Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]2[N:6]([CH2:14][CH2:15][N:16]([CH3:18])[CH3:17])[C:7]([CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[N:8][C:4]=2[CH:3]=1.[SH:21][CH:22]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1.C(N(CC)C(C)C)(C)C>O1CCOCC1.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].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH3:17][N:16]([CH3:18])[CH2:15][CH2:14][N:6]1[C:5]2[CH:19]=[CH:20][C:2]([S:21][CH:22]3[CH2:23][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:25]3)=[CH:3][C:4]=2[N:8]=[C:7]1[CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: CN(C)CCn1c(CC(C)(C)C)nc2cc(Br)ccc21
Reactant: CC(C)(C)OC(=O)N1CC(S)C1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CN(C)CCn1c(CC(C)(C)C)nc2cc(SC3CN(C(=O)OC(C)(C)C)C3)ccc21
Temperature: 160 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
A mixture of 2-(5-bromo-2-neopentyl-1H-benzo[d]imidazol-1-yl)-N,N-dimethylethanamine (STEP A, 338 mg, 1.00 mmol), tert-butyl 3-mercaptoazetidine-1-carboxylate (STEP D, 246 mg, 1.30 mmol), Xantphos (28.9 mg, 0.0500 mmol), tris(dibenzylideneacetone)dipalladium (22.3 mg, 0.0250 mmol) and N,N-diisopropylethylamine (262 microL, 1.50 mmol) in 1,4-dioxane (4 mL) was stirred at 160° C. for 1 h under microwave. The mixture was concentrated in vacuo and the residue was purified by amine gel column chromatography (hexane-ethyl acetate, gradient) to give the title compound (442 mg, 99%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH2:12]O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:33]C(Br)(Br)Br>>[Br:33][CH2:12][C:11]1[C:2]([Cl:1])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: OCc1cc2ccccc2nc1Cl
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Clc1nc2ccccc2cc1CBr
Reaction time: 2 h
Yield: 65.8 %

Procedure:
A solution under argon of 2-chloro-3-quinolylmethanol (obtained according to 4.a, 15.5 g 80 mmol) and triphenylphosphine (32 g, 120 mmol) is treated with small portions of tetrabromomethane (40 g, 120 mmol) while keeping the temperature of the reaction medium below 30° C. After agitation under argon for 2 hours at ambient temperature, the reaction medium is concentrated under reduced pressure, and the residue is purified by column chromatography (SiO2, ethyl acetate/heptane: 1/1) in order to produce 13.5 g (66%) of a white solid, m.p. 125° C.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH:4]=[C:5]([C:9]([OH:11])=[O:10])[C:6]([OH:8])=[O:7]>CCOC(C)=O.CCO.[Pd]>[CH3:1][C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][C:3]=1[CH2:4][CH:5]([C:9]([OH:11])=[O:10])[C:6]([OH:8])=[O:7]
Reactant: Cc1ccccc1C=C(C(=O)O)C(=O)O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccccc1CC(C(=O)O)C(=O)O
Reaction time: 2 h

Procedure:
Hydrogenate the acid of Step 1 (24.3 g) in EtOAc (600 ml) and EtOH (100 ml) at 60 psi with 5% Pd/C (1.0 g). After 2 hr., filter and concentrate to obtain the title compound as a beige solid, m.p. 132°-5°.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH2:11])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.Cl[C:13]1[N:18]=[C:17]([N:19]2[CH2:24][CH2:23][CH2:22][C@H:21]([C:25]([NH:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)=[O:26])[CH2:20]2)[CH:16]=[CH:15][N:14]=1>CS(C)=O>[O:1]1[CH2:2][CH2:3][O:4][C:5]2[CH:10]=[C:9]([NH:11][C:13]3[N:18]=[C:17]([N:19]4[CH2:24][CH2:23][CH2:22][C@H:21]([C:25]([NH:27][CH2:28][C:29]5[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=5)=[O:26])[CH2:20]4)[CH:16]=[CH:15][N:14]=3)[CH:8]=[CH:7][C:6]1=2
Reactant: Cc1ccc(CNC(=O)[C@H]2CCCN(c3ccnc(Cl)n3)C2)cc1
Reactant: Nc1ccc2c(c1)OCCO2
Solvent: CS(C)=O
Product: Cc1ccc(CNC(=O)[C@H]2CCCN(c3ccnc(Nc4ccc5c(c4)OCCO5)n3)C2)cc1
Temperature: 90 °C
Yield: 18 %

