Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:16](O)[CH2:17][OH:18]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>[C:8]1([C:6]2([C:5]3[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][CH:4]=3)[O:18][CH2:17][CH2:16][O:7]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: Cc1ccc(C(=O)c2ccccc2)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(C2(c3ccccc3)OCCO2)cc1
Temperature: 25 °C
Yield: 74.7 %

Procedure:
To a round-bottom flask were added 4-methylbenzophenone (11, 5.0 g, 25.5 mmol, 1.0 equiv.), ethylene glycol (57 mL, 1020 mmol, 40.0 equiv.), para-toluenesulfonic acid monohydrate (147 mg, 0.77 mmol, 0.03 equiv.), and toluene (65 mL, 0.4 M). The biphasic reaction mixture was stirred vigorously at reflux with a Dean-Stark trap for 4 days. The reaction mixture was cooled to room temperature. The reaction mixture was washed with saturated NaHCO3 (2×50 mL) and brine (2×50 mL), dried over Mg504, filtered, and concentrated. Recrystallization from hexanes yielded 12 (4.58 g, 75%) as a white solid. 1H-NMR (500 MHz, CDCl3) δ 7.58-7.55 (m, 2H), 7.45-7.40 (d, 2H, J=8.0 Hz), 7.38-7.35 (m, 2H), 7.33-7.30 (m, 1H), 7.18 (d, 2H, J=8.0 Hz), 4.09 (s, 4H), 2.37 (s, 3H). 13C-NMR (125 MHz, CDCl3): δ 142.2, 139.1, 137.7, 128.7, 128.0, 127.9, 126.1, 126.0, 109.4, 64.8, 21.1.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:10]1([NH:15][C:16]2[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=2)[CH:14]=[CH:13][N:12]=[CH:11]1>C1COCC1>[C:20]([C:19]1[CH:18]=[CH:17][C:16]([N:15]([N:10]2[CH:14]=[CH:13][N:12]=[CH:11]2)[C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])=[CH:23][CH:22]=1)#[N:21]
Reactant: O=C=Nc1ccccc1
Reactant: N#Cc1ccc(Nn2ccnc2)cc1
Solvent: C1CCOC1
Product: N#Cc1ccc(N(C(=O)Nc2ccccc2)n2ccnc2)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Phenyl isocyanate (3.6 ml, 32.6 mmol) was added to a solution of 4-[N-(1H-imidazol-1-yl)amino]benzonitrile (5 g, 27.17 mmol) in THF (50 ml). The mixture was stirred at 50° C. overnight and after evaporation was crystallised in acetone/EtOH to give white crystals (2.5 g, 30.3%, 178° C.).
Reaction SMILES: [C:1]([NH:9][NH2:10])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13](C=O)[CH:12]=1>C(O)(=O)C.C(O)C>[C:1]([NH:9][N:10]=[C:15]1[CH:14]=[CH:13][CH:12]=[N:11][CH2:16]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=Cc1cccnc1
Reactant: NNC(=O)c1cccnc1
Solvent: CC(=O)O
Solvent: CCO
Product: O=C(NN=C1C=CC=NC1)c1cccnc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Five drops of glacial acetic acid are added at room temperature to a solution of 41.1 g of nicotinic acid hydrazide and 32.1 g of pyridine-3-carbaldehyde in 300 ml of ethanol. The reaction mixture, which exotherms slightly, is stirred for ca. 2 hours at room temperature. The precipitated product is isolated by filtration, washed with ca. 100 ml of ethanol and dried, affording the title compound of formula ##STR8## with a melting point of 213°-216° C.
