Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:13]=3)[CH2:8][C:7]=2[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(OCC)C.C([Li])CCC.[Cl:32][Si:33](Cl)([CH:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]1)[CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CCCCCC>[Cl:32][Si:33]([CH:40]1[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45]1)([CH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:10]1[C:9]2[CH2:8][C:7]3[C:15](=[CH:16][CH:17]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=3)[C:14]=2[CH:13]=[CH:12][C:11]=1[C:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)c1ccc2c(c1)Cc1cc(C(C)(C)C)ccc1-2
Reactant: Cl[Si](Cl)(C1CCCCC1)C1CCCCC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)c1ccc2c(c1)Cc1c-2ccc(C(C)(C)C)c1[Si](Cl)(C1CCCCC1)C1CCCCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 101.8 %

Procedure:
A 300 ml two-necked flask equipped with a three-way cock, a dropping funnel and a magnetic stirrer, was thoroughly purged with nitrogen. Into the flask was introduced 2,7-di-tert-butylfluorene 3.01 g (10.81 mmol), and dissolved by addition of dehydrated diethyl ether 60 ml. With cooling in an ice bath, 1.56 mol/L n-hexane solution of n-butyllithium, 6.9 ml (11.0 mmol), was added to the solution, and the mixture was stirred in a nitrogen atmosphere at room temperature for 20 hours. Separately, a 500 ml three-necked flask equipped with a 100 ml dropping funnel, a three-way cock and a magnetic stirrer was thoroughly purged with nitrogen, and dehydrated n-hexane 120 ml and dichlorodicyclohexylsilane 2.6 ml (11.0 mmol) were introduced into the flask. With the flask cooled in a dry ice/methanol bath, the above-prepared solution was dropwise added over a period of 1 hour by means of the dropping funnel. While allowing the liquid temperature to rise gradually to room temperature, the contents were stirred for 3 days in a nitrogen atmosphere. The resulting slurry was filtered to remove solids, and the solvent of the filtrate was distilled away under reduced pressure to obtain 5.5 g of chlorodicyclohexyl(2,7-di-tert-butylfluorenyl)silane as a light yellow solid (11.0 mmol, 100% yield). The 1H NMR spectrum as measured with respect to the chlorodicyclohexyl(2,7-di-tert-butylfluorenyl)silane is given below:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8]COC)=[C:4]([O:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[CH:3]=1.O1CCOCC1.Cl>O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([O:12][CH:13]2[CH2:16][CH2:15][CH2:14]2)[CH:3]=1
Reactant: COCOc1ccc(Br)cc1OC1CCC1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: Oc1ccc(Br)cc1OC1CCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 49.9 %

Procedure:
To 7.26 g (25.3 mmol) of 4-bromo-2-cyclobutoxy-1-methoxymethoxybenzene obtained in Reference Example 5-(c) was added 30 ml of 1,4-dioxane solution containing 4N hydrogen chloride, and the mixture was stirred at room temperature for 24 hours. After completion of the reaction, 100 ml of water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer after separation was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=9:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 3.07 g of the title compound as a pale yellowish oil. (Yield: 50%)
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][O:6][C:7]([C:9]1[S:13][C:12]2[CH:14]=[C:15]([CH2:18]O)[CH:16]=[CH:17][C:11]=2[C:10]=1[CH3:20])=[O:8]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:5][O:6][C:7]([C:9]1[S:13][C:12]2[CH:14]=[C:15]([CH2:18][Cl:3])[CH:16]=[CH:17][C:11]=2[C:10]=1[CH3:20])=[O:8]
Reactant: COC(=O)c1sc2cc(CO)ccc2c1C
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)c1sc2cc(CCl)ccc2c1C
Reaction time: 1 h

