Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][O:11][C:12]([C:14]3[S:15][C:16]([CH3:20])=[C:17]([NH2:19])[CH:18]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1.[CH2:21]([N:28]=[C:29]=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCOCC1.C(OCC)C>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][O:11][C:12]([C:14]3[S:15][C:16]([CH3:20])=[C:17]([NH:19][C:29]([NH:28][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:30])[CH:18]=3)=[O:13])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: Cc1sc(C(=O)OCc2ccc3c(c2)OCO3)cc1N
Reactant: O=C=NCc1ccccc1
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cc1sc(C(=O)OCc2ccc3c(c2)OCO3)cc1NC(=O)NCc1ccccc1
Reaction time: 72 h
Yield: 66 %

Procedure:
5-Methyl-4-amino-thiophene-2-carboxylic acid 1,3-benzodioxol-5-ylmethyl ester from Step 2 (0.15 g, 0.5 mmol) was dissolved in hot 1,4-dioxane (6-8 mL) under an inert atmosphere, stirred, and treated with benzyl isocyanate (0.07 g, 0.5 mmol). After 72 hours at room temperature, the mixture was diluted with diethyl ether (50 mL). After another hour the precipitate was filtered off, rinsed with ether, and dried to afford 0.14 g of 4-(3-benzyl-ureido)-5-methyl-thiophene-2-carboxylic acid 1,3-benzodioxol-5-ylmethyl ester; mp 216-217° C.
Reaction SMILES: C([O:5][C:6](=[O:19])[C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][CH2:15][CH2:16][CH:17]=[CH2:18])[CH:8]=1)(C)(C)C>C(O)(C(F)(F)F)=O>[CH2:15]([NH:14][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([CH3:13])[N:10]=1)[C:6]([OH:19])=[O:5])[CH2:16][CH:17]=[CH2:18]
Reactant: C=CCCNc1cc(C(=O)OC(C)(C)C)cc(C)n1
Solvent: O=C(O)C(F)(F)F
Product: C=CCCNc1cc(C(=O)O)cc(C)n1

Procedure:
A solution of 86 mg (0.33 mmol) 2-but-3-enylamino-6-methyl-isonicotinic acid tert-butyl ester in 2 ml TFA is stirred for 18 h and evaporated. The title compound thus obtained is used in the next step without further purification.
Reaction SMILES: Cl.C(O[C:7]([NH:9][C@@H:10]([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)[C:11]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[NH:21][C:20]2=[O:28])[CH2:15][CH2:14]1)=[O:12])=O)(C)(C)C.C(N(CC)CC)C.C(=O)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.S([O-])([O-])(=O)=O.[Mg+2].[BH4-].[Na+].C(=O)([O-])O.[Na+]>CO.O.ClCCl>[ClH:38].[CH2:7]([NH:9][C@@H:10]([CH2:29][O:30][CH2:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[C:34]([Cl:39])[CH:33]=1)[C:11]([N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[NH:21][C:20]2=[O:28])[CH2:15][CH2:14]1)=[O:12])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: O=Cc1ccccc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccc(Cl)c(Cl)c1)C(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: O=C([C@H](COCc1ccc(Cl)c(Cl)c1)NCc1ccccc1)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 5 h
Yield: 135.6 %

