Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH2:11])=[O:10])=[CH:7][CH:6]=1)=[O:4].[C:16]([C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1)(=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18]>C1COCC1>[CH3:1][C:2]([CH3:15])([CH3:14])[C:3]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:11][C:26](=[O:27])[C:25]2[CH:24]=[CH:23][C:22]([C:16](=[O:21])[C:17]([CH3:18])([CH3:19])[CH3:20])=[CH:30][CH:29]=2)=[O:10])=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(C)(C)C(=O)c1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)C(=O)c1ccc(C(N)=O)cc1
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)c1ccc(C(=O)NC(=O)c2ccc(C(=O)C(C)(C)C)cc2)cc1
Temperature: 5 °C

Procedure:
A solution of 12.3 grams (60 mmol) of 4-(2,2-dimethyl-1-oxo-propyl)-benzamide dissolved in 450 ml of THF is chilled to 5° C.; and 20.6 grams of 35% potassium hydride in oil washed twice with hexane is added as a suspension in hexane. The resulting mixture is stirred for hours at 5° C. A solution of 13.8 grams (61.4 mmol) of p-pivaloyl-benzoyl chloride dissolved in 100 ml of THF is added with stirring over a period of 21/2 hours at 5° C. Sitrring is continued for an additional hour at this temperature, following which the mixture is stirred into 500 ml of an ice-cold saturated NH4Cl solution. The liquid phases are separated, and the aqueous phase is extracted with t-butyl methyl ether. The combined organic layers are washed with saturated sodium chloride solution, separated, and dried over magnesium sulfate. After filtering off the magnesium sulfate, the filtrate is evaporated to a solid, and the crude product is partially purified by chromatography on silica with CHCl3 eluant. The resulting product is twice crystallized from isopropyl alcohol and then from methylene chloride/t-butyl methyl ether, yielding the title product (mp 132°-134° C.).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11].[C:12](OC=O)(=O)C.CN1C2C(O)=CC=CC=2N=C1.CN1C2C(O)=CC=CC=2N=N1>C1COCC1.C(Cl)(Cl)Cl>[CH3:12][NH:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[OH:11]
Reactant: CC(=O)OC=O
Reactant: Nc1c(O)cccc1[N+](=O)[O-]
Agent: Cn1cnc2cccc(O)c21
Agent: Cn1nnc2cccc(O)c21
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CNc1c(O)cccc1[N+](=O)[O-]
Reaction time: 3 h

Procedure:
The title compound was prepared from 2-amino-3-nitrophenol according to a procedure adapted from Tet. Lett. 23, 3315 (1982). 2-Amino-3-nitrophenol (7.7 g, 50 mmol) in dry THF (20 mL) was treated dropwise with formic-acetic anhydride (130 mmol) in THF (10 mL) at about -5° C. under N2 (g). After stirring 3 hours the mixture was concentrated in vacuo to a viscous oil which was redissolved in THF (12 mL) and treated dropwise with 2M borane-dimethylsulfide in THF (63 mL) at about -5° C. When the addition was complete the mixture was heated to reflux (2 hours), cooled in ice and quenched with MeOH (20 mL). After stirring for 1 hour at about 22° C., anhydrous HCl was bubbled into the solution to acidity it to about pH 2. The mixture was refluxed for 1 hour and concentrated in vacuo. The residue was dissolved in H2O, neutralized with conc. NH4OH and cooled (16 hours) to produce a dark brown solid. This wet material was dissolved in CHCl3, dried over Na2SO4 and concentrated in vacuo to afford a red-brown solid (6.72 g; >95% purity) which was used directly in the syntheses of 3-methylbenzimidazol-4-ol and 3-methylbenzotriazol-4-ol (below).
Reaction SMILES: [Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)[C:4]1C=CC=C[CH:5]=1.[NH2-].[Na+].C1COCC1.[CH3:29][O:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[CH:33][C:32]=1[O:41][CH:42]([CH3:47])[C:43](=O)[CH2:44]C>C1(C)C=CC=CC=1>[CH2:4]([C:42]1([CH2:43][CH3:44])[CH2:47][C:33]2=[C:34]([C:35]([O:37][CH3:38])=[O:36])[CH:39]=[CH:40][C:31]([O:30][CH3:29])=[C:32]2[O:41]1)[CH3:5]
Reactant: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCC(=O)C(C)Oc1cc(C(=O)OC)ccc1OC
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC1(CC)Cc2c(C(=O)OC)ccc(OC)c2O1
Reaction time: 0.5 h

