Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][N:14]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:20]4[CH2:21][CH2:22][O:23][C:19]=4[CH:18]=3)[CH2:13][CH2:12]2)[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2]1.S(O[CH2:33][CH2:34][C:35]1C2CCCCCC=2C=CC=1)(=O)(=O)C>>[C:1]1([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][N:14]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:20]4[CH2:21][CH2:22][O:23][C:19]=4[CH:18]=3)[CH2:15][CH2:16]2)[C:2]2[CH2:33][CH2:34][CH2:35][CH2:7][CH2:8][C:3]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc2c(cc1N1CCN(CCC3Cc4ccccc43)CC1)OCC2
Reactant: CS(=O)(=O)OCCc1cccc2c1CCCCC2
Product: COc1cc2c(cc1N1CCN(CCc3cccc4c3CCCCC4)CC1)OCC2

Procedure:
Prepared in the same manner as the product of Example 3 but using 2-(benzocycloheptan-1-yl)ethanol mesylate instead of 2-(benzocyclobutan-1-yl)-1-bromoethane.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]([OH:19])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[CH3:29][O:30][CH2:31]Cl.Cl>ClCCl>[CH2:1]([O:3][C:4]([NH:6][C:7]1[C:17]([F:18])=[CH:16][CH:15]=[C:14]([O:19][CH2:29][O:30][CH3:31])[C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:5])[CH3:2]
Reactant: COCCl
Reactant: CCOC(=O)Nc1c(F)ccc(O)c1C(=O)OCC
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)Nc1c(F)ccc(OCOC)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
26.6 g of the resulting ethyl 2-(N-ethoxycarbonylamino)-3-fluoro-6-hydroxybenzoate was dissolved in 300 ml of dichloromethane under argon atmosphere, 20.5 ml of diisopropylethylamine and 9.0 ml of chloromethyl methyl ether were added under ice-cooling and the mixture was stirred at room temperature for 1.5 hours. Additional 20.5 ml of diisopropylethylamine and 9.0 ml of chloromethyl methyl ether were added and the mixture was stirred for 1.6 hours. Additional 5.1 ml of diisopropylethylamine and 2.2 ml of chloromethyl methyl ether were added and the mixture was stirred for 1 hour. An aqueous dilute solution of hydrochloric acid was added to the reaction solution, the mixture was extracted with dichloromethane, the organic layer was washed with water and an aqueous saturated solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give ethyl 2-(N-ethoxycarbonylamino)-3-fluoro-6-methoxymethoxybenzoate.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=2)=[CH:4][N:3]=[CH:2]1.ClC1C=CC=C(C(OO)=[O:20])C=1>C(OCC)(=O)C>[O:1]1[C:5]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][N+:7]=2[O-:20])=[CH:4][N:3]=[CH:2]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: c1ccc(-c2cnco2)nc1
Solvent: CCOC(C)=O
Product: [O-][n+]1ccccc1-c1cnco1
Temperature: 25 °C
Reaction time: 144 h
Yield: 35.7 %

Procedure:
2-(1,3-Oxazol-5-yl)pyridine (2.8 g, 19 mmol) and 3-chloroperbenzoic acid (77%, 13.6 g, 58 mmol) were dissolved in ethyl acetate, and the mixture was stirred at room temperature for 6 days. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with methanol-ethyl acetate (1:4, v/v) were collected and concentrated to give the titled compound (1.1 g, 34%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][C:8](=[O:15])[CH2:7]2)([O-])=O>CO.CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10](=[O:14])[NH:9][C:8](=[O:15])[CH2:7]2
Reactant: O=C1Cc2cc([N+](=O)[O-])ccc2C(=O)N1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccc2c(c1)CC(=O)NC2=O
Yield: 102.2 %