Procedure:
Methanolic hydrogen chloride (4M, 2 mL) was added to a solution of (S)-1-[2-t-butoxycarbonylamino-3-(3,4-dichlorobenzyloxy)propionyl]-4-(2-keto-1-benzimidazolinyl)piperidine (298 mg, 0.53 mmol) in methanol (2 mL) and the mixture was stirred at room temperature for 5 h. The solvent was evaporated under reduced pressure, dichloromethane (5 mL), triethylamine (0.148 mL, 107 mg, 1.06 mmol), benzaldehyde (0.065 mL, 67 mg, 0.64 mmol) and magnesium sulfate (300 mg) were added. The mixture was stirred at room temperature for 4 h., filtered and the solvent was evaporated under reduced pressure. Methanol (5 mL) was added, the mixture was cooled to 0° C. and sodium borohydride (40 mg, 1.06 mmol) was added. The mixture was stirred at room temperature for 1 h., aqueous sodium hydrogen carbonate (saturated, 20 mL) and water (10 mL) were added and the mixture was extracted with dichloromethane (3×20 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with CH2Cl2 /MeOH/NH3 (Aq.) (99:1:0.1 increasing to 95:5:0.5). The residue was dissolved in methanol (5 mL), cooled to 0° C. and methanolic hydrogen chloride (1M, 0.44 mL) was added. The solvent was evaporated under reduced pressure and the residue was triturated with ether (5 mL). The solid was collected and dried in vacuo to give the title compound as a colorless solid (212 mg, 68%), m.p. 148°-151° C. Found: C, 57.18; H, 5.29; N, 9.27. C29H30Cl2N4O3.HCl.H2O requires: C, 57.29; H, 5.47; N, 9.22%. m/e (ES+) 553 (MH+).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[Br:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[S:18][C:14]=4[CH:13]=3)[CH:9]=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4ccc(Br)nc43)cc2s1
Temperature: 100 °C
Yield: 21.3 %

Procedure:
A stirred mixture of 6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (50 mg, 0.123 mmol) from Step 4 of this Example, (1R,2R)-(−)-2-aminocyclohexanol (42 mg, 0.369 mmol), and DIEA (46 mg, 0.369 mmol) in anhydrous DMA (1 mL) was heated in a sealed vessel at 100° C. for 15 h. The reaction was allowed to cool to rt and then was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HOAc) and CH3CN (0.05% HOAc) as the mobile phase and Varian Pursuit XRs diphenyl column as the stationary phase to afford (1R,2R)-2-((6-((5-bromo-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (12 mg, 21%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1H), 7.98-8.10 (m, 2H), 7.64 (d, J=1.1 Hz, 1H), 7.48 (d, J=8.5 Hz, 1H), 7.31 (m, 1H), 7.18 (dd, J=1.6, 8.2 Hz, 1H), 5.46 (s, 2H), 4.79 (br s, 1H), 3.50 (m, 1H), 3.30 (m, 1H), 2.04 (m, 1H), 1.87 (m, 1H), 1.65-1.67 (m, 2H), 1.12-1.34 (m, 4H). LCMS (ESI) m/z 458 and 460 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH:8]=[CH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:16])[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:18].O1CCOCC1>[Cu-]=O.O>[C:11]1([CH3:16])[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH:9]=[CH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH2:18])[CH:7]=1
Reactant: Cc1ccccc1C=Cc1ccnc(Br)c1
Reactant: [NH4+]
Agent: O=[Cu-]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: Cc1ccccc1C=Cc1ccnc(N)c1
Temperature: 150 °C

Procedure:
A 2 mL microwave reaction tube is charged with the mixture of E and Z 2-bromo-4-(2-o-tolyl-vinyl)-pyridine (510 mg, 1.9 mmol), Copper (I) oxide (53 mg, 0.37 mmol), Ammonium Hydroxide (28%, 0.5 mL) and 1-4-dioxane (0.5 mL). The reaction mixture is heated at 150° C. for 30 min in a microwave reactor. Then water (5 mL) is added and the mixture is extracted with EtOAc (3×20 mL). The combined organic layers are washed with brine, dried over anhydrous sodium sulfate and concentrated. The crude is purified by silica flash column chromatography eluting with EtOAc in Heptane (gradient from 0% to 100%) to give the desired mixture of products (210 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1.[CH2:8](O)[CH2:9][CH2:10][CH2:11][CH2:12]C.OS([O-])(=O)=O.[Na+]>C1(C)C=CC=CC=1>[CH2:1]([O:2][C:3]1[CH:7]=[CH:6][S:5][CH:4]=1)[CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCO
Reactant: COc1ccsc1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCCCCCOc1ccsc1
Temperature: 125 °C
Reaction time: 3 h