Procedure:
10 of methyltriphenylphosphonium bromide-sodium amide mixture (FLUKA 69500) are added to 100 ml of abs. THF at about 10° C. under protective gas (nitrogen), and the mixture is warmed to RT and stirred for about 30 min. A solution of 5.3 g of methyl 4-methoxy-3-(1-methyl-2-oxobutoxy)benzoate is then added dropwise. The mixture is stirred at RT for 1 h, then poured onto water and extracted 3 times with about 50 ml of ethyl acetate. The combined extracts are dried over sodium sulfate and concentrated, and the oily residue is dried in a high vacuum. The oil obtained (3.8 g) is stirred at 190-200° C. for 1 h, cooled and dissolved in 100 ml of toluene. The solution is treated with 5 g of Amberlyst 15 and vigorously stirred at 80° C. overnight. The Amberlyst is then filtered off, the solution is concentrated and the residue is chromatographed on a silica gel column using ethyl acetate/petroleum ether 4:6. The chromatographically pure fractions are combined and concentrated, and the residue is dried in a high vacuum. 1.5 g of the title compound are obtained as a pale yellow oil.
Reaction SMILES: C(OC(=O)C[O:8][C:9]1[C:14]2[N:15]([CH2:19][C:20]3[CH:29]=[CH:28][C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:21]=3)C(=O)[O:17][C:13]=2[CH:12]=[CH:11][CH:10]=1)(C)(C)C.BrCC(OC(C)(C)C)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O.CN(C=O)C>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[CH2:19][NH:15][C:14]1[C:9]([OH:8])=[CH:10][CH:11]=[CH:12][C:13]=1[OH:17]
Reactant: CC(C)(C)OC(=O)COc1cccc2oc(=O)n(Cc3ccc4ccccc4c3)c12
Agent: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: Oc1cccc(O)c1NCc1ccc2ccccc2c1

Procedure:
Synthesis of (3-Naphthalen-2-ylmethyl-2-oxo-2,3-dihydro-benzooxazol-4-yloxy)-acetic acid tert-butyl ester, I-88. A mixture of compound I-87 (140 mg, 0.48 mmol), tert-butyl bromoacetate (136 mg, 0.7 mmol) and K2CO3 (95 mg, 0.7 mmol) in acetone (10 ml) and DMF (5 ml) was stirred at rt over night and then partitioned between EtOAc and water. Water layer was extracted with EtOAc. The combined organic phase was washed with water, brine and dried over sodium sulfate. After removal of solvent, 160 mg of compound I-88 was obtained. 1H-NMR (500 MHz, CDCl3).
Reaction SMILES: [CH2:1]([N:8]([CH3:17])[C:9]1[C:14]([F:15])=[CH:13][NH:12][C:11](=[O:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24](Cl)=[O:25].CCN(CC)CC>C(Cl)Cl>[CH2:1]([N:8]([CH3:17])[C:9]1[C:14]([F:15])=[CH:13][N:12]([C:24]([O:23][CH2:22][CH2:21][CH2:20][CH2:19][CH3:18])=[O:25])[C:11](=[O:16])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCCOC(=O)Cl
Reactant: CN(Cc1ccccc1)c1nc(=O)[nH]cc1F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCOC(=O)n1cc(F)c(N(C)Cc2ccccc2)nc1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 6.7 %