Reaction SMILES: [OH:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:14][CH3:15])[C:5]2[CH:6]=[CH:7][O:8][C:4]=2[C:3]=1[O:16][CH3:17].O.[OH-].[Na+].[H][H]>C(O)C.[Pd]>[OH:1][C:2]1[C:10]([C:11]([OH:13])=[O:12])=[C:9]([O:14][CH3:15])[C:5]2[CH2:6][CH2:7][O:8][C:4]=2[C:3]=1[O:16][CH3:17]
Reactant: COc1c(C(=O)O)c(O)c(OC)c2occc12
Reactant: [H][H]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1c(O)c(C(=O)O)c(OC)c2c1OCC2
Yield: 73.4 %

Procedure:
5 g of 6-hydroxy-4,7-dimethoxybenzofuran-5-carboxylic acid in 75 ml of ethanol/25 ml of H2O/0.8 g of NaOH are hydrogenated in the presence of 1 g of Pd/C (10%) under atmospheric pressure and at 50° C. until uptake of hydrogen is complete. The mixture is filtered, the ethanol is removed by distillation, the aqueous phase is acidified, and the solid is filtered off with suction. 3.7 g of product are obtained and reacted further without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:15]2[S:14][C:13]([NH2:16])=[N:12][C:11]=2[NH:10][N:9]=1.[C:17]([O:20][C@@H:21]([CH3:25])[C:22](Cl)=[O:23])(=[O:19])[CH3:18].C(O)C(N)(CO)CO>CN(C1C=CN=CC=1)C.C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:15]2[S:14][C:13]([NH:16][C:22]([C@@H:21]([O:20][C:17](=[O:19])[CH3:18])[CH3:25])=[O:23])=[N:12][C:11]=2[NH:10][N:9]=1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Nc1nc2[nH]nc(-c3ccccc3Cl)c2s1
Agent: CN(C)c1ccncc1
Agent: NC(CO)(CO)CO
Solvent: C1CCOC1
Product: CC(=O)O[C@@H](C)C(=O)Nc1nc2[nH]nc(-c3ccccc3Cl)c2s1
Temperature: 70 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
To a vial charged with 3-(2-chloro-phenyl)-1H-pyrazolo[3,4-d]thiazol-5-ylamine (30 mg, 0.12 mmol) and PS-DMAP (Argonaut resin, 450 mg, 5 equiv.) were added THF (0.8 mL) and (S)-(−)-2-acetoxypropionyl chloride (126 mg, 0.84 mmol). The reaction mixture was shaken at 70° C. overnight, then cooled to room temperature and treated with PS-trisamine (Argonaut resin, 1.03 g, 30 equiv.) at 50° C. for 4 hours. The resin was filtered, washed with DMF and the solvent was evaporated. Purification by reverse-phase preparative HPLC provided 21 mg (48% yield) of the title compound. 1H-NMR (d6-DMSO) δ: 7.78 (broad m, 1H), 7.61 (broad m, 1H), 7.47 (broad m, 2H), 5.13 (q, 1H), 2.09 (s, 3H), 1.44 (d, 3H); HPLC/MS m/z: 365.0 [MH]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:18]([F:25])([F:24])C(OCC)=O.O>C(#N)C>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH:18]([F:25])[F:24])=[C:4]([Cl:10])[CH:3]=1
Reactant: CCOC(=O)C(F)(F)Br
Reactant: Oc1c(Cl)cc(Br)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: FC(F)Oc1c(Cl)cc(Br)cc1Cl
Temperature: 25 °C
Yield: 86.5 %

Procedure:
To a stirred solution of 4-bromo-2,6-dichlorophenol (2.3 g) in acetonitrile (25 mL) was added potassium carbonate (1.3 g) and ethyl bromodifluoroacetate (3.8 g). The mixture was heated to reflux for 4 hours and then cooled to room temperature. The resulting mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL×1). The organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide a residue. The residue was purified by column chromatography on silica gel eluted with ethyl acetate-hexane (1:4) to afford the title compound as yellow oil (2.4 g).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@H:23]2[C:32]3[C:27](=[CH:28][C:29]([CH2:33][O:34][CH3:35])=[CH:30][CH:31]=3)[CH2:26][CH2:25][N:24]2[C:36]([C@H:38]2[CH2:41][C@H:40]([CH2:42][C:43]([O:45]C(C)(C)C)=[O:44])[CH2:39]2)=[O:37])=[O:22])[CH:12]=[C:13]2[C:17]=1[C:16]([CH3:19])([CH3:18])[CH2:15][CH2:14]2.C(=O)([O-])O.[Na+]>>[F:8][C:9]1[CH:10]=[C:11]([NH:20][C:21]([C@H:23]2[C:32]3[C:27](=[CH:28][C:29]([CH2:33][O:34][CH3:35])=[CH:30][CH:31]=3)[CH2:26][CH2:25][N:24]2[C:36]([C@H:38]2[CH2:41][C@H:40]([CH2:42][C:43]([OH:45])=[O:44])[CH2:39]2)=[O:37])=[O:22])[CH:12]=[C:13]2[C:17]=1[C:16]([CH3:19])([CH3:18])[CH2:15][CH2:14]2
