Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37].C1COCC1>>[C:1]([C:5]1[S:9][C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([NH:37][CH3:36])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])=[N:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4nnc(C(C)(C)C)s4)c(F)cc3C)c(=O)n(C)c2n1
Reactant: CN
Solvent: C1CCOC1
Product: CNc1ncc2cc(-c3cc(NC(=O)Nc4nnc(C(C)(C)C)s4)c(F)cc3C)c(=O)n(C)c2n1
Yield: 93.2 %

Procedure:
Using a procedure analogous to Example A1, 1-(5-t-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.345 g, 0.672 mmol) and 2.00M MeNH2/THF (3.36 ml, 6.72 mmol) were combined to afford 1-(5-tert-butyl-1,3,4-thiadiazol-2-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylamino)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (0.311 g, 93% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6): δ 7.822-7.75 (m, 3H), 7.69 (s, 1H), 7.39-7.37 (m, 1H), 7.34-7.30 (m, 1H), 7.16 (d, J=12.0 Hz, 1H), 2.90 (brd, J=4.8 Hz, 3H), 2.35 (s, 3H), 2.09 (s, 3H), 1.34 (s, 9H); MS (ESI) m/z: 497.0 (M+H).
Reaction SMILES: C([N:3]1[C:9]2[CH:10]=[CH:11][C:12](C3C=CC(C)=CC=3)=[CH:13][C:8]=2[CH:7]=[C:6]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH2:30][N:31]([CH3:38])[CH:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[CH:26][CH:25]=2)=[O:22])[CH2:5][CH2:4]1)=O.Cl.C(=O)([O-])O.[Na+].O>C(OCC)(=O)C>[CH3:38][N:31]([CH2:30][C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21]([C:6]2[CH2:5][CH2:4][NH:3][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[CH:7]=2)=[O:22])=[CH:29][CH:28]=1)[CH:32]1[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CN(Cc1ccc(NC(=O)C2=Cc3ccccc3NCC2)cc1)C1CCOCC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To 1-formyl-7-(4-methylphenyl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (1177 mg) was added 1N hydrochloric acid (20 ml), and the mixture was stirred at 100° C. for 1 hour. The mixture was dilute with ethyl acetate(50 ml) and made weakly basic with saturated sodium hydrogen carbonate solution (45 ml). To the mixture were added ethyl acetate (250 ml) and water (100 ml), and separated. The organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (75 g, ethyl acetate/ethanol=9:1) to give 7-(4-methyl-phenyl)phenyl)-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (Compound 318) (804 mg, 72%) as amorphous.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([F:14])([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[NH:15]1[CH2:18][CH:17]([CH2:19][OH:20])[CH2:16]1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][C:11]([F:14])([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:15]3[CH2:18][CH:17]([CH2:19][OH:20])[CH2:16]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: OCC1CNC1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: OCC1CN(c2ccc3nnc(C(F)(F)F)n3n2)C1
Yield: 30.2 %

Procedure:
A stirred solution of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (4.44 g, 20.0 mmol), azetidin-3-ylmethanol (2.25 g, 22.0 mmol) and DIPEA (5.21 mL, 30.0 mmol) in DMF (40 mL) was heated at 70° C. for 1 hour. The solution was evaporated and partitioned between water and 2M aqueous K2CO3. The organic phase was washed with water and brine and dried over MgSO4. The crude product was purified by MPLC silica chromatography, eluting with 5% MeOH in DCM. Pure fractions were evaporated to dryness and triturated with ether, giving [1-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]azetidin-3-yl]methanol (1.65 g, 30%) as a cream crystalline solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[CH:20]=[CH2:21].C1CCN2C(=NCCC2)CC1.Cl>C(#N)C>[C:12]1([CH2:11][C:5]([C:4]([O:3][CH2:1][CH3:2])=[O:18])([C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:21][CH2:20][C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CCOC(=O)C(Cc1ccccc1)C(=O)OCC
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)C(CCC(=O)OC(C)(C)C)(Cc1ccccc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 6 h
Yield: 97.8 %