Procedure:
To a stirred solution of 4-(benzyl(methyl)amino)-5-fluoropyrimidin-2(1H)-one (0.200 g, 0.858 mmol) in CH2Cl2 (18 mL) were added N-pentyl chloroformate (0.142 g, 0.944 mmol) and Et3N (0.263 mL, 1.88 mmol) at 0° C. The mixture was allowed to warm to room temperature and stirred an additional 3 h. The crude reaction mixture was evaporated to dryness and the residue was triturated with methyl t-butyl ether (MTBE; 4×5 mL) to remove triethylamine hydrochloride. The combined organic layers were evaporated in vacuo. The crude product was purified by reverse phase chromatography. Pentyl 4-(benzyl(methyl)amino)-5-fluoro-2-oxopyrimidine-1(2H)-carboxylate (20.1 mg, 6.7%) was isolated as a yellow gum: 1H NMR (methanol-d4) δ 8.04 (d, J=6.2 Hz, 1H), 7.38-7.25 (m, 5H), 4.24 (t, J=6.6 Hz, 2H), 3.21 (d, J=3.3 Hz, 2H), 1.78-1.65 (m, 3H), 1.37 (dd, J=9.2, 5.5 Hz, 6H), 0.92 (t, J=7.1 Hz, 3H); ESIMS m/z 348 ([M+H]+).
Reaction SMILES: C(=O)(O[CH2:6][CH3:7])OCC.C[O-].[Na+].[CH:12]([O:14][CH:15]1[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18][CH2:17][CH2:16]1)=[O:13]>O>[CH:12]([O:14][C:15]1([CH:7]2[CH2:6][CH2:18][CH2:17][CH2:16][CH2:15][CH2:22][CH2:21]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:13]
Reactant: O=COC1CCC=CCCC1
Reactant: CCOC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: O=COC1(C2CCCCCCC2)CCCCCCC1
Temperature: 85 °C

Procedure:
Into a 2 liter reaction flask equipped with heating mantle, stirrer, Bidwell water trap, reflux condenser, thermometer and nitrogen blanket apparatus is placed 1,000 ml (8.4 moles) of diethyl carbonate, and 25 grams (0.45 moles) of sodium methoxide. The resulting mixture is heated to 85° C. While maintaining the reaction mass at 85°-86° C. over a period of 1 hour, 695 grams (4.5 moles) of a composition containing a major proportion of 4-cyclooctenyl formate having the structure: ##STR78## and a minor proportion of bicyclooctanyl formate having the structure: ##STR79## produced according to Example I, is added while removing ethyl formate reaction product from the reaction mass using the Bidwell trap. At the end of the 1 hour period, the reaction mass is stirred at a temperature of 85°-86° C. for an additional 1 hour.
Reaction SMILES: [NH2:1][C:2]1[N:11]2[CH2:12][CH2:13][N:14]=[C:10]2[C:9]2[CH:8]=[CH:7][C:6]([O:15][CH2:16][CH2:17][CH2:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[C:5]([O:25][CH3:26])[C:4]=2[N:3]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31]([C:34](O)=[O:35])=[CH:30][N:29]=1>>[NH2:27][C:28]1[N:33]=[CH:32][C:31]([C:34]([NH:1][C:2]2[N:11]3[CH2:12][CH2:13][N:14]=[C:10]3[C:9]3[CH:8]=[CH:7][C:6]([O:15][CH2:16][CH2:17][CH2:18][S:19]([N:22]([CH3:24])[CH3:23])(=[O:20])=[O:21])=[C:5]([O:25][CH3:26])[C:4]=3[N:3]=2)=[O:35])=[CH:30][N:29]=1
Reactant: Nc1ncc(C(=O)O)cn1
Reactant: COc1c(OCCCS(=O)(=O)N(C)C)ccc2c1N=C(N)N1CCN=C21
Product: COc1c(OCCCS(=O)(=O)N(C)C)ccc2c1N=C(NC(=O)c1cnc(N)nc1)N1CCN=C21

