Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[ClH:34].[N:35]12[CH2:42][CH2:41][CH:38]([CH2:39][CH2:40]1)[C@@H:37]([NH:43][C:44]([C:46]1[S:47][C:48]3[C:54]([C:55]4[CH:56]=[C:57]([CH:61]=[CH:62][CH:63]=4)[C:58]([OH:60])=O)=[CH:53][CH:52]=[CH:51][C:49]=3[CH:50]=1)=[O:45])[CH2:36]2.[NH:64]1[CH2:69][CH2:68][O:67][CH2:66][CH2:65]1>CN(C=O)C>[ClH:34].[N:35]12[CH2:40][CH2:39][CH:38]([CH2:41][CH2:42]1)[C@@H:37]([NH:43][C:44]([C:46]1[S:47][C:48]3[C:54]([C:55]4[CH:63]=[CH:62][CH:61]=[C:57]([C:58]([N:64]5[CH2:69][CH2:68][O:67][CH2:66][CH2:65]5)=[O:60])[CH:56]=4)=[CH:53][CH:52]=[CH:51][C:49]=3[CH:50]=1)=[O:45])[CH2:36]2
Reactant: C1COCCN1
Reactant: O=C(O)c1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3cccc(C(=O)N4CCOCC4)c3)c2s1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
103 mg (0.27 mmol) of HATU and 70.8 μl (0.41 mmol) of N,N-diisopropylethylamine are added to a solution of 50 mg (0.11 mmol) of 3-(2-{[(3R)-1-azabicyclo[2.2.2]oct-3-ylamino]carbonyl}-1-benzothien-7-yl)benzoic acid hydrochloride (Example 75) and 19.7 μl (0.23 mmol) of morpholine in 0.5 ml of DMF at 0° C. The mixture is stirred at room temperature for 18 h. After purification by preparative HPLC, the product fractions are concentrated and, after addition of a 3:1 mixture of acetonitrile and 1N hydrochloric acid, again concentrated. Drying under high vacuum results in 43 mg (74% of theory) of the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:26])[CH2:3][NH:4][CH2:5][C@H:6]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9][CH2:8][N:7]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20].CCN(C(C)C)C(C)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][CH:2]([CH3:26])[CH2:3][N:4]([CH2:5][C@H:6]1[CH2:11][N:10]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:9][CH2:8][N:7]1[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])[S:37]([CH3:36])(=[O:39])=[O:38]
Reactant: CC(C)CNC[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)CN(C[C@H]1CN(C(=O)OC(C)(C)C)CCN1C(=O)OC(C)(C)C)S(C)(=O)=O
Reaction time: 0.5 h
Yield: 89.2 %

Procedure:
A 250-mL round-bottomed flask was charged with di-tert-butyl (2S)-2-(((2-methylpropyl)amino)methyl)-1,4-piperazinedicarboxylate (0.77 g, 2.1 mmol), DMAP (0.0287 g, 0.235 mmol) and DIPEA (1.45 mL, 8.29 mmol) and CH2Cl2 (10 mL). Methanesulfonyl chloride (0.321 mL, 4.15 mmol) was added drop wise at room temperature. The mixture was stirred for 30 min and partitioned between water (30 mL) and CH2Cl2 (20 mL). The aqueous phase was extracted with CH2Cl2 (30 mL) and the combined organic phases were washed with saturated aqueous NaCl (50 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (50 g of silica gel, 10 to 70% EtOAc in hexanes) to afford di-tert-butyl (2R)-2-(((2-methylpropyl)(methylsulfonyl)amino)methyl)-1,4-piperazinedicarboxylate (0.842 g) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH3:20][NH:21][C:22]([C:24]1[C:25]2[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][C:26]=2[S:27][C:28]=1[CH2:29][CH3:30])=[O:23].C([O-])([O-])=O.[Cs+].[Cs+]>>[CH3:20][NH:21][C:22]([C:24]1[C:25]2[CH:34]=[CH:33][C:32]([O:35][C:2]3[CH:7]=[CH:6][N:5]=[C:4]4[CH:8]=[C:9]([C:11]([N:13]5[CH2:17][CH2:16][C@@H:15]([O:18][CH3:19])[CH2:14]5)=[O:12])[S:10][C:3]=34)=[CH:31][C:26]=2[S:27][C:28]=1[CH2:29][CH3:30])=[O:23]
Reactant: CO[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Reactant: CCc1sc2cc(O)ccc2c1C(=O)NC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: CCc1sc2cc(Oc3ccnc4cc(C(=O)N5CC[C@@H](OC)C5)sc34)ccc2c1C(=O)NC
Yield: 27.4 %

