Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:12][C@@H:13]1[C:19](=[O:20])[N:18]2[C@H:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:23][CH2:24][N:17]2[C:16](=[O:32])[CH2:15][CH2:14]1.C([O-])(O)=O.[Na+].O1CCOCC1>CCOC(C)=O.O>[CH2:5]([O:4][C:2]([NH:12][C@@H:13]1[C:19](=[O:20])[N:18]2[C@H:21]([C:25]([O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[O:26])[CH2:22][CH2:23][CH2:24][N:17]2[C:16](=[O:32])[CH2:15][CH2:14]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](N)C(=O)N12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)[C@@H]1CCCN2C(=O)CC[C@H](NC(=O)OCc3ccccc3)C(=O)N12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
Benzyl chloroformate (1.07 g) was added dropwise to a stirred ice cold mixture of the (1S,9S) t-butyl 9-amino-6,10-dioxo-1,2,3,4,7,8,9,10-octahydro-6H-pyridazino[1,2-a][1,2]diazepine-1-carboxylate (GB 2,128,984; 1.55 g, 5.21 mmol), NaHCO3 (0.66 g, 7.82 mmol), dioxan (32 ml) and water (8 ml). The mixture was kept at 5° C. for 15 min then for 2 h at room temperature. The mixture was diluted with EtOAc (50 ml), washed twice with sat. NaHCO3 solution, dried (MgSO4) and concentrated. The oily residue was purified by flash chromatography to afford 211d (1.98 g, 88%) of a colourless oil: [α]D24 −56.4 (c 1.0, CH2Cl2); IR(thin film) 3325, 2979, 2946, 1728, 1677, 1528, 1456, 1422, 1370, 1340, 1272, 1245, 1156, 1122, 1056, 916, 734, 699; 1H NMR (CDCl3) δ 7.29 (5H, m), 5.81-5.72 (1H, m), 5.26-5.20 (1H, m), 5.05 (2H, s), 4.69-4.51 (2H, m), 3.48-3.36 (1H, m), 2.81-2.51 (2H, m), 2.34-2.19 (2H, m), 1.90-1.54 (4H, m), 1.41 (9H, s); Anal. Calcd for C22H29N3O6•H2O: C, 58.79; H, 6.92; N, 9.35. Found: C, 59.10; H, 6.57; N, 9.25; MS (ES +) 454 (M++Na, 87%), 432 (M++1, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]([CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([OH:29])=[CH:24][CH:25]=3)[CH2:20]2)[CH2:16][CH2:17][CH3:18])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:37][C:38]1[C:42]([S:43](Cl)(=[O:45])=[O:44])=[C:41]([CH3:47])[O:40][N:39]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][N:15]([CH:19]2[CH2:28][CH2:27][C:26]3[C:21](=[CH:22][C:23]([O:29][S:43]([C:42]4[C:38]([CH3:37])=[N:39][O:40][C:41]=4[CH3:47])(=[O:45])=[O:44])=[CH:24][CH:25]=3)[CH2:20]2)[CH2:16][CH2:17][CH3:18])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(O)cc2C1
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCN(CC1CCN(C(=O)OC(C)(C)C)CC1)C1CCc2ccc(OS(=O)(=O)c3c(C)noc3C)cc2C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To an ice-cold solution of 4-{[(7-hydroxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-methyl}-piperidine-1-carboxylic acid tert-butyl ester, prepared as described in Example 8, (1.0 g, 2.48 mmol) and triethylamine (0.52 mL, 2.73 mmol) in methylene chloride (75 mL) under an inert atmosphere 3,5-dimethyl-isoxazole-4-sulfonyl chloride (535 mg, 2.73 mmol) was added dropwise. The reaction was allowed to warm to room temperature and stirred for 24 h. The reaction was quenched with water and the methylene chloride layer was separated, dried (MgSO4), and concentrated to afford 4-({[7-(3,5-dimethyl-isoxazole-4-sulfonyloxy)-1,2,3,4-tetrahydro-naphthalen-2-yl]-propyl-amino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester (1.16 g).
Reaction SMILES: C(OC1C=CC(C2CC(C(O)=O)C(=O)NN=2)=CC=1)C1C=CC=CC=1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:32]=[C:33]([C:38]([O:40]CC)=[O:39])[C:34](=[O:37])[NH:35][N:36]=1.[OH-].[Na+]>Cl>[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH2:32][CH:33]([C:38]([OH:40])=[O:39])[C:34](=[O:37])[NH:35][N:36]=1
Reactant: CCOC(=O)c1cc(-c2ccccn2)n[nH]c1=O
Agent: Cl
Agent: O=C(O)C1CC(c2ccc(OCc3ccccc3)cc2)=NNC1=O
Agent: [Na+]
Product: O=C(O)C1CC(c2ccccn2)=NNC1=O
Yield: 96.2 %

