Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][OH:14])=[CH:9][CH:8]=1.O[C:22]1[CH:27]=[CH:26][C:25]([CH:28]([CH2:34][CH2:35][CH3:36])[CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:1][O:2]/[N:3]=[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)\[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH2:34][CH2:35][CH3:36])[CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=2)=[CH:9][CH:8]=1
Reactant: CCCC(CC(=O)OC)c1ccc(O)cc1
Reactant: CO/N=C(\COc1ccc(CO)cc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCCC(CC(=O)OC)c1ccc(OCc2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 21 %

Procedure:
To a 50 mL RB flask fitted with magnetic stirrer was charged dry THF (5.0 mL) and (4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}phenyl)methanol (0.134 g, 0.5 mmol). To the above mixture methyl 3-(4-hydroxyphenyl)hexanoate (0.11 g, 0.5 mmol) was added and the resulting mixture stirred at 0° C. for 5 min. Triphenyl phosphine (0.17 g, 0.65 mmol) was added to the mixture and stirred at 0° C. for 15 min followed by the addition of diethylazadicarboxylate (0.13 g, 0.65 mmol). After stirring the resulting mixture at RT for 16 h, the RM was evaporated to remove the THF. The residue was diluted with water (15 mL) and extracted with ethyl acetate (15 mL×2). The organic layer was washed with saturated brine solution (15 mL) and dried over anhydrous Na2SO4. Concentration of the solvent and purification of the resulting residue by column chromatography on silica gel (100/200 mesh), using petroleum ether and ethyl acetate as eluent, gave the product (0.05 g, yield: 21.74%)
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ON1C(=O)CCC1=O.Cl.CN(C)CCCN=C=NCC.[NH2:40][C:41]([CH3:62])([CH3:61])[CH2:42][N:43]1[C:55]2[C:54]3[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=3[N:48]=[C:47]([NH2:56])[C:46]=2[N:45]=[C:44]1[CH2:57][O:58][CH2:59][CH3:60]>CN(C=O)C.O>[NH2:56][C:47]1[C:46]2[N:45]=[C:44]([CH2:57][O:58][CH2:59][CH3:60])[N:43]([CH2:42][C:41]([NH:40][C:17](=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)([CH3:61])[CH3:62])[C:55]=2[C:54]2[CH:53]=[CH:52][CH:51]=[CH:50][C:49]=2[N:48]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)N
Reactant: O=C(O)CCCCCNC(=O)OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: O
Solvent: CN(C)C=O
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NC(=O)CCCCCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 27.3 %

Procedure:
To a solution of 6-(carbobenzyloxyamino) caproic acid (8.49 grams (g), 32.0 millimole (mmol)) in DMF (50 mL) at 0° C. was added N-hydroxysuccinimide and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC). After a short period, the solution was added to a 0° C. solution of 1-(2-amino-2-methylpropyl)-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-4-amine (prepared as described in U.S. Patent Publication No. 2004/0091491, 10 g, 32 mmol) in DMF (100 mL). The mixture was allowed to warm to room temperature and was stirred for 3 days. The solution was diluted with water (400 mL) and extracted with ethyl acetate (3×). The organic layers were combined and washed with water (2×) and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The crude product was purified by HPFC on silica gel three times (gradient elution with CMA in chloroform) to provide 4.90 g of benzyl 6-({2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}amino)-6-oxohexylcarbamate as a white foam.
Reaction SMILES: [F:1][C:2]([F:9])([CH3:8])[C:3](OCC)=[O:4].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]2[C:25]3[C:20](=[CH:21][C:22]([O:26][C@H:27]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=4)[C@@H:28]([NH2:30])[CH3:29])=[CH:23][CH:24]=3)[CH:19]=[N:18]2)=[CH:13][CH:12]=1>C(#N)C>[F:1][C:2]([F:9])([CH3:8])[C:3]([NH:30][C@@H:28]([CH3:29])[C@H:27]([O:26][C:22]1[CH:21]=[C:20]2[C:25](=[CH:24][CH:23]=1)[N:17]([C:14]1[CH:13]=[CH:12][C:11]([F:10])=[CH:16][CH:15]=1)[N:18]=[CH:19]2)[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:38])[CH:32]=1)=[O:4]
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: CCOC(=O)C(C)(F)F
Solvent: CC#N
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)C(C)(F)F)c1

