Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:11]=[CH:10][C:9]([C:12]([OH:14])=O)=[CH:8][N:7]=1.[Cl-].[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([NH3+:26])[CH:21]=[C:20]2[CH3:27].C(N(C(C)C)CC)(C)C.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CN(C=O)C>[F:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[N:22]([NH:26][C:12]([C:9]1[CH:10]=[N:11][C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)=[N:7][CH:8]=1)=[O:14])[CH:21]=[C:20]2[CH3:27]
Reactant: Cc1cn([NH3+])c2ccc(F)cc12
Reactant: O=C(O)c1cnc(-c2nccs2)nc1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cn(NC(=O)c2cnc(-c3nccs3)nc2)c2ccc(F)cc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 58 %

Procedure:
A mixture of 2-thiazol-2-yl-pyrimidine-5-carboxylic acid (50 mg, 0.244 mmol), 5-fluoro-3-methyl-indol-1-yl-ammonium chloride (49 mg, 0.244 mmol), diisopropylethylamine (31.5 mg, 0.244 mmol) in DMF (1 mL) is stirred at rt for 5 min. 4-(4,6-Dimethoxy-[1,3,5]triazin-2-yl)-4-methyl-morpholin-4-ium chloride (37 mg, 0.244 mmol) is added. The reaction is heated to 50° C. for 1.5 h and then concentrated in vacuo. The residue is taken up in DMSO-d6 then purified via reverse phase C18 HPLC chromatography eluting with water and acetonitrile containing 0.1% TFA buffer to afford 2-thiazol-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-3-methyl-indol-1-yl)-amide (58%). MS: 354 (M+H); 1H NMR (300 MHz, CDCl3): δ=2.27 (s, 3H), 7.05 (dt, 1H), 7.32 (s, 1H), 7.32-7.44 (m, 2H), 8.11 (d, 1H), 8.19 (d, 1H), 9.42 (s, 2H), 12.12 (s, 1H).
Reaction SMILES: [CH:1]1[C:6](N)=[CH:5][CH:4]=[C:3](N)[CH:2]=1.[OH2:9]>CC(O[Na])=O>[C:1]1([OH:9])[C:6]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(N)cc1
Reactant: O
Agent: CC(=O)O[Na]
Product: Oc1cccc2ccccc12

Procedure:
A 0.5 mg/ml solution of a first compound (p-phenylenediamine, "A") and a 0.5 mg/ml solution of a second compound (1-naphthol, "B") was prepared by dissolving the compound in the appropriate amount of 0.1 M CH3COONa, pH 5.5, buffer. A total volume of 100 ml was used in each LOM beaker. 100 ml "A" was added to one beaker and 50 ml "A" and 50 ml "B" were combined to form 100 ml in a second beaker. Swatches of the materials listed above were wetted in DI water and soaked in the precursor solutions. A Polyporus pinsitus laccase ("PpL") with an activity of 70 LACU/ml (100 LACU/mg) was added to each beaker at a concentration of 12.5 mg/l. The LOM beakers were sealed and mounted in the LOM. After 1 hour at 42 RPM and 30C, the LOM was stopped. The spent liquor was poured off and the swatches were rinsed in cold tap water for about 15 minutes. The swatches were dried at room temperature CIELAB values were measured for all of the swatches using the Macbeth ColorEye 7000. The results are given in Tables 14 and 15.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:18]O)[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[O:8][CH3:9].N1C=CC=CC=1.S(Cl)([Cl:28])=O>ClCCl>[Cl:28][CH2:18][C:4]1[CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([O:8][CH3:9])=[C:2]([F:1])[CH:3]=1
Reactant: COc1c(F)cc(CO)cc1OCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1c(F)cc(CCl)cc1OCc1ccccc1
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of {3-fluoro-4-(methyloxy)-5-[(phenylmethyl)oxy]phenyl}methanol (2.69 g, 10.26 mmol.) in dichloromethane (40 mL) was cooled to 0° C. followed by addition of pyridine (913 uL, 11.3 mmol.) then thionyl chloride (750 uL, 10.3 mmol.). The mixture was then allowed to warm to room temperature followed by addition of a second aliquot of pyridine (400 uL). After 5 minutes the organic solution was washed once with 0.1M aqueous hydrochloric acid then dried over anhydrous magnesium sulfate. Filtration and concentration afforded 5-(chloromethyl)-1-fluoro-2-(methyloxy)-3-[(phenylmethyl)oxy]benzene (2.88 g, 100% yield) as a clear oil that was used without further purification. GCMS for C15H14O2FCl: 280 (M+).
