Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:13][CH2:14][CH2:15][NH:16][C:17](=[O:29])[C:18]1[C:23]([Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=1[Cl:28])[CH3:12].[CH2:30](I)[CH3:31]>C1COCC1>[Cl:28][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18]=1[C:17]([N:16]([CH2:15][CH2:14][O:13][CH2:11][CH3:12])[CH2:30][CH3:31])=[O:29]
Reactant: CCI
Reactant: CCOCCNC(=O)c1c(Cl)cccc1[Si](C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCCN(CC)C(=O)c1c(Cl)cccc1[Si](C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.8 %

Procedure:
A 1M THF solution of sodium bis(trimethylsilyl)amide (7.7 mL, 7.7 mmol) was added dropwise over 5 min to a solution of N-(2-ethoxyethyl)-2-chloro-6-(trimethylsilyl)benzamide (2.1 g, 7 mmol) in THF (30 mL). The resulting mixture was stirred for 1 h at RT, then a solution of ethyl iodide (1.31 g, 8.4 mmol) in THF (15 mL) was added with a mild exotherm. The resulting reaction mixture was stirred overnight, then was partitioned between ethyl acetate and dilute aq citric acid. The ethyl acetate phase was washed with sat aq NaHCO3 followed with brine, then was dried (MgSO4) and concentrated to afford 1.9 g of the title compound as an amber oil, an 83% yield.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][C@@H:19]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH3:20])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:27][CH3:28])=[C:5]([CH3:29])[O:4][N:3]=1.CC(O)=O.[N:34]([O-])=O.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.O>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:27][CH3:28])=[CH:9][C:10]3[C:11]4[N:18]([C@@H:19]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[CH3:20])[N:34]=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: O=N[O-]
Reactant: COc1cc2c(N[C@H](C)c3ccccc3)c(N)cnc2cc1-c1c(C)noc1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1cc2c(cc1-c1c(C)noc1C)ncc1nnn([C@H](C)c3ccccc3)c12
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.5 %

Procedure:
To a solution of 7-(3,5-dimethyl-4-isoxazolyl)-6-(methoxy)-N4-[(1R)-1-phenylethyl]-3,4-quinolinediamine (for a preparation see Intermediate 39, 0.2 g, 0.515 mmol) in DCM (10 ml) cooled at 0° C., were added AcOH (0.5 ml) and a solution of sodium nitrite (0.07 g) in water (1 ml). The mixture was stirred at room temperature overnight. The reaction mixture was treated with saturated aqueous Sodium hydrogen carbonate and extracted with DCM. The organic phase was dried over Na2SO4, evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel (DCM/MeOH, 95:5). The solid was triturated in diisopropyl ether to give the title compound as a green powder (0.18 g, 87.5%).
Reaction SMILES: [S:1]1[C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][NH:5][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>ClCCl>[Cl:18][C:19]1[CH:27]=[C:26]([N+:28]([O-:30])=[O:29])[CH:25]=[CH:24][C:20]=1[C:21]([N:5]1[CH2:6][CH2:7][CH2:8][CH2:9][C:10]2[S:1][CH:2]=[CH:3][C:4]1=2)=[O:22]
Reactant: c1cc2c(s1)CCCCN2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1ccc([N+](=O)[O-])cc1Cl)N1CCCCc2sccc21
Reaction time: 0.08 h
Yield: 73.7 %

Procedure:
To a solution of 15.0 g of 5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine in 150 ml of dichloromethane cooled to 0° C. is added 27.2 ml of triethylamine. After stirring 5 minutes, a solution of 28.0 g of 2-chloro-4-nitrobenzoyl chloride in 140 ml of dichloromethane is added slowly. The solution is stirred at room temperature overnight, diluted with 450 ml of dichloromethane and the solution washed with 200 ml each of water, 2N citric acid, 1M sodium bicarbonate and brine. The organic layer is dried over Na2SO4, filtered through a thin pad of hydrated magnesium silicate and the filtrate concentrated under vacuum. The residue is crystallized from ethyl acetate to give 24.3 g of off-white crystals, m.p. 131°-134° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH2:21][C:22]([O:24]C)=[O:23].[O-2].[Li+].[Li+].Cl>O1CCOCC1.O>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH2:21][C:22]([OH:24])=[O:23]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Agent: Cl
Agent: [Li+]
Agent: [O-2]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(-c2c(CC(=O)O)c(C)nc3sc4c(c23)CCC4)cc1
Temperature: 60 °C
Yield: 63.1 %