Procedure:
A mixture of 1,4-benzodioxan-6-amine (Sigma-Aldrich, 65.8 mg, 0.435 mmol) and (S)-1-(2-chloropyrimidin-4-yl)-N-(4-methylbenzylipiperidine-3-carboxamide (M5, 100 mg, 0.290 mmol) in DMSO (0.6 mL) was heated at 90° C. for 16 hours. The mixture was then cooled to room temperature, filtered and was purified with reversed-phase HPLC (Phenomenex Gemini-NX 10 μL 110 Å, AXIA packed column, 100×50 mm, 60 mL/min, 10-95% ACN/H2O, 0.1% TFA, 10 min gradient). After concentration of the fractions by vacuum distillation, the product was diluted with saturated aqueous NaHCO3 and extracted with DCM (3×). The combined organic layers were dried over Na2SO4, filtered and concentrated to provide the desired product in 18% yield. 1H NMR (300 MHz, CDCl3) δ ppm 1.66-1.79 (m, 2H), 1.85-2.00 (m, 1H), 2.04-2.19 (m, 1H), 2.30 (s, 3H), 2.45 (br. s., 1H), 3.24 (t, J=9.9 Hz, 1H), 3.69 (dd, J=13.7, 8.0 Hz, 1H), 3.83 (d, J=12.6 Hz, 1H), 4.12 (d, J=12.1 Hz, 1H), 4.19 (s, 4H), 4.34 (d, J=5.4 Hz, 2H), 6.00 (d, J=6.1 Hz, 1H), 6.39 (br. s., 1H), 6.76 (d, J=8.6 Hz, 1H), 6.85 (dd, J=10.7, 9.1 Hz, 1H), 6.79-6.92 (m, 1H), 7.07 (s, 4H), 7.17-7.22 (m, 1H), 7.89 (d, J=6.3 Hz, 1H); M+H 460.23367.
Reaction SMILES: [C:1]1([C:7]2[O:8][CH2:9][C:10](=[O:13])[NH:11][N:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[CH:15]1[CH2:19][CH2:18][O:17][CH2:16]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.C1(C)C=CC=CC=1>O1CCCC1>[C:1]1([C:7]2[O:8][CH2:9][C:10](=[O:13])[N:11]([CH:15]3[CH2:19][CH2:18][O:17][CH2:16]3)[N:12]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1CCOC1
Reactant: O=C1COC(c2ccccc2)=NN1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: O=C1COC(c2ccccc2)=NN1C1CCOC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.8 %

Procedure:
2-Phenyl-4H-1,3,4-oxadiazine-5(6H)-one (0.30 g) synthesized according to Receuil des Travaux chimiques des Pays Bas, 1929, 48, 417, 3-hydroxy tetrahydrofuran (0.30 g) and triphenyl phosphine (0.89 g) were dissolved in tetrahydrofuran (10 ml). Under ice-cooling, 40% diethyl azodicarboxylate/toluene solution (0.59 g) diluted with tetrahydrofuran (3 ml) was added thereto, followed by stirring overnight at room temperature. The reaction solution was evaporated and purified by Cromatorex NH silica gel chromatography (hexane/ethyl acetate system), to give the title compound (0.15 g, 36%).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.[C:33]([NH:37][S:38](Cl)(=[O:40])=[O:39])(=[O:36])[CH2:34][CH3:35].C(N(CC)CC)C>ClCCl>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:38]([NH:37][C:33](=[O:36])[CH2:34][CH3:35])(=[O:40])=[O:39])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CCC(=O)NS(=O)(=O)Cl
Reactant: CC(C)CCC1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCC(=O)NS(=O)(=O)Nc1ccc2c(c1)S(=O)(=O)N=C(C1=C(O)c3ccccc3C(C)(CCC(C)C)C1=O)N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 57.4 %