Procedure:
20 cm3 of 3-methoxythiophene (0.2 mol) and 50 cm3 of 1-hexanol were dissolved in 30 cm3 of toluene, and 1 g of NaHSO4 (0.01 mol) was added. The mixture was heated to 125° C. and stirred, and about 10 cm3 of a mixture of methanol and toluene were distilled off through a Vigreux column at a head temperature of 63° to 64° C., which took about 3 hours. The mixture was then washed three times with 50 cm3 of saturated NaHCO3 solution until neutral, dried over MgSO4 and fractionated in vacuo. After the toluene had been distilled off together with excess haxanol, 34 g of 3-n-hexyloxythiophene distilled over at 70° C. and 0.13 mbar, which corresponds to 92% of the theoretical yield. 97% pure by GC; 1H-NMR and mass spectrum confirm the structure.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)([OH:14])[CH2:10][CH2:9]1)C1C=CC=CC=1.[C:23](O)(=[O:25])[CH3:24]>C(O)C.[Pd]>[C:23]([O:14][C:11]1([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)(=[O:25])[CH3:24]
Reactant: CC(=O)O
Reactant: OC1(Cc2ccc(F)cc2)CCN(Cc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(=O)OC1(Cc2ccc(F)cc2)CCNCC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 1-benzyl-4-(4-fluoro-benzyl)-piperidin-4-ol (5.87 g, 19.6 mmol) in ethanol (80 ml) is treated with acetic acid (1 ml) and with 10% Pd on carbon (1 g). The mixture is stirred at RT under an atmosphere of hydrogen for 20 hours. The mixtre is filtered and the filtrate evaporated. The crude product is treated with dichloromethane. The resultant suspension is filtered and the white solid obtained is washed with cold dichloromethane to afford 4-(4-fluoro-benzyl)-piperidin-4-ol acetate [MH]+ 210.1
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[C:4]([CH3:13])([CH2:11][CH3:12])[C:3]1=[CH2:14].[N:15]([C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][C:18]=1[OH:27])=O>C(O)C>[CH3:1][N:2]1[C:10]2=[N:9][CH:8]=[CH:7][CH:6]=[C:5]2[C:4]([CH3:13])([CH2:11][CH3:12])[C:3]21[CH:14]=[N:15][C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]([O:25][CH3:26])=[CH:19][C:18]=1[O:27]2
Reactant: C=C1N(C)c2ncccc2C1(C)CC
Reactant: COc1cc(O)c(N=O)c(OC)c1
Solvent: CCO
Product: CCC1(C)c2cccnc2N(C)C12C=Nc1c(OC)cc(OC)cc1O2

Procedure:
5.0 grams of the thus prepared 1,3-dimethyl-3-ethyl-2-methylene-1,7-diazaindane product were added to about 80 milliliters of ethanol and warmed in a 100 milliliter round bottom flask. When the internal temperature of the flask contents reached 60° C., 3.3 grams of 2-nitroso-3,5-dimethoxyphenol were added to the flask. The mixture was allowed to reflux overnight. The reaction mixture was allowed to cool down and a silica gel column was used to isolate the desired product, i.e., 1',3'-Dihydro-1',3'-dimethyl-3'-ethyl- 5,7-dimethoxyspiro-[2H-1,4-benzoxazine-2,2'-[2H]pyrrolo[2,3-b]pyridine]. Identification was confirmed by appropriate spectral analysis.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([N:13]2[CH2:17][CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[C:25]([F:28])([F:27])[F:26])[CH2:14]2)=[O:12])[CH2:3][CH2:2]1>CO.[Pd]>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([C:11]([N:13]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[CH:20][C:19]=3[C:25]([F:26])([F:28])[F:27])[CH2:14]2)=[O:12])[CH2:3][CH2:2]1
Reactant: O=C(N1CC=C(c2ccc(F)cc2C(F)(F)F)C1)N1CCOc2ccccc21
Agent: [Pd]
Solvent: CO
Product: O=C(N1CCC(c2ccc(F)cc2C(F)(F)F)C1)N1CCOc2ccccc21
Yield: 213.2 %

