Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:4]=1[NH2:5].C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27](Cl)=[O:28])=[CH:22][CH:21]=1.Cl>C(Cl)Cl>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:5][C:4]2[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:3]=2[O:2][CH3:1])=[O:28])=[CH:22][CH:21]=1
Reactant: O=C(Cl)Cc1ccc(Cl)cc1
Reactant: COc1ccc(N)c(OC)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(NC(=O)Cc2ccc(Cl)cc2)c(OC)c1
Temperature: 25 °C

Procedure:
To 3.56 g (20 mmol) of 2,4-dimethoxyaniline and 2.53 g (25 mmol) of triethylamine in 50 ml of methylene chloride are added dropwise, whilst cooling with ice, 3.97 g (21 mmol) of 4-chlorophenylacetyl chloride. The mixture is stirred for a further hour at ambient temperature, added to dilute hydrochloric acid and extracted with methylene chloride. The extracts are dried and evaporated down. The evaporation residue is triturated with petroleum ether and suction filtered. Yield: 5.2 g (85.0% of theory), Melting point: 134-135° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:34][C:35]1[CH:43]=[C:42]([F:44])[C:41]([S:45]([NH:48][CH:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)(=[O:47])=[O:46])=[CH:40][C:36]=1[C:37](O)=[O:38].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[Cl:34][C:35]1[C:36]([C:37]([N:11]2[CH2:10][CH2:9][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)([CH2:14][CH2:15][N:16]3[C@H:21]4[CH2:22][CH2:23][C@@H:17]3[CH2:18][CH:19]([N:24]3[C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[N:26]=[C:25]3[CH3:33])[CH2:20]4)[CH2:13][CH2:12]2)=[O:38])=[CH:40][C:41]([S:45]([NH:48][CH:49]2[CH2:53][CH2:52][CH2:51][CH2:50]2)(=[O:46])=[O:47])=[C:42]([F:44])[CH:43]=1
Reactant: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCNCC1
Reactant: O=C(O)c1cc(S(=O)(=O)NC2CCCC2)c(F)cc1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: Cc1nc2ccccc2n1C1C[C@H]2CC[C@@H](C1)N2CCC1(c2cccc(F)c2)CCN(C(=O)c2cc(S(=O)(=O)NC3CCCC3)c(F)cc2Cl)CC1
Yield: 40 %

Procedure:
0.103 g (0.23 mmol) 1-((1R,5S)-8-{2-[4-(3-fluorophenyl)piperidin-4-yl]ethyl}-8-azabicyclo[3.2.1]oct-3-yl)-2-methyl-1H-benzimidazole and 0.148 g (0.46 mmol) 2-chloro-4-fluoro-5-[(cyclopentylamino)sulfonyl]benzoic acid were combined following the HATU general procedure in Example 5. This compound was purified by reverse phase chromatography on a 0-100% gradient of 0.1% TFA in water in acetonitrile. 0.068 g obtained (40% yield). 1H NMR (300 MHz, DMSO-d6) δ 9.32-9.49 (br, 1H), 8.13-8.25 (m, 2H), 7.73-7.91 (m, 3H), 7.39-7.56 (m, 2H), 7.08-7.30 (m, 3H), 5.00-5.15 (m, 1H), 4.03-4.16 (m, 2H), 3.83-4.02 (m, 1H), 3.35-3.58 (m, 2H), 3.19-3.33 (m, 2H), 3.16 (s, 1H), 2.94-3.08 (m, 2H), 2.67-2.80 (m, 6H), 2.54-2.65 (m, 1H), 2.02-2.26 (m, 8H), 1.72-2.01 (m, 2H), 1.47-1.67 (m, 4H), 1.26-1.44 (m, 4H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5]C1C=C2C(C=CN2)=CC=1.COC(=O)CO[C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[N:26]([C:30](=[O:32])[NH2:31])[CH:25]=[C:24]2[N:33]=[C:34]=[O:35]>>[CH3:1][O:2][C:3](=[O:15])[CH2:4][O:5][C:29]1[CH:28]=[C:27]2[C:23]([C:24]([N:33]=[C:34]=[O:35])=[CH:25][N:26]2[C:30](=[O:32])[NH2:31])=[CH:22][CH:21]=1
Reactant: COC(=O)COc1ccc2cc[nH]c2c1
Reactant: COC(=O)COc1ccc2c(c1)c(N=C=O)cn2C(N)=O
Product: COC(=O)COc1ccc2c(N=C=O)cn(C(N)=O)c2c1