Reactant: COCc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@H](CC(=O)OC(C)(C)C)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COCc1ccc2c(c1)CCN(C(=O)[C@H]1C[C@H](CC(=O)O)C1)[C@H]2C(=O)Nc1cc(F)c2c(c1)CCC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Cooled TFA (2 mL) was added to tert-butyl 2-(trans-3-((R)-1-((7-fluoro-1,1-dimethyl-2,3-dihydro-1H-inden-5-yl)carbamoyl)-6-(methoxymethyl)-1,2,3,4-tetrahydroisoquinoline-2-carbonyl)cyclobutyl)acetate (74 mg, 0.13 mmol) at 0° C., and the mixture was stirred at 0° C. for 30 min. The pH of the reaction mixture was adjusted to 6 with cooled aqueous sodium hydrogencarbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 50→100% ethyl acetate/hexane) to give the title compound (51.0 mg, 0.098 mmol, 76%) as a pale-yellow solid.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[C:5]2[C:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:10]=[C:11]([CH3:12])[C:4]=2[N:3]=1.[Cl:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:22]([NH2:23])=[C:21]([O:27][CH3:28])[CH:20]=1.CN1CCCC1=O>O>[Cl:18][C:19]1[CH:25]=[C:24]([CH3:26])[C:22]([NH:23][C:2]2[N:6]([CH3:7])[C:5]3[C:8]([CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:9][CH:10]=[C:11]([CH3:12])[C:4]=3[N:3]=2)=[C:21]([O:27][CH3:28])[CH:20]=1
Reactant: CCC(CC)c1ccc(C)c2nc(Cl)n(C)c12
Reactant: COc1cc(Cl)cc(C)c1N
Solvent: O
Solvent: CN1CCCC1=O
Product: CCC(CC)c1ccc(C)c2nc(Nc3c(C)cc(Cl)cc3OC)n(C)c12
Temperature: 120 °C
Reaction time: 48 h
Yield: 34.4 %

Procedure:
A mixture of 2-chloro-7-(1-ethylpropyl)-1,4-dimethyl-1H-benzimidazole (100 mg, 0.399 mmol), 4-chloro-2-methoxy-6-methylaniline (205 mg, 1.20 mmol) and 1-methyl-2-pyrrolidone (0.2 mL) was stirred at 120° C. for 2 days under nitrogen atmosphere. The mixture was diluted with water and extracted with ethyl acetate, washed with brine. The organic layer was dried over magnesium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=10:1-1:1) and crystallized from iso-propanol to afford the title compound as colorless crystals (53 mg, 34%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.Cl.[CH3:14]O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:12])[C:9]([O:11][CH3:14])=[O:10])=[CH:6][CH:7]=1
Reactant: O=C(O)C(O)c1ccc(Cl)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)C(O)c1ccc(Cl)cc1
Yield: 83 %

Procedure:
A 250 mL round bottom flask containing 5.6 g (30 mmol) of p-chlorophenyl-α-hydroxyacetic acid and 100 mL of concentrated HCl:MeOH (1:9) was warmed to reflux for 12 hours. The solution was concentrated under reduced pressure, diluted with 250 mL of Et2O and washed once with 30 mL of H2O, twice with 30 mL of NaHCO3 solution, once with 30 mL of H2O and once with 30 mL of brine. The organic layer was dried (Na2SO4) and concentrated leaving 5.0 g (83%) of methyl p-chlorophenyl-α-hydroxyacetate lit m.p. 55° C.) 1H-NMR (CDCl3) δ7.36-7.28 (m, 4H), 5.13 (s, 1 H), 3.72 (s, 3H), 3.67 (br s, 1 H (exchanges with D2O)).