Procedure:
This material was prepared by reacting 7-chloro-2-{[(3R)-3-methoxypyrrolidin-1-yl]carbonyl}thieno[3,2-b]pyridine 4b (74 mg, 0.25 mmole) with 2-ethyl-6-hydroxybenzo[b]thiophene-3-carboxylic acid methylamide 134d (71 mg, 0.30 mmole) and Cs2CO3 (244 mg, 0.75 mmole) in a manner analogous to that described for example 1 to give a yellow solid (34 mg, 19%). 1H NMR (DMSO-d6, 300 MHz), δ8.59 (1H, d, J=5.31 Hz), 8.33 (1H, q, J=4.46 Hz), 8.06 (1H, s), 7.99 (1H, d, J=2.27 Hz), 7.81 (1H, d, J=8.84 Hz), 7.34 (1H, dd, J=2.27, 8.84 Hz), 6.76 (1H, d, J=5.56 Hz), 4.08-3.83 (3H, m), 3.67-3.48 (2H, m), 3.27, 3.24 (3H, s), 3.00 (2H, t, J=7.49 Hz), 2.83 (3H, d, J=4.55 Hz), 2.16-1.95 (2H, m), 1.28 (3H, t, J=7.58 Hz).
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH2:4][CH2:5][O:6][C:7](=[O:9])[CH3:8].[Cl-].[CH3:11][NH2+]C.C=O>>[CH:2]([C:3](=[CH2:11])[CH2:4][CH2:5][O:6][C:7](=[O:9])[CH3:8])=[O:1]
Reactant: C[NH2+]C
Reactant: CC(=O)OCCCC=O
Agent: C=O
Agent: [Cl-]
Product: C=C(C=O)CCOC(C)=O

Procedure:
13.0 g (100 mmol) of acetic acid (4-oxo)butyl ester, 92.0 g (112.6 mmol) of dimethylammonium chloride and 10.8 ml (117 mmol) of 37% formaldehyde solution are heated at 100° for one hour with stirring. The mixture is allowed to cool and is extracted 3 times with 30 ml of diethyl ether each time. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated to dryness by evaporation. Acetic acid (3-formyl)but-3-enyl ester is obtained in the form of a colourless oil which can be reacted further without further purification.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1Cl)=[CH:12][CH:11]=[CH:10][C:9]=2[O:16][CH3:17].[CH3:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[NH2:21]>C(O)C>[CH3:18][C:19]1[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=1[N:21]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([O:16][CH3:17])[C:8]=3[N:7]=[CH:6][C:5]=2[CH2:4][CH2:3][CH2:2]1
Reactant: COc1cccc2c(Cl)c(CCCCl)cnc12
Reactant: Cc1ccccc1N
Solvent: CCO
Product: COc1cccc2c3c(cnc12)CCCN3c1ccccc1C
Yield: 26.7 %

