Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:24]=[CH:23][C:13]3[S:14][C:15]4([C:21](=[O:22])[C:12]=3[CH:11]=2)[CH2:19]CO[C:16]4=O)(=[O:9])=[O:8])[CH2:3][CH2:2]1.CC(C)=O>O>[O:1]1[CH2:6][CH2:5][N:4]([S:7]([C:10]2[CH:24]=[CH:23][C:13]3[S:14][C:15]4([C:21](=[O:22])[C:12]=3[CH:11]=2)[CH2:19][CH2:16]4)(=[O:8])=[O:9])[CH2:3][CH2:2]1
Reactant: O=C1OCCC12Sc1ccc(S(=O)(=O)N3CCOCC3)cc1C2=O
Solvent: CC(C)=O
Solvent: O
Product: O=C1c2cc(S(=O)(=O)N3CCOCC3)ccc2SC12CC2

Procedure:
5-Morpholinosulfonylspiro[benzo[b]thiophene-2(3H),1'-cyclopropan]-3-one was prepared by a similar procedure to that of Example 8 except for the use of 5-morpholinosulfonyl-4',5'-dihydrospiro[benzo[b]thiophene-2(3H),3'(2'H)-furan]3,2'-dione obtained in Reference Example 18. Colorless needles (from acetone --H2O), mp 162.5°-165° C. Anal. Calcd. for C14H15NO4S: C, 51.67; H, 4.65; N, 4.31. Found: C, 51.45; H, 4.55; N, 4.41.
Reaction SMILES: Cl.[NH2:2][OH:3].C[O-].[Na+].[Na].[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1)#[N:9]>CS(C)=O.O.C(OCC)(=O)C.CO>[CH3:22][C:19]1[CH:18]=[CH:17][C:16]([C:11]2[C:10]([C:8](=[N:2][OH:3])[NH2:9])=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:21][CH:20]=1
Reactant: NO
Reactant: Cc1ccc(-c2ccccc2C#N)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccccc2C(N)=NO)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of hydroxylamine hydrochloride (17.9 g) in dimethyl sulfoxide (120 ml) was added a methanol solution of sodium methoxide prepared from metallic sodium (5.92 g) and anhydrous methanol (50 ml). The mixture was stirred for 10 minutes at room temperature, to which was added 2'-cyano-4-methylbiphenyl (10 g). The reaction mixture was stirred for 5 hours at 100° C. After cooling, the reaction mixture was distributed into ethyl acetate and water, and the aqueous layer was subjected to extraction with ethyl acetate. The organic layers were combined, washed with water and dried, then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography on silica gel to afford the title compound as white amorphous product (11.2 g, 96%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=O)=[CH:17][CH:16]=2)[N:10]=1.[Cl:25][C:26]1[CH:35]=[CH:34][C:29]([C:30](=[N:32]O)[NH2:31])=[CH:28][CH:27]=1.[H-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]3[O:21][N:32]=[C:30]([C:29]4[CH:34]=[CH:35][C:26]([Cl:25])=[CH:27][CH:28]=4)[N:31]=3)=[CH:17][CH:16]=2)[N:10]=1
Reactant: NC(=NO)c1ccc(Cl)cc1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(-c2nc(-c3ccc(Cl)cc3)no2)cc1
Yield: 19.1 %

