Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=[C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][C:6]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][CH:8]=2)[NH:3]1.P(Cl)(Cl)([Cl:25])=O.C(N(CC)C(C)C)(C)C>>[Cl:25][C:2]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10](=[O:18])[C:9]2[C:4](=[CH:5][C:6]([C:19]([O:21][CH3:22])=[O:20])=[CH:7][CH:8]=2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2c(=O)n(-c3ccccc3)c(=O)[nH]c2c1
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(=O)n(-c3ccccc3)c(Cl)nc2c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 77.2 %

Procedure:
Into a round bottom flask was added methyl 2,4-dioxo-3-phenyl-1,2,3,4-tetrahydroquinazoline-7-carboxylate (0.21 g, 0.70 mmol) dissolved in phosphoryl chloride (3.0 mL, 32.2 mmol) and N,N-diisopropylethylamine (0.27 mL, 1.6 mmol). The reaction mixture was heated to 120° C. and stirred overnight. The mixture was then cooled to rt and concentrated. The residue was poured over ice and the resulting solid was filtered and washed with water to afford methyl 2-chloro-4-oxo-3-phenyl-3,4-dihydroquinazoline-7-carboxylate (0.17 g, 77%). LC-MS: (FA) ES+ 315.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23](Br)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC1(C)C(C)(C)OB([C:47]2[CH:48]=[N:49][NH:50][CH:51]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>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.COCCOC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[N:16]=[N:17][C:18]([CH2:35][CH2:36][CH2:37][CH3:38])=[C:19]([C:21]3[CH:26]=[CH:25][C:24]([O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[C:23]([C:47]4[CH:48]=[N:49][NH:50][CH:51]=4)[CH:22]=3)[CH:20]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(Br)c1
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
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: COCCOC
Product: CCCCc1nnc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1-c1ccc(OC2CCCCC2)c(-c2cn[nH]c2)c1
Temperature: 90 °C
Yield: 18.6 %

Procedure:
A mixture of 4-[5-(3-bromo-4-cyclohexyloxy-phenyl)-6-butyl-pyridazin-3-yloxy]-piperidine-1-carboxylic acid tert-butyl ester (Example 65, 0.2 mmol, 118 mg), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.3 mmol, 60 mg, 98%), tetrakis(triphenylphosphine)palladium(0) (0.01 mmol, 11.6 mg), 2 N aq. sodium carbonate solution (0.5 mL) and DME (1 mL) was heated at 80° C. for 7 h and at 90° C. for 2 h. 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (0.3 mmol, 60 mg, 98%), tetrakis(triphenylphosphine)palladium(0) (0.01 mmol, 11.6 mg), 2 N aq. sodium carbonate solution (0.5 mL) and DME (1 mL) were added again and it was heated at 85° C. for 1.5 h. The reaction mixture was partitioned between ethyl acetate (15 mL) and saturated aq. sodium bicarbonate solution (15 mL). The ethyl acetate layer was dried over sodium sulfate. Purification by column chromatography on silica gel using ethyl acetate/hexanes 1:3 to 3:1 gave 4-{6-butyl-5-[4-cyclohexyloxy-3-(1H-pyrazol-4-yl)-phenyl]-pyridazin-3-yloxy}-piperidine-1-carboxylic acid tert-butyl ester (21.4 mg, 19% yield).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:26]#[N:27])[C:15]=2[O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[C:10]([CH3:28])=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-:30].[K+]>C(O)C.O>[CH2:1]([N:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([C:26]([NH2:27])=[O:30])[C:15]=2[O:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=2)[C:10]([CH3:28])=[C:9]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C)n(Cc2ccccc2)c2c(OCc3ccc(F)cc3)c(C#N)cnc12
Reactant: [OH-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1c(C)n(Cc2ccccc2)c2c(OCc3ccc(F)cc3)c(C(N)=O)cnc12
Yield: 66.7 %

