Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:4])(=O)[CH3:2].[Br:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1C=C[N:10]=[C:11]2Cl.C([O-])([O-])=O.[K+].[K+]>O>[Br:5][C:6]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:7]=1[CH:2]=[CH:1][N:4]=[C:11]2[NH2:10]
Reactant: Clc1nccc2c(Br)cccc12
Reactant: CC(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: Nc1nccc2c(Br)cccc12
Temperature: 25 °C

Procedure:
Acetamide (4.9 g, 82 mmol), 5-bromo-1-chloroisoquinoline (1.00 g, 4.1 mmol) and K2CO3 (2.8 g, 21 mmol) were combined in a sealed tube and the mixture heated at 200 C for 1.5 h. The mixture was allowed to cool to rt and the solid residue suspended in 400 mL water. The brown solid was collected as the title compound (750 mg). MS (ESI pos. ion) m/z: 223 (MH+). Calc'd exact mass for C9H7BrN2: 223.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([CH3:26])=[C:5]([C:10]2[NH:11][C:12](=[O:25])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:14]=2)[C:6]([CH3:9])=[CH:7][CH:8]=1.CN(C=O)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[O:54]1[CH2:58][CH2:57][CH2:56][C@@H:55]1[C:59](O)=[O:60]>C1COCC1>[CH3:26][C:4]1[C:5]([C:10]2[NH:11][C:12](=[O:25])[N:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:17][CH:16]=3)[N:14]=2)=[C:6]([CH3:9])[CH:7]=[CH:8][C:3]=1[CH2:2][NH:1][C:59]([C@H:55]1[CH2:56][CH2:57][CH2:58][O:54]1)=[O:60]
Reactant: Cc1ccc(CN)c(C)c1-c1nn(-c2ccc(C(F)(F)F)cc2)c(=O)[nH]1
Reactant: O=C(O)[C@H]1CCCO1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Cc1ccc(CNC(=O)[C@H]2CCCO2)c(C)c1-c1nn(-c2ccc(C(F)(F)F)cc2)c(=O)[nH]1
Reaction time: 1 h
Yield: 26.8 %

Procedure:
To a solution of 5-(3-(aminomethyl)-2,6-dimethylphenyl)-2-(4-(trifluoromethyl)phenyl)-2H-1,2,4-triazol-3(4H)-one (Intermediate-66, 0.050 g, 0.138 mmol) in dry THF:DMF (4 mL:1 mL), TBTU (0.132 g, 0.414 mmol) and TEA (1.0 mL) were added and the reaction mass was stirred for 1 h under nitrogen atmosphere. To the reaction mass, (R)-(−)-tetrahydrofuran-2-carboxylic acid (0.024 g, 0.207 mmol) was added and stirred for 18 h at room temperature. After completion of the reaction, the reaction mass was quenched in water, extracted with ethyl acetate and concentrated to afford crude product which was purified by column chromatography by eluting with solution of 2% ammonia in 10% MeOH:DCM to afford 0.017 g of the title product. 1H NMR (400 MHz, DMSO d6): δ 1.79 (m, 3H), 1.87 (m, 3H), 2.20 (s, 6H), 3.74-3.79 (m, 1H), 3.88-3.92 (m, 1H), 4.25 (d, J=4.5 Hz, 2H), 7.16 (d, J=6.0 Hz, 1H), 7.25 (d, J=6.0 Hz, 1H), 7.82 (d, J=6.6 Hz, 1H), 8.17 (d, J=6.3 Hz, 2H), 8.24 (t, J=4.8 Hz, 2H), 12.30 (br s, 1H); MS (m/z): 461.14 (M+H)+.
Reaction SMILES: C([Li])CCC.[S:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH3:11][Sn:12](Cl)([CH3:14])[CH3:13].C(=O)(O)[O-].[Na+]>CCCCCC.CCOCC>[CH3:11][Sn:12]([CH3:14])([CH3:13])[C:7]1[S:6][CH:10]=[CH:9][N:8]=1
Reactant: C[Sn](C)(C)Cl
Reactant: c1cscn1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Sn](C)(C)c1nccs1
Temperature: -78 °C
Reaction time: 1 h
Yield: 71.7 %