Procedure:
A mixture of Example 34B (52.2 mg, 0.110 mmol) and the product of Example 100A (94.6 mg, 0.55 mmol) in dichloromethane (5 mL) was treated with triethylamine (66.5 mg, 0.658 mmol). The mixture was stirred at rt for 15 minutes. The reaction mixture was partitioned between dichloromethane and 1N hydrochloric acid, and the aqueous phase extracted with additional dichloromethane. The organic phase was dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by HPLC to give the title compound (36.3 mg, 57%). 1H NMR (300 MHz, DMSO-d6) δ 0.41 (s, 2H) 0.69 (d, J=6.62 Hz, 3H) 0.72 (d, J=6.62 Hz, 3H) 0.88 (t, J=7.54 Hz, 3H) 1.33 (m, 2H) 1.57 (s, 3H) 2.04 (m, 1H) 2.14 (q, J=7.35 Hz, 2H) 2.25 (m, J=13.97, 3.31 Hz, 1H) 7.48 (dd, J=9.01, 2.39 Hz, 1H) 7.54 (m, J=8.27, 3.86 Hz, 1H) 7.59 (d, J=2.21 Hz, 1H) 7.71 (d, J=8.82 Hz, 1H) 7.76 (d, J=3.68 Hz, 2H) 8.16 (d, J=8.09 Hz, 1H) 10.94 (s, 1H) 11.98 (s, 1H) 13.80 (s, 1H).). MS (ESI+) m/z 575.2 (M+H)+, 592.2 (M+NH4)+, (ESI−).
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>O1CCCC1>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:34])=[CH:28][CH:27]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(Cl)cc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.5 %

Procedure:
To a solvent of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 4-chlorophenyl isocyanate (0.188 mg, 1.22 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 310 mg (95.4%) of the desired product as a solid.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=2[S:14](=[O:17])(=[O:16])[NH2:15])[CH2:3][CH2:2]1.[CH3:18]O>S(=O)(=O)(O)O>[CH:1]1([NH:4][C:5]2[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:18])=[O:10])=[CH:7][C:6]=2[S:14](=[O:17])(=[O:16])[NH2:15])[CH2:2][CH2:3]1
Reactant: NS(=O)(=O)c1cc(C(=O)O)ccc1NC1CC1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(NC2CC2)c(S(N)(=O)=O)c1

Procedure:
4-Cyclopropylamino-3-sulphamoylbenzoic acid (3.9 mmol), prepared according to the process described in Step B of Example 1 starting from the compound obtained in the Step above, is then dissolved in sulphuric acid (0.5 mL) and methanol (10 mL), and the mixture is heated at reflux for 4 hours. The solvent is then removed by distillation under reduced pressure and the residue is suspended in water (20 mL). The precipitate obtained is collected by filtration, washed with water and dried to yield the title product in the form of a white solid.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[S:11][C:12]1[NH:13][C:14]2[C:19]([N:20]=1)=[C:18]([NH2:21])[N:17]=[CH:16][N:15]=2.Br[CH2:23][CH2:24][CH2:25][NH:26][S:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[NH2:21][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[C:19]=1[N:20]=[C:12]([S:11][C:3]1[CH:4]=[C:5]3[C:9](=[CH:10][C:2]=1[I:1])[CH2:8][CH2:7][CH2:6]3)[N:13]2[CH2:23][CH2:24][CH2:25][NH:26][S:27]([C:29]([CH3:32])([CH3:31])[CH3:30])=[O:28]
Reactant: Nc1ncnc2[nH]c(Sc3cc4c(cc3I)CCC4)nc12
Reactant: CC(C)(C)S(=O)NCCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)S(=O)NCCCn1c(Sc2cc3c(cc2I)CCC3)nc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
To a solution of 8-((6-iodo-2,3-dihydro-1H-inden-5-yl)thio)-9H-purin-6-amine (13 mg, 0.03 mmol) in DMF (1.5 mL) was added N-(3-bromopropyl)-2-methlpropane-2-sulfinamide (23 mg, 0.1 mmol) and Cs2CO3 (21 mg, 0.06 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was condensed under vacuum and the residue was purified by Prep TLC (CH2Cl2:NH3-MeOH (7N), 20:1) to yield WS63 as a white solid (5 mg, 27%). 1H NMR (600 MHz, CDCl3): δ 8.22 (s, 1H), 7.68 (s, 1H), 7.05 (s, 1H), 5.70 (br s, 2H), 4.83 (t, J=6.7 Hz, 1H), 4.28-4.36 (m, 1H), 4.17-4.27 (m, 1H), 2.99-3.07 (m, 1H), 2.85-2.93 (m, 1H), 2.81 (t, J=7.4 Hz, 2H), 2.72 (t, J=7.5 Hz, 2H), 1.83-2.08 (m, 4H), 1.20 (m, 9H); HRMS (ESI) m/z [M+H]+ calcd. for C21H28IN6OS2, 571.0811. found 571.0809.
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[NH:15]1[CH2:20][CH2:19][S:18][CH2:17][CH2:16]1.CCOC(C)=O>C1COCC1>[S:18]1[CH2:19][CH2:20][N:15]([C:2]2[O:3][C:4]3[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=3)[N:6]=2)[CH2:16][CH2:17]1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: C1CSCCN1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2oc(N3CCSCC3)nc12
Yield: 84.1 %

