Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[CH2:22]1[C:27]2[C:28]3[C:33]([NH:34][C:26]=2[CH2:25][NH:24][CH2:23]1)=[CH:32][CH:31]=[CH:30][CH:29]=3>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C@@H:17]([OH:18])[CH2:19][N:24]4[CH2:23][CH2:22][C:27]5[C:28]6[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=6)[NH:34][C:26]=5[CH2:25]4)=[CH:13][CH:14]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: c1ccc2c3c([nH]c2c1)CNCC3
Reactant: Fc1ccc2c(-c3ccc(OC[C@@H]4CO4)cc3)noc2c1
Solvent: CN(C)C=O
Solvent: CCO
Product: O[C@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCc2c([nH]c3ccccc23)C1

Procedure:
The title compound is prepared from a mixture of (S)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and noreleagnine in ethanol essentially as described above in Example 21. Purity by LC/MS=99%, [M+H]+=458.
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([NH2:4])=[O:3].CN1CCOCC1.ClC(OCC)=O.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][NH:32][OH:33])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].[Cl-].[NH4+]>COCCOC>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:30][CH2:31][N:32]([OH:33])[C:1]([C:2]([NH2:4])=[O:3])=[O:6])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COc1ccc(CCNO)cc1OC
Reactant: NC(=O)C(=O)O
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: COCCOC
Solvent: CN1CCOCC1
Product: COc1ccc(CCN(O)C(=O)C(N)=O)cc1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 17.4 %

Procedure:
N-[2-(3,4-Dimethoxyphenyl)ethyl]-N-hydroxamide. To a suspension of oxamic acid (195 mg, 2.21 mmol) in 1,2-dimethoxyethane (7 mL) under an argon atmosphere was added dropwise N-methylmorpholine (0.27 mL, 2.42 mmol), followed by ethyl chloroformate (0.23 mL, 2.42 mmol). After stirring for 1 h at room temperature, a solution of N-[2-(3,4-dimethoxyphenyl)ethyl]-N-hydroxyamine (417 mg, 2.10 mmol) in 1,2-dimethoxyethane (5 mL) was added, and the resulting mixture was stirred for 4 h. Saturated aqueous ammonium chloride was added, and the mixture was extracted with methylene chloride (2×). The combined organic extracts were washed successively with 10% hydrochloric acid and water and dried (potassium carbonate). The solvent was removed in vacuo and the residue was purified by flash chromatography, eluting with 5% methanol/methylene chloride, and recrystallized from methanol/methylene chloride to provide the oxamide (98 mg, 17%): m.p. 143°-144° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]#[C:30][C:31]1[C:32]([O:41][CH3:42])=[CH:33][C:34]([O:39][CH3:40])=[C:35]([CH:38]=1)[CH:36]=O.C[O-].[Li+]>CN(C=O)C.CO>[NH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:29]#[C:30][C:31]1[C:32]([O:41][CH3:42])=[CH:33][C:34]([O:39][CH3:40])=[C:35](/[CH:36]=[CH:2]/[C:1]([C:4]2[CH:9]=[CH:8][C:7]([S:10]([NH:13][CH2:14][CH2:15][CH2:16][N:17]3[CH:21]=[CH:20][N:19]=[CH:18]3)(=[O:12])=[O:11])=[CH:6][CH:5]=2)=[O:3])[CH:38]=1
Reactant: CC(=O)c1ccc(S(=O)(=O)NCCCn2ccnc2)cc1
Reactant: COc1cc(OC)c(C=O)cc1C#Cc1ccccc1N
Agent: C[O-]
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(OC)c(/C=C/C(=O)c2ccc(S(=O)(=O)NCCCn3ccnc3)cc2)cc1C#Cc1ccccc1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.1 %