Procedure:
The title compound was prepared by following the procedure as described for Example-40 by using methyl 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate (step-2 of Intermediate-9, 0.100 g, 0.28 mmol), 4-chloro-N′-hydroxybenzimidamide (Intermediate-19, 0.073 g, 0.43 mmol), sodium hydride (0.018 g, 0.43 mmol) and dry THF (5.0 mL) to afford 0.025 g of desired product. 1H NMR (DMSO-d6): δ 7.51 (t, J=8.7 Hz, 1H), 7.59 (d, J=8.4 Hz, 1H), 7.67-7.73 (m, 3H), 8.11 (d, J=8.1 Hz, 2H), 8.24-8.29 (m, 4H), 12.85 (br s, 1H); MS (m/z): 467.87 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[CH2:31]([N:35]=[C:36]=[O:37])[CH2:32][CH2:33][CH3:34]>>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:36]([NH:35][CH2:31][CH2:32][CH2:33][CH3:34])=[O:37])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CCCCN=C=O
Reactant: NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Product: CCCCNC(=O)NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-butyl-urea is prepared as described in Example 26 using cis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and n-butyl isocyanate (Fluka, Buchs, Switzerland). Analytical HPLC: tR=6.54 min (Grad 2); ES-MS: m/eo=499.0.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([C:13]([F:16])([F:15])[F:14])=[C:8](Br)[N:7]=1)=[O:5])C.C([Sn](CCCC)CCCC)CCC.[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[SnH3].NC1C(C(OC)=O)=NC(C2OC=CN=2)=C(C(F)(F)F)C=1>>[NH2:12][C:11]1[C:6]([C:4]([OH:3])=[O:5])=[N:7][C:8]([C:32]2[O:31][CH:35]=[CH:34][CH:33]=2)=[C:9]([C:13]([F:14])([F:15])[F:16])[N:10]=1
Reactant: CCOC(=O)c1nc(Br)c(C(F)(F)F)nc1N
Reactant: [SnH3]c1ccco1
Agent: CCCC[Sn](CCCC)CCCC
Agent: COC(=O)c1nc(-c2ncco2)c(C(F)(F)F)cc1N
Product: Nc1nc(C(F)(F)F)c(-c2ccco2)nc1C(=O)O

Procedure:
The title compound was prepared from 3-amino-6-bromo-5-trifluoromethyl-pyrazine-2-carboxylic acid ethyl ester (Intermediate C1) and tributyltin-2-furylstannane analogously to methyl 3-amino-6-(oxazol-2-yl)-5-(trifluoromethyl)picolinate (Intermediate P)
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12](Br)[C:11]=2[F:17])[CH2:4][CH2:3]1.C(=[NH:31])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.CO.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([NH2:31])[C:11]=2[F:17])[CH2:4][CH2:3]1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: CN1CCC(NCc2cccc(Br)c2F)CC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CO
Solvent: Cc1ccccc1
Product: CN1CCC(NCc2cccc(N)c2F)CC1
Yield: 133 %

Procedure:
Mix 1-methyl-4-(N-(2-fluoro-3-bromophenyl)methylamino)piperidine (Preparation 24, 0.42 g), benzophenone imine (0.303 g), Pd2(dba)3 (25 mg), racemic BINAP (35 mg) and sodium t-butoxide (0.187 g) in toluene (10 mL) and heat at reflux for 3 hours. Dilute the reaction mixture with methanol (5 mL), load on a SCX column (10 g), wash with methanol, elute the with 2M NH3 in methanol, evaporate and further purify on a silica gel column (10 g), using a gradient of dichloromethane-2M NH3 in methanol to give 0.44 g of the title intermediate.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH3:10])[N:3]=1.[CH2:11]([C@H:13]1[NH:18][CH2:17][C@@H:16]([C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:20])[O:15][CH2:14]1)[CH3:12].CCN(C(C)C)C(C)C>CC#N.O>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][CH3:10])[N:3]=[C:2]([N:18]2[C@H:13]([CH2:11][CH3:12])[CH2:14][O:15][C@H:16]([C:19]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:20])[CH2:17]2)[CH:7]=1
Reactant: CC[C@@H]1CO[C@H](C(=O)Nc2ccccc2)CN1
Reactant: CNc1nc(Cl)cc(Cl)n1
Solvent: CC#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC[C@@H]1CO[C@H](C(=O)Nc2ccccc2)CN1c1cc(Cl)nc(NC)n1
Temperature: 100 °C
Yield: 129.1 %

