Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([NH:9][CH2:10][C:11]2[CH:21]=[CH:20][C:14]3[N:15]=[C:16]([S:18][CH3:19])[O:17][C:13]=3[CH:12]=2)[C:6]([NH2:22])=[CH:5][CH:4]=1.[CH2:23](OC(OCC)OCC)C>C(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:22]=[CH:23][N:9]([CH2:10][C:11]3[CH:21]=[CH:20][C:14]4[N:15]=[C:16]([S:18][CH3:19])[O:17][C:13]=4[CH:12]=3)[C:7]=2[CH:8]=1
Reactant: COc1ccc(N)c(NCc2ccc3nc(SC)oc3c2)c1
Reactant: CCOC(OCC)OCC
Solvent: O=CO
Product: COc1ccc2ncn(Cc3ccc4nc(SC)oc4c3)c2c1
Temperature: 90 °C
Reaction time: 0.67 h
Yield: 84.1 %

Procedure:
A mixture of 5-methoxy-N1-((2-(methylthio)benzo[d]oxazol-6-yl)methyl)benzene-1,2-diamine (920 mg, 2.92 mmol), triethoxymethane (8.8 mL) and HCOOH (0.2 mL) was stirred at 90° C. for 40 min. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:2 petroleum ether/ethyl acetate to give 6-((6-methoxy-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylthio)benzo[d]oxazole as a light brown solid (799 mg, 84.1%). 1H NMR (300 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.68 (s, 1H), 7.59 (d, J=8.1 Hz, 1H), 7.52 (d, J=9.0 Hz, 1H), 7.33 (d, J=6.6 Hz, 1H), 7.15 (s, 1H), 6.80 (d, J=6.6 Hz, 1H), 5.54 (s, 2H), 3.75 (s, 3H), 2.73 (s, 3H). LCMS (ESI) m/z 326 (M+H)+.
Reaction SMILES: C([N:4]([C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][C:20]3[C:28]([F:29])=[CH:27][C:26]([F:30])=[C:25]([NH2:31])[C:21]=3[C:22](=[O:24])[CH:23]=2)=[CH:14][C:13]=1[F:32])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]Br)(=O)C.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.O>CN(C)C=O>[NH2:31][C:25]1[C:21]2[C:22](=[O:24])[CH:23]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[C:13]([F:32])[CH:14]=3)[O:19][C:20]=2[C:28]([F:29])=[CH:27][C:26]=1[F:30]
Reactant: C1COCCN1
Reactant: CC(=O)N(CCCCCCBr)c1ccc(-c2cc(=O)c3c(N)c(F)cc(F)c3o2)cc1F
Solvent: CN(C)C=O
Solvent: O
Product: Nc1c(F)cc(F)c2oc(-c3ccc(NCCCCCCN4CCOCC4)c(F)c3)cc(=O)c12
Reaction time: 1.5 h