Procedure:
Ethyl 2,2-difluoropropanoate (400 μl) and (1R,2S)-1-(1-(4-fluorophenyl)-1H-indazol-5-yloxy)-1-(3-methoxyphenyl)propan-2-amine (6a, 135 mg, 0.34 mmol) was heated to 150° C. for 30 min. Then it was diluted with acetonitrile and purified by semiprep HPLC followed by flash chromatography on silica gel (n-heptane/ethyl acetate, 4:1) Yield 60 mg (36%).
Reaction SMILES: [NH2:1][C:2]1[C:16]([O:17][CH3:18])=[CH:15][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][C@@H:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C([Si](C)(C)[O:24][C@H:25]1[CH2:29][CH2:28][N:27]([S:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[NH:39][C:40]2[C:45]([Cl:46])=[CH:44][N:43]=[C:42](Cl)[N:41]=2)(=[O:32])=[O:31])[CH2:26]1)(C)(C)C>>[Cl:46][C:45]1[C:40]([NH:39][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[S:30]([N:27]2[CH2:28][CH2:29][C@H:25]([OH:24])[CH2:26]2)(=[O:31])=[O:32])=[N:41][C:42]([NH:1][C:2]2[C:16]([O:17][CH3:18])=[CH:15][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][C@@H:12]([OH:14])[CH3:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:43][CH:44]=1
Reactant: COc1cc2c(cc1N)CCN(C[C@H](C)O)CC2
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCN(S(=O)(=O)c2ccccc2Nc2nc(Cl)ncc2Cl)C1
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccccc3S(=O)(=O)N3CC[C@H](O)C3)n1)CCN(C[C@H](C)O)CC2
Yield: 46 %

Procedure:
In an analogous manner to Example 1534, the product was prepared from (S)-1-(7-Amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-propan-2-ol and {2-[(S)-3-(tert-Butyl-dimethyl-silanyloxy)-pyrrolidine-1-sulfonyl]-phenyl}-(2,5-dichloro-pyrimidin-4-yl)-amine. The product was isolated as an off-white foam (55 mg, 46%). MS (ESI+): 603 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 9.33 (s, 1H), 8.48 (d, J=8 Hz, 1H), 8.16 (s, 1H), 8.01 (s, 1H), 7.96 (d, J=8 Hz, 1H), 7.58-7.52 (m, 2H), 7.25 (t, J=8 Hz, 1H), 6.66 (s, 1H), 4.37 (br s, 1H), 3.88 (m, 4H), 3.42 (m, 3H), 3.31 (d, 1H), 2.91-2.52 (m, 110H), 2.27 (m, 1H), 1.17 (d, J=6 Hz, 3H).
Reaction SMILES: CC(=CC)C.P([O-])(O)(O)=O.[Na+].[Cl:12][C:13]1[N:18]=[C:17]([CH3:19])[C:16]([O:20][CH2:21][C@@:22]2([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[CH2:24][C@H:23]2[CH:25]=[O:26])=[CH:15][N:14]=1.Cl([O-])=[O:35].[Na+]>O.CC(C)=O.O>[Cl:12][C:13]1[N:18]=[C:17]([CH3:19])[C:16]([O:20][CH2:21][C@@:22]2([C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)[CH2:24][C@H:23]2[C:25]([OH:35])=[O:26])=[CH:15][N:14]=1
Reactant: Cc1nc(Cl)ncc1OC[C@@]1(c2cccc(F)c2)C[C@H]1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: Cc1nc(Cl)ncc1OC[C@@]1(c2cccc(F)c2)C[C@H]1C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 77.4 %