Procedure:
4,6-Dichloro-N-methyl-2-pyrimidinamine (0.150 g, 0.845 mmol) was added to a 20 mL microwave vial followed by the addition of (2S,5R)-5-ethyl-N-phenyl-2-morpholinecarboxamide (0.198 g, 0.845 mmol) in CH3CN (5 mL) and Hunig's base (0.738 mL, 4.23 mmol). The reaction was irradiated at 150° C. for 10 minutes. The reaction was left in the 20 mL sealed microwave vessel and heated to 100° C. over the weekend. The reaction mixture was diluted with water and extracted with EtOAc (2×). The organic layers were combined and dried to afford the crude title compound (0.410 g). LC-MS (ES) m/z=376 [M+H]+.
Reaction SMILES: OC1C=CC(C(CC2C=NC=CC=2)C[NH:10][S:11]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])=CC=1.C(N(CC)CC)C.C(Cl)(=O)OCC>O1CCCC1>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([S:11]([NH2:10])(=[O:12])=[O:13])=[CH:19][CH:18]=1
Reactant: O=S(=O)(NCC(Cc1cccnc1)c1ccc(O)cc1)c1ccc(Cl)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A portion of 53 mg of N-[2-(4-hydroxyphenyl)-3-(3-pyridyl)propyl]-4-chlorobenzenesulfonamide and 78 mg of triethylamine were dissolved in 8 ml of tetrahydrofuran, followed by addition of 25 mg of ethyl chlorocarbonate dissolved in 1 ml of tetrahydrofuran, and stirred at room temperature for 10 minutes. The crystalline deposited was filtered, and the filtrate was then concentrated under reduced pressure. The residue was subjected to chromatography on a silica gel column, and from a fraction eluted with methanol-methylene chloride (5:95 v/v) was obtained 53 mg of N-[2-(4-ethoxycarbonyloxyphenyl)-3-(3-pyridyl)}propyl]-4-chlorobenzenesulfonamide. The spectrometric data supports the structure of [32] as follows.
Reaction SMILES: CC1(C)COB([C:8]2[CH:13]=[CH:12][C:11]([CH:14]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]3)=[CH:10][CH:9]=2)OC1.Br[C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][C:36]=1[Cl:37])[NH:33][CH:32]=[C:31]2[CH:38]=[O:39].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:37][C:36]1[CH:35]=[C:34]2[C:30]([C:31]([CH:38]=[O:39])=[CH:32][NH:33]2)=[CH:29][C:28]=1[C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[CH2:15]2)=[CH:12][CH:13]=1
Reactant: O=Cc1c[nH]c2cc(Cl)c(Br)cc12
Reactant: CC1(C)COB(c2ccc(C3CCN(C(=O)OC(C)(C)C)C3)cc2)OC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(-c3cc4c(C=O)c[nH]c4cc3Cl)cc2)C1
Temperature: 120 °C
Yield: 39.7 %

Procedure:
To a degassed mixture of tert-butyl 3-[4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)phenyl]pyrrolidine-1-carboxylate (85 mg, 0.237 mmol), 5-bromo-6-chloro-1H-indole-3-carbaldehyde (67.3 mg, 0.26 mmol) and 2 N aqueous potassium carbonate (0.47 mL, 0.94 mmol) in toluene (1.12 mL) and ethanol (0.38 mL) was added [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17.3 mg, 0.0237 mmol). The reaction mixture was heated to 120° C. in a microwave for 30 min. The reaction mixture was partitioned between water and EtOAc. The EtOAc layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (EtOAc/petroleum ether=1:2) to give tert-butyl 3-[4-(6-chloro-3-formyl-1H-indol-5-yl)phenyl]pyrrolidine-1-carboxylate (40 mg) as a yellow solid. MS (ES+) 447.0 (M+Na)+.
Reaction SMILES: C[Mg]Br.[CH2:4](OCC)C.[Cl:9][C:10]1[C:15]([CH:16]=[O:17])=[CH:14][N:13]=[C:12]2[N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][C:11]=12.O.[Cl-].[NH4+]>O1CCCC1.[O-2].[O-2].[Mn+4]>[Cl:9][C:10]1[C:15]([C:16](=[O:17])[CH3:4])=[CH:14][N:13]=[C:12]2[N:18]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:19]=[CH:20][C:11]=12
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)c(C=O)cnc21
Reactant: CCOCC
Agent: [Mn+4]
Agent: C[Mg]Br
Agent: [Cl-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1cnc2c(ccn2COCC[Si](C)(C)C)c1Cl
Reaction time: 2 h
Yield: 60.6 %

Procedure:
Methylmagnesium bromide-diethyl ether solution (3.0 M, 10 mL, 30 mmol) was added dropwise to 4-chloro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (4.89 g, 15.7 mmol) obtained in Reference Synthetic Exampleb 55 in tetrahydrofuran (50 mL) under cooling with ice, and the reaction mixture was stirred for 2 hours. After dropwise addition of water and addition of saturated aqueous ammonium chloride, the reaction mixture was extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was dissolved in 1,2-dimethoxyethane (25 mL) and vigorously stirred with manganese dioxide (9.0 g, 0.10 mol) at 80° C. for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in 1,2-dimethoxyethane (25 mL) and vigorously stirred with manganese dioxide (9.0 g, 0.10 mol) at 80° C. for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1 (v/v)) to give the title compound as an orange oil (3.09 g, yield 61%). (alternative to Reference Synthetic Exampleb 33)
Reaction SMILES: [CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH:1]1([NH:6][C:7]2[N:12]3[N:13]=[C:14]([C:28]4[CH:29]=[CH:30][C:31]([O:34][CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:32][CH:33]=4)[C:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([NH:22][CH:23]5[CH2:24][CH2:25][CH2:26][CH2:27]5)[N:17]=4)=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Oc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(-c2nn3c(NC4CCCC4)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Temperature: 25 °C
Yield: 71.5 %