Reaction SMILES: [CH2:1]1[C:7]2=[C:8]3[C:12](=[CH:13][CH:14]=[C:6]2[O:5][CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O)[NH:11][CH:10]=[CH:9]3.[H-].[Na+].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31](Cl)(=[O:33])=[O:32].[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>CN(C=O)C>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([N:11]1[C:12]2[C:8](=[C:7]3[CH2:1][NH:2][CH2:3][CH2:4][O:5][C:6]3=[CH:14][CH:13]=2)[CH:9]=[CH:10]1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Cl)c1ccccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc3[nH]ccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: O=S(=O)(c1ccccc1Cl)n1ccc2c3c(ccc21)OCCNC3
Reaction time: 0.17 h

Procedure:
DMF (1 mL) was added to a mixture of tert-butyl 1,3,4,8-tetrahydro-2H-[1,4]oxazepino[6,7-e]indole-2-carboxylate (Intermediate 18, 10.0 mg, 0.035 mmol) and 60% NaH (5.56 mg, 0.139 mmol). The reaction mixture was stirred for 10 minutes at room temperature before 2-chlorophenylsulfonyl chloride (11 mg, 0.052 mmol) was added all in one portion. After 30 minutes TFA (1 mL) was added and the mixture was stirred for 10 minutes and evaporated. The crude material was purified by preparative HPLC (ACE C8, 0.1% TFA-CH3CN) to give the title compound as a white solid (9.6 mg) in the form of the trifluoroacetate salt. MS m/z 363 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:16][CH2:15][CH:14]([N:17]([CH3:25])[C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH:12]=1.I.CS[C:29]([C:31]1[S:32][CH:33]=[CH:34][CH:35]=1)=[NH:30]>C(O)C>[CH3:25][N:17]([CH:14]1[CH2:15][CH2:16][C:11]([C:5]2[C:4]3[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:29]([C:31]4[S:32][CH:33]=[CH:34][CH:35]=4)=[NH:30])[CH:3]=3)[NH:7][CH:6]=2)=[CH:12][CH2:13]1)[C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23]
Reactant: CSC(=N)c1cccs1
Reactant: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Agent: I
Solvent: CCO
Product: CN(C(=O)OC(C)(C)C)C1CC=C(c2c[nH]c3ccc(NC(=N)c4cccs4)cc23)CC1
Reaction time: 24 h
Yield: 67.6 %

Procedure:
A solution of compound 98 (0.415 g, 1.215 mmol) in dry ethanol (20 mL) was treated with thiophene-2-carboximidothioic acid methyl ester hydroiodide (0.693 g, 2.430 mmol) at room temperature and the resulting solution was stirred for 24 h. The solvent was evaporated and crude was diluted with sat. NaHCO3 solution (25 mL) and CH2Cl2 (50 mL). The organic layer was separated and aqueous layer was extracted with CH2Cl2 (2 25 mL). The combined organic layer was washed with brine (20 mL) and dried (Na2SO4). Th solvent was evaporated and crude product was purified by column chromatography on silica gel (2M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 99 (0.37 g, 68%) as a foam. 1H NMR (DMSO-d6) δ: 0.85 (t, 1H, J=7.2 Hz), 1.20-1.26 (m, 1H), 1.40 (s, 9H), 1.77-1.87 (m, 2H), 2.22-2.40 (m, 2H), 2.72 (s, 3H), 4.06-4.16 (m, 1H), 6.06 (s, 1H), 6.28 (brs, 1H), 6.66 (d, 1H, J=8.4 Hz), 7.10 (t, 1H, J=4.2 Hz), 7.22 (s, 1H), 7.25-7.32 (m, 2H), 7.60 (d, 1H, J=4.8 Hz), 7.72 (d, 1H, J=3.3 Hz), 10.94 (s, 1H); ESI-MS m/z (%): 451 (MH+, 100). N-(3-(4-(methylamino)cyclohex-1-enyl)-1H-indol-5-yl)thiophene-2-carboximidamide (100): A solution of compound 99 (0.35 g, 0.776 mmol) was treated with 20% TFA in CH2Cl2 (20 mL) at 0° C. and stirring was continued for 1 h at the same temperature. The solvent was