Procedure:
2-methyl-2-butene (11.7 ml) and sodium dihydrogen phosphate (3.98 g) were added to an acetone-water (80 ml-20 ml) solution of the compound 323-2 (7.1 g). The reaction solution was cooled on ice. Sodium chlorite (4 g) was added to the reaction solution, and the obtained mixture was stirred at room temperature for 18 hours. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The obtained organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-heptane:ethyl acetate=9:1 to 3:7), so as to obtain the title compound (5.77 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH:17]([OH:28])[C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][O:26][CH3:27])=[CH:20][CH:19]=1)[N:5]([CH3:16])[S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14].C(N(CC)CC)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.CN(C)CCCN>ClCCl.CN(C)C1C=CN=CC=1>[CH3:1][O:2][C:3](=[O:29])[C@H:4]([CH:17]([O:28][C:37](=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH2:25][O:26][CH3:27])=[CH:22][CH:23]=1)[N:5]([CH3:16])[S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: O=C(Cl)c1ccccc1
Reactant: COCOc1ccc(C(O)[C@@H](C(=O)OC)N(C)Sc2ccccc2[N+](=O)[O-])cc1
Agent: CN(C)CCCN
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1ccc(C(OC(=O)c2ccccc2)[C@@H](C(=O)OC)N(C)Sc2ccccc2[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.6 %

Procedure:
To a solution of O-methoxymethyl-N-methyl-N-(2-nitrophenylthio)-β-hydroxytyrosine methyl ester (erythro isomer) (3.85 g) in dichloromethane (30 ml) were added triethylamine (1.38 g), 4-dimethylaminopyridine (0.45 g) and benzoyl chloride (1.92 g). After stirring for 16 hours at room temperature, 3-dimethylaminopropylamine (3.3 g) was added to the mixture and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (30 ml) and washed with dil. hydrochloric acid, sodium bicarbonate aqueous solution and water. After evaporating, the residue was put on a column of silica gel (MERCK 7734, 150 g) and eluted with n-hexane-ethyl acetate (5:2, V/V) to give O-methoxymethyl-N-methyl-N-(2-nitrophenylthio)-β-benzoyloxytyrosine methyl ester (erythro isomer) (4.49 g).
Reaction SMILES: [CH3:1][NH:2][C:3]([NH:5][CH3:6])=[O:4].[CH3:7][CH:8]([C:12]([OH:14])=O)[C:9]([OH:11])=O.C(OC(=O)C)(=O)C>C(O)(=O)C>[CH3:1][N:2]1[C:9](=[O:11])[CH:8]([CH3:7])[C:12](=[O:14])[N:5]([CH3:6])[C:3]1=[O:4]
Reactant: CNC(=O)NC
Reactant: CC(C(=O)O)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: CC1C(=O)N(C)C(=O)N(C)C1=O
Temperature: 90 °C
Yield: 41.5 %

Procedure:
75 g (0.85 mol) of 1,3-dimethylurea and 102 g (0.86 mol) of methyl malonic acid were dissolved in 300 ml of glacial acetic acid at 65° C. To the solution was added 330 ml of acetic anhydride, the temperature was gradually raised and the mixture was refluxed by heating at 90° C. for 6 hours. The reaction solution was concentrated under reduced pressure, and benzene was added to the residue. The crystals thus-deposited were collected by filtration and recrystallized from benzene to obtain 60 g of 1,3,5-trimethylbarbituric acid. Yield: 42%, Melting Point: 83° to 85° C.
Reaction SMILES: [I:1]I.[CH3:3][C:4]1[N:9]=[C:8]([NH2:10])[N:7]=[C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:5]=1.[OH-].[Na+]>C(Cl)Cl.O>[I:1][C:5]1[C:6]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:7][C:8]([NH2:10])=[N:9][C:4]=1[CH3:3]
Reactant: II
Reactant: CCCCCNc1cc(C)nc(N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: CCCCCNc1nc(N)nc(C)c1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A solution of iodine (11.92 g) in DCM (300 mL) was added to a stirred mixture of the product from step (i) (8.3 g) and sodium hydroxide (3.42 g) in water (200 mL). The reaction mixture was stirred at rt overnight. The organic layer was separated and washed with sodium metabisulfate solution, then brine. The combined organic layers were dried, and the solvent evaporated under reduced pressure. The product was purified by chromatography eluting with DCM:MeOH; 95:5 to give the subtitle compound 11 g.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[S:11](Cl)(=[O:13])=[O:12])[CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18]([C:20]1([NH2:29])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:15]([O:17][C:18]([C:20]1([NH:29][S:11]([C:9]2[CH:8]=[CH:7][CH:6]=[C:5]3[C:10]=2[N:1]=[CH:2][CH:3]=[CH:4]3)(=[O:13])=[O:12])[CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:21]1)=[O:19])[CH3:16]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NS(=O)(=O)c2cccc3cccnc23)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.1 %