Procedure:
500 mg (1.07 mmol) of 5-amino-2-[4-(6-bromohexylamino)-3-fluorophenyl]-6,8-difluoro-4H-1-benzopyran-4-one obtained in Example 52 was dissolved in 15 ml of dimethylformamide, 0.93 ml of morpholine was added and the mixture was stirred at 50° to 60° C. for 1.5 hours. Water was added to the reaction solution and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol:triethylamine =200:10:1) and recrystallized from ethyl acetate/n-hexane to give Compound 55 which was converted into hydrochloride according to the same manner as that in Example 16 to give 349 mg (62%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C[Al](C)C.C([O:15][C:16]([C:18]1[N:19]=[C:20]([CH3:31])[S:21][C:22]=1[NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=O)C.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCOCC1.O>[C:27]([O:26][C:24](=[O:25])[NH:23][C:22]1[S:21][C:20]([CH3:31])=[N:19][C:18]=1[C:16](=[O:15])[NH:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: Cc1cc(N)ccn1
Reactant: CCOC(=O)c1nc(C)sc1NC(=O)OC(C)(C)C
Agent: C[Al](C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(NC(=O)c2nc(C)sc2NC(=O)OC(C)(C)C)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
A solution of 2-methyl-pyridin-4-ylamine (0.623 g, 5.77 mmol) in 20 ml dry dioxane was treated at 0° C. with trimethylaluminium (2M in hexane, 2.88 ml, 5.77 mmol). The mixture was stirred at room temperature for 1 h. 5-tert-Butoxycarbonylamino-2-methyl-thiazole-4-carboxylic acid ethyl ester (0.55 g, 1.92 mmol) was added and the reaction mixture was refluxed for 4 h. 1 ml water and 2 g sodium sulfate were sequentially added and filtered. The filtrate was evaporated and the residue purified by flash chromatography on silica gel with heptane/ethyl acetate 100:0→0:100 to yield [2-methyl-4-(2-methyl-pyridin-4-ylcarbamoyl)-thiazol-5-yl]-carbamic acid tert-butyl ester (0.555 g, 83%) as a light yellow solid, MS (ISP): m/e=349.5 (M+H+).
Reaction SMILES: [Br:1]Br.[CH2:3]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[N:10]([CH:18]2[CH2:20][CH2:19]2)[C:9]=1[CH3:21])=[O:7])[CH3:4]>C(O)(=O)C.O>[CH2:3]([O:5][C:6]([C:8]1[C:16]2[C:11](=[CH:12][C:13]([Br:1])=[C:14]([OH:17])[CH:15]=2)[N:10]([CH:18]2[CH2:19][CH2:20]2)[C:9]=1[CH3:21])=[O:7])[CH3:4]
Reactant: CCOC(=O)c1c(C)n(C2CC2)c2ccc(O)cc12
Reactant: BrBr
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1c(C)n(C2CC2)c2cc(Br)c(O)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.8 %

Procedure:
Bromine (277 μL, 5.40 mmol) is added to a suspension of 1-cyclopropyl-5-hydroxy-2-methyl-1H-indole-3-carboxylic acid ethyl ester (1.40 g, 5.40 mmol) in acetic acid (50 mL). The mixture is stirred for one hour at room temperature. The mixture is diluted with water and the resultant solids are filtered and washed with water. The solids are adsorbed onto silica gel and purified via flash chromatography eluting with 30% THF-heptane. The fractions are combined to yield the title compound (763 mg, 42%). ES/MS m/e 339.8 (M+1).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:15])[CH:12]=NO.B(F)(F)F.CC[O:22]CC>>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]2[C:3]=1[NH:10][C:11](=[O:15])[C:12]2=[O:22]
Reactant: COc1cccc(NC(=O)C=NO)c1Cl
Reactant: CCOCC
Agent: FB(F)F
Product: COc1ccc2c(c1Cl)NC(=O)C2=O
Temperature: 90 °C
Yield: 63 %

Procedure:
Compound 102d (10.46 g, 45.74 mmol) was added portionwise to BF3.Et2O at 40° C. The mixture was then heated at 90° C. for 3 hrs. After cooling down to room temperature, the reaction mixture was poured into crushed ice and extracted with EtOAc. Organics were dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by chromatography on silica gel (petroleum ether/EtOAc). The compound obtained was recrystallised from EtOH to yield compound 103d as a brown solid in 63% yield.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18](O)=[O:19])[CH:5]=[CH:6][C:7]=1[B:8]1[O:12][C:11]([CH3:14])([CH3:13])[C:10]([CH3:16])([CH3:15])[O:9]1.[Si:21]([O:28][CH2:29][C:30]([CH3:44])([CH3:43])[CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH2:36])=[CH:34][C:33]=1[C:39]([F:42])([F:41])[F:40])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Si:21]([O:28][CH2:29][C:30]([CH3:44])([CH3:43])[CH2:31][C:32]1[CH:38]=[CH:37][C:35]([NH:36][C:18](=[O:19])[CH2:17][C:4]2[CH:5]=[CH:6][C:7]([B:8]3[O:12][C:11]([CH3:13])([CH3:14])[C:10]([CH3:16])([CH3:15])[O:9]3)=[C:2]([F:1])[CH:3]=2)=[CH:34][C:33]=1[C:39]([F:40])([F:41])[F:42])([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Cc1ccc(N)cc1C(F)(F)F
Reactant: CC1(C)OB(c2ccc(CC(=O)O)cc2F)OC1(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)Cc1ccc(NC(=O)Cc2ccc(B3OC(C)(C)C(C)(C)O3)c(F)c2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.9 %