Procedure:
To a solution of methyl [2-methyl-4-p-tolyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3yl]acetate (0.071 g; 0.202 mmol) in dioxane (4 mL) and water (1 mL) was added a 1N lithium oxide solution (1 mL; 1 mmol). The reaction mixture was heated at 60° C. for 2 h. After cooling to room temperature, the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphatesulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.043 g (63%) of the title compound as a beige powder.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:2].Cl.[C:10]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)#[N:11]>C(Cl)Cl.CCOC(C)=O>[CH2:1]([N:3]([C:16](=[O:17])[C:15]1[CH:19]=[CH:20][C:12]([C:10]#[N:11])=[CH:13][CH:14]=1)[CH2:4][CH2:5][C:6]([OH:8])=[O:7])[CH3:2]
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: CCNCCC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCN(CCC(=O)O)C(=O)c1ccc(C#N)cc1
Yield: 56 %

Procedure:
A suspension of ethyl β-alanine.HCl (2.81 g, 18.3 mmol) and 4-cyano-benzoyl chloride (3.03 g, 18.0 mmol) in DCM (30 mL) was stirred overnight at RT. The mixture was diluted with EtOAc, washed with aq. citric acid (3%), sat. aq. NaHCO3 and H2O. Drying (MgSO4) and evaporation of the solvent gave compound 2 (2.52 g, 56%).
Reaction SMILES: [C:1]([O-])([O-])=[O:2].[K+].[K+].[Cl:7][C:8]1[C:9]([F:16])=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11]Br.[CH3:17][O:18][C:19]1[C:24](C)=[CH:23][C:22]([N:26]2[C:31](=[O:32])[N:30](CC3C(F)=CC(F)=CC=3F)[C:29]3[CH:43]=[CH:44][CH:45]=[CH:46][C:28]=3[S:27]2(=[O:48])=[O:47])=[CH:21][C:20]=1C>CN(C=O)C>[Cl:7][C:8]1[C:9]([F:16])=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH2:11][N:30]1[C:29]2[CH:43]=[CH:44][CH:45]=[CH:46][C:28]=2[S:27](=[O:47])(=[O:48])[N:26]([C:22]2[CH:21]=[CH:20][C:19]([O:18][CH3:17])=[C:24]([O:2][CH3:1])[CH:23]=2)[C:31]1=[O:32]
Reactant: O=C([O-])[O-]
Reactant: Fc1c(Cl)cccc1CBr
Reactant: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N2C(=O)N(Cc3cccc(Cl)c3F)c3ccccc3S2(=O)=O)cc1OC

Procedure:
The title compound (35 mg, 0.07 mmol) was prepared from (IntA1) (50 mg, 0.15 mmol), K2CO3 (62 mg, 0.45 mmol) and 3-chloro-2-fluorobenzyl bromide (40 mg, 0.18 mmol) in DMF (2 mL) using the methods of (115).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].N1C(C)=CC=CC=1C.[I-].[K+].Br[CH2:27][CH2:28][CH:29]=[C:30]1[C:36]2[CH:37]=[CH:38][CH:39]=[N:40][C:35]=2[CH2:34][O:33][C:32]2[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]1=2>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:11][CH2:12][N:13]([CH2:27][CH2:28][CH:29]=[C:30]3[C:36]4[CH:37]=[CH:38][CH:39]=[N:40][C:35]=4[CH2:34][O:33][C:32]4[CH:41]=[CH:42][C:43]([C:45]([OH:48])([CH3:47])[CH3:46])=[CH:44][C:31]3=4)[CH2:14][CH2:15]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: N#Cc1cc(Cl)ccc1N1CCNCC1
Reactant: CC(C)(O)c1ccc2c(c1)C(=CCCBr)c1cccnc1CO2
Agent: [I-]
Agent: [K+]
Solvent: Cc1cccc(C)n1
Solvent: CC(C)O
Product: CC(C)(O)c1ccc2c(c1)C(=CCCN1CCN(c3ccc(Cl)cc3C#N)CC1)c1cccnc1CO2
Temperature: 80 °C
Reaction time: 18 h
Yield: 31.9 %