Procedure:
To 99.99 ml of n-butyl lithium in hexane, dissolved in 200 ml of ether is added dropwise with stirring over 1 hour, at -78° C., a solution of 16 g of thiazole in 100 ml of ether over 1 hour. A solution of 49.81 g of trimethyltin chloride in 100 ml of ether is added dropwise over 20 minutes followed by additional stirring for 1 hour. The reaction mixture is poured into saturated sodium bicarbonate and the organic layer separated, dried and evaporated to a residue. The residue is vacuum distilled to give 33.4 g of the desired product as a colorless liquid, B.P. 60°-65° C./0.7 mm.
Reaction SMILES: [K].[C:2]1([OH:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[NH:15][C:14](=[O:16])[C:13]([F:17])=[CH:12][N:11]=1>C1(C)C=CC=CC=1>[O:8]([C:10]1[NH:15][C:14](=[O:16])[C:13]([F:17])=[CH:12][N:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccccc1
Reactant: O=c1[nH]c(Cl)ncc1F
Agent: [K]
Solvent: Cc1ccccc1
Product: O=c1[nH]c(Oc2ccccc2)ncc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
A 11.7 g quantity of metal potassium is added to 200 ml of absolute toluene, and a mixture of 28 g of phenol and 100 ml of absolute toluene is further added dropwise to dissolve the potassium. Subsequently 14.9 g of 2-chloro-5-fluoropyrimidin-4-one is added to the solution, and the mixture is stirred at 100° C for 8 hours. The reaction mixture is thereafter treated in the same manner as in Example 6 to give 13.2 g of white crystalline 2-phenoxy-5-fluoropyrimidin-4-one in a yield of 64.1%, m.p. 224°-225° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[NH2:13][CH:14]([CH2:22][CH3:23])[C:15]([O:17][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16]>>[CH2:18]([O:17][C:15](=[O:16])[CH:14]([NH:13][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)[CH2:22][CH3:23])[CH:19]([CH3:20])[CH3:21]
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: CCC(N)C(=O)OCC(C)C
Product: CCC(NC(=O)Cc1ccc(Cl)c(Cl)c1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 3,4-dichlorophenylacetic acid (Aldrich) and isobutyl 2-aminobutyrate (prepared following General Procedure BJ above) the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=O)[CH3:11].P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>>[Br:9][C:5]1[CH:6]=[C:7]2[NH:8][C:16]([C:15]3[CH:19]=[CH:20][CH:21]=[C:13]([O:12][CH2:10][CH3:11])[CH:14]=3)=[N:1][C:2]2=[N:3][CH:4]=1
Reactant: CCOc1cccc(C(=O)O)c1
Reactant: Nc1cc(Br)cnc1N
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1cccc(-c2nc3ncc(Br)cc3[nH]2)c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 51.2 %

Procedure:
A mixture of 2,3-diamino-5-bromopyridine (Compound of Reference Example 1) (1.13 g), 3-ethoxybenzoic acid (997 mg) and phosphorus oxychloride (24 ml) was stirred at 120° C. for 2 hours and poured onto ice. The mixture was neutralized with 8 N sodium hydroxide, stirred for 20 minutes and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water, dried over MgSO4. The solvent was distilled off under reduced pressure and the resulting crystals were collected by filtration to obtain 6-bromo-2-(3-ethoxyphenyl)-1H-imidazo[4,5-b]pyridine (978 mg, 51%).
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2.C([OH:24])C.C(O)(=O)C.[Br-].[Br-].[Br-].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>CC(O)(C)C.[Zn]>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH2:9][C:10](=[O:24])[NH:11]2
Reactant: CCO
Reactant: c1ccc(-c2ccccc2-c2cccc3[nH]ccc23)cc1
Agent: [Br-]
Agent: [Zn]
Agent: c1cc[nH+]cc1
Solvent: CC(=O)O
Solvent: CC(C)(C)O
Product: O=C1Cc2c(cccc2-c2ccccc2-c2ccccc2)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
To the suspension of 4-bipheny-2-yl-1H-indole (1.18 g, 4.4 mmol) in t-BuOH:ethanol:acetic acid (28 mL:17 mL:9 mL) was added pyridinium tribromide (4.39 g, 13.7 mmol) portionwise. The mixture was stirred at room temperature for 3 hours, and then to the mixture was added acetic acid (22 mL). Zinc dust (1.63 g, 25 mmol) was added to the reaction mixture portionwise. After stirring for one hour, any unreacted zinc was filtered off and most of the solvent was removed under reduced pressure. The residue was diluted with ethyl acetate, washed with water (3×), sat. NaHCO3, brine, dried over Na2SO4, concentrated and triturated with ether to give 0.93 g (74%) of 4-biphenyl-2-yl-1,3-dihydro-indol-2-one.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][NH:13]C(=O)C(C)(C)C)=[CH:6][CH:5]=1.Cl>CCO>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:5]=[CH:6][C:7]([O:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(OCCNC(=O)C(C)(C)C)cc1
Agent: Cl
Solvent: CCO
Product: COC(=O)c1ccc(OCCN)cc1
Temperature: 25 °C
Yield: 108.7 %