Procedure:
A solution of 3-(3-chloropropyl)-4-chloro-8-methoxyquinoline (6.4 g, 23.6 mmol) and 2-methylaniline (5.0 ml, 47.2 mmol) in ethanol (250 ml) was heated at reflux for 4 days, then cooled and evaporated. Dichloromethane and aqueous sodium bicarbonate solution were added, and the organic layer washed with water, dried and evaporated. Chromatography (silica gel, 1% methanolic ammonia in dichloromethane) followed by crystallisation from ethyl acetate gave 1-(2-methylphenyl)-7-methoxy-1,2,3,4-tetrahydropyridino-[3,2-c]quinoline (1.92 g, 27%), m.p. 160°-161°.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:8]=[C:9]3[C:20]4([CH2:24][S:23][C:22]([NH:25]C(=O)OC(C)(C)C)=[N:21]4)[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:33]5[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=5)[CH:18]=4)[O:13][C:10]3=[N:11][CH:12]=2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:8]=[C:9]3[C@:20]4([CH2:24][S:23][C:22]([NH2:25])=[N:21]4)[C:19]4[C:14](=[CH:15][CH:16]=[C:17]([C:33]5[C:34]([F:39])=[N:35][CH:36]=[CH:37][CH:38]=5)[CH:18]=4)[O:13][C:10]3=[N:11][CH:12]=2)[CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)NC1=NC2(CS1)c1cc(-c3cccnc3F)ccc1Oc1ncc(C3=CCOCC3)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC1=N[C@@]2(CS1)c1cc(-c3cccnc3F)ccc1Oc1ncc(C3=CCOCC3)cc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A RBF was charged with tert-butyl 3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazole]-2′-ylcarbamate (0.091 g, 0.166 mmol). The material was dissolved in 0.5 mL of CH2Cl2 and TFA (0.149 mL, 1.932 mmol) was added. The reaction was heated to 50° C. and stirred for one hour. The reaction was concentrated, diluted with CH2Cl2 and washed with saturated sodium bicarbonate solution. The aqueous layer was extracted with CH2Cl2, and the combined organic layers were washed with brine, dried with sodium sulfate, filtered, and concentrated to afford (S)-3-(3,6-dihydro-2H-pyran-4-yl)-7-(2-fluoropyridin-3-yl)-5′H-spiro[chromeno[2,3-b]pyridine-5,4′-thiazol]-2′-amine as an off-white solid. MS m/z=447.3 [M+H]+. Calculated for C24H19FN4O2S: 446.12.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]=[C:12]([CH3:15])[CH:13]=[O:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:16]([O:20][CH:21]=[CH2:22])[CH:17]([CH3:19])[CH3:18]>C1(C=CC(O)=CC=1)O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH2:22][CH:21]([O:20][CH2:16][CH:17]([CH3:19])[CH3:18])[O:14][CH2:13][C:12]=2[CH3:15])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C=O)=Cc1ccc(C(C)(C)C)cc1
Reactant: C=COCC(C)C
Agent: Oc1ccc(O)cc1
Product: CC1=C(c2ccc(C(C)(C)C)cc2)CC(OCC(C)C)OC1
Temperature: 220 °C
Yield: 30.7 %

Procedure:
3,000 g of 3-(4-tert.-butylphenyl)-2-methylprop-2-enal III and 2,000 g of vinyl isobutyl ether IV are introduced into a 10 l stirred autoclave, and 5 g of hydroquinone are added to the reaction mixture for stabilization. The autoclave is closed and then flushed with nitrogen, after which it is heated to 220° C., maintained under these conditions for 18 hours and then let down and opened. The reaction mixture (4,855 g) consists of about 39.6% of the desired product V. When the reaction mixture is worked up by fractionation in a laboratory column containing 10 sieve trays, a total of 1,379 g of the compound V of boiling point 135°-146° C. under 2 mbar are obtained from the 1,923 g shown to be present in the crude mixture by gas chromatographic analysis. This corresponds to a yield of 23%, based on the starting material III employed. 1,745 g of III, which contains some product V, are recovered. The last-mentioned amounts are reused for the reaction with vinyl isobutyl ether.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][O:11]COC.FC1C=CC2[B:23](O)[O:22]CC=2C=1>>[OH:22][B:23]1[C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=2[CH2:10][O:11]1
Reactant: OB1OCc2cc(F)ccc21
Reactant: COCOCc1cc(OC)ccc1Br
Product: COc1ccc2c(c1)COB2O

Procedure:
This compound was made from 18g in the same manner as compound 19b: mp 102-104° C.; 1H NMR (300 MHz, DMSO-d6) δ (ppm) 3.77 (s,3H), 4.91 (s, 2H), 6.88 (d, J=8.1 Hz, 1H), 6.94 (s, 1H), 7.60 (d, J=8.1 Hz, 1H), 8.95 (s, 1H); ESI-MS m/z 163 (M−H)−; HPLC purity 100%; Anal (C8HgBO3) C, H.
Reaction SMILES: [CH3:1][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([O:12]C)=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1.O.[OH-].[Li+]>>[CH3:1][CH:2]1[C:9]2[CH:8]=[C:7]([C:10]([OH:12])=[O:11])[NH:6][C:5]=2[CH2:4][CH2:3]1
Reactant: COC(=O)c1cc2c([nH]1)CCC2C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CC1CCc2[nH]c(C(=O)O)cc21
Yield: 52 %

