Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Br[CH2:18][CH2:19][CH2:20][Cl:21]>>[Cl:21][CH2:20][CH2:19][CH2:18][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:4]2[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([F:1])[CH:3]=2)=[CH:11][CH:12]=1
Reactant: ClCCCBr
Reactant: N#Cc1ccc(-c2ccc(O)cc2)cc1F
Product: N#Cc1ccc(-c2ccc(OCCCCl)cc2)cc1F
Yield: 98 %

Procedure:
The product from Example 166B and 1-bromo-3-chloropropane were processed as described in Example 164C to provide the title compound (98% yield). 1HNMR (300 MHz, CDCl3) δ2.25 (m, 2H), 3.80 (m, 2H), 4.20 (m, 2H), 7.00-7.65 (m, 7H); MS (DCI) m/z 290 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]=[C:10]3[CH:27]=[C:26](/[CH:28]=[CH:29]/[C:30]4[S:31][CH:32]=[C:33]([CH:35]([CH3:37])[CH3:36])[N:34]=4)[CH:25]=[CH:24][N:11]3[C:12](=[O:23])[C:13]=2/[CH:14]=[CH:15]/[C:16]([O:18]C(C)(C)C)=[O:17])[CH2:3]1.C(O[C@@H]1CCCN(C2N=C3C=C(/C=C/C4SC=C(C(C)C)N=4)C=C[N:50]3[C:51](=[O:62])C=2/C=C/C(OC(C)(C)C)=O)C1)=O.O[C@H]1CCCN(C2N=C3C=C(/C=C/C4SC=C(C(C)C)N=4)C=CN3C(=O)C=2/C=C/C(OC(C)(C)C)=O)C1>>[NH2:50][C:51]([O:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:9]=[C:10]3[CH:27]=[C:26](/[CH:28]=[CH:29]/[C:30]4[S:31][CH:32]=[C:33]([CH:35]([CH3:36])[CH3:37])[N:34]=4)[CH:25]=[CH:24][N:11]3[C:12](=[O:23])[C:13]=2/[CH:14]=[CH:15]/[C:16]([OH:18])=[O:17])[CH2:3]1)=[O:62]
Reactant: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCC[C@@H](O)C4)nc3c2)n1
Reactant: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCC[C@@H](OC=O)C4)nc3c2)n1
Agent: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)OC(C)(C)C)c(N4CCC[C@H](O)C4)nc3c2)n1
Product: CC(C)c1csc(/C=C/c2ccn3c(=O)c(/C=C/C(=O)O)c(N4CCC[C@@H](OC(N)=O)C4)nc3c2)n1
Yield: 84 %

Procedure:
The tert-butyl (E)-3-{2-[(3R)-3-hydroxyhexahydro-1-pyridinyl]-8-[(E)-2-(4-isopropyl-1,3-thiazol-2-yl)-1-ethenyl]-4-oxo-4H-pyrido[1,2-a]pyrimidin-3-yl}-2-propenoate (109 mg, 0.209 mmol) was treated in the same manner as in Example 103, (A) and (B) to obtain the title compound (89.7 mg, 84%).
Reaction SMILES: [CH3:1][N:2]([CH3:23])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])=[CH:9][C:8]=1[N+:20]([O-])=O>CO.Cl.[Pd]>[NH2:20][C:8]1[CH:9]=[C:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[CH:11]=[CH:12][C:7]=1[CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:23])[CH3:1]
Reactant: CN(C)CCCCc1ccc(CCCCN(C)C)c([N+](=O)[O-])c1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)CCCCc1ccc(CCCCN(C)C)c(N)c1
Yield: 85.1 %