Procedure:
The procedure used for the preparation of Example 16, Step 2 was used to prepare the title compound from 3-[(5-amino-7-methoxy-2,3-dihydroimidazo[1,2-c]quinazolin-8-yl)oxy]-N,N-dimethylpropane-1-sulfonamide (Step 1) and 2-aminopyrimidine-5-carboxylic acid. High vacuum drying gave the title compound (261 mg, 79%): HPLC MS RT=2.09 min, MH+=503.2; 1H NMR (DMSO-d6+2 drops TFA-d) δ: 2.20-2.25 (2H, m), 2.78 (6H, s), 3.20-3.25 (2H, m), 3.99 (3H, s), 4.18-4.25 (2H, m), 4.37 (2H, t), 4.48-4.55 (2H, m), 7.44 (1H, d), 8.02 (1H, d), 9.07 (2H, s).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.C(N(CC)CC)C.[CH2:17]([O:24][CH2:25]Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>ClCCl>[CH2:17]([O:24][CH2:25][N:5]1[CH:4]=[C:3]([Cl:2])[CH:8]=[N:7][C:6]1=[O:9])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=c1ncc(Cl)c[nH]1
Reactant: ClCOCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1ncc(Cl)cn1COCc1ccccc1

Procedure:
A mixture of 5-chloropyrimidin-2-one hydrochloride (10 mmol) and triethylamine (20 mmol) in dichloromethane (50 ml) were stirred together until all the solid material had dissolved, before a solution of chloromethyl benzyl ether (see Preparation 1a and 1b) (10 mmol) in dichloromethane (10 ml) was added with stirring at room temperature. The mixture was stirred for 3 hours at room temperature before the solvent was distilled off. The residue was triturated with water (40 ml), extracted into chloroform (3×40 ml) and the dried (MgSO4) solution evaporated; yield 2.40 g (96%). The product was purified by trituration with ether and had m.p. 125° C. (acetone). 1H NMR (CDCl3): δ4.68 (CH2Ph), 5.32 (CH2O), 7.30 (Ph), 7.72 and 8.48 (H-4, H-6, J 3 Hz).
Reaction SMILES: [O:1]([CH2:8][C:9]1[CH:18]=[C:12]2[C:13](=[O:17])[NH:14][CH2:15][CH2:16][N:11]2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:20][CH:21]([CH3:40])[O:22][Si:23]([C:36]([CH3:39])([CH3:38])[CH3:37])([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[H-].[Na+]>C1COCC1>[C:36]([Si:23]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[O:22][CH:21]([CH3:40])[CH2:20][N:14]1[CH2:15][CH2:16][N:11]2[N:10]=[C:9]([CH2:8][O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:18]=[C:12]2[C:13]1=[O:17])([CH3:38])([CH3:39])[CH3:37]
Reactant: CC(CBr)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: O=C1NCCn2nc(COc3ccccc3)cc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(CN1CCn2nc(COc3ccccc3)cc2C1=O)O[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Temperature: 150 °C
Reaction time: 0.25 h