Procedure:
To a solution of 5-chloro-2-piperazin-1-yl-benzonitrile (0.22 g, 1 mmol) in isopropanol (8 mL) was added 2,6-lutidine (0.16 mL, 1.33 mmol) and catalytic potassium iodide. This mixture was heated to 80° C. and treated with 2-[5-(3-bromo-propylidene)-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-yl]-propan-2-ol (0.26 g, 0.67 mmol) in portions over 2h. The solution was then stirred at 80° C. for an additional 18 h. The reaction mixture was concentrated in vacuo, then purified by flash chromatography on silica gel (gradient elution from 95% ethyl acetate/5% methanol to 90% ethyl acetate/10% methanol) to yield the title compound (0.11 g, 54%). 1H-NMR (MeOD) δ: 1.40 (6H, s), 2.30-2.58 (8H, m), 3.00-3.15 (4H, m), 5.20 (1H, br s), 6.18 (1H, t), 6.70 (1H, dd), 7.18-7.84 (7H, m), 8.50 (1H, dd). ESI-MS m/z: 515 (M+1),
Reaction SMILES: [F:1][C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]2[CH:13]=[CH:14][N:15]([C:16]3[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=3[CH3:23])[NH2:19])[C:3]=12.[OH:24][C:25]([C:28]1[CH:29]=[C:30]([CH:34]=[C:35]([S:37]([F:42])([F:41])([F:40])([F:39])[F:38])[CH:36]=1)[C:31](O)=[O:32])([CH3:27])[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(#N)C>[F:1][C:2]1[C:6]([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)=[N:5][N:4]2[CH:13]=[CH:14][N:15]([C:16]3[CH:17]=[C:18]([NH:19][C:31](=[O:32])[C:30]4[CH:34]=[C:35]([S:37]([F:42])([F:38])([F:39])([F:40])[F:41])[CH:36]=[C:28]([C:25]([OH:24])([CH3:27])[CH3:26])[CH:29]=4)[CH:20]=[CH:21][C:22]=3[CH3:23])[C:3]=12
Reactant: CC(C)(O)c1cc(C(=O)O)cc(S(F)(F)(F)(F)F)c1
Reactant: Cc1ccc(N)cc1-n1ccn2nc(-c3cccnc3)c(F)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Product: Cc1ccc(NC(=O)c2cc(C(C)(C)O)cc(S(F)(F)(F)(F)F)c2)cc1-n1ccn2nc(-c3cccnc3)c(F)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
60 mg (0.195 mmol) of the compound of Example 83A and 60 mg (0.195 mmol) of the compound of Example 19A were dissolved in 2 ml of DMF, and 89 mg (0.234 mmol) of HATU and 41 μl (0.234 mmol) of N,N-diisopropylethylamine were added in succession. After about 16 h of stirring at RT, the reaction mixture was diluted with 1 ml of acetonitrile and separated into its components by preparative HPLC (Method 36). The product fractions were combined and freed from the solvent on a rotary evaporator. The residue was dissolved in a little methanol and the solution was passed through a bicarbonate cartridge (from Polymerlabs, Stratospheres SPE, PL-HCO3 MP SPE, capacity 0.9 mmol) to convert the formate salt obtained after preparative HPLC into the free base. Evaporation and drying under high vacuum gave 42 mg (35% of theory) of the title compound.
Reaction SMILES: [CH:1]1[C:6](C(O)=O)=[CH:5][C:4]2[C:10](O[C:13](=[O:14])[C:3]=2[CH:2]=1)=[O:11].[NH2:15][NH2:16].C(O)C.C(O)(C)C>CN1CCCC1=O>[OH:11][C:10]1[C:4]2[C:3](=[CH:2][CH:1]=[CH:6][CH:5]=2)[C:13]([OH:14])=[N:16][N:15]=1
Reactant: O=C(O)c1ccc2c(c1)C(=O)OC2=O
Reactant: NN
Solvent: CCO
Solvent: CN1CCCC1=O
Solvent: CC(C)O
Product: Oc1nnc(O)c2ccccc12