Procedure:
Working as in example 19 for the preparation of 6-[4-(benzyloxy)phenyl]-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid, but starting with 4 g of ethyl 6-pyridin-2-yl-3-oxo-2,3-dihydropyridazine-4-carboxylate, 49 cm3 of one molar sodium hydroxide solution and 50 cm3 of one molar hydrochloric acid solution, 3.44 g of 6-pyridin-2-yl-3-oxo-2,3,4,5-tetrahydropyridazine-4-carboxylic acid were obtained in the form of a beige-colored solid melting at a temperature above 260° C.
Reaction SMILES: O.O.[Sn](Cl)Cl.[Cl:6][C:7]1[N:12]=[C:11]([NH:13][CH3:14])[C:10]([N+:15]([O-])=O)=[C:9]([Cl:18])[N:8]=1>CCO>[Cl:6][C:7]1[N:12]=[C:11]([NH:13][CH3:14])[C:10]([NH2:15])=[C:9]([Cl:18])[N:8]=1
Reactant: CNc1nc(Cl)nc(Cl)c1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CCO
Product: CNc1nc(Cl)nc(Cl)c1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.9 %

Procedure:
Tin (II) chloride dihydrate (2.0 g) was added to a solution of 2,6-dichloro-N-methyl-5-nitropyrimidine-4-amine (680 mg) in EtOH (13 mL) at room temperature. The mixture was stirred at room temperature for 3 hours, and stirred at 90° C. for 2 hours. The reaction mixture was cooled to room temperature, and concentrated under reduced pressure. EtOAc and a saturated aqueous NaHCO3 solution were added to the residue, and the insoluble material was separated by filtration using Celite. Extraction was performed on the filtrate using EtOAc, and the extract was washed with water and saturated brine. The organic layer was dried over MgSO4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hex:EtOAc=80:20 to 50:50), whereby 2,6-dichloro-N4-methylpyrimidine-4,5-diamine (482 mg) was obtained as a pale yellow solid.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1.[OH:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:42][C:41]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[OH:39][C:40]1[CH:45]=[CH:44][C:43]([NH:46][S:47]([CH3:50])(=[O:49])=[O:48])=[CH:42][C:41]=1[C:2]1[C:10]2[C:9]([NH:11][C@H:12]([C:14]3[N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:18](=[O:26])[C:17]4=[C:27]([CH3:30])[CH:28]=[CH:29][N:16]4[N:15]=3)[CH3:13])=[N:8][CH:7]=[N:6][C:5]=2[N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[CH:3]=1
Reactant: CS(=O)(=O)Nc1ccc(O)c(B(O)O)c1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cc(NS(C)(=O)=O)ccc3O)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 85.6 %

Procedure:
(S)-2-(1-((5-Bromo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.17 mmol) was treated with 2-hydroxy-5-(methylsulfonamido)phenylboronic acid (95 mg, 0.41 mmol, described at WO 2012013727 A1 20120202), sodium carbonate (52 mg, 0.49 mmols) and bis(triphenylphosphine)palladium(II) dichloride (41 mg, 0.05 mmol) according to the method described in Preparation 62. The residue was purified using SP1® Purification System (0% to 100%, hexane-ethyl ether) to give 102 mg (87% yield) of the title compound. Purity 100%.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH3:41])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])(C(C)(C)C)(C)C.OCCN(C)C(C1C(OCC2C=CC=CC=2)=C(O)N=C(CC2C=CC=CC=2C2C=CC=CC=2)N=1)=O>>[OH:8][CH2:9][CH2:10][N:11]([CH3:41])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Agent: CN(CCO)C(=O)c1nc(Cc2ccccc2-c2ccccc2)nc(O)c1OCc1ccccc1
Product: CN(CCO)C(=O)c1nc(CC2(c3ccccc3)CCCC2)nc(O)c1OCc1ccccc1
Yield: 74.8 %