evaporated and crude was diluted with 10% aq. NH3 (15 mL) and product was extracted into CH2Cl2 (3 20 mL). The combined CH2Cl2 layer was washed with brine (10 mL) and dried (Na2SO4). The solvent was evaporated and the crude product was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 100 (0.2 g, 74%) as a solid. mp 167-169° C.; 1H NMR (DMSO-d6) δ: 1.39-1.47 (m, 2H), 1.88-1.96 (m, 3H), 2.33 (s, 3H), 2.40-2.46 (m, 1H), 2.57-2.61 (m, 1H), 6.01 (s, 1H), 6.19 (brs, 2H), 6.65 (dd, 1H, J=1.5, 8.2 Hz), 7.09 (dd, 1H, J=4.2, 4.9 Hz), 7.20 (s, 1H), 7.28-7.31 (m, 2H), 7.59 (d, 1H, J=4.2 Hz), 7.71 (d, 1H, J=3.3 Hz), 10.87 (s, 1H); ESI-MS m/z (%): 351 (MH+, 66), 320 (54), 160 (63), 119 (100); ESI-HRMS calculated for C20H23N4S (MH+), Calculated: 351.1654; Observed: 351.1637.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:10][S:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH2:24][C:25]#[CH:26])[CH:20]=[CH:19][C:17]=3[N:18]=2)(=[O:13])=[O:12])=[CH:5][CH:4]=1.[N:41]([C@@H:44]([CH2:58][C:59]1[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][O:68][S:69]([C:72]2[CH:78]=[CH:77][C:75]([CH3:76])=[CH:74][CH:73]=2)(=[O:71])=[O:70])=[CH:61][CH:60]=1)[C:45]([N:47]1[CH2:52][CH2:51][CH:50]([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:49][CH2:48]1)=[O:46])=[N+:42]=[N-:43].C(N(C(C)C)CC)(C)C>C1COCC1.[Cu]I>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([C:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[NH:10][S:11]([C:14]2[S:15][C:16]3[CH:22]=[C:21]([O:23][CH2:24][C:25]4[N:43]=[N:42][N:41]([C@@H:44]([CH2:58][C:59]5[CH:64]=[CH:63][C:62]([O:65][CH2:66][CH2:67][O:68][S:69]([C:72]6[CH:78]=[CH:77][C:75]([CH3:76])=[CH:74][CH:73]=6)(=[O:71])=[O:70])=[CH:61][CH:60]=5)[C:45]([N:47]5[CH2:48][CH2:49][CH:50]([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH2:51][CH2:52]5)=[O:46])[CH:26]=4)[CH:20]=[CH:19][C:17]=3[N:18]=2)(=[O:13])=[O:12])=[CH:38][CH:37]=1
Reactant: C#CCOc1ccc2nc(S(=O)(=O)NC(c3ccccc3)(c3ccc(OC)cc3)c3ccc(OC)cc3)sc2c1
Reactant: CCOC(=O)C1CCN(C(=O)[C@H](Cc2ccc(OCCOS(=O)(=O)c3ccc(C)cc3)cc2)N=[N+]=[N-])CC1
Agent: [Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(=O)[C@H](Cc2ccc(OCCOS(=O)(=O)c3ccc(C)cc3)cc2)n2cc(COc3ccc4nc(S(=O)(=O)NC(c5ccccc5)(c5ccc(OC)cc5)c5ccc(OC)cc5)sc4c3)nn2)CC1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a stirring solution of N-(bis(4-methoxyphenyl)(phenyl)methyl)-6-(prop-2-ynyloxy)benzo[d]thiazole-2-sulfonamide (91 mg, 0.159 mmol) and the tosylate 145 (87 mg, 0.159 mmol) in THF (1 mL) was added copper(I) iodide (3 mg, 0.0159 mmol) then diisopropylethylamine (30 μL, 0.175 mmol). The mixture was allowed to stir for 2 h at 23° C. then concentrated in vacuo and the crude residue purified by flash chromatography on silica gel using hexanes/ethyl acetate on a Biotage purification system yielding the desired product as a white, crystalline solid (145 mg, 82%).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.Cl.[C:21]1([C@@H:27]2[CH2:29][C@H:28]2[NH2:30])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>>[C:21]1([C@@H:27]2[CH2:29][C@H:28]2[NH:30][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H]2C[C@H]2c2ccccc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, trans-2-phenyl-cyclopropylamine hydrochloride and DIEA to give 2-((1R,2S)-2-phenyl-cyclopropylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 372 (MH+).
