obtain the crude product. The residue was partitioned between water and DCM. The organic layer was separated, washed with water, dried over Na2SO4, and concentrated in vacuo to afford 5-(4-(benzyloxy)phenyl)-4-bromo-2,2-dimethylfuran-3(2H)-one (2.0 g) as a solid. This material was used in the next step without further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][N:27]([CH2:29][CH:30]=O)[CH:28]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.CC(O)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1>[CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[N:25]=[CH:26][N:27]([CH2:29][CH2:30][N:37]6[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]6)[CH:28]=5)[S:23][C:16]=34)=[C:10]([F:32])[CH:9]=2)=[O:6])[CH2:2][CH2:3]1
Reactant: CN1CCNCC1
Reactant: O=CCn1cnc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CC(=O)O
Product: CN1CCN(CCn2cnc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)c2)CC1
Temperature: 25 °C
Reaction time: 60 h
Yield: 50 %

Procedure:
To a solution of 264 (300 mg, 0.66 mmol), N-methylpiperazine (74 μl, 0.66 mmol) and AcOH (76 μl, 1.33 mmol) in NMP (10 mL) was added sodium triacetoxyborohydride (422 mg, 1.99 mmol) and the reaction mixture was stirred for 2.5 days at RT. The reaction mixture was quenched with saturated sodium bicarbonate solution and extracted with DCM. The organic extract was successively washed with water and brine, dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by Biotage (SNAP 40 g cartridge; 2% of ammonium hydroxide in MeOH/DCM: 0/100 to 15/85 over 20 CV) and by Gilson (Phenomenex, Luna 15μ, C18(2) 100A, 250×50.0 mm, 15 μm; 0.05% of formic acid in both MeOH/water:20/80 to 95/5 over 60 min, flow; 30 mL/min) to afford the title compound 266 (180 mg, 0.33 mmol, 51% yield, di-formate salt) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Mg]Br.[C:21]([C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][CH:33]=1)[C:28](Cl)=[O:29])([O:23][CH3:24])=[O:22]>O1CCCC1.C(OCC)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[C:12]2[C:28](=[O:29])[C:27]1[CH:31]=[CH:32][CH:33]=[C:25]([C:21]([O:23][CH3:24])=[O:22])[CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Agent: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: COC(=O)c1cccc(C(=O)c2c[nH]c3ccc(OCc4ccccc4)cc23)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution 5-benzyloxyindole (2.23 g, 10 mmol) in 5 ml of tetrahydrofuran (THF), cooled in an external ice bath, is added dropwise with stirring 6.15 ml of a 2 molar solution of methyl magnesium bromide in diethyl ether. The resulting mixture is stirred for an additional 15 minutes in the ice bath and a solution of 3-carbmethoxybenzoyl chloride in 10 ml of THF is added dropwise. The cooling bath is removed and the reaction mixture is stirred at room temperature for 18 hours. Water is then added, followed by ethyl acetate. The layers are separated. The organic layer is dried (MgSO4) and concentrated in vacuo. The residue obtained is purified by a silica gel column, eluting with a solvent system of 25% ethyl acetate in hexane to give 5-benzyloxy-3-(3-carbomethoxybenzoyl)indole. NMR confirms this structure.