Procedure:
A solution of 6.19 g (30 mmol) of 6-nitroisoquinoline-1,3(2H,4H)-dione in 15 ml of MeOH and 150 ml of N,N-dimethylformamide is hydrogenated at 1 atmosphere of H2 at 25° in the presence of 1.5 g of 10% Pd/C for 7 h. The catalyst is removed by filtration through Celite. The filtrate is evaporated to give 5.4 g (100%) of a tan solid, mp 200-220° (dec); MS (ES+) m/z 177.2 (M+H)+1.
Reaction SMILES: C[N:2]([C:29]1[CH:34]=CC=CC=1)[S:3]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]2[CH:26]=[CH:25][C:14]3=[N:15][CH:16]=[C:17]([C:19]4[CH:20]=[N:21][N:22]([CH3:24])[CH:23]=4)[CH:18]=[C:13]3[C:12](=[O:27])[C:11]=2[CH:28]=1)(=[O:5])=[O:4].C[N:36]1CC[CH2:38][C:37]1=O.C(N(CC)CC)C.C[S:50](C)=O>O>[CH3:24][N:22]1[CH:23]=[C:19]([C:17]2[CH:18]=[C:13]3[C:12](=[O:27])[C:11]4[CH:28]=[C:7]([CH2:6][S:3]([NH:2][CH2:29][C:34]5[S:50][CH:38]=[CH:37][N:36]=5)(=[O:5])=[O:4])[CH:8]=[CH:9][C:10]=4[CH:26]=[CH:25][C:14]3=[N:15][CH:16]=2)[CH:20]=[N:21]1
Reactant: CN(c1ccccc1)S(=O)(=O)Cc1ccc2ccc3ncc(-c4cnn(C)c4)cc3c(=O)c2c1
Reactant: CS(C)=O
Reactant: CN1CCCC1=O
Solvent: O
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cnc3ccc4ccc(CS(=O)(=O)NCc5nccs5)cc4c(=O)c3c2)cn1
Temperature: 180 °C

Procedure:
Compounds in Table 2 were prepared in analogy to the procedures described for the preparation of Compounds 5-6 and 6-1 as follows: Either Compound 5-4 (1.0 equivalents) or Compound 7-1 (1.0 equivalents) and either an amine (1.0 to 5.0 equivalents) or an amine salt (1.0 to 5.0 equivalents) were combined in a vial with enough N-methyl-2-pyrrolidinone to generate a 0.1M solution of either Compound 5-4 or Compound 7-1. Triethylamine (1:1 molar ratio to the amine salt) was then added to reactions utilizing amine salts composed of a 1:1 ratio of amine to acid. Triethylamine (2:1 molar ratio to the amine salt) was then added to reactions utilizing amine salts composed of a 1:2 ratio of amine to acid. No triethylamine was added when amine freebases were employed. The vial was then sealed and the resulting solution or suspension was heated and stirred at 180° C. with conventional heating. After the reaction was judged to be complete by LCMS analysis, the reaction was cooled to room temperature and diluted in DMSO and water. The resulting solution was filtered and purified by preparative HPLC Reverse phase (C-18), eluting with Acetonitrile/Water+0.05% TFA, to afford the title compounds.
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][S:27][CH3:28])(=[O:5])[CH2:2][CH2:3][CH3:4].[OH2:29].Cl[O-].[Na+]>C(Cl)Cl>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[Cl:23])=[CH:13][CH:12]=[CH:11][C:10]=2[O:24][CH2:25][CH2:26][S:27]([CH3:28])=[O:29])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: O
Reactant: CCCC(=O)c1cnc2c(OCCSC)cccc2c1Nc1ccccc1Cl
Agent: [Na+]
Agent: [O-]Cl
Solvent: ClCCl
Product: CCCC(=O)c1cnc2c(OCCS(C)=O)cccc2c1Nc1ccccc1Cl
Reaction time: 2 h
Yield: 71 %