Procedure:
2-Phenoxymethyl-6,7-dihydro-5H-pyrazolo[1,5-a]pyrazin-4-one (60 mg, 0.25 mmol) was added to a suspension of (rac)-(2-bromo-1-methyl-ethoxy)-tert-butyl-diphenyl-silane (0.23 g, 0.62 mmol) and 60% dispersion of sodium hydride in mineral oils (11 mg, 0.29 mmol) in THF (2 mL) at 0° C. The mixture was allowed to reach room temperature and stirred at 150° C. for 15 minutes under microwave irradiation. The mixture was used as such in the next step.
Reaction SMILES: [H-].[Na+].[CH3:3]O.[Br:5][C:6]1[C:11]([OH:12])=[CH:10][CH:9]=[CH:8][N:7]=1.CI>CN(C)C=O>[Br:5][C:6]1[C:11]([O:12][CH3:3])=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: CO
Reactant: Oc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COc1cccnc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
Under a nitrogen atmosphere, sodium hydride 60% in oil (605 mg, 15.1 mmol) was added in portions to methanol (10 ml) under ice cooling. Twenty minutes later, a dimethylformamide (20 ml) solution of 2-bromo-3-hydroxypyridine (2.5 g, 14.4 mmol) was added. From the resulting mixture, methanol was distilled off under reduced pressure. To the residue was added methyl iodide (0.94 ml, 15.1 mmol), followed by stirring at room temperature for 3 hours. After the reaction mixture was concentrated to dryness, water (50 ml) and ether (50 ml) were added to the concentrate. The organic layer was separated and washed with a saturated aqueous solution of sodium bicarbonate and brine. The extract was dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (hexane:ethyl acetate=8:1) to give the title compound (1.51 g, 56%) as colorless needle crystals.
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[O:12][C:11]3[C:6](=[CH:7][C:8]([OH:16])=[CH:9][CH:10]=3)[C:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:4]=2[CH:3]=1.[N:22]1[CH:27]=[C:26](B(O)O)[CH:25]=[N:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1.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>[OH:16][C:8]1[CH:9]=[CH:10][C:11]2[O:12][C:13]3[C:4](=[CH:3][C:2]([C:26]4[CH:27]=[N:22][CH:23]=[N:24][CH:25]=4)=[CH:15][CH:14]=3)[C:5]3([CH2:20][O:19][C:18]([NH2:21])=[N:17]3)[C:6]=2[CH:7]=1
Reactant: OB(O)c1cncnc1
Reactant: NC1=NC2(CO1)c1cc(O)ccc1Oc1ccc(Br)cc12
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: [K+]
Solvent: C1CCOC1
Product: NC1=NC2(CO1)c1cc(O)ccc1Oc1ccc(-c3cncnc3)cc12
Temperature: 25 °C

Procedure:
A 150-mL pressure vessel was charged with 2′-bromo-7′-hydroxyspiro[1,3-oxazole-4,9′-xanthen]-2-amine (845 mg, 2434 μmol) in THF (24 mL), pyrimidin-5-ylboronic acid (754 mg, 6085 μmol), tetrakis(triphenylphosphine)palladium(0) (281 mg, 243 μmol), and potassium carbonate (10.1 mL of a 1.2 M aqueous solution, 12.1 mmol). The vessel was sealed and placed in a 100° C. oil bath at for 4 h. The reaction mixture was cooled to RT and partitioned between EtOAc (50 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (50 mL), and the combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The crude material was purified by chromatography on silica gel (eluting with 30-100% of a 90:10:1 DCM/MeOH/NH4OH solution in DCM) to give 2′-hydroxy-7′-(5-pyrimidinyl)spiro[1,3-oxazole-4,9′-xanthen]-2-amine as an off-white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30](O)=[O:31])[C:25]=1[CH3:33])(=[O:12])=[O:11].[N:34]1([CH2:39][C@@H:40]2[CH2:44][CH2:43][CH2:42][NH:41]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>C(#N)C.CN(C=O)C>[CH3:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:41]2[CH2:42][CH2:43][CH2:44][C@H:40]2[CH2:39][N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:31])[C:25]=1[CH3:33])(=[O:11])=[O:12]
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)O)c1C)C(=O)N2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1cccc(C)c1CS(=O)(=O)c1ccc2c(c1)/C(=C/c1[nH]c(C)c(C(=O)N3CCC[C@H]3CN3CCCC3)c1C)C(=O)N2