Procedure:
To a solution of 3.5 g of 1,4-bis(4-dimethylaminobutyl)-2-nitrobenzene in 120 ml of methanol, 9 ml of 6N hydrochloric acid and 1.5 g of 5% palladium/carbon were added. The catalytic reduction was carried out under an atmospheric pressure and at a room temperature. When about 710 ml of hydrogen was absorbed after one hour, the reaction was terminated, and the reaction mixture was filtered to remove the catalyst and evaporated under a reduced pressure. After adding chloroform, the mixture was again evaporated under a reduced pressure. The residue was alkalized with 10% sodium hydroxide, subjected to salting out and extracted twice with 50 ml of chloroform. The extract was washed with water and a saturated sodium chloride aqueous solution and dried over magnesium sulfate. The solvent was removed under a reduced pressure to obtain 2.7 g of the title compound as a pale brown liquid.
Reaction SMILES: O=[C:2]([CH3:15])[CH2:3][CH2:4][CH:5]1[C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][C:7](=[O:13])[CH:6]1[CH3:14].S(=O)(=O)(O)O.S([O-])([O-])(=O)=O.[NH4+].[NH4+]>C(OCC)(=O)C.C(OCC)C.O.[C].[Pd]>[CH3:15][C:2]1[C:6]2([CH3:14])[CH:5]([C:10]([CH3:12])([CH3:11])[CH2:9][CH2:8][C:7]2=[O:13])[CH2:4][CH:3]=1
Reactant: CC(=O)CCC1C(C)C(=O)CCC1(C)C
Agent: [Pd]
Agent: O=S(=O)(O)O
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC1=CCC2C(C)(C)CCC(=O)C12C
Yield: 83.8 %

Procedure:
60 g of 3-(3-oxobutyl)-2,4,4-trimethyl-cyclohexanone (product of the catalytic hydrogenation of 4-ketoionone with palladium-carbon in ethyl acetate at room temperature and normal pressure, see H. Jwamuro et al., 23rd Proceedings of the Chemical Society of Japan, 86 [1979]) are dissolved in 500 ml of diethyl ether and at the reflux temperature of the solution there are immediately added dropwise while stirring 25 ml of 80% sulphuric acid. A further 25 ml of 80% sulphuric acid are added dropwise four times after a reaction time of 1 hour in each case. 30 minutes after the last addition of the brownish reaction mmixture is poured onto ice, diluted with water to about 1.5 l, the emulsion is broken with ammonium sulphate and the aqueous phase is separated. After washing with sodium bicarbonate solution and water the organic phase is dried as usual and evaporated under a vacuum. After flat distillation at 55°-60° C./0.05 Torr there are obtained 46 g of 1,4,4,7a-tetramethyl-3a,4,5,7a-tetrahydro-7(6H)-ind-1-enone.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[F:14][B-:15]([F:18])([F:17])[F:16].[CH3:19][O+](C)C>>[F:14][B-:15]([F:18])([F:17])[F:16].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[CH:10]=2)[N+:5]([CH3:19])=[C:4]([CH3:13])[CH:3]=1
Reactant: C[O+](C)C
Reactant: Cc1cc(Cl)c2cc(Cl)ccc2n1
Agent: F[B-](F)(F)F
Product: Cc1cc(Cl)c2cc(Cl)ccc2[n+]1C
Reaction time: 8 h
Yield: 78.8 %

Procedure:
The starting material may be prepared as follows. Powered 4,6-dichloro-2-methylquinoline (254 mg.) was added to a stirred solution of trimethyloxonium tetrafluoroborate (177 mg.) in acetontrile (1 ml.), and stirring was continued overnight. The solvent was evaporated and the residue was triturated with ether to give 4,6-dichloro-1,2-dimethylquinolinium tetrafluoroborate (296 mg.). N.m.r. in solvent A:-3.07(s, 3H); 4.44(s, 3H9; 7.9-8.8(complex, 4H).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[C:5]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=3)[NH:10][C:6]=2[N:7]=[CH:8][N:9]=1.[N:19]1([CH2:25][CH2:26][C:27](O)=[O:28])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.CCN(C(C)C)C(C)C>CN(C=O)C>[Cl:3][C:4]1[C:5]2[CH:12]=[C:11]([C:13]3[CH2:14][CH2:15][N:16]([C:27](=[O:28])[CH2:26][CH2:25][N:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)[CH2:17][CH:18]=3)[NH:10][C:6]=2[N:7]=[CH:8][N:9]=1
Reactant: Clc1ncnc2[nH]c(C3=CCNCC3)cc12
Reactant: O=C(O)CCN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(CCN1CCCCC1)N1CC=C(c2cc3c(Cl)ncnc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a suspension/solution of 4-chloro-6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidine bis-hydrochloride (19.1 mg, 0.0621 mmol, 1 eq), 1-piperidinepropanoic acid (24.5 mg, 0.156 mmol, 2.5 eq), 1-hydroxybenzotriazole (HOBt) (8.5 mg, 0.063 mmol, 1 eq), and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC) (36.3 mg, 0.189 mmol, 3 eq) in anhydrous DMF (1.3 mL), DiPEA (64 μL, 0.37 mmol, 6 eq) was added and the reaction was stirred at rt, under N2, for 16 h. Solvent was concentrated in vacuo and the residue was dissolved in DCM, washed with NaHCO3 (2×) and brine (1×), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude material was purified on MDPS giving the title compound as a yellow solid. 1H NMR (400 MHz, MeOH-d4): δ=1.45-1.56 (s, br, 2H), 1.64 (sextet, J=5.6 Hz, 4H), 2.46-2.78 (m, 10H), 3.81 & 3.84 (t, J=5.6 Hz, rotamers, 2H), 4.29 & 4.33 (d, J=2.0 Hz, rotamers, 2H), 6.48 (s, br, 1H), 6.62 & 6.63 (s, rotamers, 1H), 8.50 (d, 1H). MS (ES+): m/z 373.99/376.00 (100/36) [MH+]. HPLC: tR=1.86 min (ZQ2000, polar—5 min).
Reaction SMILES: [N:1]1([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Br:18]N1C(=O)CCC1=O.O>O1CCOCC1>[Br:18][C:2]1[N:1]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[C:12]#[N:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1
Reactant: N#Cc1ccccc1-n1cnc2ccccc21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccccc1-n1c(Br)nc2ccccc21