Procedure:
0.07 g of (2,3-dihydrobenzo[1,4]oxazin-4-yl)[3-(4-fluoro-2-(trifluoromethyl)phenyl)-2,5-dihydropyrrol-1-yl]methanone in 3.57 ml of methanol is hydrogenated in an H-Cube device under hydrogen at atmospheric pressure with a cartridge of 100 mg of 10% palladium-on-charcoal. After concentrating to dryness, the crude reaction product obtained is chromatographed on silica gel, elution being carried out with a mixture of 5% of ethyl acetate in dichloromethane. 0.15 g of (2,3-dihydrobenzo[1,4]oxazin-4-yl)[3-(4-fluoro-2-(trifluoromethyl)phenyl)pyrrolidin-1-yl]methanone is obtained.
Reaction SMILES: C[Si](C)(C)[CH:3]1[S:8][CH2:7][CH2:6][CH2:5][S:4]1.C([Li])CCC.[CH3:16][C@H:17]1[CH2:22][C@@H:21]([CH3:23])[CH2:20][C:19](=O)[CH2:18]1>C1COCC1>[CH3:16][C@H:17]1[CH2:22][C@@H:21]([CH3:23])[CH2:20][C:19](=[C:3]2[S:8][CH2:7][CH2:6][CH2:5][S:4]2)[CH2:18]1
Reactant: C[C@@H]1CC(=O)C[C@H](C)C1
Reactant: C[Si](C)(C)C1SCCCS1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@@H]1CC(=C2SCCCS2)C[C@H](C)C1
Temperature: -78 °C
Yield: 92 %

Procedure:
To a solution of 2-trimethylsilyl-1,3-dithiane (30.1 g, 0.16 mol) in THF (250 mL) at 0° C. under an argon atmosphere was added a solution of n-butyl lithium (2.5 M in hexanes, 64 mL, 0.16 mol) and the mixture was cooled to −78° C. A solution of cis-3,5-dimethyl cyclohexanone (10 g, 0.079 mol) in THF (30 mL) was added over 10 min. After 3.5 h the reaction mixture was quenched with saturated aqueous NH4Cl solution (100 mL). The aqueous phase was extracted with EtOAc (100 mL×4) and the combined organic layers were dried (MgSO4) and were evaporated. The reaction by-products were removed by vacuum distillation to yield the desired product (16.6 g, 92%). MH+229
Reaction SMILES: [CH2:1]([N:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:11]([O:13]C)=O)[CH3:6])[CH2:2][CH2:3][CH3:4].O.[OH-].[Li+].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[ClH:55].Cl.[NH2:57][C@@H:58]([CH2:72][C:73]1[CH:78]=[C:77]([F:79])[CH:76]=[C:75]([F:80])[CH:74]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1>C(OCC)(=O)C.O1CCCC1.CO.O>[ClH:55].[ClH:55].[CH2:1]([N:5]([CH2:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([CH3:18])[CH:17]=1)[C:11]([NH:57][C@@H:58]([CH2:72][C:73]1[CH:74]=[C:75]([F:80])[CH:76]=[C:77]([F:79])[CH:78]=1)[C@H:59]([OH:71])[CH2:60][NH:61][CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[C:65]([CH2:69][CH3:70])[CH:64]=1)=[O:13])[CH3:6])[CH2:2][CH2:3][CH3:4]
Reactant: CCc1cccc(CNC[C@@H](O)[C@@H](N)Cc2cc(F)cc(F)c2)c1
Reactant: CCCCN(C)Cc1cc(C)cc(C(=O)OC)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN(C)Cc1cc(C)cc(C(=O)N[C@@H](Cc2cc(F)cc(F)c2)[C@H](O)CNCc2cccc(CC)c2)c1
Reaction time: 16 h