Procedure:
A solution of methyl 2-chlorobenzoxazole-4-carboxylate (1.0 g, 4.7 mmol) and thiomorpholine (1.4 mL, 14 mmol) in THF (20 mL) was stirred at ambient temperature for 1 h. Then, the reaction mixture was poured into EtOAc (100 mL) and washed with 1N HCl (20 mL), H2O (20 mL), brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure. Purification by chromatography (silica gel, 5 to 50% EtOAc in hexanes) gave methyl 2-thiomorpholinobenzoxazole-4-carboxylate (1.1 g, 84%) as a yellow solid. 1H NMR and MS consistent.
Reaction SMILES: C(O[C:4](=[O:24])[C:5](=[CH:11][NH:12][C:13]1[N:17]([CH2:18][C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:16]=[CH:15][CH:14]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.C(O)C>C1(OC2C=CC=CC=2)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[C:4]([OH:24])=[C:14]2[CH:15]=[N:16][N:17]([CH2:18][C:19]3[O:20][CH:21]=[CH:22][CH:23]=3)[C:13]2=[N:12][CH:11]=1)=[O:7])[CH3:10]
Reactant: CCOC(=O)C(=CNc1ccnn1Cc1ccco1)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc2c(cnn2Cc2ccco2)c1O

Procedure:
250 g of [[[1-(2-furyl)methyl-5-pyrazolyl]amino]methylene]malonic acid diethyl ester (0.75 mol) is dissolved in 1 liter of diphenyl ether and heated to 240° for 2 hours. The ethanol formed is continuously distilled off. The solvent is removed in vacuo. The 4-hydroxy-1-(2-furyl)methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylic acid ethyl ester remains and is recrystallized from methanol, yield 248 g (86%), m.p. 103°-106°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[CH:6]([CH2:7][CH2:8][C:9](=O)[CH2:10]2)[CH2:5][CH:4]=1.[CH2:14]([NH:17][CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:14]([N:17]([CH2:18][CH2:19][CH3:20])[CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:10]1)[CH2:15][CH3:16]
Reactant: CCCNCCC
Reactant: COC1=CCC2CCC(=O)CC2=C1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCN(CCC)C1CCc2ccc(OC)cc2C1