Procedure:
2.5 g (10 mmol) of benzylmalonic acid diethyl ester and 1.45 ml (10 mmol) of t-butyl acrylate in 5 ml of acetonitrile were treated with 1.49 ml of DBU and stirred at room temperature for 6 hours. Thereafter, the mixture was poured into dilute hydrochloric acid (pH 2), extracted with ether, the organic phase was washed with a small amount of water, dried over sodium sulfate and the solvent was removed under reduced pressure. There were obtained 3.7 g (97%) of 4-t-butyl 2,2-diethyl 1-phenyl-2,2,4-butanetricarboxylate as a pale yellow oil which was used directly in the next step.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH:6]=[O:7].B(Br)(Br)Br.O>ClCCl>[OH:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH:6]=[O:7]
Reactant: COc1cc(C=O)ccc1-c1ccccc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: O=Cc1ccc(-c2ccccc2)c(O)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.2 %

Procedure:
3-Methoxy-4-phenylbenzaldehyde (23.0 g) was dissolved in dichloromethane (150 mL). To the stirred mixture was added dropwise boron tribromide (15.4 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the stirred reaction mixture was added dropwise water (20 mL) under ice-cooling, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The obtained residue was suspended in methanol (100 mL) and 2 mol/L hydrochloric acid (50 mL), and the mixture was stirred at 50° C. for 2 hours. To the reaction mixture was added brine, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the obtained residue was purified by column chromatography on silica gel (eluent: ethyl acetate/hexane=1/5) to give the title compound (13.8 g).
Reaction SMILES: [CH2:1]([O:6][N:7]=[C:8]([C:14](=O)[CH2:15]Cl)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2][CH2:3][CH2:4][CH3:5].[NH2:18][C:19]([NH2:21])=[S:20].O.O.O.C([O-])(=O)C.[Na+].C(O)C>O>[NH2:21][C:19]1[S:20][CH:15]=[C:14]([C:8](=[N:7][O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:18]=1
Reactant: CCCCCON=C(C(=O)CCl)C(=O)OCC
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCCON=C(C(=O)OCC)c1csc(N)n1
Yield: 52.1 %

Procedure:
Ethyl 2-pentyloxyimino-4-chloro-3-oxobutyrate (syn isomer, 51.1 g.), thiourea (14.7 g.), sodium acetate trihydrate (26.4 g.), ethanol (175 ml.) and water (125 ml.) were treated in a similar manner to that of Example F-(3) to give ethyl 2-(2-aminothiazol-4-yl)-2-pentyloxyiminoacetate (syn isomer, 28.7 g.), mp 86° to 88° C.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH:15]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][CH:18]1[CH2:23][NH:22][CH2:21][CH2:20][N:19]1[C:24]1[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH2:15][N:22]2[CH2:21][CH2:20][N:19]([C:24]3[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=3)[CH:18]([CH3:17])[CH2:23]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCc1cc(CCC=O)nn1C(C)(C)C
Reactant: Cc1cccc(N2CCNCC2C)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3cccc(C)c3)C(C)C2)nn1C(C)(C)C

