Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([C:11]2[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=2)=[C:9]([Cl:19])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[OH:20][C:21]1[N:25]([CH3:26])[N:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[Cl:1][C:2]1[C:10]([C:11]2[O:15][N:14]=[C:13]([CH:16]([CH3:18])[CH3:17])[N:12]=2)=[C:9]([Cl:19])[CH:8]=[CH:7][C:3]=1[C:4]([C:22]1[CH:23]=[N:24][N:25]([CH3:26])[C:21]=1[OH:20])=[O:5]
Reactant: Cn1nccc1O
Reactant: CC(C)c1noc(-c2c(Cl)ccc(C(=O)Cl)c2Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CC(C)c1noc(-c2c(Cl)ccc(C(=O)c3cnn(C)c3O)c2Cl)n1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 79.1 %

Procedure:
At 5-10° C., 2.00 g (6.3 mmol) of 2,4-dichloro-3-(3-i-propyl-1,2,4-oxadiazol-5-yl)benzoyl chloride in 10 ml of dimethoxyethane were added dropwise to 0.62 g (6.3 mmol) of 5-hydroxy-1-methyl-1H-pyrazole and 1.74 g (12.6 mmol) of potassium carbonate in 20 ml of dimethoxyethane. After 2.5 hours of stirring at room temperature, the mixture was heated under reflux for 2 hours and then once more stirred at room temperature for 12 hours. The reaction mixture was then taken up in water and washed with methylene chloride or toluene; the aqueous phase that remained was adjusted to pH=3 using hydrochloric acid and the precipitate that had formed was filtered off with suction and dried. 1.90 g (79% of theory) of 4-[2,4-dichloro-3-(3-i-propyl-1,2,4-oxadiazol-5-yl)benzoyl]-5-hydroxy-1-methyl-1H-pyrazole were obtained.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]3[CH:17]=[C:16]([N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)[N:15]=[C:14]([NH2:25])[N:13]=3)[CH2:9]2)=[CH:4][CH:3]=1.[CH2:27]([N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1)[CH3:28].C(=O)(O)[O-].[Na+].O1CCOCC1>CO.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.O>[CH2:27]([N:29]1[CH:33]=[C:32]([C:2]2[CH:11]=[C:10]3[C:5]([CH2:6][CH:7]([CH3:26])[N:8]([C:12]4[CH:17]=[C:16]([N:18]5[CH2:19][CH2:20][N:21]([CH3:24])[CH2:22][CH2:23]5)[N:15]=[C:14]([NH2:25])[N:13]=4)[CH2:9]3)=[CH:4][CH:3]=2)[CH:31]=[N:30]1)[CH3:28]
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Reactant: CCn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CCn1cc(-c2ccc3c(c2)CN(c2cc(N4CCN(C)CC4)nc(N)n2)C(C)C3)cn1
Temperature: 90 °C
Reaction time: 8 h
Yield: 63.6 %