Procedure:
Thionyl chloride (0.75 ml.) was added cautiously to a solution of 6-hydroxymethyl-3-methylbenzo[b]-thiophene-2-carboxylic acid methyl ester (0.70 g.) and pyridine (3 drops) in chloroform (7.5 ml.) and the resulting solution was allowed to stand for 1 hour. It was then washed successively with water, sodium bicarbonate solution and dried (Na2SO4). Evaporation of the solvent gave a solid which was crystallized from petrol (b.p. 60°-80°) to give 6-chloromethyl-3-methylbenzo[b]thiophene-2-carboxylic acid methyl ester (0.63 g.), m.p. 128°-129° C.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][N:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][CH:17]=O)=[C:12]([O:19][CH3:20])[CH:11]=2)[CH:7]=[N:6]1.[CH:22]1([NH:28][C:29]2[C:34]3[N:35]=C(S(C)(=O)=O)[N:37]=[CH:38][C:33]=3[CH:32]=[CH:31][N:30]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([NH:28][C:29]2[C:34]3[N:35]=[C:17]([NH:16][C:13]4[CH:14]=[CH:15][C:10]([C:8]5[CH:7]=[N:6][N:5]([CH2:4][CH2:3][N:2]([CH3:21])[CH3:1])[CH:9]=5)=[CH:11][C:12]=4[O:19][CH3:20])[N:37]=[CH:38][C:33]=3[CH:32]=[CH:31][N:30]=2)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COc1cc(-c2cnn(CCN(C)C)c2)ccc1NC=O
Reactant: CS(=O)(=O)c1ncc2ccnc(NC3CCCCC3)c2n1
Product: COc1cc(-c2cnn(CCN(C)C)c2)ccc1Nc1ncc2ccnc(NC3CCCCC3)c2n1
Yield: 25 %

Procedure:
The title compound was prepared according to Example 40 using N-(4-(1-(2-(dimethylamino)ethyl)-1H-pyrazol-4-yl)-2-methoxyphenyl)formamide (Preparation 64) and N-cyclohexyl-2-(methylsulfonyl)pyrido[3,4-d]pyrimidin-8-amine (Preparation 44). The residue was purified by silica gel column chromatography eluting with 0 to 10% MeOH in DCM to give the title compound (26 mg, 25%).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][N:8]([CH2:11][CH:12]=[CH2:13])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:14][C:15]1[CH:16]=[C:17]([C:21]#[CH:22])[CH:18]=[CH:19][CH:20]=1>CO>[CH2:11]([N:8]1[C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([C:21]#[CH:22])[CH:16]=3)[C:3]=2[CH:10]=[CH:9]1)[CH:12]=[CH2:13]
Reactant: C=CCn1ccc2c(Cl)ncnc21
Reactant: C#Cc1cccc(N)c1
Solvent: CO
Product: C#Cc1cccc(Nc2ncnc3c2ccn3CC=C)c1
Temperature: 125 °C
Yield: 40.7 %

Procedure:
To 4-chloro-7-allyl-pyrrolo[2,3-d]pyrimidine (0.5 g, 2.6 mmol) in dry MeOH (5 ml) was added m-aminophenyl acetylene (0.36 g, 3.1 mmol). The suspension was heated in a sealed pressure tube at 125° C. for 20 hours. The reaction was cooled to ambient temperature and concentrated in vacuo. The resulting oil was purified by flash chromatography on silica gel (50 g, 40 mm mesh) using 3% MeOH/CH2Cl2 to afford the title compound as a yellow powder (0.29 g, 41%): TS-MS: 275 (MH+); anal. RP18-HPLC RT: 4.62 minutes.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[NH2:8].[CH:10](S(O)(=O)=O)(O)[CH:11](S(O)(=O)=O)O.C(C=O)=O>O>[CH3:9][C:4]1[CH:3]=[C:2]2[C:7](=[CH:6][CH:5]=1)[N:8]=[CH:11][CH:10]=[N:1]2
Reactant: O=S(=O)(O)C(O)C(O)S(=O)(=O)O
Reactant: Cc1ccc(N)c(N)c1
Agent: O=CC=O
Solvent: O
Product: Cc1ccc2nccnc2c1
Temperature: 60 °C
Yield: 77.8 %