Procedure:
3-butyryl-4-(2-chlorophenylamino)-8-(2-methylthioethoxy)quinoline (0.34g, 0.82 mmol) was dissolved in methylene chloride (4 ml). Water (2 ml) and sodium hypochlorite (5% in water) (1.37 ml) were added and the mixture was stirred for 2 h. Another portion of sodium hypochlorite (0.5 ml) was added and the stirring was continued for 2 h. The organic layer was dried over sodium sulfate and evaporated. The residue crystallized from a mixture of ethyl acetate and isopropyl ether and 0.25 g (71%) of the title compound was obtained.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:16]=1[NH:15][C:14]1[CH2:13][CH2:12][CH2:11][C:10](=[O:17])[C:9]2=1.[CH3:18]I>C1COCC1.[Cl-].[Na+].O>[F:3][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:16]=1[N:15]([CH3:18])[C:14]1[CH2:13][CH2:12][CH2:11][C:10](=[O:17])[C:9]2=1
Reactant: CI
Reactant: O=C1CCCc2[nH]c3c(F)cccc3c21
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c2c(c3cccc(F)c31)C(=O)CCC2
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (80% dispersion in oil; 1.15 g) in dry THF (50 ml) under nitrogen was added 8-fluoro-1,2,3,9-tetrahydro-4H -carbazol-4-one (6.5 g) in dry THF (50 ml), and the mixture was stirred for 1 h. Methyl iodide (4.1 ml) was added, and the mixture was stirred for 3 h. The mixture was then poured into brine (300 ml) and extracted with ether (2×300 ml). The combined, dried organic extracts were evaporated in vacuo to give the title compound (5.77 g), m.p. 126°-128°.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[NH:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH:15]=O>[H][H].O=[Pt]=O>[NH:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[CH2:15][N:1]1[CH2:9][CH2:8][N:7]([CH2:15][C:11]2[NH:10][CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5][N:4]([CH2:15][C:11]2[NH:10][CH:14]=[CH:13][CH:12]=2)[CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=Cc1ccc[nH]1
Reactant: C1CNCCNCCN1
Agent: O=[Pt]=O
Product: c1c[nH]c(CN2CCN(Cc3ccc[nH]3)CCN(Cc3ccc[nH]3)CC2)c1

Procedure:
From 1,4,7-triazacyclononane (1.1.3), pyrrole-2-carboxaldehyde (commercially available) and H2/PtO2.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6](=O)[CH2:7][CH2:8][C:2]1=2.[N:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:20]([F:23])([F:22])[F:21])=[C:11]=S.C[Si](C)(C)[Si](C)(C)C.[Li].O.[NH2:34][NH2:35]>C1COCC1.O.C(O)(=O)C>[S:1]1[CH:5]=[CH:4][C:3]2[C:6]3[NH:34][N:35]=[C:11]([NH:10][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[O:19][C:20]([F:23])([F:22])[F:21])[C:7]=3[CH2:8][C:2]1=2
Reactant: NN
Reactant: FC(F)(F)Oc1ccccc1N=C=S
Reactant: O=C1CCc2sccc21
Agent: C[Si](C)(C)[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)Oc1ccccc1Nc1n[nH]c2c1Cc1sccc1-2
Reaction time: 8 h
Yield: 33 %

Procedure:
A mixture of 5,6-Dihydro-cyclopenta[b]thiophen-4-one (1.0 g, 7.4 mmol) and 1-Isothiocyanato-2-trifluoromethoxy-benzene (1.6 g, 7.4 mmol) in THF (2.0 mL) was added to lithium hexamethyl disilane (7.0 mL, 7.2 mmol) dropwise at room temperature. The reaction mixture was stirred for 8 hr. Hydrazine monohydrate (0.4 mL, 7.9 mmol) and glacial acetic acid (0.5 mL) were added to the reaction mixture, which was then heated at the reflux temperature for 24 hr. The resulting mixture was added to water (30 mL) and then extracted with ethyl acetate. The target product was purified by gravity column chromatography (50% EtOAc in hexane) to give (4,7-Dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-6-yl)-(2-trifluoromethoxy-phenyl)-amine as brown solid in 33% yield.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:49]=[CH:48][C:42]([C:43]([N:45]([CH3:47])[CH3:46])=[O:44])=[C:41]([S:50]([CH:53]([CH3:55])[CH3:54])(=[O:52])=[O:51])[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:49]=[CH:48][C:42]([C:43]([N:45]([CH3:46])[CH3:47])=[O:44])=[C:41]([S:50]([CH:53]([CH3:55])[CH3:54])(=[O:51])=[O:52])[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Reactant: CC(C)S(=O)(=O)c1cc(Br)ccc1C(=O)N(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)S(=O)(=O)c1cc(C#Cc2cc(Cl)ccc2OCC(=O)OC(C)(C)C)ccc1C(=O)N(C)C