Procedure:
Compound 1 (25.75 grams, 117.5 mmol) was dissolved in dioxane (400 mL). To this was added N-bromosuccinimide (20.91 grams, 117.5 mmol). This was stirred at reflux for 3 hours after which time the mixture was poured into water and the product was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated in vacuo and chromatographed (silica gel) using a mobile phase of dichloromethane-ethyl acetate 5:1 (v/v) to provide the title compound. Mass spectral and NMR data confirm the structure. Also synthesized analogously was the 5,6-dimethylbenzimidazole analog.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:14]([O:21][C:22]1[C:26]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:25]([C:35]([NH2:37])=O)[N:24]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:23]=1[C:46]([N:48]([CH3:50])[CH3:49])=[O:47])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C(Cl)Cl>[CH2:14]([O:21][C:22]1[C:26]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[C:25]([C:35]#[N:37])[N:24]([C:38]2[CH:43]=[CH:42][C:41]([O:44][CH3:45])=[CH:40][CH:39]=2)[C:23]=1[C:46]([N:48]([CH3:49])[CH3:50])=[O:47])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(-n2c(C(N)=O)c(OCc3ccccc3)c(OCc3ccccc3)c2C(=O)N(C)C)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COc1ccc(-n2c(C#N)c(OCc3ccccc3)c(OCc3ccccc3)c2C(=O)N(C)C)cc1
Temperature: 25 °C
Yield: 98.1 %

Procedure:
Trifluoroacetic anhydride (27.0 μL, 0.19 mmol) was added dropwise to a stirred solution of 3,4-bis(benzyloxy)-1-(4-methoxyphenyl)-N2,N2-dimethyl-1H-pyrrole-2,5-dicarboxamide (11) (88 mg, 0.18 mmol) and triethylamine (74.3 μL, 0.53 mmol) in DCM (4 mL) at 0° C. The reaction mixture was stirred for 1 h before and trifluoroacetic anhydride (27.0 μL, 0.19 mmol) was added and the mixture allowed to warm to RT. The reaction was partitioned between sat. NaHCO3 (aq.) (5 mL) and DCM (5 mL) the organic layer was separated and volatiles removed in vacuo to afford 4-bis(benzyloxy)-5-cyano-1-(4-methoxyphenyl)-N,N-dimethyl-1H-pyrrole-2-carboxamide (12) (85 mg, 100%), as a yellow oil: m/z 482 (M+H)+ (ES+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:17])[CH:5]=[C:6]([N:8]([CH3:16])[CH:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)[CH:7]=1.[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>O1CCOCC1>[Cl:18][C:19]1[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:20]=1[C:21]([NH:17][C:4]1[CH:5]=[C:6]([N:8]([CH3:16])[CH:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)[CH:7]=[C:2]([F:1])[CH:3]=1)=[O:22]
Reactant: CN1CCC(N(C)c2cc(N)cc(F)c2)CC1
Reactant: O=C(Cl)c1ccc(F)cc1Cl
Solvent: C1COCCO1
Product: CN1CCC(N(C)c2cc(F)cc(NC(=O)c3ccc(F)cc3Cl)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
Combine 5-fluoro-N-methyl-N-(1-methyl-piperidin-4-yl)-benzene-1,3-diamine (Preparation 29, 0.036 g, 0.15 mmol), 2-chloro-4-fluoro-benzoyl chloride (0.044 g, 0.23 mmol) and 1,4-dioxane (2 mL), stir and heat at reflux. After 3 hr, cool to ambient temperature. Load on a SCX column (10 g), wash with methanol, elute with 2M ammonia-methanol. Concentrate eluent to obtain 0.059 g (100%) the title compound as a free base. Dissolve this material in dichloromethane (5 mL) and treat with 1M hydrochloric acid in ether (0.15 mL, 0.15 mmol). Concentrate to give the title compound as a brown powder: high resolution mass spectrum: Obs. m/z 394.1495; Calc. m/z 394.1497; 1H NMR (CDCl3) of free base: 7.8 (bs, 1H), 7.7 (m, 1H), 7.2 (m, 1H), 7.1 (m, 1H), 6.8 (s, 1H), 6.7 (m, 1H), 6.2 (m, 1H), 3.5 (m, 1H), 2.9 (m, 2H), 2.8 (s, 3H), 2.3 (s, 3H), 2.1 (m, 2H), 1.9 (m, 2H), 1.7 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[C:9]([OH:10])=[C:8]([OH:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.CC1(C)O[C:18](=[O:19])[CH2:17][C:15](=[O:16])[O:14]1>O>[OH:11][C:8]1[C:9]([OH:10])=[C:2]2[C:3]([CH:4]=[C:17]([C:15]([OH:16])=[O:14])[C:18](=[O:19])[O:1]2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccc(O)c(O)c1O
Solvent: O
Product: O=C(O)c1cc2ccc(O)c(O)c2oc1=O
Temperature: 75 °C
Reaction time: 2 h
Yield: 74.4 %