Reaction SMILES: [Cl-].[CH2:2]([O:9][C:10]([C@@H:12]([NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][NH2+:18]1)=[O:16])[CH3:13])=[O:11])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:23]([N:30]1[CH2:37][CH2:36][CH2:35][C@H:31]1[C:32](O)=[O:33])([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>C(Cl)Cl>[CH2:2]([O:9][C:10]([C@@H:12]([NH:14][C:15]([C@@H:17]1[CH2:22][CH2:21][CH2:20][CH2:19][N:18]1[C:32]([C@@H:31]1[CH2:35][CH2:36][CH2:37][N:30]1[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:33])=[O:16])[CH3:13])=[O:11])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: C[C@H](NC(=O)[C@@H]1CCCC[NH2+]1)C(=O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](NC(=O)[C@@H]1CCCCN1C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
12.27 g (37.54 mmol) of the hydrochloride from example 21A and 10.50 g (48.81 mmol) of N-Boc-L-proline are dissolved in methylene chloride (30 ml) and cooled to 0° C. Subsequently, the solution is treated with 18.56 g (48.81 mmol) of HATU and 5.82 g (45.05 mmol) of ethyldiisopropylamine and stirred at 0° C. for 30 min. After further addition of 11.64 g (90.10 mmol) of ethyldiisopropylamine, the mixture is stirred at room temperature for 72 h and then evaporated. The residue is taken up using ethyl acetate and the solution is washed with aq. citric acid and aq. sodium hydrogencarbonate solution and sat. aq. sodium chloride solution, dried over sodium sulfate and evaporated. The residue is purified by means of silica gel chromatography using cyclohexane/ethyl acetate 5/1. 18.25 g (99% of th.) of product are obtained.
Reaction SMILES: [C:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=1[NH:10][C:11]([NH:13]C(=O)C1C=CC=CC=1)=[O:12])#[N:2].[OH-].[Na+]>CCO>[NH2:2][C:1]1[C:3]2[C:7]([CH3:8])=[C:6]([CH3:9])[S:5][C:4]=2[NH:10][C:11](=[O:12])[N:13]=1
Reactant: Cc1sc(NC(=O)NC(=O)c2ccccc2)c(C#N)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1sc2[nH]c(=O)nc(N)c2c1C
Temperature: 25 °C
Yield: 95.8 %

Procedure:
A solution of N-(3-cyano-4,5-dimethylthiophen-2-ylcarbamoyl)benzamide (example 4a) (44.35 g, 148.1 mmol) and NaOH (2 N, 204 mL) in EtOH (400 mL) was stirred at 100° C. under nitrogen for four hours. The clear reaction solution was filtered and the filtrate was cooling to room temperature, and then was carefully neutralized with 10% AcOH (˜120 mL) with vigorous stirring at 0° C. After stirring overnight from 0° C. to room temperature, the resultant precipitate was collected by filtration, washed with warm water (60-70° C., 150 mL×4) and 20% EtOH in water (200 mL×2), and then dried at 50° C. under vacuum overnight to give the final product 4-amino-5,6-dimethylthieno[2,3-d]pyrimidin-2(1H)-one (27.7 g, 96%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ7.98 (brs, 1H), 2.24 (s, 3H), 2.19 (s, 3H). MS 196 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:4](=[C:9]([CH3:14])[S:10][C:11]=2[CH:12]=O)[N:5]=[C:6]([CH3:8])[CH:7]=1.Cl.[NH2:16]O.P(Cl)(Cl)(Cl)=O>>[Cl:1][C:2]1[C:3]2[C:4](=[C:9]([CH3:14])[S:10][C:11]=2[C:12]#[N:16])[N:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Cl)c2c(C=O)sc(C)c2n1