Procedure:
For example, as outlined in Scheme I, 1,2,4-benzene tricarboxylic anhydride 1 may be reacted with hydrazine in a suitable solvent, e.g., ethanol, isopropyl alcohol, or n-methyl-2-pyrrolidinone, to produce dihydroxy-phthalazine 2. Compound 2 may then be reacted with SOCl2 and POCl3 to produce a trichloride intermediate that is reacted immediately with an amine X1X2NH (where X1 and X2 are, e.g., hydrogen, alkyl, aryl, etc.) to produce an amide compound 3. Compound 3 may then be reacted with NaI and HI in a suitable solvent, e.g., acetone, to produce a di-iodo compound 4. Compound 4 may then be further reacted with a suitable nucleophile in a suitable solvent to form a mixture of the two correspondent regioisomers 5 and 6. Replacement of any remaining iodine atoms may be achieved using standard nucleophilic substitution and/or transition metal reactions known to one of skill in the art, for example, Stille and Suzuki type reactions.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([S:12][S:13][CH2:14][CH2:15][NH:16]C(=O)OC(C)(C)C)([CH3:11])([CH3:10])[CH3:9]>C(Cl)Cl>[C:8]([S:12][S:13][CH2:14][CH2:15][NH2:16])([CH3:11])([CH3:10])[CH3:9]
Reactant: CC(C)(C)OC(=O)NCCSSC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)SSCCN
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 335.3 %

Procedure:
A solution of TFA (1.0 ml) in DCM (1.0 ml) was added to tert-butyl (2-(tert-butyldisulfanyl)ethyl)carbamate (Compound 6b-A, 100 mg, 0.377 mmol), and the mixture was stirred at room temperature for 15 minutes. The reaction solution was concentrated under reduced pressure to afford the title compound (209 mg, quant.).
Reaction SMILES: C([CH:4]([C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([Cl:16])[CH:10]=1)[C:5]([O:7][CH3:8])=[O:6])(=S)C.[S:17](=O)(=O)(O)O.[CH:22]([C:24]([CH3:26])=[O:25])=[CH2:23].C(N(CC)CC)C>C(OCC)(=O)C.CO>[Cl:16][C:11]1[CH:10]=[C:9]([CH:4]([S:17][CH2:23][CH2:22][C:24](=[O:25])[CH3:26])[C:5]([O:7][CH3:8])=[O:6])[CH:14]=[CH:13][C:12]=1[Cl:15]
Reactant: C=CC(C)=O
Reactant: COC(=O)C(C(C)=S)c1ccc(Cl)c(Cl)c1
Reactant: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C(SCCC(C)=O)c1ccc(Cl)c(Cl)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 76 %