Procedure:
To a solution of 2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetic acid (5 g, 17.85 mmol) in DCM (100 mL) was added 4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)aniline (7.10 g, 19.64 mmol), DIEA (6.24 mL, 35.7 mmol) and HATU (8.14 g, 21.42 mmol). The solution was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated to give the crude product, which was purified by silica column chromatography (PE/EA=8:1). All fractions found to contain product by TLC (PE/EA=8:1, Rf=0.6) were combined and concentrated to yield a white solid of N-(4-(3-((tert-butyldimethylsilyl)oxy)-2,2-dimethylpropyl)-3-(trifluoromethyl)phenyl)-2-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide (10 g, 12.83 mmol, 72% yield): 1H NMR (400 MHz, CD3OD) δ 7.83 (d, J=2.0 Hz, 2H), 7.35 (d, J=8.8 Hz, 2H), 6.99 (dd, J=4.8, 10.0 Hz, 2H), 3.63 (s, 2H), 3.26 (s, 2H), 2.69 (s, 2H), 1.11 (s, 12H), 0.86 (s, 9H), 0.73 (s, 6H), 0.00 (s, 6H); ES-LCMS m/z 624.2 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH2:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[CH2:12]=[C:13]1[O:17][C:15](=O)[CH2:14]1.C(OC(=O)C)(=O)C>C(Cl)(Cl)(Cl)Cl>[CH2:14]([C:15]1[O:7][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[N:11]=1)[C:13]([CH3:12])=[O:17]
Reactant: C=C1CC(=O)O1
Reactant: Cc1ccc(C(=O)O)c(N)c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Cc1nc2cc(C)ccc2c(=O)o1
Yield: 47.1 %

Procedure:
A mixture of 4-methylanthranilic acid (25.0 g., 0.17 mole) and diketene (13.95 g., 0.17 mole) in CCl4 (250 ml.) was heated at reflux for 2.5 hours. Acetic anhydride (18.3 g., 0.18 mole) was added and the mixture was stirred under reflux for 16 hours. The mixture then was cooled and the product isolated by filtration; upon recrystallization there was obtained 2-acetonyl-7-methyl-4H-3,1-benzoxazin-4-one (17.4 g., 48 percent), mp 142°-144° C.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1([CH2:28][OH:29])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.Br[CH2:31][C:32]1[CH:33]=[C:34]([C:42]2[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=2)[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1>C1COCC1>[Br:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1([CH2:28][O:29][CH2:31][C:32]2[CH:33]=[C:34]([C:42]3[CH:47]=[CH:46][C:45]([C:48]#[N:49])=[CH:44][CH:43]=3)[CH:35]=[C:36]([C:38]([F:39])([F:40])[F:41])[CH:37]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2Br)CC1
Reactant: N#Cc1ccc(-c2cc(CBr)cc(C(F)(F)F)c2)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COCc2cc(-c3ccc(C#N)cc3)cc(C(F)(F)F)c2)(c2ccc(F)cc2Br)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68.1 %