Procedure:
A solution of 3,4-diaminotoluene (Aldrich, 100 g, 0.82 mol) in 600 mL of hot water (temp. 70-75° C.) was added rapidly to a 60° C. slurry of glyoxal-sodium bisulfite adduct (Aldrich, 239.5 g, 0.9 mol, 1.1 eq) in 400 mL of water. The resulting dark-brown clear solution was heated at 60° C. for 1 hr, then 5 g (0.02 mol) of additional glyoxal adduct was added. The mixture was allowed to cool to r.t. and filtered through a paper filter. The filtrate was neutralized with 5 M aq. NaOH to pH 7.5-7.8 and then extracted with ether (4×400 mL). The extract was dried over Na2SO4 and concentrated on a rotary evaporator to afford 92 g of brown oil which was distilled in vacuum (bp. 100-102° C. at 10 mm Hg; Cavagnol, J. C.; Wiselogle, F. Y. J. Am. Chem. Soc. 1947, 69, 795; 86° C. at 1 mm Hg). Yield 89 g (75%) as a pale-yellow oil.
Reaction SMILES: [CH:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:19][C@H:13]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C@@H:12]3[CH2:11][C:10](=O)[C:9]=2[CH:21]=1)([CH3:3])[CH3:2].O.NN.[OH-].[K+].C(O)COCCO>O>[CH:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]2[CH2:19][C@H:13]3[CH2:14][N:15]([CH3:18])[CH2:16][CH2:17][C@@H:12]3[CH2:11][CH2:10][C:9]=2[CH:21]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Nc1ccc2c(c1)C(=O)C[C@H]1CCN(C)C[C@@H]1C2
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: CC(C)Nc1ccc2c(c1)CC[C@H]1CCN(C)C[C@@H]1C2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 25.0 g of trans-1,2,3,4,4a,5,11,11a-octahydro-8-isopropylamino-2-methyl-6H-benzo[5,6]-cyclohepta[1,2-c]pyridin-6-one, 16.0 ml of hydrazine hydrate, 16.0 g of potassium hydroxide and 350 ml of diethylene glycol, is heated first for 1 hour at 150° and then for 3 hours at 200° C., whereby the water formed distils off. The mixture is cooled to room temperature, diluted with water and shaken with methylene chloride. The organic phase is washed neutral with water, dried over sodium sulphate and evaporated, and the residue is reacted in ethanol with the theoretical amount of maleic acid to crystallise out the heading compound in hydrogen maleate form, which is filtered off and recrystallised from ethanol, m.p. from 185° (decomp.).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([NH2:7])[CH:3]=1.[I-].[K+].[Cl:10][C:11]1[CH:12]=[C:13]([C:18]([C:20]2[N:29]=[C:28](Cl)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[O:19])[CH:14]=[CH:15][C:16]=1[F:17].O>CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:18]([C:20]2[N:29]=[C:28]([NH:7][C:4]3[CH:3]=[C:2]([CH3:1])[NH:6][N:5]=3)[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=2)=[O:19])[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: O=C(c1ccc(F)c(Cl)c1)c1nc(Cl)c2ccccc2n1
Reactant: Cc1cc(N)n[nH]1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(C(=O)c3ccc(F)c(Cl)c3)nc3ccccc23)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.9 %

Procedure:
To a mixture of 5-methyl-1H-pyrazol-3-amine (0.26 g, 2.68 mmol), potassium iodide (0.26 g, 1.57 mmol), and TEA (0.45 mL, 3.23 mmol) in DMF (30 mL) was added (3-chloro-4-fluorophenyl)(4-chloroquinazolin-2-yl)methanone (0.495 g, 1.54 mmol) and the mixture was stirred at rt overnight. Water was added and the precipitated solid was collected by filtration to afford crude (3-chloro-4-fluorophenyl)(4-(5-methyl-1H-pyrazol-3-ylamino)quinazolin-2-yl)methanone (458 mg) which was used directly in the next step. LC-MS (ESI) m/z 382 (M+H)+.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][NH:11]2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].CC(C)([O-])C.[K+].[NH2:20]Cl>CN(C=O)C.CCOCC>[CH3:1][S:2]([C:5]1[CH:13]=[C:12]2[C:8]([CH:9]=[CH:10][N:11]2[NH2:20])=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: NCl
Reactant: CS(=O)(=O)c1ccc2cc[nH]c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc2ccn(N)c2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
A solution of 6-methanesulfonyl-1H-indole (2.66 mmol) and potassium tert-butoxide (5.32 mmol) in DMF (15 mL) is stirred at rt under N2 for 2 h. 0.15 M NH2Cl in ether (26.6 mL) is added drop-wise for 15 minutes at rt and the reaction mixture is stirred at rt for 2 h. The reaction mixture is quenched with 10% Na2S2O3 aqueous solution, and extracted with ether (3×20 mL). The combined organic layer is washed with brine (20 mL), dried (Na2SO4), filtered and concentrated in vacuo. The residue is triturated with EtOAc to give 6-methanesulfonyl-indole-1-ylamine (270 mg, 51%) as a solid. MS: 211 (M+H); 1H NMR (300 MHz, CDCl3): δ 3.09 (s, 3H), 6.49 (d, H), 7.41 (m, H), 7.61 (d, H), 7.71 (d, H), 8.12 (s, H).
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.[CH3:19][O:20][C:21]([CH2:23]P(=O)(OCC(F)(F)F)OCC(F)(F)F)=[O:22].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[CH:48]([C:50]1[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[C:51]=1[C:52]([O:54][CH:55]([CH3:57])[CH3:56])=[O:53])=O>C1COCC1.C1(C)C=CC=CC=1>[CH3:19][O:20][C:21](=[O:22])/[CH:23]=[CH:48]\[C:50]1[CH:61]=[CH:60][CH:59]=[C:58]([C:62]([F:65])([F:64])[F:63])[C:51]=1[C:52]([O:54][CH:55]([CH3:57])[CH3:56])=[O:53]
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Reactant: CC(C)OC(=O)c1c(C=O)cccc1C(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C\c1cccc(C(F)(F)F)c1C(=O)OC(C)C
Temperature: -78 °C
Reaction time: 1 h
Yield: 142.1 %