Procedure:
1-Benzyl-7-(4-fluorobenzyloxy)-2,3-dimethyl-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile (500 mg, 1.30 mmol) prepared in Example 276 was diluted with a mixture of ethanol (8 ml) and water (2 ml). Potassium hydroxide (650 mg, 13.0 mmol) was added to the reaction mixture, which was then refluxed for 2 hours. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The separated organic layer was dried on anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/methanol=10/1, (v/v)) to give 350 mg of the titled compound as a white solid.
Reaction SMILES: [CH:1]1([N:7]([CH2:41][CH:42](OC)[O:43]C)[C:8](=[O:40])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]3[CH2:39][CH2:38][C:24]4([O:29][CH2:28][CH2:27][N:26]([C:30]([C:32]5[N:33]=[C:34]([CH3:37])[S:35][CH:36]=5)=[O:31])[CH2:25]4)[CH2:23][CH2:22]3)[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH:1]1([N:7]([CH2:41][CH:42]=[O:43])[C:8](=[O:40])[CH2:9][CH2:10][O:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]3[CH2:39][CH2:38][C:24]4([O:29][CH2:28][CH2:27][N:26]([C:30]([C:32]5[N:33]=[C:34]([CH3:37])[S:35][CH:36]=5)=[O:31])[CH2:25]4)[CH2:23][CH2:22]3)[CH:15]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(CN(C(=O)CCOCCc1cccc(CN2CCC3(CC2)CN(C(=O)c2csc(C)n2)CCO3)c1)C1CCCCC1)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1nc(C(=O)N2CCOC3(CCN(Cc4cccc(CCOCCC(=O)N(CC=O)C5CCCCC5)c4)CC3)C2)cs1

Procedure:
Tosic acid monohydrate (1.38 g) was added to a solution of N-cyclohexyl-N-(2,2-dimethoxyethyl)-3-(3-((4-(2-methylthiazole-4-carbonyl)-1-oxa-4,9-diazaspiro[5.5]undecan-9-yl)methyl)phenethoxy)propanamide (0.68 g) in DCM (10 mL) and the resulting mixture stirred at RT until consumption of the acetal was complete (4 h). Saturated sodium bicarbonate solution (10 mL) was cautiously added and the mixture was stirred until bubbling ceased (10 min). The reaction mixture was diluted with DCM (50 mL) and the aqueous phase separated. The organic phase was washed with saturated sodium bicarbonate solution (2×20 mL) and brine (20 mL), dried over sodium sulphate, filtered and evaporated to give the subtitled compound as a gum. Yield 0.61 g.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[F:13].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:8][C:7]=1[F:13]
Reactant: Cc1oc(-c2ccccc2)nc1CCl
Reactant: CCO[C@@H](Cc1ccc(O)cc1F)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1F)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(2-fluoro-4-hydroxy-phenyl)-propionic acid methyl ester was reacted with 4-chloromethyl-5-methyl-2-phenyl-oxazole in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-[2-fluoro-4-(5-methyl-2-phenyl-oxazol-4-ylmethoxy)-phenyl]-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH2:5][CH:6]([OH:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH3:3].[H-].[Na+].Br[C:17]1[S:18][CH:19]=[CH:20][N:21]=1>CS(C)=O>[CH3:1][N:2]([CH2:4][CH2:5][CH:6]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[O:13][C:17]1[S:18][CH:19]=[CH:20][N:21]=1)[CH3:3]
Reactant: CN(C)CCC(O)c1ccccc1
Reactant: Brc1nccs1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)CCC(Oc1nccs1)c1ccccc1