Procedure:
93 mg (95%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50 mg, 0.225 mmol), 2-methyl-1-m-tolylpiperazine (43 mg, 0.225 mmol), DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.CN(C=O)C.Cl[CH2:23][C:24]1[N:28]([CH3:29])[N:27]=[C:26]([CH3:30])[CH:25]=1.C([O-])([O-])=O.[K+].[K+]>O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12]([O:14][CH2:23][C:24]3[N:28]([CH3:29])[N:27]=[C:26]([CH3:30])[CH:25]=3)=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: Cc1cc(CCl)n(C)n1
Reactant: COC(=O)Cc1csc2cc(O)cc(C)c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)Cc1csc2cc(OCc3cc(C)nn3C)cc(C)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
To a mixture of methyl(6-hydroxy-4-methyl-1-benzothiophen-3-yl)acetate (150 mg) and DMF (2 mL) were added 5-(chloromethyl)-1,3-dimethyl-1H-pyrazole (101 mg) and K2CO3 (175 mg) at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane). The product was crystallized from Et2O-hexane to give the title compound (155 mg).
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:14][C:15]1[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][C:16]=1[C:2]1[C:11]2[O:10][CH:9]([CH3:12])[C:8](=[O:13])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)c(C)c1
Reactant: CC1Oc2c(Br)cccc2NC1=O
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: COCCOC
Product: Cc1ccc(-c2cccc3c2OC(C)C(=O)N3)c(C)c1
Yield: 90.5 %

Procedure:
To a solution of 8-bromo-2-methyl-2H-1,4-benzoxazin-3(4H)-one (1.20 g, 4.96 mmol) in 1,2-dimethoxyethane (50 ml) were added 2,4-dimethylphenylboronic acid (818 mg, 5.45 mmol), tetrakis(triphenylphosphine)palladium(0) (286 mg, 0.245 mmol) and 2M sodium carbonate solution (4.96 ml, 9.92 mmol). The mixture was refluxed for 16 h and diluted with water. The aqueous solution was extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by column chromatography eluting with 20% ethyl acetate/n-hexane to afford 1.20 g (91%) of the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1.[C:34](Cl)(=[O:37])[CH2:35][CH3:36]>>[C:34]([N:2]1[CH2:7][CH2:6][CH2:5][C@H:4]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[C:24]([F:26])[C:23]([O:27][CH3:28])=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:32][CH2:33]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:3]1)(=[O:37])[CH2:35][CH3:36]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CCCNC4)c[nH]c23)cc1F
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N1CCC[C@H](NC(=O)c2c[nH]c3c(-c4cc(F)c(OC)cc4OCC4CC4)ncnc23)C1

Procedure:
Starting from 4-(2-cyclopropylmethoxy-5-fluoro-4-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-piperidin-3-ylamide hydrochloride (example A168) and propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)([OH:3])=O.O1CCCC1.[CH2:17]([NH2:20])[CH2:18][CH3:19]>O>[CH:8]([C:7]1[CH:10]=[CH:11][C:4]([C:1]([NH:20][CH2:17][CH2:18][CH3:19])=[O:3])=[CH:5][CH:6]=1)=[O:9]
Reactant: CCCN
Reactant: O=Cc1ccc(C(=O)O)cc1
Solvent: C1CCOC1
Solvent: O
Product: CCCNC(=O)c1ccc(C=O)cc1
Reaction time: 3 h

Procedure:
A mixture of 15.0 g. of 4-carboxybenzaldehyde, 17.0 g. of N,N'-carbonyldiimidazole and 100 ml. of tetrahydrofuran is allowed to stand at room temperature for 3 hours, then 9.8 ml. of N-propylamine are added. The reaction mixture is allowed to stand at room temperature for 18 hours and is then heated at reflux temperature for one hour, diluted with water and concentrated. The oil which separates is washed twice with water and then purified by partition chromatography to yield p-formyl-N-propylbenzamide, m.p. 71°-74° C.
Reaction SMILES: C(OC([N:8]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=O)=[CH:22][CH:21]=1)[CH2:9][CH2:10][NH:11][CH2:12][C:13](OCC)=[O:14])=O)(C)(C)C.Cl.O1CCOCC1.CC[N:38](C(C)C)C(C)C>>[N:26]1[O:28][N:38]=[C:24]2[CH:25]=[C:20]([CH2:19][CH2:18][N:8]3[CH2:9][CH2:10][NH:11][CH2:12][C:13]3=[O:14])[CH:21]=[CH:22][C:23]=12
Reactant: CCOC(=O)CNCCN(CCc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Reactant: CCN(C(C)C)C(C)C
Agent: Cl
Solvent: C1COCCO1
Product: O=C1CNCCN1CCc1ccc2nonc2c1
Temperature: 120 °C