Procedure:
A mixture of 20 g of 7-methoxytetrahydronaphthalen-2-one and 20 ml of dipropylamine in 200 ml of benzene is heated under reflux for 15 hours with 500 mg of para-toluenesulphonic acid, the water of condensation being distilled off.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][OH:5].[H-].[Na+].F[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11](=[O:19])[NH:12][CH:13]=[N:14]2>CC(N(C)C)=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([OH:19])=[N:12][CH:13]=[N:14]2
Reactant: O=c1[nH]cnc2cccc(F)c12
Reactant: COCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COCCOc1cccc2ncnc(O)c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-methoxyethanol (0.528 ml, 6.70 mmol) in DMA (6 mL) was slowly added 514 mg of a 60% dispersion of NaH (0.308 g, 12.8 mmol), and the reaction mixture was stirred at room temperature for 30 minutes. 5-Fluoroquinazolin-4(3H)-one (1.0 g, 6.09 mmol) was added and the reaction mixture was heated at 80° C. for 2 hours. The reaction was concentrated and the residue was suspended in EtOH (75 mL) and then filtered through GF/F paper. The filtrate was concentrated to afford the desired product as a yellow solid.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:5][C:6]1[S:7][C:8]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:4].[C:17](Cl)(=[O:20])[CH2:18][CH3:19]>N1C=CC=CC=1>[CH3:16][O:15][C:13]1[CH:12]=[CH:11][C:9]2[N:10]=[C:6]([NH:5][C:3](=[O:4])[CH2:2][O:1][C:17](=[O:20])[CH2:18][CH3:19])[S:7][C:8]=2[CH:14]=1
Reactant: CCC(=O)Cl
Reactant: COc1ccc2nc(NC(=O)CO)sc2c1
Solvent: c1ccncc1
Product: CCC(=O)OCC(=O)Nc1nc2ccc(OC)cc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-(Hydroxyacetylamino)-6-methoxybenzothiazole (1.2 g) prepared in Example 3 is dissolved in pyridine (50 ml) and thereto is added dropwise propionyl chloride (0.5 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting oil is solidified with addition of water. The obtained solids are filtered off and washed with water, then with diethyl ether, dried and recrystallized from ethanol to give the title compound (1.1 g) having the following physical properties.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:17]=2)[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O[C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]2[S:41][CH:42]=[CH:43][N:44]=2)[N:35]=1)(=O)=O>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].C(Cl)Cl.COCCOC>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:34]3[N:35]=[C:36]([C:40]4[S:41][CH:42]=[CH:43][N:44]=4)[CH:37]=[CH:38][CH:39]=3)[CH:17]=2)[N:12]=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OB(c2ccc3nccc(OCc4ccccc4)c3c2)OC1(C)C
Reactant: O=S(=O)(Oc1cccc(-c2nccs2)n1)C(F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: COCCOC
Solvent: ClCCl
Product: c1ccc(COc2ccnc3ccc(-c4cccc(-c5nccs5)n4)cc23)cc1
Yield: 39 %

Procedure:
A solution of 4-(benzyloxy)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (1.0 equiv.), 6-(thiazol-2-yl)pyridin-2-yl trifluoromethanesulfonate (1.0 equiv.) and Pd(dppf)Cl2—CH2Cl2 (0.1 equiv.) in 3:1 DME/2M Na2CO3 was heated in a microwave at 120° C. for 20 minutes. Upon cooling, the solution was partitioned between EtOAc and H2O. Upon separation, the organic layer was washed with NaCl(sat.), dried over MgSO4, concentrated and purified by silica gel chromatography (EtOAc eluant) to yield 2-(6-(4-(benzyloxy)quinolin-6-yl)pyridin-2-yl)thiazole (39%). LC/MS=396.0 (M+H), LC=3.34 min.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][C:25]([S:28][CH:29]5[CH2:31][CH2:30]5)=[CH:24][CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.CN(C)C(N(C)C)=N.[F:40][C:41]([F:48])([F:47])[C:42](OCC)=[O:43]>CO>[CH:29]1([S:28][C:25]2[CH:24]=[CH:23][C:22]([C@@H:18]([O:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10]4)[C@@H:19]([NH:21][C:42](=[O:43])[C:41]([F:48])([F:47])[F:40])[CH3:20])=[CH:27][CH:26]=2)[CH2:31][CH2:30]1
Reactant: CCOC(=O)C(F)(F)F
Reactant: C[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(SC2CC2)cc1
Agent: CN(C)C(=N)N(C)C
Solvent: CO
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccc(SC2CC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(1R,2S)-1-{[1-(4-Fluorophenyl)-1H-indazol-5-yl]oxy}-1-[4-(cyclopropylthio)phenyl]propan-2-amine (62 mg, 0.14 mmol) was dissolved in MeOH (2 mL), 1,1,3,3-tetramethylguanidine (100 μL, 0.8 mmol) and ethyl trifluoroacetate (83 μL, 0.7 mmol) was added. The mixture was stirred at r.t. for 2 h, the solvents was removed by evaporation and the residual material was treated with water and a few drops of dilute HCl(aq) until slightly acidic. The formed slurry was extracted with DCM and EtOAc, the combined organic phases was concentrated and purified by semi-preparative HPLC using a Kromasil® C18 250×20 mm, 5 μm column. Flow 10 mL/min, 15 min gradient of 50%-90% MeCN in water followed by isocratic final concentration until product had eluted. UV=254 nm was used for detection. Fractions with product was combined and lyophilized to afford the title compound as a colourless solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][CH2:13]1)[CH:6]=[CH:5]2.[CH2:28]([O:35][CH2:36][C@@H:37]1[CH2:40][C@H:39](O)[CH2:38]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[C:23]([O:22][C:21](=[O:27])[NH:20][C:12]1([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][C@H:39]4[CH2:38][C@H:37]([CH2:36][O:35][CH2:28][C:29]5[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH2:40]4)[CH:3]=3)[CH:8]=2)[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][CH2:13]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3cc(O)ccc3c2)COC(C)(C)OC1
Reactant: O[C@H]1C[C@@H](COCc2ccccc2)C1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc3cc(O[C@H]4C[C@H](COCc5ccccc5)C4)ccc3c2)COC(C)(C)OC1
Temperature: 23 °C
Reaction time: 48 h