Procedure:
To a methanol (2 mL) solution of methyl 2-thioacetyl-2-(3,4-dichlorophenyl)acetate (0.50 g, 1.7 mmol), concentrated sulfuric acid (0.050 mL, 0.55 equivalent amount) was added, followed by stirring at 60° C. for 3 hours. After the reaction solution was cooled to room temperature, it was dropwise added to an ethyl acetate (2 mL) solution of methyl vinyl ketone (0.17 mL, 1.2 equivalent amounts) and triethylamine (0.36 mL, 1.5 equivalent amount) at room temperature. The reaction solution was mixed with ethyl acetate (1 mL), followed by liquid separation with a mixed liquid of water-saturated salt solution (1:1, (v/v)), and further, the organic layer was washed with a saturated ammonium chloride aqueous solution and a saturated salt solution and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration, and the solvent was distilled off to give the desired product as a colorless oil (0.42 g, yield: 76%).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[O:8][CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4]1.[CH2:25]([N:27]=[C:28]=[O:29])[CH3:26]>>[ClH:16].[Cl:17][C:12]1[CH:11]=[C:10]([CH:9]2[O:8][CH2:7][CH2:6][NH:5][CH2:4][CH:3]2[CH2:2][NH:1][C:28]([NH:27][CH2:25][CH3:26])=[O:29])[CH:15]=[CH:14][C:13]=1[Cl:16]
Reactant: CCN=C=O
Reactant: CC(C)(C)OC(=O)N1CCOC(c2ccc(Cl)c(Cl)c2)C(CN)C1
Product: CCNC(=O)NCC1CNCCOC1c1ccc(Cl)c(Cl)c1
Product: Cl

Procedure:
Using tert-butyl (6RS,7SR)-6-(aminomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate and ethyl isocyanate, and in the same manner as in Example 3, steps D and E, the title compound was obtained.
Reaction SMILES: [P:1]([O-:8])([O:5]CC)[O:2]CC.O.[CH2:10](O)[CH3:11].[CH:13]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14]1>CO>[CH2:10]([P:1](=[O:2])([O-:5])[O-:8])[CH3:11].[CH:13]1([NH3+:18])[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH:13]1([NH3+:18])[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CCOP([O-])OCC
Reactant: NC1CCCC1
Reactant: CCO
Solvent: O
Solvent: CO
Product: CCP(=O)([O-])[O-]
Product: [NH3+]C1CCCC1
Yield: 91.7 %

Procedure:
A mixture of 13.81 g. (0.1 moles) of diethyl phosphite, 20 ml. of water and 20 ml. of ethanol is reacted with a mixture of 8.51 g. (0.1 moles) of cyclopentyl amine and 30 ml. of methanol as described in Example 1. 17.9 g. of cyclopentyl-ammoniumethyl phosphonate are obtained. nD30 -1.4622. Yield: 91.7%.
Reaction SMILES: O=[O+][O-].[Na].[CH3:5][O:6][C:7](=[O:27])[CH:8]([C:24](=O)[CH3:25])[CH:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10](=[N+:15](O)[O-])[C:11]([O:13][CH3:14])=[O:12].O.[NH2:29]N>CO>[CH3:14][O:13][C:11]([C:10]1[CH:9]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:8]([C:7]([O:6][CH3:5])=[O:27])=[C:24]([CH3:25])[NH:29][N:15]=1)=[O:12]
Reactant: NN
Reactant: COC(=O)C(C(c1ccccc1)C(C(C)=O)C(=O)OC)=[N+]([O-])O
Agent: O=[O+][O-]
Agent: [Na]
Solvent: CO
Solvent: O
Product: COC(=O)C1=NNC(C)=C(C(=O)OC)C1c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Dry ozone is passed, in excess, into a solution of 69.0 g (0.2 mol) of the sodium salt of 2-acetyl-4-aci-nitro-3-phenyl-glutaric acid dimethyl ester in 300 ml of absolute methanol at -78° C. until the solution becomes blue-coloured. After 30 minutes, the ozone is removed by passing dry nitrogen in and the mixture is warmed to -20°, under nitrogen. 10 g (0.2 mol) of hydrazine hydrate in 50 ml of absolute methanol are added dropwise and the mixture is stirred at room temperature for 12 hours. For working up, the methanol is distilled off in vacuo, the residue is taken up in chloroform and insoluble material is filtered off. The chloroform is distilled off from the filtrate and, after adding a little isopropanol to the residue, the product slowly crystallises out. Melting point: 187°.
Reaction SMILES: [CH3:1]OC(=O)C(C)=C.O=[C:9]1O[C@H:14]([C@H:16]([CH2:18]O)[OH:17])[C:12](O)=[C:10]1O.C1[C:26](=[N:27][C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)C=CC(=O)C=1>C1(C)C=CC=CC=1.C(O)CCC.C(O)C>[CH3:1][N:27]([C:28]1[CH:29]=[CH:30][C:31]([NH:34][CH:10]2[CH:9]=[CH:18][C:16](=[O:17])[CH:14]=[CH:12]2)=[CH:32][CH:33]=1)[CH3:26]
Reactant: C=C(C)C(=O)OC
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: Nc1ccc(N=C2C=CC(=O)C=C2)cc1
Solvent: CCCCO
Solvent: Cc1ccccc1
Solvent: CCO
Product: CN(C)c1ccc(NC2C=CC(=O)C=C2)cc1