Procedure:
5-Benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (30-01) (600 mg, 74.75%) was synthesized from 5-benzyloxy-6-hydroxy-2-(1-phenyl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (29-01) (1.0 g, 1.739 mmol) as a yellow solid following the procedure as described for 5-benzyloxy-2-biphenyl-2-ylmethyl-6-hydroxypyrimidine-4-carboxylic acid (2-hydroxyethyl)-methyl-amide (10-01).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=1.[O:11]1[C:15]2[CH:16]=[CH:17][C:18](B(O)O)=[CH:19][C:14]=2[O:13][CH2:12]1>>[O:11]1[C:15]2[CH:16]=[CH:17][C:18]([C:2]3[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[CH:3]=3)=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: Nc1c(F)cc(Br)cc1Cl
Reactant: OB(O)c1ccc2c(c1)OCO2
Product: Nc1c(F)cc(-c2ccc3c(c2)OCO3)cc1Cl
Yield: 60.5 %

Procedure:
The title compound (143 mg) was prepared from 4-bromo-2-chloro-6-fluoroaniline (200 mg, 0.89 mmol) and benzo[d][1,3]dioxol-5-ylboronic acid (192 mg, 1.16 mmol) as a white solid. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 7.36-7.30 (m, 2H), 7.20 (d, J 1.7, 1H), 7.06 (dd, J 1.4, 8.1, 1H), 6.91 (d, J 8.1, 1H), 6.01 (s, 2H), 5.42 (s, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[NH:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1>>[NH:10]1[CH2:11][CH:12]=[C:13]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[CH2:14][CH2:15]1
Reactant: O=C1CCNCC1
Reactant: c1ccc2[nH]ccc2c1
Product: C1=C(c2c[nH]c3ccccc23)CCNC1

Procedure:
Alternately, for example in step a, an appropriate indole of formula (1) is condensed with an appropriate piperid-4-one of formula (2) to give a 3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole of formula (3). The reaction may carried out in the presence of a suitable acid, typically phosphoric acid or sulfuric acid. The reaction is carried out in a suitable solvent, such as acetic acid and water. Typically, about 2-6 molar equivalents of the piperid-4-one of formula (2) are used. The reaction is generally carried out at temperatures of about 40° C. to 100° C. The reaction typically requires 8-72 hours. In general, the acidic conditions are favored for the condensation above compounds of formula (1) having a 5-hydroxy. The product can be isolated and purified by techniques well known in the art, such as precipitation, filtration, extraction, evaporation, trituration, chromatography, and recrystallization.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([O:18]C)=[O:17])=[CH:8]2)=[CH:3][CH:2]=1.[OH-].[K+]>O.CO>[N:1]1[CH:6]=[CH:5][C:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([C:16]([OH:18])=[O:17])=[CH:8]2)=[CH:3][CH:2]=1
Reactant: COC(=O)c1cn(-c2ccncc2)c2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1cn(-c2ccncc2)c2ccccc12
Temperature: 90 °C

Procedure:
To a solution of methyl 1-(pyridin-4-yl)-1H-indole-3-carboxylate (92 mg, 0.365 mmol) in water (365 μl) and MeOH (365 μl) was added KOH (102 mg, 1.823 mmol). The mixture was heated at 90° C. for 1 h then the MeOH was removed under reduced pressure. The residual aqueous layer was neutralized with 1M HCl (pH=6-7) then extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4, filtered, concentrated to afford the title compound as a yellow solid, which was used without further purification.
Reaction SMILES: O[C:2]1[C:10]([NH:11][C:12](=[O:23])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[CH2:5][CH2:6]2.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C1(C)C(C)=CC=CC=1>[C:17]1([CH2:16][CH2:15][CH2:14][CH2:13][C:12]2[O:23][C:2]3[C:3]4[C:4](=[O:24])[CH2:5][CH2:6][C:7]=4[CH:8]=[CH:9][C:10]=3[N:11]=2)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(CCCCc1ccccc1)Nc1ccc2c(c1O)C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: Cc1ccccc1C
Product: O=C1CCc2ccc3nc(CCCCc4ccccc4)oc3c21
Yield: 64 %