Procedure:
To a solution of 18-crown-6 (9.1 g, 34.6 mmol) in 100 mL of THF at −78° C. was added bis(2,2,2-trifluoroethyl) (methoxycarbonylmethyl)phosphonate (4.13 g, 12.98 mmol). Potassium bis(trimethylsilyl)amide (19.6 mL of a 15 wt % solution in toluene, 12.98 mmol) was added dropwise over 20 min and the mixture was stirred an additional 1 h at −78° C. Then there was added isopropyl 2-formyl-6-(trifluoromethyl)benzoate (1.5 g, 5.74 mmol) in 10 mL of THF and the resulting cloudy mixture was stirred at −78° C. for 1 h. The reaction was quenched with sat'd aq NH4Cl, diluted with EtOAc, washed with brine, dried (MgSO4), filtered through a pad of silica gel and concentrated in vacuo. The residue was purified by flash chromatography (elution with 6:1 hexane/ethyl acetate) to afford 2.58 g (94%) of the title compound as an oil. 1H NMR (CDCl3): δ 7.66-7.62 (m, 2H), 7.51 (t, 1H, J=7.7 Hz), 7.11 (d, 1H, J=12.1 Hz), 6.11 (d, 1H, J=12.1 Hz), 5.26 (septet, 1H), 3.63 (s, 3H), 1.32 (d, 6H, J=6.0 Hz). LRMS (ESI): 339.19 (M+H+Na)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][C:17]#[CH:18])[C:12]([Br:19])=[CH:11][N:10]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:27][N:28]1[CH:32]=[C:31]([S:33](Cl)(=[O:35])=[O:34])[N:30]=[CH:29]1>C(#N)C>[Br:19][C:12]1[C:13]([NH:15][CH2:16][C:17]#[CH:18])=[N:14][C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([NH:1][S:33]([C:31]3[N:30]=[CH:29][N:28]([CH3:27])[CH:32]=3)(=[O:35])=[O:34])=[CH:3][CH:4]=2)=[N:10][CH:11]=1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Reactant: C#CCNc1nc(Nc2ccc(N)cc2)ncc1Br
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#CCNc1nc(Nc2ccc(NS(=O)(=O)c3cn(C)cn3)cc2)ncc1Br

Procedure:
N2-(4-Amino-phenyl)-5-bromo-N4-prop-2-ynyl-pyrimidine-2,4-diamine (100 mg, 0.3 mmole prepared in analogy to procedure 21) was dissolved in acetonitrile (10 ml) and triethylamine (1 ml) and 1-Methyl-1H-imidazole-4-sulfonyl chloride (120 mg, 0.66 mmole) was added at room temperature. The reaction mixture was stirred under reflux for 5 hours, the solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel (ethyl acetate: hexanes 1:1). Yield 41 mg of 1-Methyl-1H-imidazole-4-sulfonic acid [4-(5-b bromo-4-prop-2-ynylamino-pyrimidin-2-ylamino)-phenyl]-amide. ESI-MS: 463.
Reaction SMILES: [CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:11][CH:10]1[CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N>[CH2:1]([NH:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:11][CH:10]1[CH3:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCC(NCc3ccccc3)C(C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC1CC(CNc2ccccc2)CCC1NCc1ccccc1