Procedure:
To a solution of quinoline-8-sulfonyl chloride (400 mg, 1.76 mmol), 2-amino-indan-2-carboxylic acid ethyl ester (361 mg, 1.76 mmol) in anhydrous DCM (8 mL) is added DIPEA (291 μL, 1.76 mmol). The resulting solution is stirred at RT overnight. The reaction solution is diluted with DCM (40 mL), washed with water (1×5 mL) and brine (2×5 mL). The organic layer is dried over anhydrous Na2SO4 and concentrated in vacuo. The residue is purified by flash column chromatography (115 g silica gel, gradient elution: 5-50% EtOAc in heptane) to give a pure product (35) as white solid (245 mg, 35%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:11]([C:14]([NH:16][NH2:17])=[O:15])[O:12][CH:13]=2)=[CH:5][CH:4]=1.C([O:27][CH2:28][CH3:29])(=O)C>>[C:14]([C:11]1[CH:10]=[C:9]([CH:6]=[CH:29][C:28]=1[OH:27])[C:13]([NH:17][NH:16][C:14]([C:11]1[O:12][CH:13]=[C:9]([C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:8][CH:7]=2)[C:10]=1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])=[O:12])#[N:16]
Reactant: CCOC(C)=O
Reactant: COc1ccc(-c2coc(C(=O)NN)c2-c2ccccc2)cc1
Product: COc1ccc(-c2coc(C(=O)NNC(=O)c3ccc(O)c(C#N)c3)c2-c2ccccc2)cc1
Reaction time: 8 h

Procedure:
A mixture of 4-(4-methoxyphenyl)-3-phenyl-2-furancarboxylic acid hydrazide (compound of Reference Example 10, 0.31 g) and the compound of Reference Example 63 (0.33 g) in ethyl acetate (10 ml) was heated at reflux while stirring overnight. The thus-precipitated crystals were collected by filtration and recrystallized from ethyl acetate/diisopropyl ether, thereby giving 0.31 g of the desired compound. Melting point: 146-148° C.
Reaction SMILES: [CH:1]1([CH2:7][N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([CH2:14][NH:15][C:16]([C@H:18]3[CH2:22][CH2:21][CH2:20][N:19]3[C:23]([C@@H:25]3[CH2:29][C@@H:28](OS(C)(=O)=O)[CH2:27][N:26]3[C:35](=[O:56])[CH2:36][C:37]([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)=[O:24])=[O:17])[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N-:57]=[N+:58]=[N-:59].[Na+]>CN(C)C=O.C(OCC)(=O)C>[N:57]([C@@H:28]1[CH2:27][N:26]([C:35](=[O:56])[CH2:36][C:37]([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C@H:25]([C:23]([N:19]2[CH2:20][CH2:21][CH2:22][C@@H:18]2[C:16]([NH:15][CH2:14][C@H:10]2[CH2:11][CH2:12][CH2:13][N:8]([CH2:7][CH:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH2:9]2)=[O:17])=[O:24])[CH2:29]1)=[N+:58]=[N-:59]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: [N-]=[N+]=N[C@H]1C[C@@H](C(=O)N2CCC[C@@H]2C(=O)NC[C@H]2CCCN(CC3CCCCC3)C2)N(C(=O)CC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 85 °C
Reaction time: 10 h
Yield: 81.3 %