Procedure:
was prepared from (1H-indol-6-yloxy)-acetic acid methyl ester using the protocol described for the preparation of (1-carbamoyl-3-isocyanato-1H-indol-5-yloxy)-acetic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:13][C:14]1[CH:22]=[CH:21][C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=1)[CH2:8][CH2:9][CH2:10][NH:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[Cl:24][C:25]1[N:29]=[C:28](Cl)[S:27][N:26]=1.CS(C)=O>O>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:13][C:14]1[CH:22]=[CH:21][C:17]2[O:18][CH2:19][O:20][C:16]=2[CH:15]=1)[CH2:8][CH2:9][CH2:10][N:11]([C:28]1[S:27][N:26]=[C:25]([Cl:24])[N:29]=1)[CH3:12])([CH3:4])([CH3:2])[CH3:3]
Reactant: CNCCCN(Cc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C
Reactant: Clc1nsc(Cl)n1
Solvent: CS(C)=O
Solvent: O
Product: CN(CCCN(Cc1ccc2c(c1)OCO2)C(=O)OC(C)(C)C)c1nc(Cl)ns1
Yield: 69 %

Procedure:
A solution of benzo[1,3]dioxol-5-ylmethyl-(3-methylamino-propyl)-carbamic acid tert-butyl ester (10 g, 46 mmol), 3,5-dichloro-1,2,4-thiadiazole (7.1 g, 46 mmol), DMSO (20 mL) and TEA (20 mL) was stirred at r.t. for 20 min. Water (150 mL) was added and the solution was extracted with ethyl acetate (2×150 mL), washed with brine and dried over Na2SO4. Evaporation of the solvent gave 14 g (69%) of benzo[1,3]dioxol-5-ylmethyl-{3-[(3-chloro-[1,2,4]thiadiazol-5-yl)-methyl-amino]-propyl}-carbamic acid tert-butyl ester as a clear gum. The product was used directly in the next step. 1H-NMR (400 MHz, CD3OD) δ 6.77 (m, 3H), 5.96 (s, 2H), 4.35 (s, 2H), 3.4-3.0 (m, 6H), 1.84 (br s, 3H), 1.50 (s, 9H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=[C:9]([OH:17])[CH:8]=2)[CH2:3][CH2:2]1.[CH3:18][N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH3:29])([CH3:28])[C:20]1=[CH2:30].[CH2:31](OC(OCC)OCC)C>C(OCC)C>[CH3:18][N:19]1[C:20]2([O:17][C:9]3[CH:8]=[C:7]([N:4]4[CH2:3][CH2:2][O:1][CH2:6][CH2:5]4)[C:16]4[C:11]([C:10]=3[CH:31]=[CH:30]2)=[CH:12][CH:13]=[CH:14][CH:15]=4)[C:21]([CH3:28])([CH3:29])[C:22]2[C:27]1=[CH:26][CH:25]=[CH:24][CH:23]=2
Reactant: C=C1N(C)c2ccccc2C1(C)C
Reactant: CCOC(OCC)OCC
Reactant: Oc1cc(N2CCOCC2)c2ccccc2c1
Solvent: CCOCC
Product: CN1c2ccccc2C(C)(C)C12C=Cc1c(cc(N3CCOCC3)c3ccccc13)O2
Yield: 34 %