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-bromo-2-(isopropylsulfonyl)-N,N-dimethylbenzamide (Intermediate 255), the title compound was obtained as brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[CH3:9][C:10]1[C:11]([Cl:28])=[N:12][C:13]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[CH3:27])=[N:14][C:15]=1[CH3:16]>CN(C)C=O>[ClH:28].[CH3:9][C:10]1[C:11]([NH:6][C:5]2[CH:7]=[CH:8][C:2]([F:1])=[CH:3][CH:4]=2)=[N:12][C:13]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]2[CH3:27])=[N:14][C:15]=1[CH3:16]
Reactant: Nc1ccc(F)cc1
Reactant: Cc1nc(N2CCc3ccccc3C2C)nc(Cl)c1C
Solvent: CN(C)C=O
Product: Cc1nc(N2CCc3ccccc3C2C)nc(Nc2ccc(F)cc2)c1C
Product: Cl
Yield: 51.8 %

Procedure:
After 4-fluoroaniline(0.6 ml, 6.3 mmol) was added to a mixture solution of 5,6-dimethyl-2-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)-4-chloropyrimidine(0.85 g, 3.0 mmol) and dimethylformamide(10 ml), 0.62 g of the titled compound was obtained in accordance with the same procedure as in Step 4 of Example 57.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].[CH3:10]CN(C(C)C)C(C)C.C(Cl)(Cl)=S.[CH3:23][NH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31].CI>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:23]2[N:31]([CH3:10])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[N:24]=2)[CH:6]=[C:7]([Cl:9])[CH:8]=1
Reactant: CCN(C(C)C)C(C)C
Reactant: CNc1ccccc1N
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: S=C(Cl)Cl
Solvent: ClCCl
Solvent: CI
Product: Cn1c(Nc2cc(Cl)cc(Cl)c2)nc2ccccc21
Reaction time: 0.5 h