Procedure:
To a solution of 4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenol (100 mg, 0.22 mmol) in acetone (10 mL) was added ethyl α-bromoacetate (49 μL, 0.44 mmol) and potassium carbonate (304 mg, 2.2 mmol). The mixture was heated to reflux for 3 hours. The reaction mixture was cooled to room temperature and water was added. The solution was extracted with ethyl acetate. The organics were dried (magnesium sulfate), filtered and concentrated, followed by purification with flash chromatography (1:1 ethyl acetate:hexanes) to give ethyl (4-{7-(cyclopentylamino)-3-[2-(cyclopentylamino)-4-pyrimidinyl]pyrazolo[1,5-a]pyridin-2-yl}phenoxy)acetate (85 mg, 71%) as a brown oil. 1H NMR (CDCl3): δ 7.94 (d, 1H), 7.70 (d, 1H), 7.55 (d, 2H), 7.23 (t, 1H), 6.95 (d, 2H), 6.25 (d, 1H), 5.98–5.95 (m, 2H), 5.13 (d, 1H), 4.62 (s, 2H), 4.31–4.21 (m, 3H), 3.94 (m, 1H), 2.07–1.99 (m, 4H), 1.75–1.46 (m, 12H), 1.28 (t, 3H); MS m/z 541 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][CH:7]=[C:8]([CH3:9])[C:4]=2[CH:3]=1.C([Li])CCC.CN([CH:20]=[O:21])C.[NH4+].[Cl-]>C1COCC1>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[S:6][C:7]([CH:20]=[O:21])=[C:8]([CH3:9])[C:4]=2[CH:3]=1
Reactant: Cc1csc2ccc(Cl)cc12
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: Cc1c(C=O)sc2ccc(Cl)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 115.1 %

Procedure:
To a solution of 5-chloro-3-methyl-benzo[b]thiophene (4.98 g, 27.3 mmol) in THF (50 mL) at −40° C. was added n-butyllithium (18.7 mL of a 1.6 M solution in hexanes, 30.0 mmol) dropwise. The resulting yellow solution was stirred for 1 h and then DMF (6.3 mL, 81.9 mmol) was added in one portion. The solution was warmed slowly to room temperature and stirred overnight. Saturated aqueous NH4Cl was added and the mixture was extracted with ethyl acetate (3×200 mL). The combined organics were washed with water (100 mL) and brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound (6.62 g, 89%) as a yellow solid: 1H NMR (300 MHz, CDCl3) δ 10.32 (s, 1H), 7.85 (s, 1H), 7.79 (d, J=8.7 Hz, 1H), 7.46 (dd, J=8.7, 2.0 Hz, 1H), 2.74 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12]O[C:14](=[O:15])[C:3]=12.[NH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][N:22]1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[NH2:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][N:16]([CH2:17][CH2:18][CH2:19][CH2:20][CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][N:22]3[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:14](=[O:15])[C:3]=12
Reactant: NCCCCC1CCCCN1Cc1ccccc1
Reactant: Nc1c2c(nc3ccccc13)COC2=O
Product: Nc1c2c(nc3ccccc13)CN(CCCCC1CCCCN1Cc1ccccc1)C2=O
Temperature: 200 °C
Yield: 80.5 %