Procedure:
Following the method of Example 3, reaction of N,N-dimethyl-3-hydroxy-3-phenylpropylamine, sodium hydride and 2-bromothiazole in DMSO gives the title compound.
Reaction SMILES: [NH2:1][C@H:2]([CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3]([OH:5])=[O:4].[C:12](OC(=O)C)(=[O:14])C.O>C(O)=O>[CH:12]([NH:1][C@H:2]([CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3]([OH:5])=[O:4])=[O:14]
Reactant: N[C@H](Cc1cccs1)C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: O=CO
Product: O=CN[C@H](Cc1cccs1)C(=O)O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
(2R)-2-Amino-3-(2-thienyl) propionic acid (5.00 g, 29.2 mmol) was dissolved in formic acid (50 ml). The solution was cooled to 0° C. Acetic acid anhydride (20 ml) was added dropwise. The reaction mixture was stirred for 16 h, while it was warming up to room temperature. It was cooled to 0° C. Water (20 ml) was added dropwise. The solution was warmed to room temperature. The solvent was removed in vacuo. The residue was suspended in ethyl acetate (20 ml). The precipitation was filtered off, collected, and dried in vacuo, to give 3.60 g of crude (2R)-2-(formylamino)-3-(2-thienyl)propionic acid, which was used for the following step.
Reaction SMILES: [NH:1]=[C:2]1[NH:6][C:5]([C:11]([F:14])([F:13])[F:12])([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])[S:3]1.[F:21][C:22]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:23]=1[C:24]([N:26]=[C:27]=[O:28])=[O:25]>C1(C)C=CC=CC=1>[F:14][C:11]([F:12])([F:13])[C:5]1([C:7]([F:10])([F:9])[F:8])[C:4](=[C:15]([F:20])[C:16]([F:17])([F:18])[F:19])[S:3][C:2]([NH:1][C:27]([NH:26][C:24](=[O:25])[C:23]2[C:29]([F:33])=[CH:30][CH:31]=[CH:32][C:22]=2[F:21])=[O:28])=[N:6]1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Reactant: N=C1NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)NC1=NC(C(F)(F)F)(C(F)(F)F)C(=C(F)C(F)(F)F)S1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In toluene (10 ml) was dissolved 2-imino-4,4-bis(trifluoromethyl)-5-(tetrafluoroethylidene)-1,3-thiazolidine (1.0 g), and 2,6-difluorobenzoylisocyanate (0.4 g) which is a starting compound was added thereto and the mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[C:10](OC(=O)C)(=[O:12])[CH3:11].C(OCC)C>[OH-].[K+]>[C:10]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: OCc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CC(=O)Oc1ccc(CO)cc1
Yield: 45 %