Procedure:
Ex-50A: A solution of 4-acetyl-N-(3-imidazol-1-ylpropyl)benzenesulfonamide (Ex-23A, 312 mg, 1.02 mmol) and 5-(2-amino-phenylethynyl)-2,4-dimethoxybenzaldehyde (Ex-35C, 287 mg, 1.02 mmol) in DMF (4.4 mL) and MeOH (1.9 mL) was treated with lithium methoxide (155 mg, 4.08 mmol). The reaction mixture was stirred at room temperature for 16 h under nitrogen. The reaction mixture was quenched with water (25 mL) and extracted with (3:1) ethyl acetate/THF (3×25 mL). The organic phase was brined, dried over sodium sulfate, and concentrated to a yellow oil. The crude material was purified by column chromatography (0–7.5% MeOH in dichloromethane) to give 4-{3E-[5-(2-amino-phenylethynyl)-2,4-dimethoxy-phenyl]acryloyl}-N-(3-imidazol-1-ylpropyl)benzenesulfonamide (309 mg, 53%) as a yellow oil. 1H-NMR (3.00 MHz, DMSO-d6) 8.28 (d, 2H, J=7.80), 8.20 (s, 1H), 8.01 (d, 1H, J=15.0 Hz), 7.86 (m, 5 H), 7.51 (s, 1H), 7.16 (d, 1H, J=7.5 Hz), 7.23 (m, 2H), 6.79 (d, 2H, J=10.8 Hz), 6.72 (d, 1H, J=8.1 Hz), 6.52 (t, 1H, J=7.2 Hz), 5.45 (m, 1H), 3.97 (s, 3H), 3.96 (s, 3H), 3.92 (m, 4H), 1.77 (quintet, 2H, J=6.6 Hz).
Reaction SMILES: Cl[Si:2]([CH3:8])([CH3:7])[C:3]([CH3:6])([CH3:5])[CH3:4].[Br:9][C:10]1[CH:44]=[CH:43][C:13]([C:14]([CH:16]([N:18]2[C:22](=[O:23])[N:21]([C:24]3[CH:29]=[CH:28][C:27]([N:30]4[CH2:35][CH2:34][N:33]([C:36]5[CH:41]=[CH:40][C:39]([OH:42])=[CH:38][CH:37]=5)[CH2:32][CH2:31]4)=[CH:26][CH:25]=3)[CH:20]=[N:19]2)[CH3:17])=[O:15])=[CH:12][CH:11]=1>ClCCl.N1C=CC=CC=1>[Br:9][C:10]1[CH:44]=[CH:43][C:13]([C:14]([CH:16]([N:18]2[C:22](=[O:23])[N:21]([C:24]3[CH:25]=[CH:26][C:27]([N:30]4[CH2:31][CH2:32][N:33]([C:36]5[CH:41]=[CH:40][C:39]([O:42][Si:2]([C:3]([CH3:6])([CH3:5])[CH3:4])([CH3:8])[CH3:7])=[CH:38][CH:37]=5)[CH2:34][CH2:35]4)=[CH:28][CH:29]=3)[CH:20]=[N:19]2)[CH3:17])=[O:15])=[CH:12][CH:11]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C(=O)c1ccc(Br)cc1)n1ncn(-c2ccc(N3CCN(c4ccc(O)cc4)CC3)cc2)c1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C(=O)c1ccc(Br)cc1)n1ncn(-c2ccc(N3CCN(c4ccc(O[Si](C)(C)C(C)(C)C)cc4)CC3)cc2)c1=O
Yield: 45.3 %