Procedure:
A mixture of 4-morpholino-2-naphthol (0.47 g;0.002 mol), prepared as in 2(b) above, 1,3,3-trimethyl-2-methyleneindole (0.8 g;0.0022 mol) and triethylorthoformate (10.0 ml) was stirred under nitrogen and heated to reflux for 18 hrs. The resulting purple solution was cooled and evaporated to remove the excess triethylorthoformate and the residue flash chromatographed over silica (40% diethyl ether in hexane) to yield an orange gum (0.28 g; yield 34%). Trituration of the gum with diethyl ether afforded the 1,3,3-trimethyl-6'-morpholinospiro [indoline-2,3'-[3H]-naphtho[2,1-b]pyran having the structure shown below as a pale brown solid, m.pt 191°-194° C. ##STR20##
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=[CH:4][N:3]=1.[C:16]([C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1)([CH3:19])([CH3:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O.C(OCC)C>[C:16]([C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][C:2]1[C:7]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[C:6]([N:13]([CH3:15])[CH3:14])[N:5]=[CH:4][N:3]=1)([CH3:19])([CH3:17])[CH3:18]
Reactant: CC(C)(C)c1cccc(O)c1
Reactant: COC(=O)Cc1c(Cl)ncnc1N(C)C
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(Oc2cccc(C(C)(C)C)c2)ncnc1N(C)C
Yield: 87.4 %

Procedure:
A mixture of methyl 4-chloro-6-dimethylamino-pyrimidin-5-yl-acetate (22.9 g, 100 mmol), 3-tert.butylphenol (15.0 g, 100 mmol), potassium carbonate (20.7 g, 150 mmol) and a catalytic amount of 18-crown-6 is heated in dimethylformamide (50 ml) at 130° C. for 6 hours. The reaction mixture is diluted with diethyl ether, washed with 2n NaOH and brine, dried (MgSO4) and evaporated to give methyl 4-(3-tert.butylphenoxy)-6-dimethylamino-pyrimidin-5-yl-acetate as a yellow oil (30 g).
Reaction SMILES: Br.[CH2:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:13])=[C:9]([OH:12])[CH:10]=2)[CH2:5][CH2:4][NH:3]1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].O>N1C=CC=CC=1>[CH3:18][C:17]([Si:14]([CH3:16])([CH3:15])[O:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[O:12][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:2][NH:3][CH2:4][CH2:5]2)([CH3:20])[CH3:19]
Reactant: Oc1cc2c(cc1O)CNCC2
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Br
Solvent: c1ccncc1
Solvent: O
Product: CC(C)(C)[Si](C)(C)Oc1cc2c(cc1O[Si](C)(C)C(C)(C)C)CNCC2
Yield: 100 %

Procedure:
A mixture of 1.0 g of 1,2,3,4-tetrahydro-6,7-isoquinolinediol hydrobromide and 2.45 g of t-butyl dimethylsilyl chloride in 25.0 mL of pyridine is heated under reflux for 4.5 hours, cooled, poured into water and extracted with diethyl ether. The diethyl ether extract is washed with brine, dried, filtered. The filtrate is evaporated to yield a brown oil. This oil is purified by Kugelrohr distillation to yield 1.6 g of the desired product as a yellow solid, b.p. 155° C., 350 torr.
Reaction SMILES: [CH2:1]([OH:6])[C:2]([F:5])([F:4])[F:3].[H-].[Na+].[NH:9]([C:16]1[N:17]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:18]2[C:23]([C:24](=[O:26])[CH:25]=1)=[C:22](Cl)[N:21]=[C:20]([CH3:28])[CH:19]=2)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CS(C)=O>[NH:9]([C:16]1[N:17]([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:18]2[C:23]([C:24](=[O:26])[CH:25]=1)=[C:22]([O:6][CH2:1][C:2]([F:5])([F:4])[F:3])[N:21]=[C:20]([CH3:28])[CH:19]=2)[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: OCC(F)(F)F
Reactant: Cc1cc2c(c(Cl)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Cc1cc2c(c(OCC(F)(F)F)n1)c(=O)cc(Nc1ccccc1)n2-c1ccccc1
Temperature: 60 °C
Reaction time: 16 h
Yield: 68 %