Procedure:
8.4 g 4-hydroxybenzyl-alcohol, are dissolved in 11 ml 5.45M KOH, while cooling the reaction mixture with ice. 6.48 ml acetic anhydride are then added in 15 minutes to the solution obtained. An equal volume of ethyl ether is added, and once the organic phase is separated, it is washed with a NaHCO3 oversaturated solution and dried on anhydrous sodium sulphate and finally evaporated. The obtained product is then distilled (b.p. 140°-150° C.) under vacuum (3 mm Hg), then purified by silica gel chromatographic column (eluant cyclohexane/ethyl acetate 8: 2). A substantially pure product is obtained to be used for the successive reaction (yield 45%)
Reaction SMILES: N1C=CC=CC=1.[Si:7](Cl)([C:10]([CH3:13])([CH3:12])[CH3:11])([CH3:9])[CH3:8].[CH:15]1([OH:21])[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1>C(Cl)Cl>[C:10]([Si:7]([O:21][CH:15]1[CH2:20][CH2:19][CH2:18][CH:17]=[CH:16]1)([CH3:9])[CH3:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: OC1C=CCCC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC1C=CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
Pyridine (4.74 g, 60 mmol) and tert-butyldimethylsilyl chloride (4.83 g, 32 mmol) were added to a solution of cyclohex-2-enol (1.96 g, 20 mmol) in DCM (40 mL). The reaction mixture was stirred at RT overnight. The mixture was concentrated and the residue was dispersed in EtOAc and water. The organic phase was separated and washed with brine, dried over anhydrous Na2SO4, concentrated, and purified by silica flash chromatography eluting with EtOAc and petroleum ether (5-10% EtOAc) to give the title compound as an oil (4.1 g, 97%). 1H NMR (400 MHz, CDCl3) δ ppm 0.06-0.09 (m, 6 H), 0.92 (s, 9 H), 1.50-1.57 (m, 2 H), 1.74-1.89 (m, 2 H), 1.93-2.03 (m, 2 H), 4.21-4.23 (m, 1 H), 5.61-5.64 (m, 1 H), 5.72-5.76 (m, 1 H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][CH:10]1[CH2:11][CH2:12][CH:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21]([NH:29][NH2:30])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[I-].ClC1C=CC=C[N+]=1C.C(=O)(O)[O-].[Na+]>O1CCCC1.C(N(CC)CC)C>[C:21]([NH:29][NH:30][C:18]([CH:13]1[CH2:12][CH2:11][CH:10]2[CH2:17][N:14]1[C:15](=[O:16])[N:9]2[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:20])(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NNC(=O)c1ccccc1
Reactant: O=C(O)C1CCC2CN1C(=O)N2OCc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: O=C([O-])O
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NNC(=O)C1CCC2CN1C(=O)N2OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
To a solution of (2SR,5RS)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid (100.0 mg, 0.36 mmol) and benzohydrazide (54.2 mg) in tetrahydrofuran (4 mL) were added triethylamine (231 μL) and 2-chloro-1-methylpyridine-1-ium iodide (138.7 mg), followed by stirring at room temperature overnight. To the reaction solution was added saturated sodium bicarbonate aqueous solution, followed by extracting with chloroform. The organic layer was dried over sodium sulfate and then concentrated. The resulting crude product was purified by silica gel column chromatography to afford 123.0 mg of the title compound (yield 86%). MS m/z 395 [M+H]+.
Reaction SMILES: [CH3:1][P:2](=[O:15])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Li]CCCC.CN([CH:24]=[O:25])C>C1COCC1>[C:3]1([P:2]([CH2:1][CH:24]=[O:25])([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[O:15])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CP(=O)(c1ccccc1)c1ccccc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=CCP(=O)(c1ccccc1)c1ccccc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of methyldiphenylphosphine oxide (2.0 g, 9.0 mmol) in THF (60 mL) at 0° C. was added BuLi (1.6 M in hexane, 6.94 mL, 11.0 mmol) and after 2 h at 0° C., the mixture was cooled to −78° C. and then DMF (0.85 mL, 11 mmol) was added. After 2 h at −78° C. the mixture was quenched with HCl (1 N, 25 mL) and the resulting mixture warmed up to room temperature. The mixture was extracted with ethyl acetate and the combined organic layers were then washed with water and brine and then dried over sodium sulfate, filtered and evaporated. The crude product (off-white oil, 2.41 g) was used directly in the next step. MS: m/e=245.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].I[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2cc[nH]c2c1
Reactant: Ic1ccccc1
Product: O=[N+]([O-])c1ccc2ccn(-c3ccccc3)c2c1

Procedure:
Prepared by Procedure C and Scheme O using 6-nitro-1H-indole and iodobenzene: ESMS m/e: 238.2 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1Cl)=[O:4].[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([NH2:23])=[N:19][C:20]=1[O:21][CH3:22]>C(#N)C>[CH3:1][O:2][C:3]([C:5]1[N:6]=[N:7][C:8]([Cl:12])=[CH:9][C:10]=1[NH:23][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH3:13])=[C:20]([O:21][CH3:22])[N:19]=1)=[O:4]
Reactant: COC(=O)c1nnc(Cl)cc1Cl
Reactant: COc1ccc(N)nc1OC
Solvent: CC#N
Product: COC(=O)c1nnc(Cl)cc1Nc1ccc(OC)c(OC)n1
Temperature: 70 °C
Yield: 52.9 %