Procedure:
A solution of 2-(chlorodimethylsilyl)-2-methylpropane (0.011 mol) in dichloromethane (20 ml) was added to a stirred solution of 2-[1-(4-bromobenzoyl)ethyl]-2,4-dihydro-4-[4-[4-(4-hydroxyphenyl)-1-piperazinyl]phenyl]-3H-1,2,4-triazol-3-one (0.009 mol) in pyridine (20 ml) under a nitrogen atmosphere. Stirring was continued for 1 week at room temperature. The reaction mixture was evaporated and the residue was dissolved in dichloromethane. This solution was purified over silica gel on a glass filter (eluent: dichloromethane). The pure fractions were collected and the solvent was evaporated. The residue (3.5 g) was recrystallized from ethyl acetate. The product was filtered off and dried, yielding 2.7 g (45 %) of 2-[1-(4-bromobenzoyl)ethyl]-4-[4-[4-[4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]-1-piperazinyl]phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one; mp. 177.8° C. (comp. 47).
Reaction SMILES: [CH:1]([C:4]1[C:12]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].Cl.N1C=CC=CC=1>O>[CH:1]([C:4]1[C:12]([S:13]([C:16]2[CH:17]=[CH:18][C:19]([OH:22])=[CH:20][CH:21]=2)(=[O:15])=[O:14])=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(S(=O)(=O)c2c(C(C)C)nn3ccccc23)cc1
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: CC(C)c1nn2ccccc2c1S(=O)(=O)c1ccc(O)cc1
Temperature: 220 °C

Procedure:
A mixture of 0.012 mol of 2-isopropyl-3-(4-methoxybenzenesulphonyl) pyrazolo[1,5-a]pyridine and 0.054 mol of pyridine hydrochloride was heated at 220° C. for & hour. Water was then added and the mixture was distilled in the presence of ethyl acetate. The medium was dried on sodium sulphate, filtered and concentrated. The solid so obtained was then recrystallized from isopropyl ether to provide a white crystalline product.
Reaction SMILES: [C:1]1([CH:7]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19](O)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:34]1([CH2:40][CH2:41][NH2:42])[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.O>O1CCCC1>[C:1]1([CH:7]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:8][NH:9][C:10]2[N:18]=[C:17]([C:19]([NH:42][CH2:41][CH2:40][N:34]3[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]3)=[O:20])[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][N:14]3[CH:22]2[CH2:27][CH2:26][CH2:25][CH2:24][O:23]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCCN1CCCCC1
Reactant: O=C(O)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCCN1CCCCC1)c1nc(NCC(c2ccccc2)c2ccccc2)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C

Procedure:
To a suspension of 6-[(2,2-diphenylethyl)amino]-9-(tetrahydro-2H-pyran-2-yl) 9H-purine-2-carboxylic acid (249 g, 0.561 moles) (Preparation 21) in anhydrous tetrahydrofuran (2500 ml) was added N,N′-carbonyldiimidazole (109 g, 0.672 moles) in two portions over 10 minutes. The resulting mixture was stirred at ambient temperature under an atmosphere of nitrogen whereupon the solid gradually dissolved to give a cloudy pale orange solution. After stirring for 2.5 h, the reaction mixture was cooled in an ice-bath, and a solution of 2-(1-piperidinyl)ethylamine (86.4 g, 0.674 moles) in anhydrous tetrahydrofuran (100 ml) was added over a period of 55 minutes during which time a clear orange solution formed. The reaction mixture was stirred at room temperature for a further 17.5 hours. Deionised water (10 ml) was then added and the reaction mixture was then distilled at atmospheric pressure until approximately 2400 ml of distillate had collected. To the resultant amber oil was added isopropanol (2000 ml) and distillation at atmospheric pressure was continued until approximately 50 ml of distillate had collected. The resultant dark orange solution was allowed to cool to ambient temperature and further isopropanol (600 ml) was added to give a solution of the title compound in isopropanol that may be used directly without further purification.
Reaction SMILES: [C:1]([C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[C:10]([C:12]3[C@H:13]([CH3:26])[C@@H:14]4[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:15]4[C:16]=3[C:17]([O-:19])=[O:18])[S:9][C:8]=12)(=[O:3])[CH3:2].[Na+].[CH2:28]([O:30][C:31]([O:33][CH:34](I)[CH3:35])=[O:32])[CH3:29].C(OCC)(=O)C>CN(C=O)C>[C:1]([C:4]1[N:5]=[CH:6][N:7]2[CH:11]=[C:10]([C:12]3[C@H:13]([CH3:26])[C@@H:14]4[C@@H:21]([C@H:22]([OH:24])[CH3:23])[C:20](=[O:25])[N:15]4[C:16]=3[C:17]([O:19][CH:28]([O:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[CH3:29])=[O:18])[S:9][C:8]=12)(=[O:3])[CH3:2]
Reactant: CCOC(=O)OC(C)I
Reactant: CC(=O)c1ncn2cc(C3=C(C(=O)[O-])N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)sc12
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)OC(C)OC(=O)C1=C(c2cn3cnc(C(C)=O)c3s2)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12
Temperature: -10 °C
Reaction time: 2 h
Yield: 64.5 %