Procedure:
To a solution of 4-[2-(2,2-dimethyl-propionylamino)ethoxy]-benzoic acid methyl ester (350 mg) in EtOH (6 mL) at 0° C. was added concentrated HCl (3 mL). The solution was warmed to room temperature and was concentrated in vacuo to provide the hydrochloride salt of 4-(2-amino-ethoxy)-benzoic acid methyl ester (266 mg) as a white solid which was used in the next step without further purification.
Reaction SMILES: Cl.[CH:2]1([C:5]2[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=2)[CH2:4][CH2:3]1.[C:14]([C:16]([C:19]1[CH:20]=[C:21]([CH:37]=[CH:38][CH:39]=1)[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32](O)=[O:33])=[CH:29][CH:30]=2)[C:25]([CH3:35])=[C:24]1[CH3:36])([CH3:18])[CH3:17])#[N:15]>>[C:14]([C:16]([C:19]1[CH:20]=[C:21]([CH:37]=[CH:38][CH:39]=1)[CH2:22][N:23]1[C:31]2[C:26](=[CH:27][C:28]([C:32]([NH:13][C@H:11]([C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]4[CH2:4][CH2:3]4)[CH:6]=3)[CH3:12])=[O:33])=[CH:29][CH:30]=2)[C:25]([CH3:35])=[C:24]1[CH3:36])([CH3:18])[CH3:17])#[N:15]
Reactant: C[C@H](N)c1cccc(C2CC2)c1
Reactant: Cc1c(C)n(Cc2cccc(C(C)(C)C#N)c2)c2ccc(C(=O)O)cc12
Agent: Cl
Product: Cc1c(C)n(Cc2cccc(C(C)(C)C#N)c2)c2ccc(C(=O)N[C@@H](C)c3cccc(C4CC4)c3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 4, Example 1, using (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and 1-(3-(2-cyanopropan-2-yl)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 490 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:24]=[C:5]2[N:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:7](=[O:17])[C:8]3[CH:13]=[N:12][C:11]4[NH:14][N:15]=[CH:16][C:10]=4[C:9]=3[N:4]2[N:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>N1C=CC=CC=1>[C:25]([N:14]1[C:11]2[N:12]=[CH:13][C:8]3[C:7](=[O:17])[N:6]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:5]4[N:4]([N:3]=[C:2]([CH3:1])[CH:24]=4)[C:9]=3[C:10]=2[CH:16]=[N:15]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1cc2n(-c3ccccc3)c(=O)c3cnc4[nH]ncc4c3n2n1
Reactant: O=C(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1cc2n(-c3ccccc3)c(=O)c3cnc4c(cnn4C(=O)c4ccccc4)c3n2n1

Procedure:
0.01 mol. of 2-methyl-4-phenyl-4H-pyrazolo[1,5-a]-pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one and 0.02 mol. of benzoyl chloride are stirred overnight in 50 ml. of dry pyridine at room temperature. On addition of 50 ml. of water, 8-benzoyl-2-methyl-4-phenyl-4H-pyrazolo-[1,5-a]pyrazolo[4',3':5,6]pyrido[3,4-e]pyrimidin-5(8H)-one is filtered off.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][N:4]=1>[O-2].[O-2].[Mn+4].C(Cl)(Cl)Cl>[CH:2]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[CH:5][N:4]=1)=[O:1]
Reactant: OCc1ccc(CO)nc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ccc(CO)cn1
Reaction time: 0.5 h