Procedure:
To 1.74 gm of 9-aminofuro[3,4-b]quinolin-1(3H)-one was added 3.20 gm of 4-aminobutyl-1-benzylpiperidine, and the mixture was heated in a sealed tube for 6 hours at 200° C. while stirring. After cooling, the reaction mixture was recrystallized from ethyl acetate to obtain 3.00 gm of 9-amino-2-(4-(1-benzylpiperidyl)butyl)-2,3-dihydropyrrolo-[3,4-b]quinolin-1-one (Compound (I) with R1 =R3 =H, R2 =NH2, A=>N--(CH2)n --, Y=>C=O, m=1, and n=4).
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:11](=[O:13])[NH:10][C:9](=[O:14])[NH:8][C:7]=2[N:6]=[CH:5]1)[CH:2]=[CH2:3].C(=O)([O-])[O-].[Na+].[Na+].[CH2:21](I)[CH2:22][CH2:23][CH2:24][CH3:25]>CN(C=O)C>[CH2:21]([N:8]1[C:7]2[N:6]=[CH:5][N:4]([CH2:1][CH:2]=[CH2:3])[C:12]=2[C:11](=[O:13])[NH:10][C:9]1=[O:14])[CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCI
Reactant: C=CCn1cnc2[nH]c(=O)[nH]c(=O)c21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCn1cnc2c1c(=O)[nH]c(=O)n2CCCCC
Yield: 56 %

Procedure:
7-(2-propen-1-yl)-3,7-dihydro-1H-purine-2,6-dione (0.61 g, 3.2 mmol), sodium carbonate (0.60 g, 5.7 mmol) and pentyl iodide (0.64 g, 3.2 mmol) were stirred in DMF (5 ml) at 50° C. for 18 h. The solution was cooled, separated between ethyl acetate and brine and the organics isolated, dried (MgSO4) and concentrated. Chromatography over silica (gradient elution dichloromethane to 5:1 dichloromethane/ethyl acetate) provided the title compound as a pale yellow solid (0.47 g, 56%). m/z 263 [MH+]
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[NH2:26][CH2:27][C:28]1([N:32](CC2C=CC=CC=2)CC2C=CC=CC=2)[CH2:31][O:30][CH2:29]1>>[NH2:32][C:28]1([CH2:27][NH:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=[C:4]([N:13]3[CH2:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]3)[CH:3]=2)[CH2:31][O:30][CH2:29]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: NCC1(N(Cc2ccccc2)Cc2ccccc2)COC1
Product: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(NCC3(N)COC3)c2c1

Procedure:
The title compound was prepared in analogy to Example 2-1 in Scheme 4 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine. MS obsd. (ESI+) [(M+H)+] 439, 1H NMR (400 MHz, CD3OD) δ ppm 7.98 (dd, J=1.2, 7.6 Hz, 1 H), 7.90 (d, J=6.8 Hz, 1 H), 7.66 (s, 1 H), 7.62 (td, J=1.2, 7.6 Hz, 1 H), 7.47-7.43 (m, 2 H), 7.30 (dd, J=1.6, 8.4 Hz, 1 H), 6.20 (s, 1 H), 5.18 (s, 2 H), 4.63 (d, J=6.4 Hz, 2 H), 4.59 (d, J=6.8 Hz, 2 H), 4.59 (brs, 2 H), 3.68 (s, 2 H), 3.59 (t, J=4.4 Hz, 2 H), 2.42 (s, 3 H).
Reaction SMILES: C([O:5][C:6](=[O:18])[CH2:7][NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1)(C)(C)C.[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][CH2:30]O>>[CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][C:20]=1[CH2:29][CH2:30][O:16][C:13]1[CH:12]=[CH:11][C:10]([C:9]([NH:8][CH2:7][C:6]([OH:5])=[O:18])=[O:17])=[CH:15][CH:14]=1
Reactant: OCCc1ccc2ccccc2c1
Reactant: CC(C)(C)OC(=O)CNC(=O)c1ccc(O)cc1
Product: O=C(O)CNC(=O)c1ccc(OCCc2ccc3ccccc3c2)cc1
Yield: 89.9 %

Procedure:
The same reaction as in Example 1 (1b) was conducted using N-(4-hydroxybenzoyl)glycine tert-butyl ester (251 mg, 1.00 mmol) prepared in Example 1 (1a) and 2-(2-naphthyl)ethanol (207 mg, 1.20 mmol) to give 314 mg of the title compound (white powder, yield: 90%).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:2].[SH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH2:18]O.Cl>ClCCl>[S:11]1[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:18][O:2][CH:1]1[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: OCc1ccccc1S
Agent: Cl
Solvent: ClCCl
Product: N#Cc1ccc(C2OCc3ccccc3S2)cc1