Reaction SMILES: [O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[N:4][C:3]1=2.[CH3:16][N:17]([CH3:22])[CH2:18][CH:19](O)[CH3:20]>>[O:1]=[C:2]1[NH:10][CH:9]=[N:8][C:7]2[N:6]([CH2:11][CH2:12][C:13]([O:15][CH:19]([CH3:20])[CH2:18][N:17]([CH3:22])[CH3:16])=[O:14])[CH:5]=[N:4][C:3]1=2
Reactant: CC(O)CN(C)C
Reactant: O=C(O)CCn1cnc2c(=O)[nH]cnc21
Product: CC(CN(C)C)OC(=O)CCn1cnc2c(=O)[nH]cnc21

Procedure:
3-(1,6-dihydro-6-oxo-9H-purin-9-yl)propanoic acid, compd with 1-(dimethylamino)-2-propanol (1:1)
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.Cl.[CH3:22][N:23]([CH3:30])[CH2:24][CH2:25][CH2:26][C:27](O)=[O:28].Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.ClCCl>[CH3:22][N:23]([CH3:30])[CH2:24][CH2:25][CH2:26][C:27](=[O:28])[N:1]1[C:9]2[C:4](=[CH:5][C:6]([N:10]3[C:14]4=[N:15][C:16]([CH:19]=[CH2:20])=[CH:17][CH:18]=[C:13]4[N:12]=[CH:11]3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4)c2n1
Reactant: CN(C)CCCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: C=Cc1ccc2ncn(-c3ccc4c(c3)CCN4C(=O)CCCN(C)C)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-5-yl)-5-vinyl-3H-imidazo[4,5-b]pyridine (48.0 mg, 0.14 mmol) (Intermediate 10.1), 4-(dimethylamino)butyric acid hydrochloride (36.3 mg, 0.21 mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (54.9 mg, 0.29 mmol), 4-dimethylaminopyridine (122.5 mg, 1.00 mmol), and dichloromethane (8 ml) is stirred for 24 h at ambient temperature. The mixture is successively extracted with saturated aqueous ammonium chloride and saturated aqueous sodium bicarbonate. The organic layer is dried over sodium sulfate and concentrated in vacuo to render 50.4 mg (94%) of the respective amide. HPLC (over 10 min 10-85% MeCN/100 mM aq. NaOAc): 92% purity, tR 6.27 min (tR(SM) 6.61 min).