Procedure:
A mixture of 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (10 mg, 0.02 mmol; Peak 1, Example 49, Step 7), 1-ethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (5.8 mg, 0.026 mmol), tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol), and sodium bicarbonate (6.0 mg, 0.072 mmol) in a solution of 1,4-dioxane (0.2 mL) and water (0.1 mL) in a reaction vial was stirred at 90° C. overnight. It was diluted with methanol. After filtration the filtrate was purified with RP-HPLC (pH=10) to afford the desired product (5.5 mg). LCMS (M+H)+: m/z=433.3.
Reaction SMILES: [OH-].[NH4+:2].[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([C@H:14]([CH3:33])[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH2:19][CH2:18]1)=[O:16])[CH2:9][CH2:8][CH2:7]2.Cl>C(#N)C>[F:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([C@H:14]([CH3:33])[C:15]([N:17]1[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][C:26]([S:29]([NH2:2])(=[O:31])=[O:30])=[CH:25][CH:24]=3)[CH2:19][CH2:18]1)=[O:16])[CH2:9][CH2:8][CH2:7]2
Reactant: C[C@H](C(=O)N1CCN(c2ccc(S(=O)(=O)Cl)cc2)CC1)N1CCCc2cc(F)ccc21
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CC#N
Product: C[C@H](C(=O)N1CCN(c2ccc(S(N)(=O)=O)cc2)CC1)N1CCCc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Ammonium hydroxide (28-30% solution, 7.5 mL) was added dropwise to a solution of the (R)-4-(4-(2-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)benzene-1-sulfonyl chloride (375 mg, 0.56 mmol) in acetonitrile (5 mL) at 0° C. The reaction mixture was stirred at 0° C. for 4 h. The solution was cooled to 0° C. and aqueous 1.0 M HCl was added dropwise. The reaction mixture was extracted with CH2Cl2 (3×50 mL). The combined organic phases were dried over MgSO4. After evaporating the solvents under reduced pressure, the residue was purified by silica gel chromatography using 2-10% methanol in CH2Cl2 to give (R)-4-(4-(2-(6-fluoro-3,4-dihydroquinolin-1(2H)-yl)propanoyl)piperazin-1-yl)benzene sulfonamide as colourless oil (94 mg). LC/MS (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)), m/z: M+1 obs=447.1; tR=2.68 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[CH3:22][N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>C1(C)C(C)=CC=CC=1>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:16][CH2:17]1
Reactant: CN1CCNCC1
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: Cc1ccccc1C
Product: CN1CCN(c2c(F)c(N)c3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)CC1

Procedure:
In the same manner as described in Example 1 (1), a mixture of 5-amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 1-methylpiperazine, and xylene was refluxed for 3 hours to give 5-amino-1-cyclopropyl-6,8-difluoro-7-(4-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, m.p. 254°-255° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([N:25]2[CH2:28][CH:27]([C:29]([OH:31])=[O:30])[CH2:26]2)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].[CH3:33]N1CCOCC1.ClC(OCC(C)C)=O>ClCCl>[C:1]([O:5][C:6](=[O:32])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23]([N:25]2[CH2:28][CH:27]([C:29]([O:31][CH3:33])=[O:30])[CH2:26]2)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCOCC1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CC(C(=O)O)C2)no1
Agent: CC(C)COC(=O)Cl
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)c2noc([C@H](CCCC3CCCCC3)CC(=O)OC(C)(C)C)n2)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.4 %

Procedure:
A solution of 1-[(5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazol-3-yl)carbonyl]-3-azetidinecarboxylic acid (Preparation 41) (480 mg, 1.07 mmol) and N-methylmorpholine (130 μl, 1.17 mmol) in dichloromethane (10 ml) was cooled to 0° C. and then treated with isobutyl chloroformate (150 μl, 1.17 mmol). The mixture was stirred at 0° C. for 30 minutes then allowed to warm to room temperature over 1 hour. The mixture was quenched with methanol (5 ml) and the solvent removed under reduced pressure. The residue was partitioned between ethyl acetate and hydrochloric acid (1M). The combined organic layers were washed with brine, dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:ethyl acetate (95:5) gradually changing to dichloromethane:ethyl acetate (90:10) to afford the title compound (230 mg)
Reaction SMILES: C([O:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH:14]([N:19]=[N+]=[N-])[CH2:13][CH2:12][C:11]=2[C:10]=1[C:22]([NH2:24])=[O:23])C1C=CC=CC=1>[Pd].C(O)C>[OH:8][C:9]1[CH:18]=[CH:17][C:16]2[CH2:15][CH:14]([NH2:19])[CH2:13][CH2:12][C:11]=2[C:10]=1[C:22]([NH2:24])=[O:23]
Reactant: [N-]=[N+]=NC1CCc2c(ccc(OCc3ccccc3)c2C(N)=O)C1
Agent: [Pd]
Solvent: CCO
Product: NC(=O)c1c(O)ccc2c1CCC(N)C2