Procedure:
2,3,4-trihydroxybenzaldehyde (106.7 mg, 0.69 mmol) and Meldrum's acid (100 mg, 0.69 mmol) were combined in H2O (1 mL). The solution was stirred at 75° C. for 2 h. After cooling to room temperature, the precipitate was filtered and dried at suction to give 114.1 mg of 7,8-dihydroxy-3-carboxy-coumarin in a 74% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([OH:19])=O)=[CH:4][CH:3]=1.[NH:20]1[C:28]2[C:23](=[CH:24][C:25]([NH2:29])=[CH:26][CH:27]=2)[CH:22]=[N:21]1.C(Cl)CCl.CCN(CC)CC>CN(C=O)C.CCOC(C)=O.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:13][C:12](=[O:14])[N:11]([CH3:15])[C:10]([CH3:16])=[C:9]2[C:17]([NH:29][C:25]2[CH:24]=[C:23]3[C:28](=[CH:27][CH:26]=2)[NH:20][N:21]=[CH:22]3)=[O:19])=[CH:6][CH:7]=1
Reactant: Nc1ccc2[nH]ncc2c1
Reactant: CC1=C(C(=O)O)C(c2ccc(Cl)cc2)CC(=O)N1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1=C(C(=O)Nc2ccc3[nH]ncc3c2)C(c2ccc(Cl)cc2)CC(=O)N1C
Temperature: 25 °C
Reaction time: 120 h
Yield: 12.7 %

Procedure:
The product of step 2 (335 mg, 1.20 mmol, 1.00 equiv), 1H-indazol-5-amine (191 mg, 1.44 mmol, 1.20 equiv) and EDC (276 mg, 1.44 mmol, 1.20 equiv) were suspended in 10.0 mL DMF. Et3N (0.191 mL, 1.44 mmol, 1.20 equiv) was added and the solution was stirred 5 days at room temperature. The reaction mixture was diluted with EtOAc and 1N HCl. The phases were separated, and the organic phase was washed twice with 1N HCl, once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (40% 100% EtOAc) to provide 0.060 g (13%) of the title compound as a white solid. MS (ES+) m/e 395 [M+H]+
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[CH:24]([O:27][C:28]1[CH:29]=[N:30][CH:31]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:33]=1)([CH3:26])[CH3:25]>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:32]5[CH:31]=[N:30][CH:29]=[C:28]([O:27][CH:24]([CH3:26])[CH3:25])[CH:33]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: CC(C)Oc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(OC(C)C)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and 3-isopropoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (Stage 58.1.1) to give the title compound as a white solid. (HPLC: tR 2.30 min (Method A); M+H=429 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.33-8.28 (m, 1H), 8.28-8.23 (m, 1H), 8.16-8.08 (m, 2H), 8.02-7.96 (m, 1H), 7.61-7.55 (m, 1H), 7.38-7.33 (m, 1H), 4.84-4.73 (m, 1H), 3.89 (s, 3H), 3.58 (s, 3H), 1.96 (s, 3H), 1.33 (d, 6H))
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][C:5]([N:9]=[C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]3[CH:12]([CH3:19])[O:11]2)=[C:4]([F:20])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:28]([CH3:30])[CH3:29]>CC(C)=O>[Cl:1][C:2]1[C:7]([O:8][CH:28]([CH3:30])[CH3:29])=[CH:6][C:5]([N:9]=[C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][CH2:18][CH:13]3[CH:12]([CH3:19])[O:11]2)=[C:4]([F:20])[CH:3]=1
Reactant: CC(C)Br
Reactant: CC1OC(=Nc2cc(O)c(Cl)cc2F)N2CCCCC12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)Oc1cc(N=C2OC(C)C3CCCCN23)c(F)cc1Cl