Procedure:
Sodium (1S,5R,6S)-2-(7-acetylimidazo[5,1-b]thiazol-2-yl)-6-((1R)-1-hydroxyethyl)-1-methyl-1-carbapen-2-em-3-carboxylate (71.9 mg) was dissolved in 2.0 ml of DMF. 1-(Ethoxycarbonyloxy)ethyl iodide (66.3 mg) was added to the solution in an argon atmosphere at −20° C. The mixture was stirred for 2 hr while raising the temperature to −10° C. Ethyl acetate (20 ml) was added to the reaction solution. The mixture was extracted twice, followed by washing twice with 10 ml of semisaturated brine. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under the reduced pressure to a volume of 2 ml. The residue was purified by column chromatography on silica gel (chloroform:methanol=15:1) and Sephadex LH-20 (dichloromethane:methanol=1:1) in that order to give 57.4 mg of the title compound.
Reaction SMILES: [Na].[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([N:19]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)[C:20]([O:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:21])=[C:14]([CH:18]=1)[C:15](O)=[O:16])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:73]([NH2:84])[C:74]1[CH:83]=[CH:82][C:79]([O:80][CH3:81])=[C:76]([O:77][CH3:78])[CH:75]=1>CN(C=O)C>[CH2:2]([O:9][C:10]1[CH:11]=[CH:12][C:13]([N:19]([C:20]([O:22][CH2:23][CH:24]([CH3:25])[CH3:26])=[O:21])[CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[C:14]([C:15](=[O:16])[NH:84][CH2:73][C:74]2[CH:83]=[CH:82][C:79]([O:80][CH3:81])=[C:76]([O:77][CH3:78])[CH:75]=2)[CH:18]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC(C)COC(=O)N(c1ccc(OCc2ccccc2)cc1C(=O)O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: COc1ccc(CN)cc1OC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CNC(=O)c2cc(OCc3ccccc3)ccc2N(C(=O)OCC(C)C)C2CCN(C(=O)OC(C)(C)C)CC2)cc1OC
Reaction time: 0.25 h