Procedure:
To a flask charged with ethyl [(2-{(tert-butoxycarbonyl)[2-(4-nitrophenyl)ethyl]amino}ethyl)amino]acetate (500 mg, 1.3 mmol) and a stir bar was added 4N HCl in dioxane (3.2 mL, 13 mmol). When LC indicated the reaction was done, solvents were removed under reduced pressure. The resulting residue was dissolved in ethanol (20 mL), and Hunig's base (1.1 mL, 6.4 mmol) was added to the solution. The reaction was heated to 120° C. for 16 hours. LC showed formation of the desired product, which was purified by silica gel chromatography to provide 1-[2-(2,1,3-Benzoxadiazol-5-yl)ethyl]piperazin-2-one. LC-MS (IE, m/z): 247 [M+1]+.
Reaction SMILES: [OH-].[Na+].[S:3]1[C:7]([NH2:8])=[N:6][CH:5]=[N:4]1.[C:9]([C:11]1[CH:12]=[C:13]([S:18](Cl)(=[O:20])=[O:19])[CH:14]=[CH:15][C:16]=1[F:17])#[N:10].Cl>O.O1CCOCC1>[C:9]([C:11]1[CH:12]=[C:13]([S:18]([NH:8][C:7]2[S:3][N:4]=[CH:5][N:6]=2)(=[O:20])=[O:19])[CH:14]=[CH:15][C:16]=1[F:17])#[N:10]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: Nc1ncns1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(S(=O)(=O)Nc2ncns2)ccc1F
Reaction time: 0.08 h

Procedure:
Sodium hydroxide (5.08 g, 0.127 mmol) was dissolved in water (60 mL) and 1,4-dioxane (300 mL). 1,2,4-thiadiazol-5-amine (10 g, 100 mmol) was added and the reaction stirred for 5 minutes. 3-Cyano-4-fluorobenzene-1-sulfonyl chloride (8.25 g, 37.6 mmol) was added and the reaction was allowed to stir for 3 hours at 20° C. After this time, the reaction was poured into a 1M aqueous solution of hydrogen chloride (150 mL). This solution was extracted with ethyl acetate (3×50 mL). The combined organics were dried over sodium sulfate, filtered and concentrated to give the title compound as a brown solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][CH:9]([OH:23])[CH2:10][NH:11][CH:12]([CH3:22])[CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:5][CH:4]=1.CN(C)[CH:28]=[O:29]>>[Si:15]([O:14][CH2:13][CH:12]([N:11]1[CH2:10][CH:9]([CH2:8][O:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][CH:24]=2)[O:23][C:28]1=[O:29])[CH3:22])([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17]
Reactant: COc1ccc(OCC(O)CNC(C)CO[Si](C)(C)C(C)(C)C)cc1
Reactant: CN(C)C=O
Product: COc1ccc(OCC2CN(C(C)CO[Si](C)(C)C(C)(C)C)C(=O)O2)cc1