Procedure:
Trifluoroethanol (0.08 mL, 1.1 mmol) was added to a suspension of NaH (60% oil dispersion, 44 mg, 1.1 mmol) in DMSO (4 mL) at 0° C., and the mixture was heated at 60° C. for 1 h. The mixture was cooled to room temperature and a solution of 2-anilino-5-chloro-7-methyl-1-phenyl-1,6-naphthyridin-4(1H)-one (200 mg, 0.55 mmol) in DMSO (2 mL) was added. The resulting mixture was stirred at 50° C. for 16 h. The reaction mixture was cooled, poured into ice water and extracted with CH2Cl2. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by a Biotage silica gel chromatography (2:1 EtOAc:Hex) to provide 2-anilino-7-methyl-1-phenyl-5-(2,2,2-trifluoroethoxy)-1,6-naphthyridin-4(1H)-one (159 mg, 68%): LCMS RT: 2.65 min, MH+: 426.4. This transformation can be accomplished by using other aprotic solvents such as DMF, THF and dioxane with temperatures appropriate for these solvents. Commercially available alkoxides can also be used in the absence of base.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][C@H:8]3[N:13]([CH2:14][CH:15]4[CH2:17][CH2:16]4)[CH2:12][CH2:11][C@:10]45[C@H:18]([C:20]([CH2:22][CH2:23][C@@:9]34[OH:24])=O)[O:19][C:4]([C:5]=25)=[C:3]([OH:25])[CH:2]=1.Cl.[CH3:27][NH2:28].[H][H]>CO.[Pt]=O>[CH:15]1([CH2:14][N:13]2[CH2:12][CH2:11][C@:10]34[C:5]5[C:4]6[O:19][C@H:18]3[C@@H:20]([NH:28][CH3:27])[CH2:22][CH2:23][C@@:9]4([OH:24])[C@H:8]2[CH2:7][C:6]=5[CH:1]=[CH:2][C:3]=6[OH:25])[CH2:17][CH2:16]1
Reactant: CN
Reactant: [H][H]
Reactant: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Agent: O=[Pt]
Agent: Cl
Solvent: CO
Product: CN[C@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 79.5 %

Procedure:
Naltrexone (1.0 g) and methylamine hydrochloride (0.99 g, 5 equivalents) were dissolved in methanol (15 ml) followed by stirring for 20 minutes at room temperature. This reaction solution was added to platinum oxide (0.05 g, 5 w %) in methanol (10 ml) activated in advance in a hydrogen atmosphere followed by hydrogenation for 4 hours at room temperature and atmospheric pressure. The catalyst was removed by Celite filtration and the solvent was distilled off. After adding saturated aqueous sodium bicarbonate (20 ml) and extracting with chloroform (20 ml×2), the extract was washed with saturated brine and dried with anhydrous sodium sulfate, and the solvent was distilled off. The resulting dark reddish-violet oily substance was dissolved in chloroform (2 ml) followed by addition of ethyl acetate (4 ml) to obtain the target compound (0.83 g, yield: 79%) by crystallization. A portion of this compound was removed and various spectra were measured in the form of a hydrochloride. mp 270° C. (decomposition)
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH3:10][NH:11][CH:12]=[O:13].[H-].[Na+]>>[CH3:10][N:11]([CH2:8][C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1)[CH:12]=[O:13]
Reactant: ClCc1ccncc1
Reactant: CNC=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CN(C=O)Cc1ccncc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 4-picolyl chloride-HCl (15 g, 91.4 mmol) and N-methylformamide (53.4 mL, 914 mmol) in 300 mL of TMF was added 80% NaH in mineral oil (5.48 g, 183 mmol). After stirring at rt for 18 h the mixture was quenched with ice water and partitioned between CH2 Cl2 and H2O. The organic extract was washed with aqueous NaCl and dried over MgSO4. The solvent was removed in vacuo, and the residue was purified by flash chromatography, eluting with 50:1 CH2 Cl2 /MeOH. The title compound was obtained as a pale yellow oil (10.5 g, 76%): ESMS (m/z): 151 (M+ +H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:23])=[CH:4][C:5]2[CH:11]([C:12]3[C:20]4[O:19][CH2:18][CH2:17][C:16]=4[CH:15]=[CH:14][CH:13]=3)[CH2:10][N:9]([CH3:21])[CH2:8][CH2:7][C:6]=2[CH:22]=1.[CH3:24][O:25]CCl.O1CCC[CH2:29]1>>[Cl:1][C:2]1[C:3]([O:23][CH3:29])=[CH:4][C:5]2[CH:11]([C:12]3[C:20]4[O:19][CH2:18][CH2:17][C:16]=4[CH:15]=[CH:14][CH:13]=3)[CH2:10][N:9]([CH3:21])[CH2:8][CH:7]([O:25][CH3:24])[C:6]=2[CH:22]=1
Reactant: CN1CCc2cc(Cl)c(O)cc2C(c2cccc3c2OCC3)C1
Reactant: COCCl
Reactant: C1CCOC1
Product: COc1cc2c(cc1Cl)C(OC)CN(C)CC2c1cccc2c1OCC2
Temperature: 35 °C
Reaction time: 3 h