Procedure:
To a solution of 33 mg of (2R)-N-{((3R)-1-cyclohexylmehyl-3-piperidyl)methyl}-1-{(2S,4R)-4-(methylsulfonyloxy)-1-(3,3,3-triphenylpropanoyl)pyrrolidin-2-yl}carbonylpyrrolidine-2-carboxamide in 1 ml of N,N-dimethylformamide, 8.3 mg of sodium azide was added at room temperature, followed by 10 hours' stirring at 85° C. under heating. The reaction liquid was diluted with ethyl acetate, washed with water and dried over anhydrous sodium sulfate. Distilling the solvent off under reduced pressure, the resultant residue was purified by means of a preparative thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (Merck), chloroform/methanol/28% aqueous ammonia=100/10/1) to provide 25 mg of the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=O)=[N:2]1.[F:12][CH:13]([F:29])[C:14]1[N:18]2[N:19]=[C:20]([N:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)[CH:21]=[CH:22][C:17]2=[N:16][N:15]=1>>[F:29][CH:13]([F:12])[C:14]1[N:18]2[N:19]=[C:20]([N:23]3[CH2:24][CH2:25][N:26]([CH2:10][C:3]4[C:4]5[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=5)[NH:1][N:2]=4)[CH2:27][CH2:28]3)[CH:21]=[CH:22][C:17]2=[N:16][N:15]=1
Reactant: FC(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: O=Cc1n[nH]c2ccccc12
Product: FC(F)c1nnc2ccc(N3CCN(Cc4n[nH]c5ccccc45)CC3)nn12
Yield: 65 %

Procedure:
A mixture of indazole-3-carboxaldehyde and 3-(difluoromethyl)-6-(piperazin-1-yl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 5 to give 3-(difluoromethyl)-6-[4-(1H-indazol-3-ylmethyl)piperazin-1-yl][1,2,4]triazolo[4,3-b]pyridazine in 65% yield.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@@H:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([O:28]C)=[O:27])=[C:20]([C:30]([O:32]C)=[O:31])[CH:19]=1)[C:14](O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:41][CH2:42][C:43]1([OH:59])[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[O:46][CH:45]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH2:44]1>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:10]([NH:12][C@H:13]([C:14]([NH:41][CH2:42][C:43]1([OH:59])[C:52]2[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=2)[O:46][CH:45]([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)[CH2:44]1)=[O:15])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]([OH:28])=[O:27])=[C:20]([CH:19]=1)[C:30]([OH:32])=[O:31])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCC1(O)CC(c2ccccc2)Oc2ccccc21
Reactant: COC(=O)COc1ccc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)O)cc1C(=O)OC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc(OCC(=O)O)c(C(=O)O)c1)C(=O)NCC1(O)CC(c2ccccc2)Oc2ccccc21
Yield: 13 %

Procedure:
Synthesis was performed from (2S)-2-({(2S)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl}amino)-3-[3-(methoxycarbonyl)-4-(2-methoxy-2-oxoethoxy)phenyl]propanoic acid (82 mg, 0.15 mmol) and 4-(aminomethyl)-2-phenyl-4-chromanol (45 mg, 0.18 mmol) according to Method C with HPLC purification to give the title compound (15 mg). 1H-NMR (400 MHz, CD3OD) d 7.64 (s, 1H), 6.84 (dd, J=1.0 Hz, J=8.3 Hz, 1H), 5.33 (d, J=12.0 Hz, 1H), 4.64 (s, 2H), 4.63 (m, 1H), 4.28 (m, 1H), 3.95 (m, 1H), 3.19 (m, 1H), 1.35 (s, 3H), 1.32 (s, 6H); HRMS m/z 767.3084 (calc. of monoisotopic mass for C42H45N3O11 gives 767.3054).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1.IC.[C:28](=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[N:12]([CH3:28])[C:11]([C:21]2[S:22][CH:23]=[CH:24][N:25]=2)=[N:10]1
Reactant: CCOC(=O)C1=C(C)NC(c2nccs2)=NC1c1ccc(F)cc1Cl
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CI
Product: CCOC(=O)C1=C(C)N(C)C(c2nccs2)=NC1c1ccc(F)cc1Cl
Temperature: 70 °C
Reaction time: 12 h
Yield: 47.9 %