Procedure:
A procedure similar to that described in Preparation 11 was repeated, except that 3.36 g of 1-(4-methoxyphenoxymethyl)-2-(2-t-butyldimethylsilyloxy-1-methylethylamino)ethanol (prepared as described in Preparation 75), 1.78 g of N,N'-carbonyldiimidazole and 30 ml of anhydrous dimethylformamide were used, to give 1.42 g of the title compound having an Rf value of 0.41 (on silica gel thin layer chromatography, using a 1:2 by volume mixture of ethyl acetate and hexane as the developing solvent) from a polar diastereomer and 1.62 g of the title compound, melting at 81° C. to 85° C. from a less polar diastereomer.
Reaction SMILES: C(N[C:9](=[O:37])[CH:10]([CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1)[N:11]1[C:15]2[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=2[N:13]=[C:12]1[C@@H:22]([O:29][CH3:30])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)C1C=CC=CC=1.C([O:42]C(OC(OC(C)(C)C)=O)=O)(C)(C)C.O.[OH-].[Li+].Cl>C(#N)C.O>[CH:31]1([CH:10]([N:11]2[C:15]3[CH:16]=[C:17]([F:21])[C:18]([F:20])=[CH:19][C:14]=3[N:13]=[C:12]2[C@@H:22]([O:29][CH3:30])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:9]([OH:42])=[O:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CO[C@@H](c1ccccc1)c1nc2cc(F)c(F)cc2n1C(C(=O)NCc1ccccc1)C1CCCCC1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: CO[C@@H](c1ccccc1)c1nc2cc(F)c(F)cc2n1C(C(=O)O)C1CCCCC1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of N-benzyl-2-cyclohexyl-2-[5,6-difluoro-2-((S)-methoxy-phenyl-methyl)-benzoimidazol-1-yl]-acetamide (2.16 g, 4 mmol, 1.0 equiv) in acetonitrile (25 ml) were added di-tert.-butyl-dicarbonate (1.123 g, 5 mmol, 1.2 equiv., [CAS RN 24424-99-5]) and N,N-dimethylaminopyridine ((0.051 g, 0.1 equiv., [CAS RN 1122-58-3]). The mixture was stirred 48 h at room temperature. A solution of lithium hydroxide monohydrate (0.54 g, 3.0 equiv., [CAS RN 1310-66-3]) in water (4 ml) was added, and the mixture vigorously stirred overnight at room temperature, and 2 h at 70° C. The mixture was allowed to cool to room temperature and poured into 1M aqueous hydrochloric acid (25 ml). The product was extracted with ethyl acetate (3×50 ml) and the combined organic phases washed with brine and dried over magnesium sulfate. The brown residue was purified by column chromatography on silica gel (75 g, 1:0 to 98:2 EtOAc/AcOH eluant) to afford the product as an off-white mixture of diastereomers. MS (ISN): 413.1 [M−H]−.
Reaction SMILES: [CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:29]4[C:20](=[N:21][C:22]5[C:27]([C:28]4=[O:30])=[C:26]([F:31])[C:25]([F:32])=[CH:24][CH:23]=5)[C:19]4[CH:33]=[CH:34][N:35]([S:36]([C:39]5[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:49][CH:50]([NH2:52])[CH3:51]>C1COCC1.C(OCC)(=O)C>[CH3:1][N:2]([CH3:48])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:46][CH3:47])=[C:12]([NH:15][C:16]3[N:29]=[C:20]([NH:21][C:22]4[C:27]([C:28]([NH:52][CH:50]([CH3:51])[CH3:49])=[O:30])=[C:26]([F:31])[C:25]([F:32])=[CH:24][CH:23]=4)[C:19]4[CH:33]=[CH:34][N:35]([S:36]([C:39]5[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=5)(=[O:38])=[O:37])[C:18]=4[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: COc1cc2c(cc1Nc1nc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c3nc4ccc(F)c(F)c4c(=O)n13)N(C(=O)CN(C)C)CC2
Reactant: CC(C)N
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(cc1Nc1nc(Nc3ccc(F)c(F)c3C(=O)NC(C)C)c3ccn(S(=O)(=O)c4ccc(C)cc4)c3n1)N(C(=O)CN(C)C)CC2
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 31 %