Procedure:
N-(4-Hydroxy-3-oxo-2,3-dihydro-1H-inden-5-yl)-5-phenylpentanamide (205 mg, 0.634 mmol) and pyridinium p-toluenesulfonate (31.9 mg, 0.127 mmol) were heated under reflux in xylene (6 mL) for 3 hr. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=10/90→40/60) to give the title compound (124 mg, yield 64%).
Reaction SMILES: [CH3:1][O:2][C:3](OC)(OC)[CH3:4].[N:9]1([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)[N:19]=2)[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C([BH3-])#N.[Na+]>Cl.C(#N)C.C([O-])(=O)C.[Na+]>[CH3:1][O:2][CH2:3][CH2:4][N:12]1[CH2:13][CH2:14][N:9]([C:15]2[S:16][CH:17]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:27][CH:28]=3)[N:19]=2)[CH2:10][CH2:11]1
Reactant: O=C(O)c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: COC(C)(OC)OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [BH3-]C#N
Solvent: CC#N
Product: COCCN1CCN(c2nc(-c3ccc(C(=O)O)cc3)cs2)CC1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 51.8 %

Procedure:
4-[4-(4-Carboxy-phenyl)-thiazol-2-yl]-piperazine-1-carboxylic acid tert-butyl ester (5.0 mmol) was dissolved in hydrochloric acid in dioxane (4N, 25 ml) and the reaction stirred at RT for 2 h. The reaction was concentrated in vacuo to yield 4-(2-piperazin-1-yl-thiazol-4-yl)-benzoic acid. Trimethoxyethane (6.5 mmol) was dissolved in aqueous hydrochloric acid (1N, 10 ml) and the reaction heated at 50° C. for 1.5 h. The reaction was allowed to cool to RT and was then added to a suspension of 4-(2-piperazin-1-yl-thiazol-4-yl)-benzoic acid (5.0 mmol) in acetonitrile (25 ml) and sodium acetate buffer (1N, pH 5.5, 10 ml). The reaction was stirred at RT for 1.5 h. Sodium cyanoborohydride (6.5 mol) was added and the reaction stirred at RT for 16 h. The reaction was concentrated in vacuo and the product purified by flash chromatography (silica gel, 10% methanol in dichloromethane) to give the title product as a colourless oil (0.9 g). m/z=348 (100% M+H) in MS ES+.
Reaction SMILES: [C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24](=[O:29])OC(C)=C)[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH:31]1[CH2:35][CH2:34][CH2:33][CH2:32]1.CN1CCCC1>O1CCOCC1>[C:1]([NH:7][C:8](=[O:30])[NH:9][C:10]1[N:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C:24]([N:31]3[CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:29])[CH:18]=2)=[CH:12][CH:11]=1)(=[O:6])[C:2]([CH3:3])([CH3:4])[CH3:5]
Reactant: C=C(C)OC(=O)Nc1cc(Oc2ccc(NC(=O)NC(=O)C(C)(C)C)nc2)ccn1
Reactant: C1CCNC1
Agent: CN1CCCC1
Solvent: C1COCCO1
Product: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(NC(=O)N3CCCC3)c2)cn1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
A mixture of Example C2 (0.163 g, 0.394 mmol), pyrrolidine (0.028 g, 0.394 mmol) and N-methylpyrrolidine (0.017 g, 0.197 mmol) in dioxane (3 mL) was heated at 80° C. for 45 min, cooled to RT, and concentrated to dryness. The residue was suspended in MeCN and the mixture was sonicated for a few minutes. The light beige solid was collected by filtration, washed with MeCN and dried overnight at 80° C. to provide N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-1-carboxamide (0.118 g, 67%). 1H NMR (400 MHz, DMSO-d6): δ 11.22 (s, 1H), 10.44 (s, 1H), 8.72 (s, 1H), 8.23 (d, J=2.9 Hz, 1H), 8.13-8.04 (m, 2H), 7.71 (dd, J=9.0, 2.9 Hz, 1H), 7.47 (d, J=2.4 Hz, 1H), 6.60 (dd, J=5.7, 2.4 Hz, 1H), 3.39-3.30 (m, 4H), 1.84-1.71 (m, 4H), 1.21 (s, 9H); MS (ESI) m/z: 427.2 (M+H+).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]([NH:16][C:17](=O)[CH3:18])=[CH:14][C:13]=2[CH3:23])=[C:7]([CH3:24])[CH:6]=1)(=O)[CH3:2].[CH3:25][C:26]1[CH:31]=CC(I)=[CH:28][CH:27]=1>>[CH3:24][C:7]1[CH:6]=[CH:5][C:1]([NH:4][C:5]2[C:10]([CH3:11])=[CH:9][C:8]([C:12]3[CH:21]=[C:20]([CH3:22])[C:15]([NH:16][C:17]4[CH:28]=[CH:27][C:26]([CH3:25])=[CH:31][CH:18]=4)=[CH:14][C:13]=3[CH3:23])=[C:7]([CH3:24])[CH:6]=2)=[CH:2][CH:8]=1
Reactant: Cc1ccc(I)cc1
Reactant: CC(=O)Nc1cc(C)c(-c2cc(C)c(NC(C)=O)cc2C)cc1C
Product: Cc1ccc(Nc2cc(C)c(-c3cc(C)c(Nc4ccc(C)cc4)cc3C)cc2C)cc1