Procedure:
A solution was prepared by dissolving 0.7 g. of dl-2-benzyloxy-6-azido-5,6,7,8-tetrahydro-1-naphthalenecarboxamide in 50 ml. of ethanol. The solution was placed in a low pressure hydrogenation apparatus and hydrogenated over a palladium-on-carbon catalyst at about 60 psi. After the theoretical quantity of hydrogen had been absorbed, the hydrogenation mixture was removed from the apparatus and the catalyst separated by filtration. Evaporation of the solvent from the filtrate yielded dl-2-hydroxy-6-amino-5,6,7,8-tetrahydro-1-naphthalenecarboxamide. The residue was dissolved in methanol and gaseous hydrogen chloride passed into the methanol solution, thus forming the hydrochloride salt. Ether was added to the solution to the point of incipient precipitation and the solution was cooled. Crystalline dl-2-hydroxy-6-amino-5,6,7,8-tetrahydro-1-naphthalenecarboxamide hydrochloride thus obtained melted at 245° C.; yield=0.3 g.
Reaction SMILES: [C:1]1([CH:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:8][CH2:9][C:10]([N:13]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22](OCC)=[O:23])=[CH:18][CH:17]=2)[CH3:14])([CH3:12])[CH3:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[ClH:39]>CCOCC>[ClH:39].[C:27]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[O:8][CH2:9][C:10]([N:13]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([CH2:22][OH:23])=[CH:20][CH:21]=2)[CH3:14])([CH3:11])[CH3:12])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: CCOC(=O)c1ccc(CN(C)C(C)(C)COC(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: CN(Cc1ccc(CO)cc1)C(C)(C)COC(c1ccccc1)c1ccccc1

Procedure:
The free base of the title compound was prepared similarly to the procedure of Example 40 using 1-diphenylmethoxy-2-[N-(4-ethoxycarbonylbenzyl)-N- methylamino]-2-methylpropane (see Example 28) and lithium aluminium hydride. The resulting oil was dissolved in ether and the solution treated with an excess of saturated ethereal hydrogen chloride. The resulting precipitated oil was collected, washed with ether and dried to give the title compound as a colourless foam which was characterised as a hydrochloride containing 0.25 molar equivalents of water (377 mg, 38%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([O:25][CH3:26])[CH:24]=1)[CH:20]=O.COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[CH3:26][O:25][C:23]1[CH:22]=[C:19]([C:20]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:18]=[C:17]([O:16][CH3:15])[CH:24]=1
Reactant: COc1cc(C=O)cc(OC)c1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc(OC)cc(-c2nc3cc(OC)cc(OC)c3c(=O)[nH]2)c1
Yield: 46 %

Procedure:
2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 3,5-dimethoxybenzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(3,5-dimethoxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (120 mg, 46%) was isolated as a yellow solid. Selected data: MS (m/z): 343.05; MP 270-272° C.
Reaction SMILES: [CH2:1]([C:9]1[C:10]([C:22]([F:25])([F:24])[F:23])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:26]([O:29][CH2:30][C:31](Cl)=[O:32])(=[O:28])[CH3:27].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:26]([O:29][CH2:30][C:31](=[O:32])[CH:20]1[NH:19][CH2:18][C:16]2=[C:15]3[C:11](=[C:10]([C:22]([F:25])([F:24])[F:23])[C:9]([CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:17]2)[CH:12]=[CH:13][N:14]3[CH2:21]1)(=[O:28])[CH3:27]
Reactant: CC(=O)OCC(=O)Cl
Reactant: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)OCC(=O)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1
Temperature: 0 °C
Yield: 32.1 %

Procedure:
To a solution of 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (prepared as described in Example 2 above, 53 mg, 0.14 mmol) in CH2Cl2 at 0° C. was added 2-acetoxyacetyl chloride (19 mg, 0.14 mmol) and diisopropylethylamine (0.072 mL, 0.42 mmol) and the resulting mixture stirred at 0° C. Upon completion of the reaction completion, the solvent was evaporated and the resulting residue triturated with methanol-diethyl ether to yield 2-oxo-2-(6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-2(1H)-yl)ethyl acetate (20 mg) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH:6]([N+:12]([O-])=O)[CH2:5]2>C(O)(=O)C.[Zn]>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH:6]([NH2:12])[CH2:5]2
Reactant: O=[N+]([O-])C1COc2ccc(Br)cc2C1
Agent: [Zn]
Solvent: CC(=O)O
Product: NC1COc2ccc(Br)cc2C1
Temperature: 100 °C
Yield: 62.6 %