Procedure:
Analogous to the method in EXAMPLE SP-188, methyl 3-{[butyl(methyl)amino]methyl}-5-methylbenzoate (122 mg, 0.49 mmol) is dissolved in 2:1:1 tetrahydrofuran/methanol/water (4 mL), and lithium hydroxide monohydrate is added (41 mg, 1.0 mmol), and the reaction stirred 16 h. The solution is concentrated under reduced pressure. The residue is redissolved in DMF (5 mL), and diisopropylethylamine (350 μL, 2 mmol), HATU (240 mg, 0.63 mmol), and (2R,3S)-3-amino-4-(3,5-difluorophenyl)-1-[(3-ethylbenzyl)amino]butan-2-ol dihydrochloride prepared by the method in EXAMPLE SP-272 (203 mg, 0.5 mmol) are added. The reaction stirred at room temperature 16 h. The reaction mixture is diluted with ethyl acetate, washed with water, saturated sodium bicarbonate, brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/methylene chloride) provides the title compound as the free base. The residue is dissolved in diethyl ether (3 mL) and 1N hydrochloric acid in diethyl ether (1 mL) is added. The mixture is concentrated under reduced pressure to yield the title compound. ESI MS m/z 552.3 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:18])[CH:5]([O:9][C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[C:12]([Cl:17])[CH:11]=1)[O:6][CH2:7][CH3:8])C.[OH-].[K+].O.Cl>C(O)C>[Cl:16][C:14]1[CH:15]=[C:10]([CH:11]=[C:12]([Cl:17])[CH:13]=1)[O:9][CH:5]([O:6][CH2:7][CH3:8])[C:4]([OH:18])=[O:3]
Reactant: CCOC(=O)C(OCC)Oc1cc(Cl)cc(Cl)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOC(Oc1cc(Cl)cc(Cl)c1)C(=O)O
Temperature: 45 °C
Yield: 62.1 %

Procedure:
A solution of 50.0 g (0.17 mole) of the ethyl-2-(3,5-dichlorophenoxy)-2-ethoxyacetate in 50 ml ethanol was added slowly to a solution of 13.2 g (0.20 mole) 85% KOH in 150 ml 2B ethanol. The mixture was heated at 45° C for one-half hour, then cooled to room temperature and poured into 300 ml H2O. The pH of the resulting mixture was adjusted to 2 with dilute HCl. An oil separated which was removed by two 150 ml extractions with chloroform. The chloroform extracts were combined, washed with three 150 ml portions of water, and dried over magnesium sulfate. Removal of the solvent in vacuum left 41.7 g of a solid which was recrystallized from hexane to give 28.0 g 2-(3,5-dichlorophenoxy)-2-ethoxyacetic acid, m.p. 83.5°-86.5° C, characterized by infrared spectroscopy.
Reaction SMILES: C([N:14]1[CH2:17][CH:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1>CO.[Pd]>[C:25]([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[O:18][CH:16]1[CH2:15][NH:14][CH2:17]1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccccc1OC1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1ccccc1OC1CNC1
Yield: 39.8 %

Procedure:
To a solution of 1-benzhydryl-3-(2-tert-butylphenoxy)azetidine (9.10 g, 24.5 mmol) and 10% Pd/C (10% on carbon, 1.90 g) in methanol (300.0 mL) was stirred under hydrogen atmosphere (1 atm) at room temperature. After 24 h the reaction mixture was filtered through a pad of Celite, the Celite pad was washed with methanol and the filtrate was concentrated under reduced pressure. Purification by flash column chromatography (silica gel; 70:30 to 0:100 heptane/ethyl acetate, 98:2 ethyl acetate/methanol, 90:9:1 ethyl acetate/methanol/7.0 N ammonia-methanol) provided 3-(2-tert-butylphenoxy)azetidine (2.00 g, 40%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=1.Cl.C(OCC)C>CC(O)C.C(#N)C.O>[ClH:8].[Br:1][C:2]1[C:3]([NH:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[N:4][C:5]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:27][CH:28]=2)=[N:6][CH:7]=1
Reactant: CC(=O)Nc1ccc(N)cc1
Reactant: COc1cc(Nc2nc(Cl)ncc2Br)cc(OC)c1OC
Agent: Cl
Solvent: CC#N
Solvent: CCOCC
Solvent: CC(C)O
Product: COc1cc(Nc2nc(Nc3ccc(NC(C)=O)cc3)ncc2Br)cc(OC)c1OC
Temperature: 90 °C
Yield: 71.7 %