Procedure:
To a solution of 3,5-dichloroaniline (6.2 mmol, 1.0 g) and DIEA (6.8 mmol, 1.2 mL) in 10 mL of DCM was slowly added thiophosgene (6.2 mmol, 472 μL) (exothermic). After 30 min, N-methyl-1,2-phenylenediamine (6.2 mmol, 704 μL) was added and the reaction mixture was allowed to stand at ambient temperature for 1 h. MeI (6.2 mmol, 386 μL), followed by DIEA (6.8 mmol, 1.2 mL) were then added, and the reaction mixture was allowed to stand at ambient temperature overnight. The crude reaction was partitioned between DCM/brine. The organic layer was collected and the aqueous phase was extracted twice with DCM. The combined organic layer was concentrated under reduced pressure, and the residue was purified by flash chromatography on silica eluting with 2% MeOH/DCM and 4% MeOH/DCM, affording the product as a tan solid. 1H NMR (500 MHz, d6-DMSO) δ 9.35 (s, 1H), 8.04 (s, 2H), 7.48 (m, 2H), 7.36 (m, 2H), 7.08-7.14 (overlapping m, 2H), 3.73 (s, 3H). MS (ESI): m/z 292 (M+H). HPLC A: 1.38 min.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]([CH2:7][P:8]([O:12][CH3:13])([O:10][CH3:11])=[O:9])=[O:6].[I-].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][N+](C)(C)C)=[CH:16]1>CN(C=O)C.O>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH:7]([P:8]([O:12][CH3:13])([O:10][CH3:11])=[O:9])[C:5]([O:4][CH3:3])=[O:6])=[CH:16]1
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: C[N+](C)(C)Cc1c[nH]c2ccccc12
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1c[nH]c2ccccc12)P(=O)(OC)OC
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of indole (5.6 g, 47.8 mmol) in acetonitrile (130 ml) is added Eschenmoser's salt (10 g, 54 mmol) under nitrogen atmosphere and the mixture is stirred for 30 min. The mixture is concentrated in vacuo and the residue is diluted with 1M sodium hydroxide solution and extracted with methylene chloride. The organic layer is dried over sodium carbonate and concentrated in vacuo to give 3-(dimethylaminomethyl)indole as a brown oil. To a solution of 3-(dimethylaminomethyl)indole in methylene chloride (200 ml) is dropped methyl iodide (5 ml, 80 mmol). The mixture is stirred at r.t. for 6 hrs. and concentrated in vacuo to give (3-indolylmethyl)trimethylammonium iodide as a brown foam. To a cooled (0° C.) suspension of sodium hydroxide (1.5 g, 37 mmol) in DMF (100 ml) is added trimethyl phosphonoacetate (6.7 ml, 41 mmol) and the mixture is stirred at 0° C. for 30 min. To the mixture is added (3-indolylmethyl)trimethylammonium iodide and the whole is stirred at r.t. overnight. The mixture is diluted with water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate and concentrated in vacuo. The residue is chromatographed on silica gel with ethyl acetate to give methyl 3-(3-indolyl)-2-(dimethylphosphono)propionate a a brown oil.
Reaction SMILES: C12BC(CCC1)CCC2.[C:10]1([CH3:35])[CH:15]=[CH:14][C:13]([S:16]([N:19]2[C:27]3[C:22](=[CH:23][C:24]([C:28]#[N:29])=[CH:25][CH:26]=3)[C:21]([CH:30]3[CH2:32][CH:31]3[CH:33]=[CH2:34])=[CH:20]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1.[OH-:36].[Na+].OO>C1COCC1.C(O)C>[OH:36][CH2:34][CH2:33][CH:31]1[CH2:32][CH:30]1[C:21]1[C:22]2[C:27](=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)[N:19]([S:16]([C:13]2[CH:12]=[CH:11][C:10]([CH3:35])=[CH:15][CH:14]=2)(=[O:18])=[O:17])[CH:20]=1
Reactant: C=CC1CC1c1cn(S(=O)(=O)c2ccc(C)cc2)c2ccc(C#N)cc12
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C3CC3CCO)c3cc(C#N)ccc32)cc1
Temperature: 30 °C
Yield: 45 %

Procedure:
9-Borabicyclo[3.3.1]nonane (4.1 ml of 0.5 M THF solution, 2.05 mmol) was added drop wise under a nitrogen atmosphere to a stirred solution of 1-(toluene-4-sulfonyl)-3-(2-vinyl-cyclopropyl)-1H-indole-5-carbonitrile (735 mg, 2.01 mmol) in dry THF (6 ml). The solution was heated to 30° C. for 6 hr and then cooled to 20° C. Absolute ethanol (12 ml), sodium hydroxide (2.6 ml of a 1N solution, 2.6 mmol), and hydrogen peroxide (0.85 ml of a 30% solution) were added sequentially to the stirred solution. The mixture was heated to 40° C. for 1 hr and then cooled to room temperature. Sodium hydroxide (2 ml of a 1N solution) was added and the mixture was extracted with ethyl acetate. The ethyl acetate extract was dried over sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica gel using 3% acetone in methylene chloride as the eluent to give 3-[2-(2-hydroxy-ethyl)-cyclopropyl]-1-(toluene-4-sulfonyl)-1H-indole-5-carbonitrile (300 mg, 45%). 1H NMR (300 MHz, CDCl3): δ 8.01 (d, 2H), 7.97 (s, 1H), 7.73(d, 1H), 7.28(s, 1H), 7.24 (d, 2H), 3.80 (m, 2H), 2.35 (s, 3H), 1.74-1.62 (m, 4H), 1.08 (m, 1H), 0.90 (m, 1H), 0.83 (m, 1H). MS m/e 381.17 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[Br:12][C:13]1[C:14]([O:23][CH3:24])=[C:15]([O:21][CH3:22])[CH:16]=[C:17]([CH:20]=1)[CH:18]=O.[C:25](#[N:29])[CH2:26][C:27]#[N:28].C1N2CCN(CC2)C1>C(O)C.O>[NH2:29][C:25]1[O:1][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][N:10]=3)[CH:5]=[CH:4][C:3]=2[CH:18]([C:17]2[CH:16]=[C:15]([O:21][CH3:22])[C:14]([O:23][CH3:24])=[C:13]([Br:12])[CH:20]=2)[C:26]=1[C:27]#[N:28]
Reactant: Oc1cccc2cccnc12
Reactant: COc1cc(C=O)cc(Br)c1OC
Reactant: N#CCC#N
Agent: C1CN2CCN1CC2
Solvent: CCO
Solvent: O
Product: COc1cc(C2C(C#N)=C(N)Oc3c2ccc2cccnc32)cc(Br)c1OC
Temperature: 80 °C
Reaction time: 432 h
Yield: 61.6 %