Procedure:
According to the same manner as that described in Synthesis Example 1, 16.19 of N,N'-diacetyl-2,5,2',5'-tetramethylbenzidine was reacted with 21.8 g of 4-methyliodobenzene to give N,N'-bis(4-methylphenyl)-2,5,2',5'-tetramethylbenzidine. Further, 12.0 g of N,N'-bis(4-methylphenyl)-2,5,2',5'-tetramethylbenzidine was reacted with 13.0 g of 4-tert-butyliodobenzene according to the same manner as that described in Synthesis Example 1 to give N,N'-bis(4-methylphenyl)-N,N'-bis(4-tert-butylphenyl)-2,5,2',5'-tetramethylbenzidine of the formula (4-a) (9.0 g, yield: 27.1%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:14][C:15]1[N:19]2[N:20]=[C:21](Cl)[CH:22]=[CH:23][C:18]2=[N:17][N:16]=1.O>CN(C)C=O>[Cl:14][C:15]1[N:19]2[N:20]=[C:21]([N:1]3[CH2:6][CH2:5][O:4][CH2:3][CH2:2]3)[CH:22]=[CH:23][C:18]2=[N:17][N:16]=1
Reactant: C1COCCN1
Reactant: Clc1ccc2nnc(Cl)n2n1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Clc1nnc2ccc(N3CCOCC3)nn12
Temperature: 20 °C
Reaction time: 19 h

Procedure:
0.9 cm3 of morpholine and 1.4 cm3 of triethylamine are added to a solution of 1.89 g of commercial 3,6-dichloro[1,2,4]triazolo[4,3-b]pyridazine in 20 cm3 of N,N-dimethylformamide. The reaction is stirred at 20° C. for 19 h. 60 cm3 of water are added and the mixture is extracted with ethyl acetate. The organic phase is washed with water and with brine and then dried over magnesium sulphate and concentrated to dryness, to give a beige solid. The latter is chromatographed by solid deposit on a Merck cartridge of 70 g of silica 15-40 μm, elution being carried out with a gradient of 100% dichloromethane to 95/5 dichloromethane/methanol. 1.97 g of 3-chloro-6-(morpholin-4-yl)[1,2,4]triazolo[4,3-b]pyridazine are obtained in the form of a very pale yellow solid, the characteristics of which are as follows:
Reaction SMILES: C([O:3][C:4](=[O:27])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]([CH2:16][CH2:17][O:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=1)[S:12]([CH3:15])(=[O:14])=[O:13])C.[OH-].[Na+]>>[Cl:26][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([Cl:25])[CH:22]=1)[O:18][CH2:17][CH2:16][N:11]([S:12]([CH3:15])(=[O:13])=[O:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:27])=[O:3]
Reactant: CCOC(=O)CCCCCCN(CCOc1cc(Cl)cc(Cl)c1)S(C)(=O)=O
Agent: [Na+]
Agent: [OH-]
Product: CS(=O)(=O)N(CCCCCCC(=O)O)CCOc1cc(Cl)cc(Cl)c1