Procedure:
2,5-Di(hydroxymethyl)pyridine (10 g.) in 300 ml. of hot chloroform is treated with 100 g of manganese dioxide. After 1/2 hour of stirring, the mixture is filtered and the filtrate is evaporated to dryness to give 2-formyl-5-hydroxymethylpyridine.
Reaction SMILES: [CH:1]1([CH2:7]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])(C)(C)C.[F:14][C:15]1[CH:16]=[CH:17][C:18]([O:33][CH3:34])=[C:19]([C:21]([CH3:32])([CH3:31])[CH2:22][C:23](N2CCOCC2)=[O:24])[CH:20]=1>C1COCC1>[CH:1]1([CH2:7][C:23](=[O:24])[CH2:22][C:21]([C:19]2[CH:20]=[C:15]([F:14])[CH:16]=[CH:17][C:18]=2[O:33][CH3:34])([CH3:32])[CH3:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)N1CCOCC1
Reactant: BrCC1CCCCC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(=O)CC1CCCCC1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
To a solution of cyclohexylmethyl bromide (0.26 g) in THF (1 mL) cooled to −70° C. under argon, tert-butyl lithium (1.7 M in pentane, 1.8 mL) was added dropwise over 5 minutes. The mixture was stirred at −70° C. for 30 minutes. A solution of 3-(5-fluoro-2-methoxyphenyl)-3-methyl-1-morpholin-4-ylbutan-1-one (0.33 g) in THF (1 mL) was added all at once and the mixture was stirred for one hour. The reaction temperature rose to approximately coming to −20° C. The reaction was quenched with EtOH (0.3 mL), and warmed to room temperature. The mixture was diluted with EtOAc, washed with water, dried, filtered, and evaporated. Chromatography of the residue over silica gel (eluent: hexanes-methylene chloride gradient) gave the title compound as an oil (0.2 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl.[F:13][C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[CH3:21].FC1C(C)=CC([CH:27]=[O:28])=CC=1C>Cl>[F:13][C:14]1[C:19]([CH3:20])=[C:18]([CH:17]=[CH:16][C:15]=1[CH3:21])[CH:27]=[O:28]
Reactant: Cc1cccc(C)c1F
Reactant: Cc1cc(C=O)cc(C)c1F
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Product: Cc1ccc(C=O)c(C)c1F
Temperature: 50 °C
Yield: 68.6 %

Procedure:
62.4 g of aluminum chloride (mol. Wt. 133.34; 468.0 mmol), 450.0 g of 1,2-dichlorobenzene (mol. Wt. 147.00; 3,061 mmol), and about 48.00 g of 2-fluoro-m-xylene (mol. Wt. 124.16; 386.6 mmol) were charged to a 2 liter Parr®-brand 4522 stainless steel reaction vessel. To this mixture was added 5 drops of concentrated HCl. The vessel was sealed, heated to 50° C., and purged three times with carbon monoxide with the pressure of the vessel increased to 100 psi for each purging. After the third purge, the vessel was vented and a final introduction of CO was made at a pressure of about 200 psi, the pressure at which the reaction was maintained for the total reaction time of about 16 hours (the reaction temperature was maintained at 50° C. for the duration as well). Once the reaction was complete, the resultant mixture (exhibiting a dark orange color) was poured into about 500 mL of ice water (which turned the solution a yellow color), to which was added 500 mL of cyclohexane. The top, organic layer was removed and washed three times with water using a separatory funnel and dried over magnesium sulfate. The residual organic phase was then distilled under vacuum to remove excess cyclohexane, 2-fluoro-m-xylene, 1,2-dichlorobenzene, and left about 40.39 g of a benzaldehyde mixture consisting of 4-fluoro-3,5-dimethylbenzaldehyde (73.8%) and 3-fluoro-2,4-dimethylbenzaldehyde (26.2%) (mol. Wt. 152.17; 265.4 mmol; yield of approximately 68.6%).
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[S:13]1[C:17]([C:18](O)=[O:19])=[CH:16][C:15]2[S:21][CH:22]=[CH:23][C:14]1=2.N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:18]([C:17]3[S:13][C:14]4[CH:23]=[CH:22][S:21][C:15]=4[CH:16]=3)=[O:19])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cc2sccc2s1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc2sccc2s1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and thieno[3,2-b]thiophene-2-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.37 (d, J=5.1 Hz, 1H), 7.71 (d, J=5.1 Hz, 1H), 8.12 (s, 1H). MS (DCI/NH3) m/z 319.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[CH:10][C:9]([C:12]3([CH3:17])OCC[O:13]3)=[CH:8][C:7]=2[C:18]2[C:19]3[NH:26][C:25]([CH3:27])=[C:24]([C:28]([NH:30][CH:31]4[CH2:36][CH2:35][N:34](C(OC(C)(C)C)=O)[CH2:33][CH2:32]4)=[O:29])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH2:3][CH2:2]1.[ClH:44]>CC(C)=O.O1CCOCC1>[ClH:44].[C:12]([C:9]1[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)=[C:7]([C:18]2[C:19]3[NH:26][C:25]([CH3:27])=[C:24]([C:28]([NH:30][CH:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[O:29])[C:20]=3[N:21]=[CH:22][N:23]=2)[CH:8]=1)(=[O:13])[CH3:17]
Reactant: Cc1[nH]c2c(-c3cc(C4(C)OCCO4)ccc3OCC3CC3)ncnc2c1C(=O)NC1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)c1