Procedure:
To a mixture of 5-bromo-2-chloro-N-(3,4,5-trimethoxyphenyl)pyrimidin-4-amine (67 mg, 0.178 mmol) and N-(4-aminophenyl)acetamide (28 mg, 0.185 mmol) in 2-propanol (2 mL) was added 1N HCl in diethyl ether (50 uL, 0.05 mmol). The reaction mixture was heated at 90° C. for approx. 36 hours. After the reaction was cooled to room temperature the mixture was taken up in 1:1 acetonitrile/H2O (60 mL) and lyopholized to give N-[4-({5-bromo-4-[(3,4,5-trimethoxyphenyl)amino]pyrimidin-2-yl}amino)phenyl]acetamide hydrochloride (67 mg, 72%) as a grey solid. 1H NMR (DMSO-d6/D2O): δ 8.21 (s, 1H), 7.25-7.67 (m, 4H), 6.87 (s, 2 H), 3.70 (s, 3 H), 3.69 (s, 6 H), 2.00 (s, 3H). MS m/z 488 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1[CH2:12][CH2:11][C@@H:10]([NH:13]C(OCC2C=CC=CC=2)=O)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:24])[NH:7][C@H:8]1[CH2:12][CH2:11][C@@H:10]([NH2:13])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](NC(=O)OCc2ccccc2)C1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](N)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 102.5 %

Procedure:
A mixture of ((1S,3R)-3-benzyloxycarbonylamino-cyclopentyl)-carbamic acid tert-butyl ester (635 mg, 1.90 mmol) and 10% Pd on carbon (202 mg, 0.19 mmol) in ethanol (15 mL) was stirred at ambient temperature under an atmosphere of hydrogen for 16 hours. The reaction mixture was filtered through Celite® which was washed with ethanol and the filtrate concentrated under vacuum to afford 390 mg (quant.) of ((1S,3R)-3-amino-cyclopentyl)-carbamic acid tert-butyl ester as a colorless oil. LCMS (Method H, ESI): RT=0.38 min, m+H=200.9; 1H NMR (400 MHz, DMSO) δ: 6.82 (d, 1H), 3.75-3.66 (m, 1H), 3.17 (m, 2H), 1.98 (m, 1H), 1.70 (m, 3H), 1.49 (m, 1H), 1.37 (s, 9H), 1.31 (m, 1H), 1.14 (m, 1H).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.[Cl:11][C:12]1[C:13](=[O:20])[CH:14]=[C:15]([Cl:19])[C:16](=[O:18])[CH:17]=1.Cl.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1.CCOC(C)=O>[Cl:11][C:12]1[C:13](=[O:20])[CH:14]=[C:15]([Cl:19])[C:16](=[O:18])[C:17]=1[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]=1[CH3:1]
Reactant: Cc1cc2ccccc2[nH]1
Reactant: O=C1C=C(Cl)C(=O)C=C1Cl
Agent: Cl
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1[nH]c2ccccc2c1C1=C(Cl)C(=O)C=C(Cl)C1=O
Temperature: 25 °C
Reaction time: 5 h
Yield: 96.9 %