Procedure:
To a solution of [5-(6-Hydroxynaphthalen-2-yl)-2,2-dimethyl-1,3-dioxinan-5-yl]-carbamic acid tert-butyl ester (Example 13, 30.0 mg, 0.0000723 mol), cis-3-benzyloxymethyl-cyclobutanol (13.9 mg, 0.0000723 mol), and triphenylphosphine (22.8 mg, 0.0000868 mol) in THF (2 mL), a solution of diisopropyl azodicarboxylate (18.7 mg, 0.0000868 mol) in THF (1 mL), was added dropwise at 23° C. The reaction mixture was then allowed to stir at 23° C. for 2 days. Solvent was removed, and the crude mixture was purified via chromatography (SiO2, 4 g, ethyl acetate 0-35%) to give a pure product (18 mg, 45%). MS (ES, M−113): 434.30.
Reaction SMILES: C(OC([NH:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24](=[O:26])[OH:25])=[N:19][C:18]=3[C:17]([O:27][CH3:28])=[CH:16][CH:15]=2)[N:13]=1)=O)(C)(C)C>Cl.CO>[NH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[C:22]3[S:21][C:20]([NH:23][C:24](=[O:25])[OH:26])=[N:19][C:18]=3[C:17]([O:27][CH3:28])=[CH:16][CH:15]=2)[N:13]=1
Reactant: COc1ccc(-c2c[nH]c(NC(=O)OC(C)(C)C)n2)c2sc(NC(=O)O)nc12
Agent: Cl
Solvent: CO
Product: COc1ccc(-c2c[nH]c(N)n2)c2sc(NC(=O)O)nc12
Yield: 16 %

Procedure:
0.04 g of [7-(2-tert-butoxycarbonylamino-1H-imidazol-4-yl)-4-methoxy-benzothiazol-2-yl]-carbamic acid methyll ester (0.0001 Mol) were heated to 60° C. in HCl/MeOH (2.5 M, 2 ml). After evaporation of the solvent the residue was dissolved in water (5 ml) and the pH was adjusted to 8 with sat. NaHCO3. The water was evaporated and the residue triturated in ethyl acetate where a precipitation formed. This was isolated and dried to yield the title compound as a grey solid (16%); F.p.: 225-235° C.
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([OH:24])=[C:19]([O:22][CH3:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:25])[NH:6]2.[C:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36]Cl)[CH2:31][CH2:30]1)(=[O:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+].O>CN1CCCC1=O>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][O:24][C:18]2[CH:17]=[C:16]3[C:21]([C:12]([O:11][C:10]4[C:2]([F:1])=[C:3]5[C:7](=[CH:8][CH:9]=4)[NH:6][C:5]([CH3:25])=[CH:4]5)=[N:13][CH:14]=[N:15]3)=[CH:20][C:19]=2[O:22][CH3:23])[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CC(=O)N1CCN(CCCl)CC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCN1CCN(C(C)=O)CC1
Temperature: 90 °C
Yield: 84.9 %

Procedure:
A mixture of 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-hydroxy-6-methoxyquinazoline (250 mg, 0.74 mmol), 1-acetyl-4-(2-chloroethyl)piperazine (144 mg, 0.81 mmol) and potassium carbonate (112 mg, 0.81 mmol) in N-methylpyrrolidinone (6 ml) was heated at 90° C. for 2 hours. The mixture was cooled and water added. After 30 minutes the solid was filtered off and dried under vacuum. The residue was purified by column chromatography eluting with methylene chloride/methanol (saturated with ammonia) (96/4) to give 7-[2-(4-acetylpiperazin-1-yl)ethoxy]-4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxyquinazoline (310 mg, 58%) as a white solid.