Procedure:
(+)-8-chloro-5-(2,3-dihydrobenzofuran-7-yl)-3-methyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-ol (4.95 g, 0.015 mol) and potassium-tert butylate (1.85 g, 0.016 mol) are dissolved in dry tetrahydrofuran (40 ml) at 5° C. Chloromethyl methyl ether (1.51 g, 0.019 mol) is added, the temperature raising to 35° C. The reaction mixture is stirred for three hours, then evaporated to dryness under reduced pressure. The residue is partitioned between water and toluene after adjusting the pH to 8.0 by addition of 1N sodiumhydroxide. The toluene phase is dried over magnesium sulphate, and evaporated to dryness under reduced pressure. The residue is crystallized from ethylacetate (11 ml).
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])[CH3:3].C([Li])CCC.[C:32](=[O:34])=[O:33].Cl>C1COCC1>[CH3:4][C:2]([NH:5][S:6]([C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]([CH2:18][CH2:19][O:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][O:22]2)[C:10]=1[C:32]([OH:34])=[O:33])(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: O=C=O
Reactant: CC(C)(C)NS(=O)(=O)c1cn(CCOC2CCCCO2)c2ccccc12
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1c(C(=O)O)n(CCOC2CCCCO2)c2ccccc12
Temperature: -60 °C
Yield: 90.2 %

Procedure:
A solution of 1.8 g (4.7 mmol) of N-(1,1-dimethylethyl)-1-[2-(tetrahydro-2-pyranyloxy)-ethyl]-1H-indole-3-sulfonamide was dissolved in 30 mL anhydrous THF and cooled to -60° C. under nitrogen atmosphere. To this was added dropwise, with stirring, 8.0 mL (12.8 mmol) 1.6M butyllithium in hexanes and the mixture allowed to warm to 0° C. for 20 minutes then recooled to -60° C. A large excess of crushed dry ice (4 g CO2) was added all at once then the mixture was stirred overnight at ambient temperature. Hydrochloric acid (1N, 15 mL) plus ice was then added and the mixture extracted three times with ethyl acetate. The organic extracts were washed once with brine, dried (Na2SO4) and evaporated in vacuo. The solid residue was triturated and collected by filtration with n-butyl chloride and hexane to afford 1.80 g of the title compound, m.p. 149°-151° C. dec.
Reaction SMILES: [CH:1]1([N:4]([CH3:11])[CH2:5]/[CH:6]=[CH:7]/[C:8]([OH:10])=O)[CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[Cl:18][C:19]1[N:35]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([NH:42][CH3:43])[CH:37]=2)[C:22]2[N:23]=[CH:24][N:25]=[C:26]([NH:27]C(=O)OC(C)(C)C)[C:21]=2[C:20]=1[C:44]1[CH:49]=[CH:48][C:47]([Cl:50])=[CH:46][CH:45]=1.C(O)(C(F)(F)F)=O>CC#N.CN(C=O)C>[NH2:27][C:26]1[C:21]2[C:20]([C:44]3[CH:45]=[CH:46][C:47]([Cl:50])=[CH:48][CH:49]=3)=[C:19]([Cl:18])[N:35]([C:36]3[CH:37]=[C:38]([N:42]([CH3:43])[C:8](=[O:10])/[CH:7]=[CH:6]/[CH2:5][N:4]([CH:1]4[CH2:2][CH2:3]4)[CH3:11])[CH:39]=[CH:40][CH:41]=3)[C:22]=2[N:23]=[CH:24][N:25]=1
Reactant: CNc1cccc(-n2c(Cl)c(-c3ccc(Cl)cc3)c3c(NC(=O)OC(C)(C)C)ncnc32)c1
Reactant: CN(C/C=C/C(=O)O)C1CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CC#N
Product: CN(C(=O)/C=C/CN(C)C1CC1)c1cccc(-n2c(Cl)c(-c3ccc(Cl)cc3)c3c(N)ncnc32)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 36.2 %