Procedure:
A mixture of 4,6-dichloro-pyridazine-3-carboxylic acid methyl ester (1.0 g, 4.83 mmol) and 5,6-dimethoxypyridin-2-amine (968 mg, 6.28 mmol) was dissolved in acetonitrile (5 mL) and heated at 70° C. for 16 h. The mixture was concentrated in vacuo and the crude mass obtained was purified by chromatography (silica, 100-200 mesh, 10-70% ethyl acetate in hexane) to give 6-chloro-4-(5,6-dimethoxy-pyridin-2-ylamino)-pyridazine-3-carboxylic acid methyl ester (830 mg, 53%) as a yellow solid. LC-MS: 325.2 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[C:14]3[C:13]([C:24]([CH2:27][OH:28])([CH3:26])[CH3:25])=[N:12][NH:11][C:10]=3[C:9]2=[O:29])=[CH:4][CH:3]=1.[S:30]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>O>[OH:28][CH2:27][C:24]([C:13]1[C:14]2[CH:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[O:22][CH3:23])[N:8]([C:5]3[CH:4]=[CH:3][C:2]([C:32]4[CH:33]=[CH:34][S:30][CH:31]=4)=[CH:7][CH:6]=3)[C:9](=[O:29])[C:10]=2[NH:11][N:12]=1)([CH3:25])[CH3:26]
Reactant: OB(O)c1ccsc1
Reactant: COc1ccccc1C1c2c(C(C)(C)CO)n[nH]c2C(=O)N1c1ccc(Br)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: COc1ccccc1C1c2c(C(C)(C)CO)n[nH]c2C(=O)N1c1ccc(-c2ccsc2)cc1
Yield: 25.1 %

Procedure:
A mixture of 5-(4-bromophenyl)-3-(1-hydroxymethyl-1-methylethyl)-4-(2-methoxyphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazole-6-one (0.15 g, 0.33 mmol), thiophene-3-yl boronic acid (0.063. g, 0.49 mmol), tripotassium phosphate (0.21 mg, 0.99 mmol), 1,2-Dimethoxyethane (3 mL) and water (0.6 mL) was placed in a flask under nitrogen. To the mixture was added 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (0.027 mg, 0.033 mmol) and the resulting mixture was heated at reflux for 5 hours. After the reaction was completed, the reaction mixture was purified on a silica gel column chromatography (ethyl acetate/n-hexane). The resulting aimed compound was triturated with ethyl acetate and n-hexane to give 3-(1-hydroxymethyl-1-methylethyl)-4-(2-methoxyphenyl)-5-(4-thiophene-3-ylphenyl)-4,5-dihydro-1H-pyrrolo[3,4-c]pyrazole-6-one (0.038 g, yield: 25%) as colorless solid.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Br.O.[C-:11]#[N:12].[K+]>CN(C)C=O>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:11]#[N:12]
Reactant: BrCc1ccccc1Br
Reactant: [C-]#N
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccccc1Br
Temperature: 0 °C
Yield: 96.4 %

Procedure:
25 g (100 mmol) of 2-bromobenzyl bromide is mixed in 100 ml of N,N-dimethylformamide and 64 ml of water with 9.75 g (150 mmol) of potassium cyanide and stirred overnight at room temperature. The reaction mixture is poured into ice water. After being extracted three times with methyl tert-butyl ether, the combined organic extracts are washed with brine, dried, and the solvent is spun off. The residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 18.9 g (96.4%) of the desired compound is obtained.
Reaction SMILES: O.[N:2]([N:4]1[CH2:9][CH2:8][N:7]([CH:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH:14]=[C:13]([C:21]#[N:22])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]2=3)[CH2:6][CH2:5]1)=O.[OH-].[NH4+]>[Zn].C(O)(=O)C>[NH2:2][N:4]1[CH2:5][CH2:6][N:7]([CH:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH:14]=[C:13]([C:21]#[N:22])[C:12]3[CH:23]=[CH:24][CH:25]=[CH:26][C:11]2=3)[CH2:8][CH2:9]1
Reactant: N#CC1=Cc2ccccc2C(N2CCN(N=O)CC2)c2ccccc21
Agent: [NH4+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: N#CC1=Cc2ccccc2C(N2CCN(N)CC2)c2ccccc21
Reaction time: 1 h