Procedure:
A mixture comprising toluene-4-sulfonic acid 4-benzylamino-3-methyl-cyclohexylmethyl ester (350 mg, 0.90 mmol), aniline (126, mg, 1.35 mmol) and potassium carbonate (250 mg, 1.80 mmol) in MeCN (1 mL) is heated using microwave radiation at 180° C. for 1 hour. The reaction mixture is partitioned between DCM and water and passed through a phase separator. The solvent is removed in vacuo and purification of the crude residue by chromatography on silica eluting with iso-hexane:EtOAc (25:1 increasing to 10:1) affords the title compound. [MH+309.34].
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[CH:7][C:8]2[C:9]3[S:18][C:17]([CH2:19][CH2:20][CH3:21])=[N:16][C:10]=3[C:11]([NH2:15])=[N:12][C:13]=2[CH:14]=1)(=O)[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].CN(C=O)C.I.I[CH2:35][C:36]1[CH:37]=[N:38][CH:39]=CC=1>ClCCl>[CH2:19]([C:17]1[S:18][C:9]2[C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:1][C:2]4[CH:39]=[N:38][CH:37]=[CH:36][CH:35]=4)=[CH:14][C:13]=3[N:12]=[C:11]([NH2:15])[C:10]=2[N:16]=1)[CH2:20][CH3:21]
Reactant: CCCc1nc2c(N)nc3cc(OC(C)=O)ccc3c2s1
Reactant: ICc1cccnc1
Agent: I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCc1nc2c(N)nc3cc(OCc4cccnc4)ccc3c2s1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 45.7 %

Procedure:
A mixture of 4-amino-2-propylthiazolo[4,5-c]quinolin-7-ol acetate (318 mg, 1.0 mmol), cesium carbonate (1.3 g, 4.0 mmol), and DMF (20 mL) was stirred at 75° C. for 10 minutes. 3-(Iodomethyl)pyridine hydroiodide (381 mg, 1.1 mmol) was added in portions over a period of 3 hours. The heat source was removed and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water (250 mL), stirred for 1 hour, and then filtered. The isolated solid was rinsed with water and then dried to provide a brown powder. This material was dissolved in dichloromethane and then purified by HPFC eluting with a gradient of 0-20% CMA in chloroform over 1400 mL and then 20% CMA in chloroform over 600 mL. The resulting solid was recrystallized from acetonitrile to provide 160 mg of 2-propyl-7-[(pyridin-3-yl)methoxy]thiazolo[4,5-c]quinolin-4-amine as an off-white solid, mp 167.0-169.0° C. MS (APCI) m/z 351 (M+H)+; Anal. calcd for C19H18N4OS: C, 65.12; H, 5.18; N, 15.99. Found C, 65.25; H, 5.06; N, 16.03.
Reaction SMILES: [CH2:1]([C:3]1[N:4]([C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])=[CH:30][CH:29]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[H-].[Na+].[CH3:42]I>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([C:3]1[N:4]([C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][C:36]([O:39][CH3:42])([CH3:37])[CH3:38])=[CH:32][CH:33]=2)[C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:17][CH:18]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2]
Reactant: CI
Reactant: CCCc1nc(CC)n(-c2ccc(OCC(C)(C)O)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCc1nc(CC)n(-c2ccc(OCC(C)(C)OC)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 0.25 h
Yield: 29 %

Procedure:
To a solution of 4′-({2-ethyl-1-[4-(2-hydroxy-2-methylpropoxy)phenyl]-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl}methyl)biphenyl-2-carbonitrile (0.33 g) in N,N-dimethylformamide (5 mL) was added sodium hydride (0.05 g, 60%), and the mixture was stirred for 15 min. Then methyl iodide (0.08 mL) was added, and the mixture was further stirred for 2 hr. Small pieces of ice were added to the reaction mixture, and the mixture was stirred for 15 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.10 g, 29%).
Reaction SMILES: [CH3:1][CH:2]([CH3:23])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][OH:22])=[CH:17][CH:16]=3)[N:11]=2)=[CH:6][CH:5]=1.[CH3:24][Mg]I>C1COCC1>[CH3:1][CH:2]([CH3:23])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH:21]([OH:22])[CH3:24])=[CH:19][CH:20]=3)[N:11]=2)=[CH:6][CH:5]=1
Reactant: C[Mg]I
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(CO)cc3)no2)cc1
Solvent: C1CCOC1
Product: CC(C)Cc1ccc(-c2nc(-c3ccc(C(C)O)cc3)no2)cc1
Temperature: 25 °C

Procedure:
A solution of 0.5 g (1.63 mmol) of Aldehyde 1 in 10 mL of THF was treated with 1.1 mL (3.3 mmol) of methylmagnesium iodide (3.0 M in diethyl ether) at −78° C. and was allowed to warm to rt over 30 min. The resulting mixture was quenched with 5 mL of 1 N HCl and was extracted with 30 mL of ethyl acetate. The extract was washed, dried and concentrated to afford the title compound: ESI-MS 323 (M+H); LC-1: 4.2 min.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>N(C(C)(C)C#N)=NC(C)(C)C#N.C(Cl)(Cl)(Cl)Cl>[Br:17][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:16][CH:15]=2)=[O:7])=[CH:9][CH:10]=1
Reactant: Cc1ccc(C(=O)c2ccc(F)cc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(c1ccc(F)cc1)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 91.4 %