Reactant: NO
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Cl)c2c(C#N)sc(C)c2n1

Procedure:
4-Chloro-2,7-dimethylthieno[3,4-b]pyridine-5-carboxaldehyde is reacted with hydroxylamine hydrochloride and phosphoryl chloride by standard procedures to give 4-chloro-2,7-dimethylthieno[3,4-b]pyridine-5-carbonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:4][C:3]=1[C:14]1[O:15][C:16]2[C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.[CH:26](=O)[CH2:27][CH3:28]>CO.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:26][CH2:27][CH3:28])[CH:5]=[CH:4][C:3]=1[C:14]1[O:15][C:16]2[C:22]([C:23]([NH2:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1
Reactant: NC(=O)c1cccc2nc(-c3ccc(C4CCCCN4)cc3F)oc12
Reactant: CCC=O
Agent: [Pd]
Solvent: CO
Product: CCCN1CCCCC1c1ccc(-c2nc3cccc(C(N)=O)c3o2)c(F)c1
Yield: 56 %

Procedure:
A solution of 2-(2-fluoro-4-(piperidin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide (200 mg, 0.44 mmol), 10% Pd/C (100 mg) and propanal (10 ml, 4 mmol) in methanol (10 ml) was hydrogenated at room temperature for two days. The solution was filtered off and concentrated; the residue was purified by prep-HPLC to give 2-(2-fluoro-4-(1-propylpiperidin-2-yl)phenyl)benzo[d]oxazole-7-carboxamide (94 mg, yield 43%). 1H-NMR (400 MHz, CD3OD) δ (ppm): 0.80 (s, 3H), 1.60-1.77 (m, 3H), 1.97-2.13 (m, 5H), 2.86 (s, 2H), 3.18 (s, 1H), 3.78-3.80 (m, 1H), 4.39-4.413 (m, 1H), 7.302-7.43 (m, 1H), 7.50-7.70 (m, 3H), 7.92-7.93 (m, 2H), 8.39 (s, 1H); LC-MS (ESI) m/z: 382 (M+1)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([CH:24]([CH3:26])[CH3:25])=[N:7][C:8]([CH:21]([CH3:23])[CH3:22])=[C:9]([CH2:18][CH:19]=O)[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)=O.[Br-].[CH3:28][C:29]1[CH:54]=[CH:53][CH:52]=[CH:51][C:30]=1[CH2:31][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C(OCC)(=O)C.CCCCCC>[CH:24]([C:6]1[C:5]([CH2:3][OH:2])=[C:10]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)[C:9]([CH2:18][CH2:19][CH2:28][C:29]2[CH:54]=[CH:53][CH:52]=[CH:51][C:30]=2[CH3:31])=[C:8]([CH:21]([CH3:23])[CH3:22])[N:7]=1)([CH3:26])[CH3:25]
Reactant: COC(=O)c1c(C(C)C)nc(C(C)C)c(CC=O)c1-c1ccc(F)cc1
Reactant: Cc1ccccc1C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccccc1CCCc1c(C(C)C)nc(C(C)C)c(CO)c1-c1ccc(F)cc1

Procedure:
The title compound was prepared from methyl-2,6-diisopropyl-4(4-fluorophenyl)-5-(2-oxoethyl)-3-pyridinecarboxylate (Example 82, Step A) and 2-methylbenzyl triphenylphosphonium bromide according to the procedures described in Example 1, Steps F-H. 1H NMR (300 MHz, CDCl3): δ 7.07 (m, 7 H), 6.90 (m, 1 H), 4.31 (s, 2 H), 3.39 (sept, J=6.6 Hz, 1 H), 3.15 (sept, J=6.6 Hz, 1 H), 2.43 (t, J=7.5 Hz, 2 H), 2.34 (m, 2 H), 2.17 (s, 3 H), 1.6 (m, 2 H), 1.31 (d, J=6.6 Hz, 6 H), 1.27 (d, J=6.6 Hz, 6 H), 1.15 (m, 1 H). FAB-MS: calcd for (C28H34FNO) 419, found 420 (M+H). Anal. Calcd for C28H34FNO: C, 80.15; H, 8.17; N, 3.34. Found: C, 80.12; H, 8.01; N, 3.25. mp 65-70° C. Rf=0.4 (20% ethyl acetate/hexane).