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)([O:3][CH2:4][CH3:5])=[O:2].Br[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.C(=O)([O-])[O-].[K+].[K+]>N1C=CC=CC=1.[Cu]=O>[C:1]([C:6]1[N:7]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)([O:3][CH2:4][CH3:5])=[O:2]
Reactant: Brc1cccnc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: O=[Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: c1ccncc1
Product: CCOC(=O)c1cc2ccccc2n1-c1cccnc1

Procedure:
A solution of 10.0 g of 2-carboethoxyindole and 5 ml of 3-bromopyridine in 50 ml of pyridine is refluxed with 5.0 g of copper oxide and 5.0 g of potassium carbonate for 72 hours. Filtration and evaporation yields an oil which is chromatographed on 110 g of silica with 15% ethyl acetate in toluene to yield 2-carboethoxy-N-(3-pyridyl)indole as an oil; IR (CH2Cl2) 1705 cm-1.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]3[NH:22][C@H:21]([CH3:23])[CH2:20][O:19][C:11]3=2)[N:6]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:30](Br)[CH:31]=[CH2:32].Cl>CN(C=O)C.O>[CH2:32]([N:22]1[C:10]2[C:11](=[C:12]3[C:7](=[CH:8][CH:9]=2)[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[C:13]3[C:15]([F:18])([F:17])[F:16])[O:19][CH2:20][C@H:21]1[CH3:23])[CH:31]=[CH2:30]
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@H](C)CO3
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2OC[C@H]1C
Temperature: 50 °C
Reaction time: 12 h
Yield: 68.5 %

Procedure:
To a suspension of (R)-3,4-dihydro-8-isopropoxy-3-methyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline (13 mg, 0.04 mimol) and K2CO3 (28 mg, 0.2 mmol, 5 eq) in 1 ml DMF (0.04 M) was added allylbromide (0.03 mL, 0.4 mmol, 10 eq). The reaction was heated to 50° C. and allowed to stir for 12 h, whereupon the reaction was poured into 10 mL water and neutralized with 1N HCl. The aqueous layer was extracted with EtOAc (2 ×40 mL/mmol) and the combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated to afford 10 mg (75%) of (R)-4-allyl-3,4-dihydro-8-isopropoxy-3-methyl-10-(trifluoromethyl)-2H-[1,4]oxazino[2,3-f]quinoline. This material (10 mg, 0.03 mmol) was carried on directly according to General Method 4 (EXAMPLE 1) by treatment with 2 mL concentrated HCl (001.M) and heated at 50° C. for 6 h to afford 6 mg (67%) of Compound 106 after silica gel column chromatography (gradient 3:1 hexanes:EtOAc to 1:1 hexanes:EtOAc, gradient elution) 1H NMR (500 MHz, CDCl3) δ 11.89 (bs, 1H), 7.11 (s, 1H), 7.00 (d, J=8.8, 1H), 6.93 (d, J=8.8, 1H), 5.86 (m, 1H), 5.24 (m, 2H), 4.10 (m, 2H), 3.90 (m, 2H), 3.55 (m, 1H), 1.22 (d, J=6.8, 3H).
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4](=[O:52])[CH2:5][C:6]1[CH:11]=[C:10]([C@H:12]2[C@H:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:16]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:15]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:14]([CH2:42][O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[O:13]2)[CH:9]=[CH:8][C:7]=1[Cl:51].[C:53](O)(=[O:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1.Cl>CN(C=O)C>[Cl:51][C:7]1[CH:8]=[CH:9][C:10]([C@H:12]2[C@H:17]([O:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@@H:16]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:15]([O:34][CH2:35][C:36]3[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=3)[C@@H:14]([CH2:42][O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[O:13]2)=[CH:11][C:6]=1[CH2:5][C:4](=[O:52])[CH2:3][NH:2][C:53](=[O:60])[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: O=C(O)c1ccccc1
Reactant: NCC(=O)Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(CNC(=O)c1ccccc1)Cc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 51.5 %

Procedure:
To a mixture of 1-amino-3-(2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)phenyl)propan-2-one hydrochloride (1.75 g, 2.35 mmol), benzoic acid (430 mg, 3.53 mmol), EDCI (901 mg, 4.70 mmol) and HOBt (699 mg, 5.17 mmol) in DMF (15 mL) was added NMM (1.29 mL, 11.8 mmol). The resulting mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 1.0 M HCl solution, and extracted with EtOAc. The organic phase was dried over anhydrous MgSO4 and evaporated under vacuum. The residue was further purified by silica column chromatography to provide the titled amide intermediate (980 mg, 51%). MH+706.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[N:35]1[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[CH:36]=1>>[F:20][C:18]1[CH:19]=[C:14]([CH:15]=[C:16]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:24][C:23]=2[C:37]2[CH:36]=[N:35][CH:40]=[CH:39][CH:38]=2)[CH:17]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:34])=[C:8]([CH3:33])[CH:9]=1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(F)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: OB(O)c1cccnc1
Product: Cc1cc(Oc2cc(F)cc(Oc3ccc(C(F)(F)F)cc3-c3cccnc3)c2)ccc1CCC(=O)O

Procedure:
The title compound is prepare by reacting the compound of 3-{4-[3-(2-Bromo-4-trifluoromethyl-phenoxy)-5-fluoro-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with pyridine-3-boronic acid as in Example 38 to afford 0.115 g (66%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C29H21NO4F4 511, found 512 (M+1, 100%).