Procedure:
To a solution of 6-bromo-3-nitro-chroman (2.18 g, 8.4 mmol) in glacial acetic acid (150 mL) was added zinc dust (11 g, 170 mmol). The mixture was heated to 100° C. for 20 min. The zinc dust was filtered off and washed with CH2Cl2. The solvent was evaporated in vacuo and the residue partitioned between 1N aqueous HCl (40 mL) and CH2Cl2 (40 mL). The aqueous phase was separated and its pH was adjusted to 11 with 2N NaOH, which was then extracted with CH2Cl2 (50 mL×3). The combined organic phase was dried (Na2SO4) and concentrated in vacuo to give 1.2 g (63%) of 6-bromo-chroman-3-ylamine as a brown solid. 1H NMR (300 MHz, CDCl3): δ 7.13 (m, 2H), 6.63 (d, J=7.8Hz, 1H), 4.05 (d, J=10.2Hz, 1H), 3.74 (dd, J=1.5, 6.6 Hz, 1H), 3.31 (br.s, 1H), 2.94 (dd, J=16.2, 6.9 Hz, 1H), 1.35 (br.s, 2H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][N:6]=[C:5]([O:9][C:10]2[CH:11]=[C:12]([CH3:26])[C:13]3[CH:17]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:16][B:15]([OH:24])[C:14]=3[CH:25]=2)[CH:4]=1)#[N:2].Cl.[NH2:28][OH:29].C(N(CC)CC)C>>[OH:24][B:15]1[C:14]2[CH:25]=[C:10]([O:9][C:5]3[CH:4]=[C:3]([C:1](=[NH:2])[NH:28][OH:29])[CH:8]=[CH:7][N:6]=3)[CH:11]=[C:12]([CH3:26])[C:13]=2[CH:17]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[O:16]1
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3cc(C#N)ccn3)cc(C)c21
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cc(C(=N)NO)ccn3)cc(C)c21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.9 %

Procedure:
To a solution of ethyl 2-(6-(4-cyanopyridin-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (0.8 g, 2.27 mmol, 1 eq.) and hydroxylamine hydrochloride (0.4 g, 5.68 mmol, 2.5 eq.) in methanl was added triethylamine (1.11 ml, 7.95 mmol, 3.5 eq.). After stirring at room temperature overnight, the starting material was gone but no right mass was observed. The reaction mixture was evaporated under reduced pressure. The residue was dissolved in EtOAc and then washed with water. The organic layers were collected, dried with Na2SO4 and evaporated to give the crude product as a colorless oil (0.83 g, yield 95%). The crude was used in subsequent steps without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C@H:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:5].C(Cl)CCl.[NH:19]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:20]([C:23](O)=[O:24])[CH2:21][CH3:22].CN(C=O)C>C(Cl)Cl.N(C(OC(C)(C)C)=O)[C@H](C(O)=O)CC>[CH3:1][O:2][C:3](=[O:14])[C@H:4]([N:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:23](=[O:24])[C@@H:20]([NH:19][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:21][CH3:22])[CH3:5]
Reactant: CC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](C)NCc1ccccc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC[C@H](NC(=O)OC(C)(C)C)C(=O)N(Cc1ccccc1)[C@H](C)C(=O)OC
Reaction time: 18 h
Yield: 87.6 %