Procedure:
To a solution of 5-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-8,9-difluoro-3-[(4-methylphenyl)sulfonyl]pyrrolo[2′,3′:4,5]pyrimido[6,1-b]quinazolin-7(3H)-one (300 mg, 0.445 mmol) in THF (5 mL) was added (1-methylethyl)amine (0.765 mL, 8.91 mmol). The resulting mixture was let stir at rt for 40 min at which time it was diluted with ethyl acetate and washed with water and a saturated brine solution. Organics were dried over sodium sulfate and solvents removed under reduced pressure. The residue was purified via chromatography on SiO2 and afforded 6-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-2,3-difluoro-N-(1-methylethyl)benzamide (101 mg, 0.138 mmol) as a yellow solid (only 85% pure by LCMS) (ESIMS (M+H)+=733)
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:14][CH2:15][CH:16]=[CH2:17])(=[O:13])[CH2:9][C:10]([CH3:12])=[O:11].C1(C)C=CC(S([N:27]=[N+:28]=[N-])(=O)=O)=CC=1>C(#N)C>[N+:27](=[C:9]([C:10](=[O:11])[CH3:12])[C:8]([O:14][CH2:15][CH:16]=[CH2:17])=[O:13])=[N-:28]
Reactant: C=CCOC(=O)CC(C)=O
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C=CCOC(=O)C(=[N+]=[N-])C(C)=O
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 94.9 %

Procedure:
55.4 ml (0.4 mole - 2 equivalents) of triethylamine were added dropwise to a solution, which had been cooled to 0° C., of 28.43 g (0.2 mole) of allyl acetoacetate and 43.39 g (0.22 mole - 1.1 equivalents) of p-toluenesulphonyl azide in 400 ml of anhydrous acetonitrile. The mixture was stirred at 0° C. for 3.5 h, then 50 g of kieselguhr were added, evaporation in vacuo was carried out and then chromatography on 400 g of silica gel (toluene:ethyl acetate 96:4). 31.9 g (95%) of the title compound were obtained as a pale yellow oil, Rf: 0.36 (toluene:ethyl acetate 9:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([SH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:16][CH2:17][CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([S:8][CH2:16][CH2:17][CH3:18])[CH:3]=1
Reactant: Sc1cccc(Br)c1
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCSc1cccc(Br)c1
Temperature: 50 °C
Yield: 90.1 %

Procedure:
A solution of 3-bromobenzenethiol (5.00 g, 26.4 mmol) in anhydrous DMF (30 mL) was treated with K2CO3 (7.30 g, 52.8 mmol) followed by 1-bromopropane (3.90 g, 31.7 mmol) and the mixture was heated to about 50° C. under nitrogen for 12 h. The solvent was distilled out completely, and the residue was dissolved in DCM and washed with water and brine. The organic layer was dried over sodium sulphate and evaporated to afford 5.50 g (90%) of the title compound as pale yellow liquid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=O)[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]([C:23]([C:25]1[CH:30]=[CH:29][C:28]([S:31]([NH:34][CH3:35])(=[O:33])=[O:32])=[CH:27][CH:26]=1)=[O:24])[NH2:22]>C(O)(C)C>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17](=[N:22][NH:21][C:23]([C:25]3[CH:26]=[CH:27][C:28]([S:31]([NH:34][CH3:35])(=[O:32])=[O:33])=[CH:29][CH:30]=3)=[O:24])[CH3:18])[C:12]=2[OH:20])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CNS(=O)(=O)c1ccc(C(=O)NN)cc1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(C)(C)C)cc2)c1O
Solvent: CC(C)O
Product: CNS(=O)(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1
Temperature: 100 °C
Reaction time: 19 h
Yield: 27.5 %

Procedure:
1-[5-(4-t-Butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl]ethanone (0.228 mmol, 62 mg), 4-(hydrazinocarbonyl)-N-methylbenzenesulfonamide (0.228 mmol, 52 mg) and p-tosylic acid monohydrate (30 mol %, 11.8 mg) were dissolved in isopropyl alcohol (6 mL) and stirred at 100° C. for 19 hours. Then, the solvent was evaporated, and the residue was purified by silica gel thin layer chromatography (chloroform/methanol=10/1) to give the desired product as a yellow solid (30.3 mg, yield 28%).