Procedure:
The title compound was synthesized from methyl 4-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate and lithium hydroxide monohydrate (17 mg, 0.40 mmol) according to General Procedure 7. The crude product was dried onto Silica gel and was purified by flash chromatography (0-80% EtOAc/Heptane) to give 8.6 mg of 4-methyl-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylic acid (4) as a light yellow solid (52%). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.17 (d, J=6.78 Hz, 3H), 1.85-1.96 (m, 1H), 2.56-2.77 (m, 3H), 2.95-3.06 (m, 1H), 6.59 (s, 1H); LCMS-MS (ESI+) 166.0 (M+H); HPLC (UV=100%).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:24])=[C:11]([N:16]4[CH2:21][CH:20]([CH3:22])[NH:19][CH:18]([CH3:23])[CH2:17]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:25])[C:6]([C:26]([NH:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=3[Cl:37])=[O:27])=[CH:5]2)[CH2:3][CH2:2]1.[N:38]([CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])=[C:39]=[O:40]>ClCCl>[CH2:45]([O:44][C:42](=[O:43])[CH2:41][NH:38][C:39]([N:19]1[CH:18]([CH3:23])[CH2:17][N:16]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[C:8]([C:7](=[O:25])[C:6]([C:26]([NH:28][CH2:29][C:30]4[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=4[Cl:37])=[O:27])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:24])[CH2:21][CH:20]1[CH3:22])=[O:40])[CH3:46]
Reactant: COc1c(N2CC(C)NC(C)C2)c(F)cc2c(=O)c(C(=O)NCc3ccc(Cl)cc3Cl)cn(C3CC3)c12
Reactant: CCOC(=O)CN=C=O
Solvent: ClCCl
Product: CCOC(=O)CNC(=O)N1C(C)CN(c2c(F)cc3c(=O)c(C(=O)NCc4ccc(Cl)cc4Cl)cn(C4CC4)c3c2OC)CC1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.18 mmol) of the compound from Example 39A are added to a solution of 25 mg (0.22 mmol) of ethyl isocyanatoacetate in 5 ml of dichloromethane. The reaction mixture is stirred at RT overnight. After the removal of the solvent on a rotary evaporator, the residue is purified by RP-HPLC (method 6). 73 mg (59% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[CH:20]=[CH:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]3[CH:21]=2)[CH:6]=[CH:7][CH:8]=1.C(O)C>[Pd].C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[N:10]=[C:11]3[CH2:20][CH2:19][C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[N:12]3[CH:21]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(-c2cn3c(ccc4ccccc43)n2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cccc(-c2cn3c(n2)CCc2ccccc2-3)c1
Reaction time: 5 h

Procedure:
2-(3-Methoxyphenyl)imidazo[1,2-a]quinoline (2.74 g) together with 0.5 g. of 10% palladium on charcoal, 35 ml. of ethanol and 25 ml. of acetic acid is hydrogenated at 90° C. and 10 atmospheres for five hours. After filtration of the catalyst, the solution is evaporated to dryness and the residue is washed with water and aqueous solution carbonate. The resulting solid is extracted with ethyl ether and the organic solution, after drying, is evaporated to yield a product which, after crystallization from a hexane dichloromethane mixture, melts at 107°-9° C.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][C:8]2[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:9]=2[OH:10])=[CH:4][CH:3]=1.CC(N(C)C)=O.[CH2:24]([S:32](Cl)(=[O:34])=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31].Cl>N1C=CC=CC=1>[CH2:24]([S:32]([NH:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][CH2:7][C:8]2[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:9]=2[OH:10])=[CH:4][CH:3]=1)(=[O:34])=[O:33])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: Nc1ccc(CCc2cc(O)ccc2O)cc1
Reactant: CCCCCCCCS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: CCCCCCCCS(=O)(=O)Nc1ccc(CCc2cc(O)ccc2O)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In 1 l-volume three-necked flask were charged 100 g of (4-aminophenethyl)hydroquinone, 500 ml of dimethylacetamide, and 36 ml of pyridine, and 85 ml of octanesulfonyl chloride were slowly added dropwise thereto at room temperature while stirring. After the dropwise addition, the stirring was continued for 4 hours. The reaction mixture was poured into a hydrochloric acid aqueous solution and extracted with ethyl acetate. The extract was washed with water, dried over magnesium sulfate, and concentrated to obtain 129 g of the entitled compound as an oily substance.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][C:8]1[CH:13]=[C:12]([Br:14])[CH:11]=[C:10]([CH3:15])[C:9]=1[OH:16].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O>CN(C=O)C>[CH2:17]([O:16][C:9]1[C:8]([CH3:7])=[CH:13][C:12]([Br:14])=[CH:11][C:10]=1[CH3:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1cc(Br)cc(C)c1O
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Br)cc(C)c1OCc1ccccc1
Reaction time: 0.33 h