Procedure:
Approximately 500 parts of water is slowly added to a solution of 98 parts of 5-(4-nitroso-1-piperazinyl)-5H-dibenzo[a,d]cycloheptene-10-carbonitrile in 1200 parts of glacial acetic acid. To the resultant mixture is added, at a rate such that the temperature does not exceed 35°, approximately 150 parts of zinc dust. When the addition is complete, the reaction mixture is stirred at 28°-30° for 1 hour, whereupon insoluble solids are filtered out and washed with 300 parts of 65% acetic acid. Washings and filtrate are combined and diluted with 3 volumes of water. The solution thus obtained is cooled to 5°-10° and maintained thereat while sufficient 30% ammonium hydroxide is added to induce alkalinity. The resultant mixture is extracted with chloroform. The chloroform extract is dried over anhydrous potassium carbonate and stripped of solvent by vacuum distillation. The residual viscous oil crystallizes from hexane to give 5-(4-amino-1-piperazinyl)-5H-dibenzo[a,d]cycloheptene-10-carbonitrile as a colorless solid which, dried in air, melts at 137°-146°.
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+].[CH3:9][CH:10]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][C:12](Cl)=[O:13]>O>[CH3:9][CH:10]([CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][C:12]([O:6][O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:13]
Reactant: CC(C)(C)OO
Reactant: CC(CC(=O)Cl)CC(C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(CC(=O)OOC(C)(C)C)CC(C)(C)C

Procedure:
The reaction is effected in a reactor arrangement of a first reactor of type E with a downstream reactor of type C. Before the start of the reaction, the first reactor is filled with a solution of 25.6% by weight of tert-butyl hydroperoxide and 15.0% by weight of potassium hydroxide in water. 20.2 kg/h of a solution of 70% by weight of tert-butyl hydroperoxide in water, 18.2 kg/h of a solution of 45% by weight of potassium hydroxide in water, 16.2 kg/h of water and 19.2 kg/h of 3,5,5-trimethylhexanoyl chloride are then fed to the first reactor. Cooling with cooling water keeps the internal temperature in the first reactor at 25° C. and in the second reactor at 25° C. The organic phase is removed from the reaction mixture withdrawn from the second reactor. The organic phase is washed successively with an 8% by weight solution of sodium hydroxide in water, with a solution of 10% by weight of sodium sulphite in water comprising acetic acid and with a 1% by weight solution of sodium hydrogen-carbonate in water, and then dried by stripping in a packed column at 34° C. and 47 mbar. 24.6 kg/h of tert-butyl peroxy-3,5,5-trimethylhexanoate are obtained (98.2% based on 3,5,5-trimethylhexanoyl chloride). The space-time yield is 1.98 kg/l·h.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:47]=[CH:46][C:45]([CH2:48][C:49]([N:51]2[CH2:56][CH2:55][N:54]([CH2:57][CH3:58])[CH2:53][CH2:52]2)=[O:50])=[CH:44][CH:43]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:42]5[CH:43]=[CH:44][C:45]([CH2:48][C:49]([N:51]6[CH2:52][CH2:53][N:54]([CH2:57][CH3:58])[CH2:55][CH2:56]6)=[O:50])=[CH:46][CH:47]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Reactant: CCN1CCN(C(=O)Cc2ccc(Br)cc2)CC1
Product: CCN1CCN(C(=O)Cc2ccc(N3CCc4c(-c5cnc(N(Cc6ccc(OC)cc6)Cc6ccc(OC)cc6)nc5)nc(N5CCOCC5)nc43)cc2)CC1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (200 mg) and 2-(4-bromo-phenyl)-1-(4-ethyl-piperazin-1-yl)-ethanone (137 mg) instead of 4-chloropicolinic acid t-butylamide, in the same manner as Example 1-D-07, a crude product of 2-[4-(4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidin-7-yl)-phenyl]-1-(4-ethyl-piperazin-1-yl)-ethanone was obtained, and further PMB group was removed according to the above Deprotection method 2, to obtain the desired compound (D-185) as a yellow powder (92 mg, 47%).