Procedure:
8-Hydroxychinoline (14.5 g, 100 mmol), 5-bromo-3,4-dimethoxy-benzaldehyde (20.4 g, 83.33 mmol) and malononitrile (5.5 g, 83.33 mmol) were taken in 250 ml ethanol at room temperature, charged with DABCO (917 μl, 8.33 mmol) and then stirred at 80° C. under LC-MS control for 18 days. The reaction mixture was cooled down to room temperature, diluted with water to about 500 ml and extracted with ethyl acetate (2×100 ml). The ethyl acetate solution was washed with 5% sodium bicarbonate solution (2×100 ml), dried over magnesium sulfate, solvent was then evaporated under vacuum at 40° C. and the solids were dried under high vacuum to yield 22.5 g (61.6%) of the title compound.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1)[CH2:7][NH:8][C:9]1[CH:10]=[C:11]([N:21]2[CH2:26][CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23][CH2:22]2)[CH:12]=[CH:13][C:14]=1[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17]>C(OCC)C.ClCCl>[ClH:1].[CH3:38][O:37][C:35]1[CH:34]=[C:6]([CH:5]=[C:4]([O:3][CH3:2])[CH:36]=1)[CH2:7][NH:8][C:9]1[CH:10]=[C:11]([N:21]2[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]2)[CH:12]=[CH:13][C:14]=1[C:15](=[O:20])[C:16]([F:19])([F:18])[F:17]
Reactant: COc1cc(CNc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2C(=O)C(F)(F)F)cc(OC)c1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: COc1cc(CNc2cc(N3CCNCC3)ccc2C(=O)C(F)(F)F)cc(OC)c1
Reaction time: 0.5 h
Yield: 81 %