Procedure:
A carbon tetrachloride solution (200 ml) of 4-fluoro-4'-methylbenzophenone (16 g), N-bromosuccinimide (14.2 g) and 2,2'-azodi-isobutyronitrile (0.1 g) was heated for 16 hours with refluxing. After the mixture was cooled to a room temperature, the precipitates were collected by filtration, and the solvent was distilled off to obtain 4-bromomethyl-4'-fluorobenzophenone (20 g).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=1.N1C(C)=CC=CC=1C.[Cl:19][C:20]1[CH:21]=[C:22]([C@@H:30]([CH2:34][C@H:35]2[CH2:39][CH2:38][C:37](=[O:40])[CH2:36]2)[C:31](Cl)=[O:32])[CH:23]=[CH:24][C:25]=1[S:26]([CH3:29])(=[O:28])=[O:27]>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[C:22]([C@@H:30]([CH2:34][C@H:35]2[CH2:39][CH2:38][C:37](=[O:40])[CH2:36]2)[C:31]([NH:1][C:2]2[CH:6]=[CH:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[N:3]=2)=[O:32])[CH:23]=[CH:24][C:25]=1[S:26]([CH3:29])(=[O:28])=[O:27]
Reactant: Nc1ccn(CCCO)n1
Reactant: CS(=O)(=O)c1ccc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Cl)cc1Cl
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CS(=O)(=O)c1ccc([C@@H](C[C@H]2CCC(=O)C2)C(=O)Nc2ccn(CCCO)n2)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 88 %

Procedure:
In a round bottom flask was placed 3-(3-amino-pyrazol-1-yl)-propan-1-ol (prepared in Example 23, 32 mg, 0.22 mmol), 2,6-lutidine (35 μL, 0.30 mmol) and methylene chloride (5 mL) which was then cooled to 0° C. in an ice bath. To this solution was then added dropwise a solution of (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-3-((R)-3-oxo-cyclopentyl)-propionyl chloride in methylene chloride (prepared as in Example 96, ˜0.10 M solution, 2 mL, 0.20 mmol). The reaction was then allowed to warm up to 25° C. and stirred for 16 h. After this time the reaction mixture was diluted with methylene chloride (5 mL) transferred to a separatory funnel and washed with a saturated aqueous sodium bicarbonate solution (10 mL) and then a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (4 g column, 70% ethyl acetate/hexanes to 100% ethyl acetate/hexanes) afforded (R)-2-(3-chloro-4-methanesulfonyl-phenyl)-N-[1-(3-hydroxy-propyl)-1H-pyrazol-3-yl]-3-((R)-3-oxo-cyclopentyl)-propionamide (83 mg, 88%) as a white foam: [α]30589=−88.0° (c=0.10, methylene chloride); ES-HRMS m/e calcd for C21H26N3O5SCl (M+H)+ 468.1355, observed 468.1354; 1H NMR (300 MHz, DMSO-d6) δ 1.51 (m, 1H, CH), 1.78-2.32 (m, 10H, 5×CH2), 3.34 (brs, 5H, OCH2 and SO2CH3), 3.95 (m, 1H, ArCHCO), 4.02 (t, J=6.5 Hz, 2H, NCH2), 4.56 (t, J=4.7 Hz, 1H, OH), 6.41 (s, 1H, Ar), 7.56 (s, 1H, Ar), 7.61 (d, Jo=8.3 Hz, 1H, Ar), 7.73 (s, 1H, Ar), 8.02 (d, Jo=8.3 Hz, 1H, Ar), 10.84 (s, 1 H, NH).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:17])=O>ClCCl.CN(C)C=O>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([Cl:17])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCCc1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100 %

Procedure:
To a solution of 5-phenylpentanoic acid (0.14 g, 0.81 mmol) in anhydrous dichloromethane (5 mL) was added two drops of N,N-dimethylformamide, followed by the addition of oxalyl chloride (0.11 g, 0.89 mmol). The reaction was stirred at ambient temperature for 2 hours. The solvent was removed in vacuo to dryness to afford 5-phenylpentanoyl chloride (0.16 g, 0.81 mmol) as a yellow oil.