Reaction SMILES: I.[CH2:2]([N:9]1[CH2:13][C:12](=[O:14])[N:11]=[C:10]1SC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:17]1([CH2:23][C:24]2[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=2)[O:27][CH2:28][CH2:29][CH2:30][NH2:31])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C(N(CC)CC)C.[ClH:42]>C(O)C>[ClH:42].[ClH:42].[N:17]1([CH2:23][C:24]2[CH:25]=[C:26]([CH:32]=[CH:33][CH:34]=2)[O:27][CH2:28][CH2:29][CH2:30][NH:31][C:10]2[N:9]([CH2:2][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH2:13][C:12](=[O:14])[N:11]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: NCCCOc1cccc(CN2CCCCC2)c1
Reactant: CSC1=NC(=O)CN1Cc1ccccc1
Agent: Cl
Agent: I
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C1CN(Cc2ccccc2)C(NCCCOc2cccc(CN3CCCCC3)c2)=N1

Procedure:
1-Benzyl-2-methylthio-2-imidazolin-4-one hydroiodide (2.09 g) from the previous stage, 3-(3-piperidinomethylphenoxy)propylamine (1.49 g) and triethylamine (1.27 g) were refluxed in ethanol (35 ml) for 7 hours with stirring. The solution was allowed to cool overnight and evaporated under reduced pressure to give a residue. This residue was dissolved in 2N hydrochloric acid (30 ml), and extracted with chloroform (3×20 ml). The aqueous layer was taken to pH 10 with 2N sodium hydroxide and extracted with chloroform (3×30 ml). The latter chloroform extracts were dried (MgSO4) and evaporated under reduced pressure. The residue was washed thoroughly with cold diethyl ether and treated with dilute ethanolic HCL. Excess solvent was evaporated and the residue recrystallised from isopropanolacetone to afford 2-[3-(3-piperidinomethylphenoxy)propylamino]-1-benzylimidazolin-4-one dihydrochloride, m.p. 95°-98° C.
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C(N(C(C)C)CC)(C)C.[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[C:30](Br)[CH:29]=[CH:28][C:27]=1[F:33].[C:35]([C:37]1[CH:38]=[N:39][CH:40]=[C:41]([CH:44]=1)[C:42]#[N:43])#[CH:36]>O1CCOCC1.[Cu]I>[CH3:23][O:24][C:25](=[O:34])[C:26]1[CH:31]=[C:30]([C:36]#[C:35][C:37]2[CH:38]=[N:39][CH:40]=[C:41]([C:42]#[N:43])[CH:44]=2)[CH:29]=[CH:28][C:27]=1[F:33]
Reactant: C#Cc1cncc(C#N)c1
Reactant: COC(=O)c1cc(Br)ccc1F
Agent: [Cu]I
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: COC(=O)c1cc(C#Cc2cncc(C#N)c2)ccc1F
Reaction time: 2 h
Yield: 44.1 %

Procedure:
Sequentially add tri-tert-butylphosphine (88 mg, 0.437 mmol) in anhydrous 1,4-dioxane (1 mL), diisopropylethylamine (1.5 mL, 8.74 mmol), 5-bromo-2-fluorobenzoic acid methyl ester, (prepared as described in PREPARATION 42), (1.69 g, 7.28 mmol) and a solution of 5-ethynylnicotinonitrile, (prepared as described in PREPARATION 4), (0.93 g, 7.28 mmol) in anhydrous 1,4-dioxane (4 mL), to a stirring mixture of dichloro(benzonitrile)palladium (II) (84 mg, 0.218 mmol) and copper (I) iodide (28 mg, 0.146 mmol) in anhydrous 1,4-dioxane (1 mL) under nitrogen. Stir for 2 h and concentrate. Purify the residue twice by silica gel chromatography, eluting with 10:90 ethyl acetate:hexanes, to give the title compound as a white solid (0.9 g, 44%).