Procedure:
Potassium tert-butoxide (266 mg, 2.37 mmol) was added to a 0° C. solution of tert-butyl 4-(2-bromo-4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (460 mg, 1.18 mmol) and 3′-(bromomethyl)-5′-(trifluoromethyl)biphenyl-4-carbonitrile (524 mg, 1.54 mmol) in THF (10 mL) and was allowed to warm to ambient temperature and stir for 24 hours. The solvent was evaporated and the residue was purified by chromatography on SiO2 with a gradient of ethyl acetate/hexanes from 5% to 40%. The product tert-butyl 4-(2-bromo-4-fluorophenyl)-4-(((4′-cyano-5-(trifluoromethyl)biphenyl-3-yl)methoxy)methyl)piperidine-1-carboxylate (520 mg, 68%) was isolated as a clear syrup. 1H-NMR (CDCl3, 400 MHz) δ 7.75 (d, J=8.3 Hz, 2H), 7.67 (s, 1H), 7.58 (d, J=8.3 Hz, 2H), 7.36 (m, 3H), 7.22 (m, 1H), 6.99 (m, 1H), 4.49 (s, 2H), 3.94 (s, 2H), 3.57 (m, 1H), 3.24 (m 1H), 2.48 (m, 2H), 2.05 (m, 2H), 1.42 (s, 9H). Mass spec.: 647.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:24]=[O:25])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=3)[CH2:12][CH2:13][CH2:14][N:7]21.C[Si](C)(C)[C:28]([F:31])([F:30])[F:29].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.Cl>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[C:16]([CH3:23])=[N:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=4)[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:24]([OH:25])[C:28]([F:31])([F:30])[F:29])=[CH:4][CH:3]=1
Reactant: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C=O)c23)c(C)n1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(N2CCCn3c2nc2c(Cl)ccc(C(O)C(F)(F)F)c23)c(C)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.3 %

Procedure:
To a solution of 9-chloro-1-(6-methoxy-2-methylpyridin-3-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole-6-carbaldehyde (2.20 g, 6.17 mmol) in tetrahydrofuran (28.0 mL) was added trimethyl(trifluoromethyl)silane (2.73 mL, 18.50 mmol) and tetrabutylammonium fluoride (1.0 M solution in tetrahydrofuran, 0.617 mL, 0.617 mmol) at 0° C. After 30 min, to the mixture was added 1N hydrochloric acid (9.0 mL) and the reaction mixture was stirred at 0° C. for 1 hr. The mixture was quenched with aqueous saturated sodium hydrogen carbonate and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The resulting solid was washed with diisopropyl ether to give the title compound as a colorless solid (2.49 g, 5.82 mmol, 94%).
Reaction SMILES: [NH2:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[NH:4][C:3]1=[O:14].[CH2:22]([N:24]([CH2:38][CH3:39])[C:25](=[O:37])[NH:26][C:27]1[CH:32]=[CH:31][C:30]([S:33](Cl)(=[O:35])=[O:34])=[CH:29][CH:28]=1)[CH3:23]>>[NH2:1][C:2]1([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[Cl:21])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:12][CH3:13])[CH:9]=2)[N:4]([S:33]([C:30]2[CH:29]=[CH:28][C:27]([NH:26][C:25]([N:24]([CH2:38][CH3:39])[CH2:22][CH3:23])=[O:37])=[CH:32][CH:31]=2)(=[O:35])=[O:34])[C:3]1=[O:14]
Reactant: CCN(CC)C(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOc1ccc2c(c1)C(N)(c1ccccc1Cl)C(=O)N2
Product: CCOc1ccc2c(c1)C(N)(c1ccccc1Cl)C(=O)N2S(=O)(=O)c1ccc(NC(=O)N(CC)CC)cc1