Procedure:
5-[5-(2,6-Dimethyl-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (120 mg, 0.26 mmol) was coupled with (S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (50 mg, 1.2 eq.), HOBt (42 mg, 1.2 eq.), EDAC.HCl (60 mg, 1.2 eq.) and TEA (3 eq.) in acetonitrile: DMF (3:1) to give the titled compound.
Reaction SMILES: N1C=CN=C1.[Cl:6][C:7]1[N:8]=[C:9]([CH2:21][OH:22])[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:11]=1[Cl:12].Cl[Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25].[NH4+].[Cl-]>C(Cl)Cl>[Cl:6][C:7]1[N:8]=[C:9]([CH2:21][O:22][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[N:10]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:18])([CH3:19])[CH3:20])[C:11]=1[Cl:12]
Reactant: C[Si](C)(C)CCOCn1c(CO)nc(Cl)c1Cl
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1nc(Cl)c(Cl)n1COCC[Si](C)(C)C
Reaction time: 8 h
Yield: 99.2 %

Procedure:
Imidazole (282 mg, 4.14 mmol) was added to a solution of [4,5-dichloro-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazol-2-yl]methanol (614 mg, 2.07 mmol) and chloro(1,1-dimethylethyl)dimethylsilane (345 mg, 2.28 mmol) in DCM (8 mL) at RT under N2. The mixture was stirred overnight. Aqueous NH4Cl was then added. Extracted with DMC and the extracts were dried over sodium sulfate and concentrated. The residue was purified by column chromatography (0-10% EtOAc in hexane) to give the title compound (845 mg, 99%) as a colorless oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 5.42 (2H, s) 4.74 (2H, s) 3.53-3.59 (2H, m) 0.87-0.95 (11H, m) 0.09 (6H, s) 0.00 (9H, s). LCMS: m/z 411 (M+1).
Reaction SMILES: Br[C:2]1[S:3][C:4]([NH:12][CH3:13])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:23]([O:22][C:20]([N:14]1[CH2:19][CH2:18][N:17]([C:2]2[S:3][C:4]([NH:12][CH3:13])=[C:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[N:6]=2)[CH2:16][CH2:15]1)=[O:21])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)c1nc(Br)sc1NC
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(N2CCN(C(=O)OC(C)(C)C)CC2)sc1NC
Temperature: 100 °C
Yield: 35.2 %

Procedure:
To a solution of ethyl 2-bromo-5-methylamino-thiazole-4-carboxylate (401 mg, 1.512 mmol) and tert-butyl piperazine-1-carboxylate (1.06 g, 5.69 mmol) in anhydrous dioxane (15 ml) was added DIPEA (2 ml, 11.5 mmol) and the reaction was heated at 100° C. in a sealed flask for 23 hours. The mixture was cooled to room temperature, partitioned between DCM and sat. sodium bicarbonate solution and the phases were separated. The aqueous layer was extracted twice with DCM and the combined organic layers were dried (sodium sulfate) and concentrated under reduced pressure. The residue was purified by column chromatography (silica, gradient from 10 to 70% ethyl acetate in n-heptane) to yield 197 mg of a white solid (0.532 mmol, yield 35%) MS (multi-mode) m/z=371.2 [M+1]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8]([NH2:15])[N:7]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Br:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][CH:24]=1)[CH2:20][N:12]1[CH:11]=[N:10][C:9]2[C:13]1=[N:14][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:7][C:8]=2[NH2:15]
Reactant: COCCOc1nc(N)c2[nH]cnc2n1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCOc1nc(N)c2ncn(Cc3cccc(Br)c3)c2n1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(2-methoxyethoxy)-9H-purin-6-amine (15) (1.0 g, 4.78 mmol), 3-bromobenzyl bromide (1.5 g, 6.00 mmol) and anhydrous potassium carbonate (0.85 g, 6.15 mmol) were combined in DMF (15 mL) and stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate (150 mL) and washed with water and brine. The organic phase was dried with sodium sulfate and the solvent was removed under vacuum. The resulting residue was triturated with a mixture of diethylether and ethyl acetate (4:1) and filtered. 9-(3-bromobenzyl)-2-(2-methoxyethoxy)-9H-purin-6-amine, Compound (39) (0.77 g, 43%) was obtained as a yellowish solid. 1H-NMR (DMSO) δ: 8.07 (s, 1H), 7.57 (s, 1H), 7.52-7.46 (m, 1H), 7.34-7.22 (m, 4H), 5.26 (s, 2H), 4.32 (t, J=4.5 Hz, 2H), 3.60 (t, J=4.5 Hz, 2H), 3.27 (s, 3H). MS: 378/380 (MH+)
Reaction SMILES: C(N1CC[C@@H]([CH2:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[S:16]([NH:19][C:20]2[C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]3[C:23]([CH:24]4[CH2:34][CH:25]4[CH2:26][O:27]3)=[CH:22][CH:21]=2)(=[O:18])=[O:17])C1)C.[CH2:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42]CC1C=C(F)C=CC=1S(Cl)(=O)=O)[CH3:36].NC1C(C(OC)=O)=C2C([C@H]3C[C@H]3CO2)=CC=1>>[CH2:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@H:38]1[CH2:42][CH2:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[S:16]([NH:19][C:20]1[C:29]([C:30]([O:32][CH3:33])=[O:31])=[C:28]2[C:23]([C@H:24]3[CH2:34][C@H:25]3[CH2:26][O:27]2)=[CH:22][CH:21]=1)(=[O:17])=[O:18])[CH3:36]
Reactant: CCN1CC[C@@H](Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Reactant: CCN1CCC[C@H]1CCc1cc(F)ccc1S(=O)(=O)Cl
Agent: COC(=O)c1c(N)ccc2c1OC[C@@H]1C[C@H]21
Product: CCN1CCC[C@H]1CCc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)OC)OC[C@@H]1C[C@H]21