Procedure:
Following the same procedure as outlined in Example 1 step b), 4-formylbenzonitrile (0.78 g, 5.95 mmol) and (2-mercaptophenyl)methanol (1 g, 7.14 mmol) in dichloromethane (30 ml) were treated with hydrogen chloride gas. After workup and chromatography, as in example 1 step b), the subtitle compound was obtained (1.12 g, 75%) as a white solid. 1H NMR (300 MHz, CDCl3, ppm) δ 5.10 (s, 2H); 6.15 (s, 1H); 7.04-7.21 (m, 4H); 7.59-7.68 (m, 4H); 13C NMR (75 MHz, CDCl3, ppm) δ 70.2; 81.7; 112.8; 118.6; 125.6; 126.1; 127.1; 127.6; 127.7; 129.9; 132.0; 132.6; 143.4; MS calculated for C15H11NOS+H 254 observed 254.
Reaction SMILES: [NH2:1][C:2]1[C:3]([I:26])=[C:4]([C:18]([NH:20][CH2:21][CH:22]([OH:25])[CH2:23][OH:24])=[O:19])[C:5]([I:17])=[C:6]([C:15]=1[I:16])[C:7]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])=[O:8]>CN(C)C(=O)C>[NH2:1][C:2]1[C:15]([I:16])=[C:6]([C:7]([NH:9][CH2:10][CH:11]([O:14][C:7](=[O:8])[CH3:6])[CH2:12][O:13][C:12](=[O:13])[CH3:11])=[O:8])[C:5]([I:17])=[C:4]([C:3]=1[I:26])[C:18]([NH:20][CH2:21][CH:22]([O:25][C:23](=[O:24])[CH3:22])[CH2:23][O:24][C:18](=[O:19])[CH3:4])=[O:19]
Reactant: Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Solvent: CC(=O)N(C)C
Product: CC(=O)OCC(CNC(=O)c1c(I)c(N)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O

Procedure:
acetylating 5-amino-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide with an acetylating agent in N,N,-dimethylacetamide and a catalyst to produce 5-amino-N,N'-bis(2,3-diacetoxypropyl)-2,4,6-triiodoisophthalamide,
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[N+:10]([O-])=O)=[CH:4][C:3]=1[F:13].[Li+].[BH4-].Cl[Si](C)(C)C>C1COCC1>[F:13][C:3]1[CH:4]=[C:5]([CH2:8][CH2:9][NH2:10])[CH:6]=[CH:7][C:2]=1[F:1]
Reactant: O=[N+]([O-])/C=C/c1ccc(F)c(F)c1
Agent: C[Si](C)(C)Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NCCc1ccc(F)c(F)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 98.9 %

Procedure:
Using an analogous procedure and workup as described in for the preparation of intermediate I-15b above. (E-1,2-difluoro-4-(2-nitrovinyl)benzene (I-49a: 5 g, 27.027 mmol) in dry THF (81 mL) as reacted with LiBH4 (2.35 g, 108.1081 mmol) and chloro trimethyl silane (27.63 ml, 216.216 mmol) at 0° C. The resulting mixture was stirred at room temperature for 3 days to afford 4.2 g of the product (100% yield).
Reaction SMILES: [CH2:1]([N:4]([C:14](=[O:25])[CH2:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:17]=1[CH3:24])[C:5]1[N:6]=[CH:7][S:8][C:9]=1[C:10]([O:12]C)=O)[CH:2]=[CH2:3].[H-].[Na+].O>CN(C)C=O>[CH2:1]([N:4]1[C:14](=[O:25])[C:15]([C:16]2[C:17]([CH3:24])=[CH:18][C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])=[C:10]([OH:12])[C:9]2[S:8][CH:7]=[N:6][C:5]1=2)[CH:2]=[CH2:3]
Reactant: C=CCN(C(=O)Cc1c(C)cc(C)cc1C)c1ncsc1C(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C=CCn1c(=O)c(-c2c(C)cc(C)cc2C)c(O)c2scnc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 91.9 %

Procedure:
1.8 g (5 mmol) of methyl 4-[allyl(mesitylacetyl)amino]-1,3-thiazole-5-carboxylate were initially charged in 5 ml of N,N-dimethylformamide and cooled to 0° C. 1.5 eq of sodium hydride (60%) were added and allowed to warm up gradually to room temperature (RT). After stirring at RT for one hour, 5 ml of water were added and the mixture was acidified to pH 1-2. The precipitate formed was filtered off with suction. 1.5 g of inventive compound I-a-2 were thus obtained.