Procedure:
This compound is prepared according to the procedure described in EXAMPLE 30 from 3-amino-3-(2-chlorophenyl)-5-ethoxy-1,3-dihydroindol-2-one and 4-(N',N'-diethylureido)benzenesulfonyl chloride.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[CH3:6][C:7]1[N:8]=[C:9]([CH3:26])[N:10]2[C:15]=1[C:14](=O)[NH:13][C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)=[N:11]2.[NH:27]1[CH:31]=[N:30][CH:29]=[N:28]1>N1C=CC=CC=1>[CH3:6][C:7]1[N:8]=[C:9]([CH3:26])[N:10]2[C:15]=1[C:14]([N:27]1[CH:31]=[N:30][CH:29]=[N:28]1)=[N:13][C:12]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=1)=[N:11]2
Reactant: c1nc[nH]n1
Reactant: Cc1nc(C)n2nc(-c3cccc([N+](=O)[O-])c3)[nH]c(=O)c12
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1nc(C)n2nc(-c3cccc([N+](=O)[O-])c3)nc(-n3cncn3)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2.35 g (15.35 mmol) of phosphoryl chloride are added dropwise under argon to a solution of 1.46 g (5.12 mmol) of 5,7-dimethyl-2-(3-nitrophenyl)imidazo-[5,1-f][1,2,4]triazin-4-(3H)one from example 9A in 50 ml of dry pyridine at 0° C. and the mixture is stirred for 30 min at RT. Subsequently, 3.18 g (46.06 mmol) of 1,2,4-triazole are added, and the mixture is stirred for 3 h at 20° C. The reaction mixture is concentrated, the residue is treated with aqueous sodium hydrogencarbonate solution and the mixture is extracted with dichloromethane. The organic phase is dried (sodium sulfate) and the solvent is removed in vacuo. The residue is purified by flash chromatography (eluent: dichloromethane/methanol 100:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][NH:7][C:6]2=O.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O=S(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]([N+:16]([O-:18])=[O:17])=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: Nc1ccccc1
Reactant: COc1cc2nc[nH]c(=O)c2c([N+](=O)[O-])c1OC
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: COc1cc2ncnc(Nc3ccccc3)c2c([N+](=O)[O-])c1OC
Temperature: 90 °C
Reaction time: 3 h

Procedure:
To a solution of 6,7-dimethoxy-5-nitro-3H-quinazolin-4-one (1.0 g, 3.98 mmol) (from Example 1, Step A, supra) in SOCl2 (20 mL) (Aldrich) were added a few drops of DMF. The reaction mixture was then heated with stirring at 90° C. for 3 hours. The solvents were evaporated and the residue was dried in vacuo. The residue was dissolved in 2-propanol (30 mL), then aniline (0.36 mL, 3.98 mmol) (Aldrich) was added. The reaction mixture was heated at 110° C. for 3 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography using EtOAc/CH2Cl2/NEt3 (1:1:0.05) as eluent to give the desired (6,7-dimethoxy-5-nitro-quinazolin-4-yl)-phenyl-amine as a yellow solid. (Yield 0.9 g, 70%).
Reaction SMILES: CO[C:3]([C@H:5]1[CH2:9][C@H:8]([OH:10])[C@@H:7]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[CH2:6]1)=[O:4].[NH2:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][C:28]2=[O:33])=[CH:23][C:22]=1[F:34]>>[F:34][C:22]1[CH:23]=[C:24]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][C:28]2=[O:33])[CH:25]=[CH:26][C:21]=1[NH:20][C:3]([C@@H:5]1[CH2:6][C@H:7]([NH:11][C:12]([C:14]2[S:15][C:16]([Cl:19])=[CH:17][CH:18]=2)=[O:13])[C@@H:8]([OH:10])[CH2:9]1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@H](NC(=O)c2ccc(Cl)s2)[C@@H](O)C1
Reactant: Nc1ccc(N2CCOCC2=O)cc1F
Product: O=C(N[C@H]1C[C@@H](C(=O)Nc2ccc(N3CCOCC3=O)cc2F)C[C@@H]1O)c1ccc(Cl)s1