Procedure:
Prepared by proceeding in a similar manner to Intermediate 95, starting from 2-[2-((R)-1-ethyl-pyrrolidin-2-yl)-ethyl]-4-fluorobenzenesulfonyl chloride (intermediate 230) and methyl (1aR,7bS)-5-amino-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 42A).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][C:5]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:3])=[O:2].[CH3:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.C(N(CC)CC)C>ClCCl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][N:13]([S:30]([C:27]3[CH:28]=[CH:29][C:24]([CH3:23])=[CH:25][CH:26]=3)(=[O:32])=[O:31])[CH2:12][CH2:11]2)=[CH:6][C:5]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1Nc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCN(c3ccc([N+](=O)[O-])c(Nc4ccccc4)c3)CC2)cc1
Yield: 39 %

Procedure:
A solution of 2-nitro-N-phenyl-5-(piperazin-1-yl)benzenamine (0.5 g, 1.7 mmol), 4-methylbenzene-1-sulfonyl chloride (0.32 g, 1.7 mmol) and triethylamine (0.60 ml, 4.2 mmol) in 20 ml dichloromethane was stirred at 0° C. for 2 hours. The mixture was washed with water (2×10 ml) and dried over anhydrous sodium sulfate before removing the solvents. N-(2-nitro-5-(4-tosylpiperazin-1-yl)phenyl)benzenamine (0.30 g, 40%) was obtained by flash column chromatograph (50% ethyl acetate in hexanes). 1H NMR (500 MHz, CDCl3) δ (ppm) 2.46 (s, 3H), 3.24 (t, J=4.5 Hz, 4H), 3.42 (t, J=4.5 Hz, 4H), 6.42 (d, J=9.6 Hz, 1H), 6.64 (s, 1H), 7.28-7.65 (m, 9H), 8.14 (d, J=9.5 Hz, 1H), 9.90 (s, 1H). 13C NMR (125 MHz, CDCl3): δ (ppm) 22.0, 45.5, 48.4, 48.5, 99.5, 99.6, 125.0, 106.8, 126.4, 128.2, 129.6, 130.3, 130.4, 132.7, 138.9, 144.8, 145.6.