Procedure:
tert-Butyl 4-[({4-[2-(cyclopropylmethoxy)-5-(2-methyl-1,3-dioxolan-2-yl)phenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl}carbonyl)amino]piperidine-1-carboxylate from example D.e55 (1.77 g; 2.99 mmol) is dissolved in dry acetone (30 mL). After addition of 4M HCl in dioxane (3 mL) the stirred mixture is gently refluxed until the starting material is consumed according to LC-MS. At ambient temperature the product is precipitated by addition of tert.-butyl methyl ether, isolated by suction filtration, washed with several portions of tert.-butyl methyl ether and dried in high vacuo at 40° C. to yield 1.40 g of the title compound as pale yellow solid.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH3:13][C:14]1[C:19]([O:20][CH3:21])=[C:18]([CH3:22])[C:17]([CH3:23])=[C:16]([O:24][CH3:25])[C:15]=1[CH2:26][CH2:27][OH:28].O[C:30]1[CH:62]=[CH:61][C:33]([CH2:34][CH:35]2[S:39][C:38](=[O:40])[N:37]([C:41]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)([C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]2=[O:60])=[CH:32][CH:31]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.O>[CH3:13][C:14]1[C:19]([O:20][CH3:21])=[C:18]([CH3:22])[C:17]([CH3:23])=[C:16]([O:24][CH3:25])[C:15]=1[CH2:26][CH2:27][O:28][C:30]1[CH:62]=[CH:61][C:33]([CH2:34][CH:35]2[S:39][C:38](=[O:40])[N:37]([C:41]([C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)([C:48]3[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=3)[C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C:36]2=[O:60])=[CH:32][CH:31]=1
Reactant: O=C1SC(Cc2ccc(O)cc2)C(=O)N1C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1c(C)c(C)c(OC)c(CCO)c1C
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: COc1c(C)c(C)c(OC)c(CCOc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)c1C
Temperature: 25 °C
Reaction time: 5 h

Procedure:
3.2 g of diethyl azodicarboxylate were added dropwise, whilst ice-cooling and under an atmosphere of nitrogen, to a solution of 3.5 g of 2-(2,4,5-trimethyl-3,6-dimethoxypenyl)ethanol, 7.3 g of 5-(4-hydroxybenzyl)-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 32) and 4.9 g of triphenylphosphine in 100 ml of tetrahydrofuran, and the resulting mixture was stirred at room temperature for 5 hours. At the end of this time, the reaction mixture was poured into water, after which it was extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was then removed from the extract by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, using a 4:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 5-{4-[2-(2,4,5-trimethyl-3,6-dimethoxyphenyl)ethoxy]benzyl}-3-triphenylmethylthia zolidine-2,4-dione as an oily intermediate. 50 ml of trifluoroacetic acid were added, whilst ice-cooling, to 7.9 g of the intermediate, and the resulting mixture was stirred for 1 hour. At the end of this time, the reaction mixture was diluted with water, after which it was extracted with ethyl acetate. The extract was washed twice, each time with a saturated aqueous solution of sodium hydrogencarbonate; it was then dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure, and the residue thus obtained was purified by column chromatography through silica gel, using a 3:1 by volume mixture of hexane and ethyl acetate as the eluent, to give 3.6 g of the title compound softening at 44°-45° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([OH:13])=O)[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[C:14]([C:18]1[CH:36]=[CH:35][C:21]([CH2:22][NH:23][CH2:24][CH2:25][N:26]([C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=2)[CH3:27])=[CH:20][CH:19]=1)([CH3:17])([CH3:16])[CH3:15].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[C:14]([C:18]1[CH:36]=[CH:35][C:21]([CH2:22][N:23]([CH2:24][CH2:25][N:26]([C:28]2[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=2)[CH3:27])[C:11]([C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]3[C:8]=2[NH:7][CH:6]=[CH:5]3)=[O:13])=[CH:20][CH:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CN(CCNCc1ccc(C(C)(C)C)cc1)c1ccc(Cl)cc1
Reactant: O=C(O)c1cc(Cl)cc2cc[nH]c12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CN(CCN(Cc1ccc(C(C)(C)C)cc1)C(=O)c1cc(Cl)cc2cc[nH]c12)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 55.1 %