Procedure:
In analogy to example 1C, (1R,3S,4S)-3-[(5-chloro-thiophene-2-carbonyl)-amino]-4-hydroxy-cyclopentanecarboxylic acid methyl ester (example 1B) was reacted with 4-(4-amino-3-fluoro-phenyl)-morpholin-3-one (CAS 438056-69-0) to give 5-chloro-thiophene-2-carboxylic acid {(1S,2S,4R)-4-[2-fluoro-4-(3-oxo-morpholin-4-yl)-phenylcarbamoyl]-2-hydroxy-cyclo-pentyl}-amide. Yellow solid. MS: 482.3 ([M+H]+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]Br>>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([O:18][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][Br:19])=[CH:15][CH:16]=2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCc2cc(O)ccc21
Reactant: BrCCCCCCBr
Product: CC(C)(C)OC(=O)N1CCCc2cc(OCCCCCCBr)ccc21
Yield: 40 %

Procedure:
In analogy to example 2.2, 6-Hydroxy-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester and 1,6-dibromohexane were converted to yield 6-(6-Bromo-hexyloxy)-3,4-dihydro-2H-quinoline-1-carboxylic acid tert-butyl ester (40%) as light green oil, MS: 412 (MH+, 1Br);
Reaction SMILES: O[C:2]([CH3:13])([CH3:12])[C:3]#[C:4][C:5]([C:7]1[N:8]=[CH:9][S:10][CH:11]=1)=[O:6].C(NCC)C.C([OH:21])C>>[CH3:12][C:2]1([CH3:13])[C:3](=[O:21])[CH:4]=[C:5]([C:7]2[N:8]=[CH:9][S:10][CH:11]=2)[O:6]1
Reactant: CCO
Reactant: CC(C)(O)C#CC(=O)c1cscn1
Solvent: CCNCC
Product: CC1(C)OC(c2cscn2)=CC1=O
Reaction time: 0.75 h

Procedure:
To a stirred solution of 4-hydroxy-4-methyl-1-(thiazol-4-yl) pent-2-yn-1-one (0.1 g, 0.53 mmol) in ethanol (1 mL) was added diethyl amine (0.057 mL, 0.59 mmol) in EtOH (0.5 mL) dropwise at RT and the reaction mixture was stirred for additional 45 min. Then the EtOH was removed, diluted with EtOAc (10 mL), washed with water (5 mL), brine (5 mL), dried over Na2SO4, filtered and concentrated in vacuo to afford 2,2-dimethyl-5-(thiazol-4-yl) furan-3(2H)-one (0.1 g) as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2OC(=O)[S:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:15]([C:21]([O:23][CH3:24])=[O:22])#[C:16][C:17]([O:19][CH3:20])=[O:18]>ClC1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([C:21]([O:23][CH3:24])=[O:22])[S:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=c1oc(-c2ccc(Cl)c(Cl)c2)ns1
Reactant: COC(=O)C#CC(=O)OC
Solvent: Clc1ccccc1
Product: COC(=O)c1snc(-c2ccc(Cl)c(Cl)c2)c1C(=O)OC
Yield: 70.7 %