Procedure:
To a solution of (R)-2-benzylamino-propionic acid methyl ester (3.5 g, 18.1 mmol) and EDC (3.65 g, 19.0 mmol) in anhydrous DCM (30 mL) was added Boc-Abu-OH (3.68 g, 18.1 mmol). The reaction was stirred for 18 h, then additional Boc-Abu-OH (0.74 mmol, 3.62 mmol), EDC (1.35 g 7.1 mmol) and DMF (2.4 mL) were added to the reaction, followed by stirring for 18 h. The solvent was removed in vacuo and the resulting oil was dissolved in EtOAc (50 mL) and washed with 1 M hydrochloric acid (50 mL×3), 1 M aqueous NaOH (50 mL×3), brine (50 mL), dried over sodium sulfate, filtered and concentrated, to give (R)-2-[benzyl-((S)-2-tert-butoxycarbonylamino-butyryl)-amino]-propionic acid methyl ester (6.0 g, 87%) as a pale colourless oil. An aliquot (3.9 g, 10.3 mmol) was dissolved in DCM (52 mL) and HCl gas was bubbled through the reaction for 30 min at ambient temperature. The reaction was stirred for an additional hour and then solvent removed in vacuo. The resultant solid was triturated with Et2O, to give (R)-2-[((S)-2-amino-butyryl)-benzyl-amino]-propionic acid methyl ester hydrochloride (3.0 g, 93%) as a colourless solid. This material was slurried in EtOAc (47 mL) at ambient temperature and saturated aqueous sodium bicarbonate (14 mL) added. After stirring for 18 h, the organic layer was separated and washed with brine, dried over sodium sulfate, filtered and concentrated, to give the title compound (1.68 g, 72%) as a colourless oil. 1H NMR (Me-d3-OD): 7.44-7.23 (5H, m), 5.19 (1H, d), 4.28-4.08 (2H, m), 3.86 (1H, q), 2.18-1.99 (1H, m), 1.96-1.79 (1H, m), 1.46 (3H, d), 0.95 (3H, t).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([NH:10][C:11](=[O:36])[CH2:12][N:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH:24]=[CH:25][CH2:26][CH2:27][OH:28])[CH:20]=2)[N:15]=[C:14]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>ClCCl>[C:6]([NH:10][C:11]([CH2:12][N:13]1[C:22](=[O:23])[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([CH:24]=[CH:25][CH2:26][CH2:27][O:28][S:2]([CH3:1])(=[O:4])=[O:3])[CH:20]=2)[N:15]=[C:14]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=1)=[O:36])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)NC(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(C=CCCO)cc2c1=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)Cn1c(-c2cccc(Cl)c2)nc2ccc(C=CCCOS(C)(=O)=O)cc2c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.6 %

Procedure:
Methanesulfonyl chloride (114 μL, 1.46 mmol) was added to a stirred solution of N-tert-butyl-2-[2-(3-chlorophenyl)-6-(4-hydroxybut-1-enyl)-4-oxo-4H-quinazolin-3-yl]acetamide (536 mg, 1.22 mmol) and triethylamine (510 μL, 3.66 mmol) in dry dichloromethane (12 mL) at 0° C. The cooling bath was removed after 2 h, and the mixture was stirred for an additional 3 h at room temperature. The reaction mixture was diluted with ethyl acetate (40 mL), and washed with 1 N HCl (aq.) (25 mL), sat. NaHCO3 (aq.) (25 mL) and brine (25 mL). The organic layer was dried (MgSO4) and concentrated in vacuo to afford methanesulfonic acid 4-[3-(tert-butylcarbamoylmethyl)-2-(3-chlorophenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]but-3-enyl ester (528 mg, 1.02 mmol, 84%) as a yellow foam.
Reaction SMILES: [CH2:1]([O:5]/[N:6]=[N+:7](/[N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[CH2:14][OH:15])\[O-:8])[CH2:2][CH2:3][CH3:4].I([O-])(=O)(=O)=[O:17].[Na+]>CC#N.C(Cl)(Cl)(Cl)Cl.O.O.[Ru](Cl)(Cl)Cl>[CH2:1]([O:5]/[N:6]=[N+:7](/[N:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([OH:17])=[O:15])\[O-:8])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCO/N=[N+](\[O-])N1CCC[C@H]1CO
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: Cl[Ru](Cl)Cl
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Product: CCCCO/N=[N+](\[O-])N1CCC[C@H]1C(=O)O
Temperature: 25 °C