Procedure:
A mixture of 6 g of sodium salt of 5-(benzyloxy)-2-({1-[(1,1-dimethylethoxy)carbonyl]piperidin-4-yl}[(2-methylpropoxy)carbonyl]amino)benzoic acid obtained in stage 1.3 and 4.42 g of DIEA in 250 ml of DMF is stirred at AT for 15 min. 6.48 g of HBTU are added and the mixture is left stirring for 30 min. 2.48 g of veratrylamine are added and the reaction mixture is stirred for 48 h 00. It is evaporated under reduced pressure, the residue is taken up in AcOEt, washed with a saturated NH4Cl solution and with a saturated NaHCO3 solution, dried over Na2SO4 and filtered, and the solvent is evaporated under reduced pressure. The residue is chromatographed on silica gel, elution being carried out with an AcOEt/heptane mixture, (20/80, v/v) as far as (60/40, v/v), to give 7.5 g of expected product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([S:12][CH3:13])=[N:10][OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C)([O-])C.[K+].[Cl:20][C:21]1[N:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH2:34]Cl)[C:23](=[O:27])[N:24]([CH3:26])[N:25]=1>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([S:12][CH3:13])=[N:10][O:11][CH2:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:22]2[C:23](=[O:27])[N:24]([CH3:26])[N:25]=[C:21]2[Cl:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cn1nc(Cl)n(-c2ccccc2CCl)c1=O
Reactant: CSC(=NO)c1ccc(Cl)c(Cl)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CSC(=NOCc1ccccc1-n1c(Cl)nn(C)c1=O)c1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
The product from Step C (2.07 g) was dissolved in 10 mL of tetrahydrofuran and 10 mL of 1.0 M potassium t-butoxide in THF was added dropwise. After the addition was complete, the mixture was stirred 15 min, and then the title compound of Step E (2.06 g) was added. The reaction mixture was stirred at room temperature overnight, and then diluted with 20 mL of water and extracted with three 30 mL portions of ethyl acetate. The combined organic extracts were dried (MgSO4), filtered, and concentrated to give 3.53 g of the title compound of Step F as an oil. 1H NMR (CDCl3): δ 7.5 (m,5H), 7.25 (m,2H), 5.34 (d,1H), 5.18 (d,1H), 3.49 (s,3H), 2.08 (s,3H). The crude product contained minor amounts of impurities and solvent, but the material was not further purified before Step G.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=2[O:19]1>>[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH:23][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[N:3]=3)=[CH:21][C:20]=2[O:19]1
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Reactant: Nc1ccc2c(c1)OCO2
Product: FC(F)(F)c1cc(Nc2ccc3c(c2)OCO3)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3,4-methylenedioxyaniline (53 mg, 0.386 mmol) similar to Example 58 and isolated as a purple solid (24 mg, 35%). 1H NMR (CDCl3): 8.85–8.83 (m, 1H), 8.57–8.54 (m, 1H), 7.90–7.84 (m, 1H), 7.45–7.41 (m, 1H), 7.39 (s, 1H), 6.87 (d, J=8.1 Hz, 1H), 6.84 (s, 1H), 6.80 (s, 1H), 6.77 (dd, J=2.1, 8.1 Hz, 1H), 6.05 (s, 2H).
Reaction SMILES: [OH:1][CH2:2][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[CH:8]=1)([CH3:6])[CH2:4][OH:5].[N:22]1([CH2:28][CH2:29][O:30][C:31]2[CH:49]=[CH:48][C:34]3[N:35]4[CH:40]=[C:39]([C:41]5[CH:46]=[CH:45][C:44]([NH2:47])=[CH:43][CH:42]=5)[N:38]=[C:36]4[S:37][C:33]=3[CH:32]=2)[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CN(C)C1C=CN=CC=1.C1COCC1>[OH:5][CH2:4][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:13]([NH:47][C:44]2[CH:43]=[CH:42][C:41]([C:39]3[N:38]=[C:36]4[N:35]([CH:40]=3)[C:34]3[CH:48]=[CH:49][C:31]([O:30][CH2:29][CH2:28][N:22]5[CH2:23][CH2:24][O:25][CH2:26][CH2:27]5)=[CH:32][C:33]=3[S:37]4)=[CH:46][CH:45]=2)=[O:21])[CH:8]=1)([CH2:2][OH:1])[CH3:6]
Reactant: CC(CO)(CO)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: Nc1ccc(-c2cn3c(n2)sc2cc(OCCN4CCOCC4)ccc23)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(CO)(CO)c1cc(NC(=O)Nc2ccc(-c3cn4c(n3)sc3cc(OCCN5CCOCC5)ccc34)cc2)no1