Procedure:
A suspension of (E)-4-(cyclopropyl(methyl)amino)but-2-enoic acid (110 mg, 0.34 mmol) in dry MeCN (5.0 mL) was cooled to 0° C. Oxalyl chloride (0.5 mL, 0.69 mmol) and one drop of DMF were added, respectively. The resulting mixture was stirred at 0° C. for 2 hrs. After the suspension was gradually turned into a clear solution, the solvents were removed under reduced pressure (below 35° C.). Dry DCM (5.0 mL) was added and evaporated to remove excess oxalyl chloride. The freshly generated acid chloride was dissolved in dry DCM (5.0 mL) was added dropwise to a solution of tert-butyl 6-chloro-5-(4-chlorophenyl)-7-(3-(methylamino)phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylcarbamate (22) (81 mg, 0.18 mmol). After the resulting mixture was stirred at r.t. for 1 hr, TFA (2.0 mL) was introduced. Stirring was continued for 30 min before it was finally quenched with MeOH (1.0 mL). The reaction mixture was concentrated under reduced pressure. The residue was purified by preparative HPLC (RP, C18, 10 to 95% acetonitrile in water (0.2% NH3H2O)) to afford (E)-N-(3-(4-amino-6-chloro-5-(4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)phenyl)-4-(cyclopropyl(methyl)amino)-N-methylbut-2-enamide (23) (34 mg, 39% yield) as a white solid. LC-MS (ESI): m/z (M/M+2) 521.2/523.1. 1H NMR (400 MHz, DMSO) δ 8.12 (s, 1H), 7.64 (t, J=7.9 Hz, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.53-7.43 (m, 5H), 6.75-6.63 (m, 1H), 6.24 (br, 1H), 6.09-5.96 (m, 1H), 3.29 (s, 3H), 3.11 (d, J=6.2 Hz, 2H), 2.10 (s, 3H), 1.63-1.54 (m, 1H), 0.38-0.26 (m, 2H), 0.25-0.15 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9]([CH3:11])[NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:14][Si:15]([CH3:22])([CH3:21])[CH2:16][CH2:17][O:18][CH2:19]Cl.N1C=CC=CC=1>O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]([CH2:19][O:18][CH2:17][CH2:16][Si:15]([CH3:22])([CH3:21])[CH3:14])[C:9]([CH3:11])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: Cc1nc2cc(Br)cnc2[nH]1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: c1ccncc1
Product: Cc1nc2ncc(Br)cc2n1COCC[Si](C)(C)C
Yield: 40 %

Procedure:
8.00 g of 6-bromo-2-methyl-3H-imidazo[4,5-b]pyridine in 275 ml of tetrahydrofuran is initially introduced in a flask. 1.66 g of sodium hydride (60% in paraffin oil) are added in portions with ice-cooling. 7.00 ml of 2-trimethylsilylethoxy-methyl chloride is subsequently added dropwise at about −30° C., and the mixture is stirred at 25° C. under nitrogen until the pyridine has reacted completely (HPLC check, about 4 hours). The cooled reaction solution is added to about 200 ml of water and extracted three times with EA. The combined organic phases are dried over sodium sulfate and purified by means of column chromatography (gradient heptane: EA 5-100% in 34 min.), giving 5.30 g of 6-bromo-2-methyl-1-(2-trimethylsilanylethoxymethyl)-1H-imidazo[4,5-b]pyridine as white solid (yield 40%, content 99%); MS-FAB (M+H+)=343.1; Rf (polar method): 2.59 min.
Reaction SMILES: O1CCCC1.[Cl:6][C:7]1[CH:13]=[C:12]([Cl:14])[C:11]([F:15])=[CH:10][C:8]=1[NH2:9].[F:16][B-:17]([F:20])([F:19])[F:18].[H+].[N:22]([O-])=O.[Na+]>O>[F:16][B-:17]([F:20])([F:19])[F:18].[Cl:6][C:7]1[CH:13]=[C:12]([Cl:14])[C:11]([F:15])=[CH:10][C:8]=1[N+:9]#[N:22]
Reactant: Nc1cc(F)c(Cl)cc1Cl
Reactant: O=N[O-]
Agent: F[B-](F)(F)F
Agent: [H+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: N#[N+]c1cc(F)c(Cl)cc1Cl