Procedure:
39.9 g (286 mmol) K2CO3 were added to a solution of 50.0 g (249 mmol) 2,6-dimethyl-4-bromophenol in 500 mL DMF and stirred for 20 min. Then 34.0 mL (286 mmol) benzylchloride were slowly added dropwise and the reaction mixture was stirred for 3 h at 100° C. bath temperature. After the reaction had ended the mixture was poured onto 500 mL water and exhaustively extracted with EtOAc. The organic phases were combined, dried over Na2SO4 and evaporated down i. vac.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[C:15]1[C:16]2[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)=[O:26])[C:17]=2[N:18]=[CH:19][N:20]=1)[CH3:3].[C:34](Cl)(=[O:36])[CH3:35]>>[C:34]([N:31]1[CH2:30][CH2:29][CH:28]([NH:27][C:25]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:6]4[CH:7]=[C:8]([C:11]([F:13])([F:12])[F:14])[CH:9]=[CH:10][C:5]=4[O:4][CH2:2][CH3:3])[C:16]=3[NH:23][C:22]=2[CH3:24])=[O:26])[CH2:33][CH2:32]1)(=[O:36])[CH3:35]
Reactant: CCOc1ccc(C(F)(F)F)cc1-c1ncnc2c(C(=O)NC3CCNCC3)c(C)[nH]c12
Reactant: CC(=O)Cl
Agent: Cl
Product: CCOc1ccc(C(F)(F)F)cc1-c1ncnc2c(C(=O)NC3CCN(C(C)=O)CC3)c(C)[nH]c12

Procedure:
Starting from 4-[2-ethoxy-5-(trifluoromethyl)phenyl]-6-methyl-N-(piperidin-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f34) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.[Li]CCCC.[F:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.Cl>CCOCC>[F:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]([NH2:3])=[NH:21])=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: N=C(N)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cold solution of hexamethyldisilazane (7 ml) in Et2O (40 ml) was added n-BuLi (1.6M in hexanes, 20.6 ml), followed by a solution of 4-fluorobenzonitrile (2 g) in Et2O (10 ml). After stirring at 0° C. for 10 min, the mixture was allowed to warm to RT and was stirred at RT for 20 h. The mixture was acidified to pH 1 by adding a 1M HCl solution and was washed with CHCl3. The aqueous layer was then basified to pH 14 by adding Na2CO3 and NaOH and was extracted twice with CHCl3. The org. layers were dried (Na2SO4) and evaporated off to afford 1.59 g of the desired compound.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[N:16]=[CH:15][C:14]([C:17]4[O:21][C:20]([CH:22]([NH:32]C(=O)OC(C)(C)C)[CH2:23][O:24][Si](C(C)(C)C)(C)C)=[N:19][N:18]=4)=[C:13]([NH:40][CH:41]([CH3:43])[CH3:42])[CH:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CCOCC.Cl>C(Cl)Cl>[NH2:32][CH:22]([C:20]1[O:21][C:17]([C:14]2[CH:15]=[N:16][C:11]([NH:10][C:7]3[CH:8]=[CH:9][C:4]4[N:3]=[CH:2][S:1][C:5]=4[CH:6]=3)=[CH:12][C:13]=2[NH:40][CH:41]([CH3:43])[CH3:42])=[N:18][N:19]=1)[CH2:23][OH:24]
Reactant: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(C(CO[Si](C)(C)C(C)(C)C)NC(=O)OC(C)(C)C)o1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1-c1nnc(C(N)CO)o1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-butyl (1-(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)-2-((tert-butyldimethylsilyl)oxy)ethyl)carbamate (56) (60 mg, 0.096 mmol) was dissolved in DCM (5 mL), cooled to 0° C. Added ether.HCl (5 mL) to the reaction mixture, stirred at 0° C. for 10 min. Gradually the reaction temperature was raised to room temperature and stirred for 30 min. The reaction mass was concentrated under reduced pressure. The crude material obtained was purified by prep. HPLC to afford the desired compound, 2-amino-2-(5-(6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)pyridin-3-yl)-1,3,4-oxadiazol-2-yl)ethanol. 1H NMR: 400 MHz, CD3OD: δ 1.39 (d, J=6.40 Hz, 6H), 3.88-3.94 (m, 1H), 4.15 (d, J=8.00 Hz, 2H), 4.97 (t, J=4.80 Hz, 1H), 6.27 (s, 1H), 7.58 (dd, J=2.40, 8.80 Hz, 1H), 8.17 (d, J=2.40 Hz, 1H), 8.23 (d, J=8.80 Hz, 1H), 8.39 (s, 1H), 9.35 (s, 1H). LC/MS: Purospher@star RP-18, 4×55 mm, 3 μm; Solvent A=10% ACN: 90% H2O: 20 mM NH4OAc; Solvent B=90% ACN: 10% H2O: 20 mM NH4COOAc; gradient 0-100% B over 1.5 min (3.2 min run time); retention time: 1.359 min; LCMS (ES-API), m/z 412.2 (M+H). HPLC: Sunfire C18 (150×4.6 mm), 3.5 micron; Solvent A=5% ACN: 95% H2O: 0.05% TFA pH=2.5; Solvent B=95% ACN: 5% H2O: 0.05% TFA pH=2.5; gradient 0-100% B over 30 min (36 min run time); Flow rate: 1.0 μL/min; Retention time: 8.639 min; Purity: 98.4%.
Reaction SMILES: [CH3:1][NH2:2].Cl[C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][C:5]=1[N+:14]([O-:16])=[O:15]>O>[CH3:1][NH:2][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[CH:6][C:5]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: CN
Solvent: O
Product: CNc1c([N+](=O)[O-])cnc2ccccc12