Procedure:
To a solution of {(2S)-1-[(Z)-1-butoxy-NNO-azoxy]pyrrolidin-2-yl}methanol (360 mg, 1.66 mmol) and sodium periodate (1.06 g, 4.97 mmol) in 17.5 mL of CH3CN/CCl4/H2O (2:2:3) was added ruthenium(III) chloride hydrate (34 mg, 1.66 mmol). After stirring at rt over night, the mixture was extracted with CH2Cl2 (3×50 mL), dried over MgSO4 and concentrated to give the title product, which was used directly.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:6][C@H:5]([N:7]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH2:16])[C:10]=3[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8]2)[CH2:4]1.[CH3:31][CH:32]([N:34]=[C:35]=[O:36])[CH3:33]>>[NH2:16][C:15]1[C:10]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([O:23][CH2:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)=[CH:8][N:7]([C@@H:5]3[CH2:4][C@H:3]([CH2:2][NH:1][C:35]([NH:34][CH:32]([CH3:33])[CH3:31])=[O:36])[CH2:6]3)[C:11]=2[N:12]=[CH:13][N:14]=1
Reactant: CC(C)N=C=O
Reactant: NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1
Product: CC(C)NC(=O)NC[C@H]1C[C@@H](n2cc(-c3cccc(OCc4ccccc4)c3)c3c(N)ncnc32)C1

Procedure:
cis-1-{3-[4-Amino-5-(3-benzyloxy-phenyl)-pyrrolo[2,3-d]pyrimidin-7-yl]-cyclobutylmethyl}-3-isopropyl-urea is prepared as described in Example 26 using cis-7-(3-aminomethyl-cyclobutyl)-5-(3-benzyloxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine and 2-propylisocyanate (Fluka, Buchs, Switzerland). Analytical HPLC: tR=6.37 min (Grad 2); ES-MS: m/eo=484.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[Si](C)(C)CC[Si]2(C)C)[CH:5]=[CH:6][CH:7]=1.C([Li])(CC)C.[CH3:22][C:23]([O:26][C:27]([N:29]1[CH2:34][CH:33]=[C:32](OS(C(F)(F)F)(=O)=O)[CH2:31][CH2:30]1)=[O:28])([CH3:25])[CH3:24]>O1CCCC1.[Cl-].[Zn+2].[Cl-].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>[CH3:25][C:23]([O:26][C:27]([N:29]1[CH2:30][CH:31]=[C:32]([C:7]2[CH:6]=[CH:5][C:4]([NH2:8])=[CH:3][C:2]=2[F:1])[CH2:33][CH2:34]1)=[O:28])([CH3:22])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC=C(OS(=O)(=O)C(F)(F)F)CC1
Reactant: C[Si]1(C)CC[Si](C)(C)N1c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc(N)cc2F)CC1
Temperature: -78 °C
Reaction time: 2.25 h

Procedure:
A solution of 1-(3-fluorophenyl)-2,2,5,5-tetramethyl-1-aza-2,5-disilacyclopentane (EXAMPLE 20, Step 1, 19.1 g) in dry tetrahydrofuran (150 mL) at −78° C. under N2 is treated with sec-butyllithium (1.3 M in cyclohexane, 60.3 mL) dropwise over ten minutes, and the resulting mixture is stirred at −78° C. for 2.25 hours. A solution of zinc chloride (0.5 M in tetrahydrofuran, 150 mL) is then added over 15 minutes, and the mixture is allowed to warm to ambient temperature over one hour with stirring. A solution of 3,6-dihydro-4-[[(trifluoromethyl)-sulfonyl]oxy]1(2 H)-pyridinecarboxylic acid 1,1-dimethylethyl ester (EXAMPLE 20, Step, 2, 20.8 g) in dry tetrahydrofuran (63 mL) and tetrakis(triphenylphosphine)palladium(0) (1.45 g) is added, and the mixture is degassed, heated up to reflux, refluxed for five minutes, cooled to ambient temperature and stirred for 12 hours. The mixture is then diluted with water (150 mL), the layers are separated, the aqueous phase is extracted with diethyl ether (2×100 mL) and the combined organic phase is washed with water (100 mL) and saline (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is then dissolved in methanol (630 mL) and treated with anhydrous potassium carbonate (17.3 g), and the mixture is stirred at ambient temperature for 40 minutes, concentrated under reduced pressure, diluted with water (100 mL) and extracted with diethyl ether (2×150 mL). The combined organic phase is washed with water (50 mL) and saline (50 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the crude product which is chromatographed on silica gel (230-400 mesh, 1 kg), eluting with a gradient of ethyl acetate/hexane (15/85-50/50). Pooling and concentration of those fractions with an Rf=0.17 by TLC (ethyl acetate/hexane, 26/75) gives the title compound, mp 123-125° C.