Procedure:
The title compound was prepared from 7-{[2-(3,5-dichloro-phenoxy)-ethyl]-methanesulfonyl-amino}-heptanoic Acid ethyl ester using the procedure described in Step B of Example 1 with 2N NaOH. Purification by flash chromatography (1% MeOH in CH2Cl2) provided the title acid. 1HNMR (400 MHz, CDCl3) δ 6.95 (m, 1H), 6.75 (m, 2H), 4.07 (t, 2H), 3.56 (t, 2H), 3.23 (t, 2H), 2.86 (s, 3H), 2.33 (t, 2H), 1.61 (m, 4H), 1.33 (m, 4H); MS 411 (M−1).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([O:14][CH2:15][CH3:16])(=[O:13])[CH2:10][CH2:11][CH3:12].[C:17](OCC)(=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19].C(O)(=O)C>C1COCC1.O>[CH2:11]([CH:10]([C:17](=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:9]([O:14][CH2:15][CH3:16])=[O:13])[CH3:12]
Reactant: CCCC(=O)OCC
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)C(CC)C(=O)OCC
Temperature: -75 °C
Reaction time: 1 h

Procedure:
27.8 mL of lithium diisopropylamide (50.0 mmol, 1.00 eq, 1.8 M in THF/heptane/ethylbenzene) were dissolved in 50 mL of dry THF and an argon atmosphere and cooled to −75° C. 6.64 mL of ethyl butanoate (50.0 mmol, 1.00 eq) were dissolved in 25 mL of dry THF and added to the previous solution at a bath temperature of −60 to −75° C. and stirred for an additional 1 h at a bath temperature of −75° C. 6.92 mL of diethyl ethanedioate (51.0 mmol, 1.02 eq) were dissolved in 25 mL of dry THF and added to the previous solution at a bath temperature of −60 to −75° C. and stirred for an additional 30 min at a bath temperature of −75° C. The mixture was allowed to come to. −20° C., at which temperature 6.47 mL of acetic acid (113.0 mmol, 2.26 eq), followed by 100 mL of water. The mixture was then allowed to come to rt. The separated organic layer was washed, once with water, once with sodium bicarbonate solution and once with brine, before being dried over sodium sulfate and concentrated in vacuo. The crude reaction product was used for the next transformation without any further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[C:22](S(C)(=O)=O)[C:23]=2[C:24](=[O:31])[NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1.C[O-].[Na+].O.[C:40](OCC)(=[O:42])C>O1CCCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]2[N:12]([N:21]=[C:22]([O:42][CH3:40])[C:23]=2[C:24](=[O:31])[NH:25][CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1
Reactant: CS(=O)(=O)c1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1nn2c(-c3ccc(Cl)cc3)c(-c3ccccc3Cl)cnc2c1C(=O)NC1CCCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To a solution of the compound obtained in Example 33 (100 mg) in tetrahydrofuran/methanol (3 mL/3 mL) was added sodium methoxide (102 mg) and the mixture was stirred at 50° C. overnight. After cooling to room temperature, to the reaction mixture was added water and ethyl acetate and the mixture was stirred. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by a column chromatography on silica gel (solvent; hexane/ethyl acetate=80/20 to 60/40) to give 6-(2-chlorophenyl)-7-(4-chlorophenyl)-3-(N-cyclopentylcarbamoyl)-2-methoxypyrazol o[1,5-a]pyrimidine (57.2 mg; yield: 63%) as a pale yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([CH3:10])[CH:3]=1.F[C:12]1[CH:20]=[N:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:17]2[CH:18]=[N:19][CH:20]=[CH:12][C:13]=2[C:14]([OH:16])=[O:15])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1CN
Reactant: O=C(O)c1ccncc1F
Product: Cc1cc(Cl)ccc1CNc1cnccc1C(=O)O
Yield: 45 %

Procedure:
The title compound was prepared in 45% yield from 4-chloro-2-methylbenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.50 (br s, 1H), 8.10 (s, 1H), 7.85 (d, 1H, J=5.0 Hz), 7.61 (br s, 1H), 7.59 (d, 1H, J=5.0 Hz), 7.31 (s, 1H), 7.19-7.25 (m, 2H), 4.52 (s, 2H), 2.34 (s, 3H). [M+H] calc'd for C14H13ClN2O2, 277, 279. found 277, 279.