Procedure:
165 ml of tetrahydrofuran are added to 100 g of 2,4-dichloro-5-fluoroaniline at room temperature. To this solution are added 333 ml of tetrafluoroboric acid (50% strength) with cooling. 57.5 g of sodium nitrite in 117 ml of water are added to the reaction mixture cooled to 5°-10° C. in such a way that the internal temperature is 7°-13° C. After addition is completed, the 0° C. solution is filtered. The residue is washed with tetrahydrofuran and ice-cold water. 121 g of product remain.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:14])([CH3:13])[C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1)[CH3:2].[I:15]N1C(=O)CCC1=O.S(=O)(=O)(O)O.S([O-])(O)=O.[Na+]>C(O)(=O)C.O>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:13])([CH3:14])[C:10]([OH:12])=[O:11])=[CH:5][C:4]=1[I:15])[CH3:2]
Reactant: O=C1CCC(=O)N1I
Reactant: CCc1ccc(C(C)(C)C(=O)O)cc1
Agent: O=S(=O)(O)O
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCc1ccc(C(C)(C)C(=O)O)cc1I
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(4-Ethylphenyl)-2-methylpropanoic acid (58.1 g, 302.2 mmol) was dissolved in acetic acid (175 ml), added with N-iodosuccinimide (71.4 g, 317.3 mmol, 1.05 eq.) and conc. sulfuric acid (75 ml) at 0° C. Thereafter, the mixture was stirred at room temperature for 2 hrs. After cooling the reaction solution to 0° C., 10% aqueous solution of sodium hydrogen sulfite (100 ml) was added and the mixture was stirred for 1 hr. H2O (450 ml) was added to the mixture and the precipitated solid was filtered to obtain the title compound as a crude product. Ethanol (150 ml) and 10% aqueous solution of sodium hydrogen sulfite (50 ml) were added to the crude product, and the mixture was dissolved under heating at 50° C. After confirming the dissolution, the solution was cooled to room temperature, added with H2O (300 ml), and then stirred at 0° C. for 1 hr. The precipitated solid was filtered to obtain the title compound (95.8 g, 99%).
Reaction SMILES: CC1[N:3]([C:8]2[CH:9]=[C:10]([C:18](O)([CH3:20])C)[CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=2)C(C)=CC=1.Cl.NO.[OH-:25].[K+].[CH3:27]CO>O>[NH2:3][C:8]1[CH:9]=[C:10]([CH2:18][CH:20]([OH:25])[CH3:27])[CH:11]=[C:12]([C:14]([F:15])([F:16])[F:17])[CH:13]=1
Reactant: Cc1ccc(C)n1-c1cc(C(C)(C)O)cc(C(F)(F)F)c1
Reactant: CCO
Reactant: [OH-]
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: O
Product: CC(O)Cc1cc(N)cc(C(F)(F)F)c1
Temperature: 110 °C

Procedure:
To a solution of 2-[3-(2,5-dimethyl-1H-pyrrol-1-yl)-5-(trifluoromethyl)phenyl]-propan-2-ol (2.29 g, 7.70 mmol) in EtOH (70 mL) and water (41 mL), was added hydroxylamine hydrochloride (16.1 g, 23.1 mmol) and potassium hydroxide (8.64 g, 154 mmol). The reaction mixture was heated at 110° C. for 18 h, and then allowed to cool to rt. The solvents were evaporated and the residue was dissolved in water and extracted with EtOAc (2×). The organic solutions were combined, washed with brine, dried over Na2SO4, filtered and evaporated. The residue was triturated with Et2O and the filtrate was evaporated to provide -[3-amino-5-(trifluoromethyl)phenyl]propan-2-ol (1.70 g, quant). 1H NMR (400 MHz,CDCl3) δ: 7.08 (s, 1H), 6.99 (s, 1H), 6.79 (s, 1H), and 1.56 (s, 6H).