Procedure:
The fifth layer consisted of the magenta/cyan barrier polymer and the magenta reactants. A polymer premix was prepared by dissolving 64.5 g of a methylmethacrylate polymer in 178.5 g of toluene and 15.05 g of n-butyl alcohol. The leuco indoaniline magenta developer was prepared by reducing the dye with ascorbic acid. This was done by dissolving 0.63 g of ascorbic acid in 45 g of ethanol. Then 1.2 g of the magenta indoaniline dye was added. ##STR22##
Reaction SMILES: CCCP(=O)=O.[N:7]1[C:15]2[C:10](=[N:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=O)=[CH:18][CH:17]=2)[CH:8]=1.[CH3:26][N:27]([CH3:42])[CH2:28][C:29]#[C:30][C:31]1[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][C:32]=1[C:38]([F:41])([F:40])[F:39].CCN(CC)CC>CN(C1C=CN=CC=1)C.CN(C=O)C.CCOC(C)=O>[CH3:42][N:27]([CH3:26])[CH2:28][C:29]#[C:30][C:31]1[CH:36]=[CH:35][C:34]([NH:37][C:23](=[O:25])[CH2:22][C:19]2[CH:18]=[CH:17][C:16]([N:9]3[C:10]4=[N:11][CH:12]=[CH:13][CH:14]=[C:15]4[N:7]=[CH:8]3)=[CH:21][CH:20]=2)=[CH:33][C:32]=1[C:38]([F:39])([F:40])[F:41]
Reactant: O=C(O)Cc1ccc(-n2cnc3cccnc32)cc1
Reactant: CN(C)CC#Cc1ccc(N)cc1C(F)(F)F
Agent: CCCP(=O)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)CC#Cc1ccc(NC(=O)Cc2ccc(-n3cnc4cccnc43)cc2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Propylphosphonic anhydride (50% in DMF, 0.69 mL, 1.19 mmol, 2 equiv) is added to a solution of (4-imidazo[4,5-b]pyridin-3-yl-phenyl)acetic acid (Step 7.1) (0.150 g, 0.59 mmol), 4-(3-dimethylamino-prop-1-ynyl)-3-trifluoromethyl-phenylamine (0.138 g, 0.57 mmol, 0.95 equiv), DMAP (10 mg), and Et3N (0.82 mL, 5.93 mmol, 10 equiv) in DMF (2.0 mL), at rt and under an argon atmosphere. The reaction mixture is stirred at rt for 18 h, diluted with EtOAc and washed with H2O. The aqueous layer is extracted with EtOAc. The combined organic phase is washed with brine, dried (Na2SO4), filtered and concentrated. The residue is purified by reversed phase MPLC (CH3CN/H2O/TFA) to provide the title compound as a white solid: ES-MS: 477.9 [M+H]+; single peak at tR=3.20 min (System 1); Rf=0.06 (CH2Cl2/NH3 (2 N in MeOH), 95:5).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[CH:3]=1.[OH:9][CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=O)=[CH:15][CH:14]=1.[C:21]([CH2:23][C:24](=[S:26])N)#[N:22].C(O)(=O)C>CC(O)C>[OH:9][CH2:10][CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([C:17]2[C:3]3[C:4](=[O:8])[NH:5][CH:6]=[CH:7][C:2]=3[N:1]=[C:24]([SH:26])[C:23]=2[C:21]#[N:22])=[CH:15][CH:14]=1
Reactant: N#CCC(N)=S
Reactant: O=Cc1ccc(OCCO)cc1
Reactant: Nc1cc[nH]c(=O)c1
Solvent: CC(C)O
Solvent: CC(=O)O
Product: N#Cc1c(S)nc2cc[nH]c(=O)c2c1-c1ccc(OCCO)cc1