Procedure:
A mixture of ethyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (2 g, 5.3 mmol), iodomethane (0.97 g, 6.84 mmol) and potassium carbonate (1.47 g, 10.6 mmol) in acetonitrile (50 mL) was stirred at 70° C. for 12 hours, and cooled to 25° C. The reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by a silica gel column chromatography (PETROLEUM ETHER/EtOAc (V/V)=3/1) to give the title compound as a tawny solid (1.0 g, 48%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH:1]1([C:5](O)=O)[CH2:4][CH2:3][CH2:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.N1C=CC=CC=1.[CH3:26][NH:27][C:28](=[S:31])[NH:29][NH2:30]>CN(C)C=O>[CH3:26][N:27]1[C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[N:30][N:29]=[C:28]1[SH:31]
Reactant: CNC(=S)NN
Reactant: O=C(O)C1CCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cn1c(S)nnc1C1CCC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.6 %

Procedure:
5 g of cyclobutyl carboxylic acid (49.9 mmol) were dissolved in 50 ml of dimethylformamide. Within 10 min. 12.15 g of 1,1′-carbonyldiimidazol (74.91 mmol) were added in portions. After stirring for 1 h at room temperature 23 ml of pyridin were added followed by the addition of 10.5 g of 4-methyl-3-thiosemicarbazide (99.88 mmol). The solution was stirred at room temperature for 72 h and then poured into 600 ml of ice water. Stirring was continued for 30 min. before the aqueous layer was extracted three times with 50 ml dichloromethane and three times with 50 ml ethyl acetate each. The combined organic layers were dried over magnesium sulfate, filtered, and the solvent was evaporated, thereby yielding 5.2 g of the crude title product which was used without further purification.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[C:17]([CH3:23])([CH2:20][CH2:21][CH3:22])[NH:16][S:15]2(=[O:25])=[O:24])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CI.[Cl-].[NH4+]>C1COCC1>[C:7]1([CH2:13][N:14]2[C:18](=[O:19])[C:17]([CH3:23])([CH2:20][CH2:21][CH3:22])[N:16]([CH3:1])[S:15]2(=[O:24])=[O:25])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CCCC1(C)NS(=O)(=O)N(Cc2ccccc2)C1=O
Reactant: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCC1(C)C(=O)N(Cc2ccccc2)S(=O)(=O)N1C
Reaction time: 1 h
Yield: 98.2 %

Procedure:
Potassium t-butoxide (3.93 g, 35.06 mmol) was added in one portion to a solution of 2-phenylmethyl-4-methyl-4-propyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (9 g, 31.87 mmol) in 250 ml of THF at 0° C. and the mixture was stirred under nitrogen at this temperature for 1 hour. To the mixture was added methyl iodide (27.14 g, 191.22 mmol) at 0° C. and the resulting mixture was allowed to stir at 0° C. for 1/2 hour and at room temperature for 11 hours. The resulting mixture was poured into 400 ml of saturated ammonium chloride solution, extracted with ethyl acetate, and the organic layer was washed with water and brine. The organic layer was dried over sodium sulfate, concentrated in vacuo to afford 9.28 g (98%) of 2-phenylmethyl-4-methyl-4 -propyl-5-methyl-1,2,5-thiadiazolidin-3-one 1,1-dioxide (Formula XI: R1 =propyl; R2 =CH3 ; R3 =methyl ) as an oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[C:21]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=2)[C:26](=O)[CH2:25]1)(=[O:23])[CH3:22].[B][B][B][B][B][B][B][B][B][B]>>[C:21]([N:24]1[C:32]2[C:27](=[CH:28][CH:29]=[C:30]([F:33])[CH:31]=2)[CH:26]([NH:19][C:17]2[CH:16]=[CH:15][C:14]([F:20])=[C:13]([C@@:4]3([CH3:12])[N:3]=[C:2]([NH2:1])[N:7]([CH3:8])[C:6](=[O:9])[C:5]3([CH3:10])[CH3:11])[CH:18]=2)[CH2:25]1)(=[O:23])[CH3:22]
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: CC(=O)N1CC(=O)c2ccc(F)cc21
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CC(=O)N1CC(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)c2ccc(F)cc21

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and 1-acetyl-6-fluoro-1,2-dihydro-indol-3-one using decaborane yielded a mixture of epimers of the title compound as a light red waxy solid. MS (ESI): m/z=456.4 [M+H]+.