Procedure:
A mixture of phenyl 5-(1,3-dihydroxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (1 equivalent), 7-(2-morpholin-4-yl-ethoxy)-2-(4-aminophenyl)imidazo[2,1-b]benzothiazole (4) (1 equivalent) and 4-(dimethylamino)pyridine (0.05-0.5 equivalents) in anhydrous THF is stirred at a temperature between rt and 50° C. until the reaction is substantially complete as monitored by LCMS or TLC. The mixture is concentrated under reduced pressure and the residue is purified by preparative reverse-phase HPLC or silica gel flash chromatography to afford 1-[5-(2-hydroxy-1-hydroxymethyl-1-methyl-ethyl)-isoxazol-3-yl]-3-{4-[7-(2-morpholin-4-yl-ethoxy)-benzo[d]imidazo[2,1-b]thiazol-2-yl]-phenyl}-urea (I-1a).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:38]=[CH:37][C:6]([C:7]([NH:9][C:10]2[C:14]3[N:15]=[C:16]([C:18](=[O:29])[NH:19][C:20]([CH3:28])([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH3:21])[S:17][C:13]=3[N:12](C(OC(C)(C)C)=O)[N:11]=2)=[O:8])=[CH:5][CH:4]=1.Cl.[Cl-].[Na+]>C(O)C.O1CCOCC1>[CH3:28][C:20]([NH:19][C:18]([C:16]1[S:17][C:13]2[NH:12][N:11]=[C:10]([NH:9][C:7](=[O:8])[C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:38][CH:37]=3)[C:14]=2[N:15]=1)=[O:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:21]
Reactant: COc1ccc(C(=O)Nc2nn(C(=O)OC(C)(C)C)c3sc(C(=O)NC(C)(C)c4ccccc4)nc23)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: COc1ccc(C(=O)Nc2n[nH]c3sc(C(=O)NC(C)(C)c4ccccc4)nc23)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 76.3 %

Procedure:
0.16 g (0.31 mmol) of tert-butyl 3-(4-methoxybenzoylamino)-5-(1-methyl-1-phenylethylcarbamoyl)-1H-pyrazolo[4,3-d]thiazole-1-carboxylate dissolved in 7 ml of ethanol is placed in a 100 ml round-bottomed flask. 1.5 ml (6.0 mmol) of a 4M solution of hydrochloric acid in dioxane are then added and the reaction mixture is stirred for 15 hours at 25° C. A further 1.5 ml (6.0 mmol) of 4M solution of hydrochloric acid in dioxane are added and the mixture is stirred for 15 hours at 25° C. The reaction medium is then concentrated to dryness under reduced pressure (40° C.) and the residue is taken up in 30 ml of dichloromethane and 30 ml of water, and basified with 0.1N sodium hydroxide solution. The emulsion obtained is resorbed by saturation with sodium chloride. After separation of the phases by settling, the organic phase is dried over magnesium sulfate and concentrated to dryness under reduced pressure (40° C.). The residue is purified by flash chromatography (msilica=30 g; eluent: 95/5 dichloromethane/methanol). 0.103 g of N-(1-methyl-1-phenylethyl)-3-(4-methoxybenzoylamino)-1-H-pyrazolo[4,3-d]thiazole-5-carboxamide is thus obtained in the form of a cream-coloured foam. m.p.K=226° C. 1H NMR (400 MHz, DMSO-d6): δ ppm 1.70 (s, 6H); 3.86 (s, 3H); 7.09 (d, J=8.5 Hz, 2H); 7.20 (t, J=7.5 Hz, 1H); 7.30 (t, J=7.5 Hz, 2H); 7.41 (d, J=7.5 Hz, 2H); 8.07 (d, J=8.5 Hz, 2H); 8.53 (broad s, 1H); from 10.0 to 15.0 (very broad m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:10]([C@@H:11]([C:13]3[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[C:15]([F:21])[C:14]=3[Cl:22])[CH3:12])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:23][C:24]1[N:28]([C@H:29]2[CH2:34][CH2:33][C@H:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]2)[N:27]=[CH:26][C:25]=1B1OC(C)(C)C(C)(C)O1.[F-].[K+].O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[Cl:22][C:14]1[C:15]([F:21])=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:13]=1[C@H:11]([C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([C:25]3[CH:26]=[N:27][N:28]([C@H:29]4[CH2:30][CH2:31][C@H:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:33][CH2:34]4)[C:24]=3[CH3:23])[CH:3]=2)[NH:8][CH:9]=1)[CH3:12]
Reactant: CCOC(=O)[C@H]1CC[C@H](n2ncc(B3OC(C)(C)C(C)(C)O3)c2C)CC1
Reactant: COc1ccc(F)c(Cl)c1[C@@H](C)c1c[nH]c2ncc(Br)cc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [F-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)[C@H]1CC[C@H](n2ncc(-c3cnc4[nH]cc([C@H](C)c5c(OC)ccc(F)c5Cl)c4c3)c2C)CC1