Procedure:
1 g (9.08 mmol) of 4-aminopyridin-2(1H)-one [Searls, T., McLaughlin, L. W., Tetrahedron 55, 11985-11996 (1999)], 1.509 g (9.08 mmol) of 4-(2-hydroxyethoxy)benzaldehyde and 0.909 g (9.08 mmol) of 2-cyanoethanethioamide were initially charged in 50 ml of 2-propanol, 0.78 ml (13.62 mmol) of acetic acid was added and the mixture was stirred at reflux overnight.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:15]([CH2:16]O)[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH2:25]([N:27](CC)CC)C.CS(Cl)(=O)=O.O>C1COCC1>[C:25]([CH2:16][CH:15]1[O:14][CH2:13][CH2:12][N:11]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:10][CH:9]1[C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)#[N:27]
Reactant: CC(C)(C)OC(=O)N1CCOC(CO)C(c2ccc(Cl)c(Cl)c2)C1
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCOC(CC#N)C(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl (6RS,7SR)-6-(3,4-dichlorophenyl)-7-(hydroxymethyl)-1,4-oxazepane-4-carboxylate (2.0 g) in THF (40 mL) were added triethylamine (2.22 mL) and methanesulfonyl chloride (0.82 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. To a solution of the obtained residue (1.6 g) in DMF (9.0 ml) was added sodium cyanide (345 mg), and the mixture was stirred at 80° C. for 2 days. The reaction solution was allowed to cool to room temperature, water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (331 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=C(C(O)=O)[C:3]=1Br.[CH3:22][S-:23].[Na+].[C:25]([O:28][CH2:29]C)(=[O:27])[CH3:26].Cl>CN(C=O)C.O>[CH3:29][O:28][C:25]([C:26]1[C:3]([S:23][CH3:22])=[C:2]([NH2:1])[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[F:17])[N:5]=1)=[O:27]
Reactant: CCOC(C)=O
Reactant: C[S-]
Reactant: COc1c(Cl)ccc(-c2nc(N)c(Br)c(C(=O)O)n2)c1F
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2F)nc(N)c1SC
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 12.7 %

Procedure:
6-Amino-5-bromo-2-(4-chloro-2-fluoro-3-methoxyphenyl)-pyrimidine-4-carboxylic acid (830 mg, 2.2 mmol; see WO 2007/082076 A1 for preparation) was combined with sodium methanthiolate (470 mg, 6.7 mmol) and cuprous iodide (1.6 g, 8.3 mmol) in 12 mL dry DMF and heated to 50° C. After heating for 4 h, the mixture was cooled, taken up in water and ethyl acetate and acidified with 2M HCl. A small amount of solid was removed by filtration and the separated aqueous phase was extracted again with ethyl acetate. The combined organic phases were washed twice with water, washed once with brine, dried and evaporated. The crude product was dissolved in 7 mL THF and 5 L methanol and treated with 1.5 mL of 2.0M (trimethylsilyl)diazomethane and stirred at room temperature for 30 min. A few drops of acetic acid were added to destroy excess reagent. The reaction solution was heated briefly to reflux and then concentrated. The product was purified by flash chromatography on silica gel (ethyl acetate/hexane gradient with 2% acetic acid) to yield the title compound (100 mg, 12.7% yield): 1H NMR (CDCl3): δ 7.65 (m, 1H), 7.23 (m, 1H), 5.98 (br s, 2H), 4.00 (s, 3H), 3.99 (d, 3H), 2.35 (s, 3H).