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:6]=[CH:7][C:8]([CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:19]3[NH:18][C:17]4[CH:22]([CH2:25][C:26]([O:28]CC)=[O:27])[CH2:23][CH2:24][C:16]=4[C:15]=3[CH:14]=2)=[N:9][CH:10]=1)([CH3:3])[CH3:2].[Li+].[OH-].O.Cl>O1CCOCC1>[CH:1]([O:4][C:5]1[N:6]=[CH:7][C:8]([CH2:11][O:12][C:13]2[CH:21]=[CH:20][C:19]3[NH:18][C:17]4[CH:22]([CH2:25][C:26]([OH:28])=[O:27])[CH2:23][CH2:24][C:16]=4[C:15]=3[CH:14]=2)=[N:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3cnc(OC(C)C)cn3)cc21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)Oc1cnc(COc2ccc3[nH]c4c(c3c2)CCC4CC(=O)O)cn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 2-(7-hydroxy-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (0.035 g, 0.135 mmol) and cesium carbonate (0.048 g, 0.148 mmol) were dissolved in DMF (0.5 mL) and stirred at room temperature for 5 min. To this mixture at 0° C. was added a solution of 2-(bromomethyl)-5-isopropoxypyrazine (0.034 g, 0.148 mmol) in DMF (0.20 mL) and was stirred at room temperature for 60 h. The solids were removed by filtration. The filtrate was purified by HPLC to give ethyl 2-(7-((5-isopropoxypyrazin-2-yl)methoxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (11 mg). To the ester dissolved in dioxane (288 μL) was added aqueous LiOH (1 N, 72 μL). The mixture was stirred at room temperature for 16 h; before more aqueous LiOH (1 N, 200 μL) was added. Stirring was continued for 1 h. To the reaction mixture was added water (1.5 mL) and the reaction mixture was acidified to pH 3 with 1 N HCl. The mixture was purified by HPLC to give the title compound as a yellow solid (7 mg). LCMS m/z=382.4 [M+H]+; 1H NMR (500 MHz, CDCl3) δ ppm 1.32 (d, J=6.31 Hz, 6H), 1.95-2.18 (m, 1H), 2.28-2.41 (m, 1H), 2.56-2.79 (m, 4H), 3.36-3.56 (m, 1H), 5.09 (s, 2H), 5.15-5.33 (m, 1H), 6.71 (d, J=8.83 Hz, 1H), 6.94 (s, 1H), 7.20 (d, J=8.83 Hz, 1H), 8.20 (s, 1H), 8.30 (s, 1H), 10.37 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21](Cl)(=[O:23])=[O:22]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21]([NH:12][C:9]1[CH:10]=[CH:11][C:2]([Cl:1])=[C:3]2[C:8]=1[N:7]=[CH:6][CH:5]=[CH:4]2)(=[O:23])=[O:22]
Reactant: Nc1ccc(Cl)c2cccnc12
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Product: O=S(=O)(Nc1ccc(Cl)c2cccnc12)c1ccc(Cl)cc1Cl
Yield: 36.9 %

Procedure:
In a similar fashion using route 14 general procedure 26, 5-chloroquinolin-8-amine (Intermediate 27) (50 mg, 0.28 mmol), 2,4-dichlorobenzenesulfonyl chloride (103 mg, 0.42 mmol) gave the title compound (40 mg, 40%) after purification by column chromatography with DCM as the eluent.