Procedure:
To a stirred solution of 40% aqueous methylamine was added, in small portions, 30.Og (0.144 mole) of 4-chloro-3-nitroquinoline. The reaction mixture was heated at its reflux temperature for about 0.75 hour. After cooling, the mixture was poured into 300 ml of water. The solid was separated by filtration, and was then suspended in 300 ml of water. Acidification with 6N hydrochloric acid to pH 3 to 4 effected dissolution of most of the solid. Filtration was followed by basification of the filtrate with concentrated ammonium hydroxide to pH 8 to 10 to provide a yellow precipitate. The solid was separated by filtration, washed with water, and recrystallized from ethanol to provide yellow 4-methylamino-3-nitroquinoline, m.p. 168-170° C. Analysis: Calculated for C10H9N3O2 %C, 59.1; %H, 4.5: %N, 20.7: Found: %C, 59.0; %H, 4.2; %N, 20.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH2:10][C@@H:11]([CH3:14])[CH2:12][Cl:13])[CH:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: C[C@@H](CCl)CBr
Product: C[C@@H](CCl)COc1cccc(Cl)c1

Procedure:
Prepared by Procedure U and Scheme AK using 3-chlorophenol and (2S)-1-bromo-3-chloro-2-methylpropane.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:25])[CH:10]([NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:33](Cl)([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:25])[CH:10]([NH:17][C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:11][C:12]1[N:13]=[CH:14][N:15]([C:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC(Cc1c[nH]cn1)C(=O)OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NC(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
A solution of 2-tert-butoxycarbonylamino-3-(1H-imidazol-4-yl)-propionic acid benzyl ester (6.062 g, 17.57 mmol) and triethylamine (3.57 g, 4.90 mL, 35.14 mmol) in CHCl3 (50 mL) was cooled to 0° C. under argon. Trityl chloride (4.9 g, 17.57 mmol) in CHCl3 was added and after 20 minutes the solution became opaque. The solution was stirred at 0° C. overnight, warmed to room temperature, washed with water and brine, dried over MgSO4 and filtered. The solvent was removed and the crude material was chromatographed (silica gel, 25% EA/PE, Rf 0.78 75% EA/PE) to afford the title compound as a viscous gum (7.58 g, 74%). ESMS 588 (M+H+) 1H NMR (500 MHz, CDCl3) δ 1.42 (9H, s), 2.98 (1H, dd, J=4.65, 14.53 Hz), 3.05 (1H, dd, J=5.05, 14.53 Hz), 4.58 (1H, m), 5.02 (2H, d, J=2.55 Hz), 6.06 (1H, d, J=8.25 Hz), 6.47 (1H, s), 7.09 (6H, m), 7.26 (4H, m), 7.29 (10H, m), 7.36 (1H, s). 13C NMR (CDCl3) δ 28.11, 29.87, 53.61, 66.37, 74.95, 79.12, 119.30, 127.78, 128.16, 129.48, 135.29, 136.23, 138.48, 142.01, 155.34, 171.44.