Procedure:
5-(3,4-Dichlorophenyl)-1,3,4-oxathiazol-2-one (99.2 g, 0.4 mol) and dimethyl acetylenedicarboxylate (113.5 g, 0.8 mol) were heated in 240 ml of chlorobenzene at reflux for 47 hours. The product, from hot methanol, was recrystallized twice from hot methanol to give 97.8 g (0.283 mol, 70.7%) of white solid, m.p. 105°-107°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9]C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:28]=[CH:27][C:26]([S:29](=[O:35])(=[O:34])[NH:30][CH:31]2[CH2:33][CH2:32]2)=[CH:25][C:19]=1[C:20]([N:22]=[C:23]=[O:24])=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:18]1[CH:28]=[CH:27][C:26]([S:29]([NH:30][CH:31]2[CH2:33][CH2:32]2)(=[O:35])=[O:34])=[CH:25][C:19]=1[C:20]1[NH:22][C:23](=[O:24])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1
Reactant: CC(C)(C)OC(=O)NNc1ccc(Cl)cc1
Reactant: O=C=NC(=O)c1cc(S(=O)(=O)NC2CC2)ccc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(-c2cc(S(=O)(=O)NC3CC3)ccc2Cl)nn1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared by following the procedure as described for Example-83 by using tert-butyl 2-(4-chlorophenyl)hydrazinecarboxylate (Intermediate-62, 0.050 g, 0.20 mmol), 2-chloro-5-(N-cyclopropylsulfamoyl)benzoyl isocyanate (step-4 of Intermediate-40, 0.123 g, 0.41 mmol), DCM (10 mL) and TFA (3 mL) to afford 0.025 g of pure product. 1H NMR (400 MHz, DMSO d6): δ 0.39-0.41 (m, 2H), 0.49-0.52 (m, 2H), 2.17-2.20 (m, 1H), 7.52-7.55 (d, J=8.0 Hz, 2H), 7.91-8.00 (m, 5H), 8.14 (m, 1H), 12.60 (br s, 1H); MS (m/z): 425.10 (M+).
Reaction SMILES: [NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14](=[NH:17])[O:15]C)[N:9]=1)[C:2]([NH2:4])=[NH:3]>C(O)C.O>[NH:1]([C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][CH2:12][CH2:13][C:14]([NH2:17])=[O:15])[N:9]=1)[C:2]([NH2:4])=[NH:3]
Reactant: COC(=N)CCSCc1csc(NC(=N)N)n1
Solvent: O
Solvent: CCO
Product: N=C(N)Nc1nc(CSCCC(N)=O)cs1
Yield: 67.5 %

Procedure:
In a mixture of 30 ml of ethanol and 30 ml of water was dissolved 5.0 g of methyl 3-(2-guanidinothiazol-4-ylmethylthio)propionimidate and after allowing to stand the solution for 20 hours at 40° C., the solvent was distilled off under reduced pressure. The residue formed was purified by a column chromatography using a mixture of chloroform and methanol and recrystallized from methanol to provide 3.2 g 3-(2-guanidinothiazol-4-ylmethylthio)propionamide showing a melting point of 193°-194° C. (decompd.).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[C:16](=[O:31])[C:17]4[N:18]=[CH:19][N:20]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]#[N:27])[C:21]=4[N:22]=3)=[CH:10][CH:9]=2)=[N:6][CH:7]=1.Cl.C(=O)([O-])[O-].[NH4+:44].[NH4+]>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]([C:32]4[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=4)[C:16](=[O:31])[C:17]4[N:18]=[CH:19][N:20]([C:23]5[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=5)[C:26]([NH2:44])=[NH:27])[C:21]=4[N:22]=3)=[CH:12][CH:13]=2)=[N:6][CH:7]=1
Reactant: N#Cc1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)cn5)cc4)nc32)c1
Reactant: [NH4+]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CO
Product: N=C(N)c1cccc(-n2cnc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)cn5)cc4)nc32)c1

Procedure:
To 3-[2-[4-(5-amino-pyridin-2-yl)-phenyl]-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzonitrile (prepared as described in example 43, 0.29 g, 0.56 mmol), methanol saturated with hydrogen chloride gas (15 mL) is added at 0° C. with stirring. The reaction mixture is allowed to reach rt and stirred there for 12 h. The reaction mixture is then concentrated to a dry residue. It is taken in dry methanol (15 mL) and ammonium carbonate (0.520 g, 3.37 mmol) is added. After stirring at rt for 24 h, the reaction mixture is concentrated and the residue obtained is purified by column chromatography to afford 3-[2-[4-(5-amino-pyridin-2-yl)-phenyl]-1-(4-chloro-phenyl)-6-oxo-1,6-dihydro-purin-9-yl]-benzamidine. 1H NMR (DMSO-d6, 400 MHz) δ 8.65 (s, 1H), 8.29 (s, 1H), 8.14 (s, 1H), 7.96-8.03 (m, 3H), 7.77 (d, 2H), 7.69 (m, 1H), 7.63 (m, 2H), 7.34-7.43 (m, 5H), 6.96 (br, 1H), 5.60 (br, 2H); LC-MS calculated for C29H21ClN8O (M+H+) 533.2, found 534.2.