Reaction SMILES: CS([S:5][CH2:6][CH2:7][O:8][C:9]1[C:10]([CH3:20])=[C:11]([CH:17]=[CH:18][CH:19]=1)[C:12]([O:14][CH2:15][CH3:16])=[O:13])(=O)=O.[Cl-].[Cl-].[Cl-].[Al+3].Cl.CCOCC>[N+](C)([O-])=O>[CH3:20][C:10]1[C:9]2[O:8][CH2:7][CH2:6][S:5][C:19]=2[CH:18]=[CH:17][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: CCOC(=O)c1cccc(OCCSS(C)(=O)=O)c1C
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOCC
Solvent: C[N+](=O)[O-]
Product: CCOC(=O)c1ccc2c(c1C)OCCS2
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
1.0 g (3.4 mmol) of ethyl 3-(2-methylsulfonylthioethoxy)-2-methylbenzoate are dissolved in 5 ml of nitromethane. 0.42 g (3.14 mmol) of aluminum trichloride is added. The mixture is stirred at room temperature for 45 min. Working-up is carried out by addition of 10 ml of 2N hydrochloric acid and subsequent extraction with MTB ether. The combined organic phases are washed with water and sodium carbonate solution, dried over sodium sulfate and the solvent is distilled off.
Reaction SMILES: [C:1]1([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:22]4[C:21](Cl)=[N:20][CH:19]=[N:18][C:17]=4[N:16]([C@H:24]4[CH2:29][CH2:28][C@H:27]([N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[CH2:26][CH2:25]4)[CH:15]=3)=[CH:10][C:9]=2[CH3:37])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C.COC1C=C(C2C3C(N)=NC=NC=3[N:59]([C@H]3CC[C@H](N4CCN(C)CC4)CC3)C=2)C=CC=1OC1C=CC=CC=1.CO[C@@H]1[C@@H](C(OC)=O)[C@@H]2[C@@H](CN3[C@H](C2)C2NC4C=C(OC)C=CC=4C=2CC3)C[C@H]1OC(C1C=C(OC)C(OC)=C(OC)C=1)=O>C(#N)C>[CH3:37][C:9]1[CH:10]=[C:11]([C:14]2[C:22]3[C:21]([NH2:59])=[N:20][CH:19]=[N:18][C:17]=3[N:16]([C@H:24]3[CH2:29][CH2:28][C@H:27]([N:30]4[CH2:31][CH2:32][N:33]([CH3:36])[CH2:34][CH2:35]4)[CH2:26][CH2:25]3)[CH:15]=2)[CH:12]=[CH:13][C:8]=1[O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1cc(-c2cn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1Oc1ccccc1
Reactant: Cc1cc(-c2cn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(Cl)c23)ccc1Oc1ccccc1
Agent: COC(=O)[C@H]1[C@H]2C[C@@H]3c4[nH]c5cc(OC)ccc5c4CCN3C[C@H]2C[C@@H](OC(=O)c2cc(OC)c(OC)c(OC)c2)[C@@H]1OC
Solvent: CC(=O)O
Solvent: CC#N
Product: Cc1cc(-c2cn([C@H]3CC[C@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1Oc1ccccc1

Procedure:
The title compound was prepared in a 75% yield from trans-4-{4-chloro-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-5-yl}-2-methylphenyl phenyl ether in a similar manner to that described for the preparation of trans-5-(3-methoxy-4-phenoxyphenyl)-7-[4-(4-methylpiperazino)cyclohexyl]-7H-pyrrolo[2,3-d]pyrimidin-4-amine acetate: 1H NMR (DMSO-d6, 400 MHz) δ 8.13(s, 1H), 7.42(m, 4H), 7.37(t, 2H), 7.27(m, 1H), 7.10 (t, 1H), 6.97(m, 3H), 6.11(bs, 2H), 4.55(m, 1H), 2.2-2.6(m, 9H), 2.22(s, 3H), 2.14 (s, 3H), 1.7-2.0(m, 6H), 1.45(m, 2H); MS MH+497.4; RP-HPLC (Hypersil HS, 5 μm, 100 A 4.6×250 mm; 5%-100% acetonitrile—0.05 M ammonium acetate over 25 min, 1 ml/min) tr 15.93 min.