Procedure:
To a solution of 2-methylindole (0.500 g, 3.81 mmol) in THF (30 mL) was added 2,5-dichloro-1,4-benzoquinone (1.35 g, 7.62 mmol) at room temperature. To this mixture was added concentrated HCl (12 N, 0.38 mL, 4.57 mmol) dropwise. After the reaction mixture was stirred for 5 hours (5 h–12 h) at room temperature, DDQ (1.73 g, 7.62 mmol) was added. After stirring for 3 hours (3 h–12 h) at room temperature, the mixture was diluted with EtOAc (100 mL). The organic solution was washed with saturated NaHCO3 (3×100 mL) and brine (100 mL), and dried over Na2SO4. The residue was concentrated and purified by flash column chromatography using 15% EtOAc in hexane as eluent to afford pure 2,5-dichloro-3-(2-methyl-1H-indol-3-yl)-[1,4]benzoquinone (1.13 g, 97%) as a blue solid. Melting point 158–159° C. Rf=0.35 (3:7, EtOAc/hexane). 1H NMR (CDCl3) δ 8.40 (bs, NH), 7.24–7.11 (m, 5H), 2.26 (s, 3H). 1H NMR (d6-acetone): δ 10.60 (1H, br s), 7.39 (1H, s), 7.36 (1H, d, J=7.8 Hz), 7.24 (1H, d, J=7.8 Hz), 7.10 (1H, t, J=7.8 Hz), 7.01 (1H, t, J=7.8 Hz). 13C NMR (CDCl3) δ 177.7, 176.6, 144.3, 139.8, 139.3, 136.9, 135.1, 133.1, 126.6, 122.0, 120.5, 119.6, 110.8, 104.8, 13.9. IR (KBr): 3388, 3061, 1676, 1566, 1459, 1250, 1032, 749 cm−1. Anal. Calcd. for C15H9Cl2NO2: C, 58.85; H, 2.96; Cl, 23.16; N, 4.58. Found: C, 58.85; H, 2.96; Cl, 23.16; N, 4.58. HRMS (EI) Calcd. For C15H9Cl2NO2 [M+]: 305.0010. Found: 305.0002.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:11]=1.ClC1N=CN=C(NC2C=C(CS(N)(=O)=O)C=CC=2)N=1.ClC1N=CN=C(NC2C=C(S(N)(=O)=O)C=CC=2)N=1>>[CH3:1][O:2][CH2:3][C@H:4]1[CH2:9][CH2:8][CH2:7][CH2:6][N:5]1[C:10]1[N:15]=[CH:14][N:13]=[C:12]([NH:16][C:17]2[CH:18]=[C:19]([CH2:23][S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:11]=1
Reactant: COCC1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1
Agent: NS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Agent: NS(=O)(=O)c1cccc(Nc2ncnc(Cl)n2)c1
Product: COC[C@H]1CCCCN1c1ncnc(Nc2cccc(CS(N)(=O)=O)c2)n1

Procedure:
B5 was prepared following the procedure reported for B4 using the intermediates A1 and A2 and obtained as a white crystalline solid; yield: 90 mg (25%). 1H NMR (300 MHz, d6-DMSO, 300K) δ 1.27-1.90 (m, 4H), 2.48-2.60 (m, 2H), 2.90-3.03 (m, 1H), 3.38 (s, 3H), 3.61 (bs, 2H), 4.26 (s, 2H), 4.61-4.75 (m, 1H), 5.03-5.15 (m, 1H), 6.90 (bs, 2H), 7.03-7.10 (m, 1H), 7.28-7.40 (m, 1H), 7.62-7.73 (m, 1H), 7.82 (bs, 1H), 8.28 (s, 1H), 9.68 (bs, 1H). MS (ES) C17H24N6O3S requires: 392. found: 393 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.[BH3-]C#[N:15].[Na+]>C(O)(C)C>[F:1][C:2]1[C:10]([F:11])=[C:9]2[C:5]([CH2:6][CH2:7][CH:8]2[NH2:15])=[CH:4][CH:3]=1
Reactant: [BH3-]C#N
Reactant: O=C1CCc2ccc(F)c(F)c21
Agent: [Na+]
Solvent: CC(C)O
Product: NC1CCc2ccc(F)c(F)c21
Yield: 49.7 %

Procedure:
A solution of 6,7-difluoro-1-indanone (6.00 g, 35.70 mmol), NaBH3CN (15.70 g, 0.25 mol) and NH4OAc (82.60 g, 1.07 mol) in isopropanol was reacted according to the protocols as outlined in general procedure B to give 3.00 g of the crude title compound, which was used in the next step without further purification. Spectroscopic data: 1H NMR (300 MHz, CDCl3) □ 1.7 (br s, 2H), 1.78-1.90 (m, 1H), 2.44-2.57 (m, 1H), 2.72-2.87 (m, 1H), 2.95-3.09 (m, 1H), 4.7 (t, 1H, J=6.7 Hz), 6.86-7.00 (m, 2H).