Procedure:
A mixture of 5-bromo-3-[(S)-1-(2-chloro-3-fluoro-6-methoxyphenyl)-ethyl]-1H-pyrrolo[2,3-b]pyridine (57.8 mg, 0.150 mmol), ethyl trans-4-[5-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]cyclohexanecarboxylate (60.0 mg, 0.166 mmol), Pd(PPh3)4 (8.70 mg, 0.00753 mmol), potassium fluoride (26.2 mg, 0.452 mmol) and 4:1 dioxane:H2O (3 mL, 30 mmol) was heated to 90° C. for 2 h. The organic solvent was removed in vacuo, and the material was extracted with DCM and water. The organic layer was purified via column chromatography, eluting with 1-3% MeOH/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z=539.16/541.16 (100/50) [MH+]. HPLC: tR=3.98 min (polar—5 min, ZQ3).
Reaction SMILES: [CH3:1][C:2]1[NH:8][C:7]([NH2:9])=[N:6][C:4](=[O:5])[CH:3]=1.[C:10]([O:15][CH2:16][CH2:17][N:18]=[C:19]=[O:20])(=[O:14])[C:11]([CH3:13])=[CH2:12].CC(C)=O>N1C=CC=CC=1>[CH3:1][C:2]1[NH:8][C:7]([NH:9][C:19](=[O:20])[NH:18][CH2:17][CH2:16][O:15][C:10](=[O:14])[C:11]([CH3:13])=[CH2:12])=[N:6][C:4](=[O:5])[CH:3]=1
Reactant: C=C(C)C(=O)OCCN=C=O
Reactant: Cc1cc(=O)nc(N)[nH]1
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: C=C(C)C(=O)OCCNC(=O)Nc1nc(=O)cc(C)[nH]1
Yield: 74.1 %

Procedure:
A suspension of 6-methylisocytosine (0.98 g, 7.8 mmol), and 2-isocyanatoethyl methacrylate (2.20 g, 14.1 mmol) in dry pyridine (35 mL) was heated under reflux for 2 h, giving a clear solution. Cooling induced the formation of crystals. Acetone was added (20 mL), and the resulting microcrystalline powder was filtered. Recrystallization from ethanol/CHCl3 (1:1, v/v) gave analytically pure product (1.62 g, yield is 74%) 1H NMR (400 MHz, CDCl3) 13.00 (s, 1H, intramol H-bonding), 11.97 (s, 1H, CH2—NH—CO), 10.53 (s, 1H, CH2—NH—CO—NH), 6.20 (s, 1H, CHH.═.C), 5.80 (s, CCH3CH—CO), 5.56 (s, 1H, CHH═C), 4.31-4.28 (t, J=5.6, 2H, OCH2CH2N), 3.62-3.58 (q, J=5.6 Hz, 2H, OCH2CH2N), 2.26 (s, 3H, CH3—C—NH), 1.96 (s, 3H, CH3—C═CH2), IR (neat) 3250-2800, 1726, 1699, 1664, 1641, 1583, 1521, 1253, 1172, 939 cm-1; Melting point Tm=206.7° C.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:20]#[C:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>>[C:22]1([C:21]#[C:20][C:17]2[CH:18]=[CH:19][C:10]3[N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:3]=4)[CH2:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CC(c2cccc(I)c2)=Nc2ccc(C#Cc3ccccc3)cc2N1
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1cccc(C2=Nc3ccc(C#Cc4ccccc4)cc3NC(=O)C2)c1
Yield: 47.2 %

Procedure:
Prepared from 4-(3-iodophenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 11) (231 mg, 0.5 mmol) and trimethylsilylacetylene (0.4 mL, 1.0 mmol) according to the general procedure F. Obtained as a light brown solid (102 mg).