Procedure:
3.5 g 3-(4-Chloro-2-fluoro-5-hydroxyphenylimino)-1-methylhexahydro-3H-oxazolo[3,4-a]pyridine and 6.6 g potassium carbonate in 40 ml acetone was treated at room temperature with 3.1 g 2-bromopropane and heated under reflux for 6 hours. It was then treated again with 3.1 g 2-bromopropane and heated under reflux for 6 hours. After cooling the mixture was filtered, the filtrate concentrated and the residue purified by column chromatography (silica gel, eluent; hexane/ethyl acetate).
Reaction SMILES: [Br:1][C:2]1N=C[C:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.BrC1[CH:21]=[N:22]C(C=O)=CC=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[N:22][CH:21]=1
Reactant: COc1ccc2nc(-c3ccc(Br)nc3)oc2c1
Reactant: O=Cc1ccc(Br)cn1
Product: COc1ccc2nc(-c3ccc(Br)cn3)oc2c1

Procedure:
The title compound was synthesized according to a procedure similar to that as described for 2-(6-bromopyridin-3-yl)-6-methoxy-1,3-benzoxazole starting from 3-bromo-6-formylpyridine to give 578.1 mg as an off white solid: 1H NMR δ ppm 8.91 (dd, 1H) 8.26-8.32 (m, 1H) 8.20 (dd, 1H) 7.75 (d, 1H) 7.46 (d, 1H) 7.06 (dd, 1H) 3.86 (s, 3 H); MS m/z 305, 307 (M+H, Bromo isotopes).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=O)[CH3:10])=[C:4]([S:12]([CH2:15][C:16]#[N:17])(=[O:14])=[O:13])[CH:3]=1.C>[OH-].[Na+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[NH:8][C:9]([CH3:10])=[C:15]([C:16]#[N:17])[S:12](=[O:14])(=[O:13])[C:4]=2[CH:3]=1
Reactant: CC(=O)Nc1ccc(Cl)cc1S(=O)(=O)CC#N
Agent: [Na+]
Agent: [OH-]
Product: CC1=C(C#N)S(=O)(=O)c2cc(Cl)ccc2N1
Temperature: 0 °C
Yield: 96.8 %