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:5][S:6][CH3:7].C(N(CC)CC)C.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[CH3:23][S:24]([O:1][CH2:2][C@@H:3]([NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH2:4][CH2:5][S:6][CH3:7])(=[O:26])=[O:25]
Reactant: CSCC[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSCC[C@@H](COS(C)(=O)=O)NC(=O)OC(C)(C)C
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
To a solution of (S)-tert-butyl 1-hydroxy-4-(methylthio)butan-2-ylcarbamate (1.0 g, 1.0 eq, Chem-Impex, Catalog #03206) in DCM at −25° C. was added triethylamine (2.5 eq), followed by methanesulfonyl chloride (2.0 eq). The mixture was stirred at −25° C. for 1 h and RT for 30 min, washed with 1 N HCl, sat. NaHCO3 and brine, dried and concentrated to give a residue, which was purified by flash chromatography column on silica gel using ethyl acetate and hexane (1:2) as eluent to give (S)-2-(tert-butoxycarbonylamino)-4-(methylthio)butyl methanesulfonate (1.1 g, 75%). 1H NMR (CDCl3, 300 MHz) d 4.25 (m, 2H, OCH2), 4.0 (br s, 1H, BocNHCH), 3.05 (s, 3H, SO2CH3), 2.55 (m, 2H, SCH2), 2.15 (s, 3H, SCH3), 1.85 (m, 2H, BocNHCHCH2CH2S), 1.45 (s, 9H, OC(CH3)3).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[I-].[CH2:45]([N+:49]1[N:53]=[C:52]([CH3:54])[S:51][C:50]=1[CH3:55])[CH2:46][CH2:47][CH3:48]>>[CH2:45]([N:49]1[N:53]=[C:52]([CH3:54])[S:51]/[C:50]/1=[CH:55]\[C:5]([C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=1)=[O:7])[CH2:46][CH2:47][CH3:48]
Reactant: CCCC[n+]1nc(C)sc1C
Reactant: O=C(O)c1cccc(Cl)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: CCCCN1N=C(C)S/C1=C\C(=O)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL vial 3-chlorobenzoic acid (0.9 mL of 0.2 M in DMA, 1.10 equiv) was added followed by the addition of HATU (76 mg in 0.7 mL of DMA, 0.2 mmol, 1.20 equiv.), DIEA (51 mg in 0.7 mL of DMA, 0.4 mmol, 2.40 equiv.), and finally 3-butyl-2,5-dimethyl-1,3,4-thiadiazol-3-ium iodide (49 mg in 0.7 mL of DMA, 0.17 mmol, 1 equiv.). The mixture was shaken overnight at room temperature and then concentrated in vacuo. The resulting residue was taken up in 1:1 DMSO/MeOH and purified by reverse phase HPLC using a method analogous to that described in Example 53 to provide the title compound. 1H NMR (500 MHz, DMSO-D6/D2O) δ ppm 0.92 (t, 3 H) 1.27-1.40 (m, 2 H) 1.72-1.80 (m, 2 H) 2.47-2.50 (m, 3 H) 4.27 (t, 2 H) 6.76 (s, 1 H) 7.46-7.53 (m, 1 H) 7.52-7.57 (m, 1 H) 7.94-7.99 (m, 1 H) 8.01-8.05 (m, 1 H); MS (ESI) m/z 309 (M+H)+.