Procedure:
98 mg (0.50 mol) of 5-chloro-1H-indole-7-carboxylic acid, 165 mg (0.5 mmol) of N′-(4-tert-butyl-benzyl)-N-(4-chloro-phenyl)-N-methyl-ethane-1,2-diamine and 108 mg (0.55 mmol) of EDC.HCl were dissolved in 5 ml DCM. The reaction mixture was stirred at rt over night. The solvent was evaporated and the residue was dissolved in diethyl ether. The organic layer was washed with 1N aqueous HCl solution, once with 1N aqueous NaOH solution and once with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated to leave 140 mg (55%) product as a colorless oil. MS (ISP) 508.4 (M+H)+.
Reaction SMILES: [N:1]1([C:7]([O:9][CH2:10][C:11]([CH3:39])([CH3:38])[C:12]([N:14]([C@H:24]2[CH2:29][CH2:28][C@H:27]([NH:30]C(OC(C)(C)C)=O)[CH2:26][CH2:25]2)CC2C=CC(OC)=CC=2)=[O:13])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>ClCCl>[N:1]1([C:7]([O:9][CH2:10][C:11]([CH3:39])([CH3:38])[C:12]([NH:14][C@H:24]2[CH2:25][CH2:26][C@H:27]([NH2:30])[CH2:28][CH2:29]2)=[O:13])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: COc1ccc(CN(C(=O)C(C)(C)COC(=O)N2CCOCC2)[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(COC(=O)N1CCOCC1)C(=O)N[C@H]1CC[C@H](N)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 15C (30 mg, 0.055 mmol) in dichloromethane (0.5 mL) was treated with TFA (0.5 mL), and stirred at room temperature for 1.5 h. The reaction mixture was concentrated, and the residue was triturated with Et2O. The resulting off white solid was collected by filtration and air dried to provide 15D. This material was used without purification in the next step.
Reaction SMILES: [CH:1]([Si:3]([CH3:11])([CH3:10])[O:4][Si](C=C)(C)C)=[CH2:2].[Cl:12][Si:13]([Cl:16])(Cl)[Cl:14].C(N(CCCC)CCCC)CCC>C(Cl)Cl>[Cl:12][Si:13]([Cl:16])([Cl:14])[O:4][Si:3]([CH:1]=[CH2:2])([CH3:11])[CH3:10]
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: C=C[Si](C)(C)O[Si](C)(C)C=C
Solvent: CCCCN(CCCC)CCCC
Solvent: ClCCl
Product: C=C[Si](C)(C)O[Si](Cl)(Cl)Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 114.6 %

Procedure:
A mixture containing 595 g (3.2 mol) of 1,3-divinyl-1,1,3,3-tetramethyldisiloxane, 136 g (0.8 mol) of tetrachlorosilane and 2 ml of a 25% solution of phosphonitrile chloride in methylene chloride is stirred at room temperature for 8 hours. About 2.3 ml of tri-n-butylamine are then added to deactivate the phosphonitrile chloride. The reaction mixture is stirred for 30 minutes and then subjected to fractional distillation. About 216 g of 1,1,1-trichloro-3-vinyl-3,3-dimethyldisiloxane are obtained at 20° to 22° C. and at 2 mbar; about 53 g of 1,5-divinyl1,1,5,5-tetramethyl 3,3-dichlorotrisiloxane are obtained at 23° to 42° C. and at 2 mbar, and 9 g of a 1:1 mixture of 1,5divinyl-1,1,5,5-tetramethyl-3,3-dichlorotrisiloxane and 1,5-divinyl-1,1,5,5-tetramethyl-3-chloro-3-trimethylsiloxytrisiloxane are obtained at 42° to 72° C. and at 2 mbar. About 372 g of vinyldimethylchlorosilane are collected in the cold trap. The desired 1,5-divinyl-1,1,5,5-tetramethyl-3,3-bis(vinyldimethylsiloxy)trisiloxane is not obtained.