Procedure:
N-(4-Chloro-2-cyanomethylsulfonylphenyl)acetamide (0.73 g) was added at room temperature to 0.5 M aqueous NaOH (10 ml) to form a yellow solution. After 45 min 0.1 g of charcoal was added and the mixture was filtered through celite. The filtrate was cooled to 0° C. and 1 M HCl (7.5 ml) was added. After 30 min the precipitate was collected by filtration and dried to give 0.66 g of the title compound. Recrystallization from methanol gave pale crystals. Yield 0.45 g (66%); mp 297-299° C.; 1H-NMR(CD3OD) δ (ppm): 7.91 (d, J=2.8 Hz, 1H); 7.68 (dd, 1H); 7.37 (d, J=9 Hz, 1H); 4.88 (br, H2O+NH); 2.51 (s, 3H); 13C-NMR (DMSO-d6) δ (ppm): 155.9, 134, 133.9, 129.6, 125.0, 121.40, 121.36, 112.7, 85.7, 20.3. IR (KBr) ν (cm−1): 3259, 3176, 3100, 2214, 1531, 1482, 1305, 1144. An additional crop of the title compound (0.09 g, 13%) was obtained from the mother liqueor.
Reaction SMILES: [CH2:1]([C:4]1([C:37]([O:39]CC)=[O:38])[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]([C:31]4[CH:36]=[N:35][CH:34]=[CH:33][N:32]=4)[C:19]4[S:23][C:22]([NH:24][C:25]([NH:27][CH2:28][CH3:29])=[O:26])=[N:21][C:20]=4[CH:30]=3)=[CH:12][N:11]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].CC(C)([O-])C.[K+].O>CS(C)=O>[CH2:1]([C:4]1([C:37]([OH:39])=[O:38])[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[CH:14][C:13]([C:16]3[CH:17]=[C:18]([C:31]4[CH:36]=[N:35][CH:34]=[CH:33][N:32]=4)[C:19]4[S:23][C:22]([NH:24][C:25](=[O:26])[NH:27][CH2:28][CH3:29])=[N:21][C:20]=4[CH:30]=3)=[CH:12][N:11]=2)[CH2:8][CH2:9]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(C(=O)OCC)CCN(c2ncc(-c3cc(-c4cnccn4)c4sc(NC(=O)NCC)nc4c3)cn2)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCC1(C(=O)O)CCN(c2ncc(-c3cc(-c4cnccn4)c4sc(NC(=O)NCC)nc4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53 %

Procedure:
To an ice-cold solution of ethyl 4-allyl-1-(5-(2-(3-ethylureido)-7-(pyrazin-2-yl)benzothiazol-5-yl)pyrimidin-2-yl)piperidine-4-carboxylate (0.26 g, 0.45 mmol) in DMSO (2.0 mL) was added potassium tert-butoxide (0.25 g, 2.25 mmol). The resulting mixture was stirred at rt for 2 h. After completion of reaction (by TLC), water (10 mL) was added followed by extraction with EtOAc (2×50 mL). The organic layer was discarded and the pH of the aqueous layer was adjusted up to 4-5, then extracted with hot EtOAc (3×100 mL) and the combined organic layer dried over Na2SO4, filtered and evaporated under reduced pressure. The residue thus obtained was triturated with ether to afford Compound 139 as a beige solid (0.13 g, 53% yield). 1H NMR (DMSO-d6): δ 1.09 (t, J=7.20 Hz, 3H), 1.44 (m, 2H), 2.05 (m, 2H), 2.29 (m, 2H), 3.17-3.22 (m, 4H), 4.43 (m, 2H), 5.07 (m, 2H), 5.71 (m, 1H), 6.90 (br s, 1H), 8.03 (s, 1H), 8.40 (s, 1H), 8.69 (d, J=2.80 Hz, 1H), 8.87 (d, J=2.0 Hz, 1H), 8.94 (s, 2H), 9.77 (s, 1H), 10.71 (br s, 1H) and 12.69 (br s, 1H). MS: 545.26 [M+H]+.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][NH:30][CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:8]=2[C:15]2[C:16]3[NH:23][C:22]([CH3:24])=[C:21]([C:25]([NH:27][C@@H:28]4[CH2:32][CH2:31][N:30]([C:36](=[O:37])[CH2:35][O:34][CH3:33])[CH2:29]4)=[O:26])[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:4][CH2:3]1
Reactant: COCC(=O)Cl
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC4)c(C)[nH]c23)c1
Agent: Cl
Product: COCC(=O)N1CC[C@@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-N-[(3R)-pyrrolidin-3-yl]-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f26) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[S:10][C:11]2[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:12]=2[N:13]=1)=[O:7])(=O)C.N>CO>[CH3:19][C:15]1[C:16]([CH3:18])=[CH:17][C:11]2[S:10][C:9]([NH:8][C:6](=[O:7])[CH2:5][OH:4])=[N:13][C:12]=2[CH:14]=1
Reactant: CC(=O)OCC(=O)Nc1nc2cc(C)c(C)cc2s1
Agent: N
Solvent: CO
Product: Cc1cc2nc(NC(=O)CO)sc2cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.7 %

Procedure:
2-(Acetoxyacetylamino)-5,6-dimethylbenzothiazole (4.2 g) prepared in Example 6 is dissolved in methanol (200 ml) and thereto is added 28% aqueous ammonia (20 ml) and the mixture is stirred at room temperature for 1 hour. The solvent is distilled off and the resulting solids are washed with water, dried and recrystallized from ethanol to give the title compound (3.2 g) having the following physical properties.