Procedure:
A saturated solution of HCl gas in anhydrous diethyl ether was added portion wise to a solution of tert-butyl 4-(3-(3,5-dimethoxybenzylamino)-4-(2,2,2-trifluoroacetyl)-phenyl)piperazine-1-carboxylate (230 mg, 0.44 mmol) in anhydrous dichloromethane (1.5 mL). The resulting mixture was allowed to stand at room temperature for 30 min, and conversion was monitored by LCMS. The supernatant was pipetted out and the residue was concentrated down in vacuo and co-evaporated with diethyl ether to yield 150 mg (81%) of the title compound: 1H NMR (400 MHz, CD3OD): δ 7.65 (dd, 1H), 6.54 (d, 2H), 6.42-6.39 (m, 2H), 6.07 (d, 1H), 4.48 (br s, 2H), 3.76 (s, 6H), 3.63-3.60 (m, 4H), 3.30-3.25 (m, 4H). MS (ESI) m/z: Calculated: 423.18; Observed: 847.4 (2M++1)
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[CH:25]1([CH2:28][NH2:29])[CH2:27][CH2:26]1>O>[CH:25]1([CH2:28][NH:29][C:2]2[N:3]=[C:4]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[C:5]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:9][S:8][C:6]=3[N:7]=2)[CH2:27][CH2:26]1
Reactant: NCC1CC1
Reactant: Clc1nc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Solvent: O
Product: c1ccc(-c2csc3nc(NCC4CC4)nc(NCc4ccccn4)c23)cc1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
In a 10 ml glass tube were placed 2-chloro-N-(2-pyridyl)methyl-5-phenylthieno[2,3-d]pyrimidin-4-ylamine (0.03 g, 0.0852 mmol) and cyclopropylmethylamine (0.5 ml). The vessel was sealed with a septum and placed in the microwave cavity. Microwave irradiation of 200 W was used, the temperature being ramped from room temperature to 200° C. Once 200° C. was reached, the reaction mixture was held at this temperature for 40 minutes. After cooling to ambient temperature, water (4 ml) was added and the mixture stirred for 2.5 hours. The resulting solid was collected by filtration, washed with water and dried under reduced pressure to give N2-Cyclopropylmethyl-5-phenyl-N4-pyridin-2-ylmethyl-thieno[2,3-d]pyrimidine-2,4-diamine (0.025 g) as a yellow solid, m.p.t. 109-111° C.
Reaction SMILES: C(N)C1C=CC=CC=1.[CH2:9]([NH2:11])[CH3:10].[CH3:12][C:13]1[N:14]=[C:15]([N:21]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=3)[C:22]2=[O:38])[S:16][C:17]=1[C:18](O)=[O:19]>>[CH2:9]([NH:11][C:18]([C:17]1[S:16][C:15]([N:21]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([O:33][C:34]([F:35])([F:36])[F:37])=[CH:31][CH:32]=3)[C:22]2=[O:38])=[N:14][C:13]=1[CH3:12])=[O:19])[CH3:10]
Reactant: CCN
Reactant: Cc1nc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)sc1C(=O)O
Solvent: NCc1ccccc1
Product: CCNC(=O)c1sc(N2CCN(Cc3ccc(OC(F)(F)F)cc3)C2=O)nc1C
Yield: 25 %

Procedure:
Following the procedure as describe in Example 8, making variations as required to replace benzylamine with ethylamine to react with 4-methyl-2-(2-oxo-3-(4-(trifluoromethoxy)benzyl)imidazolidin-1-yl)thiazole-5-carboxylic acid, the title compound was obtained as a white powder in 25% yield: mp 218-219° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 7.32 (d, J=8.4 Hz, 2H), 7.18 (d, J=8.4 Hz, 2H), 5.60 (s, 1H), 4.47 (s, 2H), 4.10-4.04 (m, 2H), 3.51-3.35 (m, 4H), 2.57 (s, 3H), 1.18 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 162.3, 157.0, 155.4, 152.3, 148.9, 134.4, 129.7, 121.4, 120.4, 117.8, 47.3, 42.0, 41.8, 35.1, 34.8, 17.0, 14.8; MS (ES+) m/z 429.2 (M+1).
Reaction SMILES: C([O:3][C:4](=[O:32])[CH2:5][N:6]([CH2:26][C:27]1[O:28][CH:29]=[CH:30][CH:31]=1)[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]([CH3:25])([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:11][CH:10]=1)C.[OH-].[Na+]>C(O)C>[C:4]([CH2:5][N:6]([CH2:26][C:27]1[O:28][CH:29]=[CH:30][CH:31]=1)[CH2:7][CH2:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]([CH3:24])([CH3:25])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[CH:13][CH:14]=1)([OH:32])=[O:3]
Reactant: CCOC(=O)CN(CCc1ccc(SC(C)(C)C(=O)OC(C)(C)C)cc1)Cc1ccco1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)C(C)(C)Sc1ccc(CCN(CC(=O)O)Cc2ccco2)cc1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
1.0 g of 1,1-dimethylethyl 2-[[4-[2-[(2-ethoxy-2-oxoethyl)(2-furanylmethyl)amino]ethyl]phenyl]thio]-2-methyl-propanoate is treated with 6.5 ml of 1 N NaOH in 10 ml of ethanol. The mixture is stirred at 80° C. for 1 h, concentrated, dissolved in water and acidified with 1 N HCl. Three extractions with ethyl acetate and chromatography (dichloromethane/methanol 5+1) gives 744 mg as a colourless oil.