Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[Cl:19][C:20]1[CH:21]=[C:22]([CH2:26][N:27]2[CH:31]=[CH:30][N:29]=[C:28]2[CH3:32])[N:23]=[N:24][CH:25]=1>>[ClH:19].[CH:1]([C:4]1[CH:9]=[C:8]([C:20]2[CH:21]=[C:22]([CH2:26][N:27]3[CH:31]=[CH:30][N:29]=[C:28]3[CH3:32])[N:23]=[N:24][CH:25]=2)[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1nccn1Cc1cc(-c2cccc(C(C)C)c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e=293.3 (M+H+), was prepared from 2-(3-isopropyl-phenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([OH:11])=[O:10])=[C:4]([NH:12][C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[N:3]=1.[C:20]([O-])(O)=O.[Na+].IC>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([C:9]([O:11][CH3:20])=[O:10])=[C:4]([NH:12][C:13]2[CH:14]=[C:15]([CH3:19])[CH:16]=[CH:17][CH:18]=2)[N:3]=1
Reactant: Cc1cccc(Nc2nc(Cl)nc(Cl)c2C(=O)O)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(Cl)nc(Cl)nc1Nc1cccc(C)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 65.8 %

Procedure:
To a solution of 2,4-dichloro-6-(m-tolylamino)pyrimidine-5-carboxylic acid (7.67 g, 25.7 mmol) in DMF (80 mL) was added NaHCO3 (3.30 g, 39.3 mmol) and iodomethane (1.605 mL, 25.7 mmol) at 0° C. The mixture was stirred at RT for 14 h, after which saturated aq NaHCO3 was added. The mixture was extracted with EtOAc. The organic layers were washed with aqueous NaHOC3, water, and brine, were dried over anhydrous Na2SO4, and then filtered through SiO2. The filtrate was concentrated under reduced pressure. The residue was triturated with isopropyl ether and filtered to give a first batch (5.28 g) of the title compound. The filtrate was concentrated, triturated with IPE, and filtered to give a second batch (0.66 g) of the title compound as a yellow solid (total 5.94 g, 74%). 1H NMR (500 MHz, CDCl3) δ ppm 2.38 (s, 3H), 4.00 (s, 3H), 7.02-7.03 (m, 1H), 7.27-7.33 (m, 2H), 7.44-7.46 (m, 1H), 10.30 (br s, 1H). [M+H] calc'd for C13H12Cl2N3O2, 312. found, 312.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][CH2:12][C:13]2[C:14]([NH2:21])=[N:15][C:16]([S:19][CH3:20])=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[N:22]#[C:23]Br>CN(C)C=O>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([N:11]2[CH2:12][C:13]3[C:14](=[N:15][C:16]([S:19][CH3:20])=[N:17][CH:18]=3)[N:21]=[C:23]2[NH2:22])[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: N#CBr
Reactant: COc1cc(NCc2cnc(SC)nc2N)cc(OC)c1
Solvent: CN(C)C=O
Product: COc1cc(OC)cc(N2Cc3cnc(SC)nc3N=C2N)c1
Temperature: 25 °C
Yield: 27.1 %

Procedure:
Into a solution of 25.0 g (81.6 mmol) of 5-[(3,5-dimethoxy-phenylamino)-methyl]-2-methylsulfanyl-pyrimidin-4-ylamine in 125 mL of dry dimethylformamide cooled to 5° C., was added a solution of 10.1 g (95.5 mmol) of cyanogen bromide in 25 mL of dry dimethylformamide portionwise. After the addition of the cyanogen bromide solution the ice bath was removed, and the reaction was allowed to warm to room temperature over 30 minutes. The reaction was warmed to 80° C. for 4 hours, then added to 500 mL of 1N NaOH. The aqueous suspension was extracted with dichloromethane (7×150 mL). The dichloromethane layers were combined and concentrated in vacuo. The residue was dissolved in dichloromethane, extracted three times with a saturated solution of sodium chloride, dried over magnesium sulfate, and concentrated in vacuo. The residue was dissolved in tetrahydrofuran, added silica gel, and concentrated in vacuo. The residue was chromatographed down silica gel, eluting first with ethyl acetate, then switching to ethyl acetate/ethanol (9:1 v/v), giving product which was slightly impure. This product was rechromatographed down silica gel, eluting with first chloroform, then switching to chloroform/methanol (9:0.5 v/v), to give 7.34 g (24%) of the title compound: mp 198-204° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[C:11]([O:15][C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26]([C:28]1[CH:33]=[CH:32][C:31]([CH2:34][NH:35][CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40])=[CH:30][N:29]=1)=[O:27])=[O:17])([CH3:14])([CH3:13])[CH3:12].O.C1C[O:46][CH2:45]C1>>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:45](=[O:46])[N:35]([CH2:34][C:31]1[CH:32]=[CH:33][C:28]([C:26]([NH:25][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[NH:18][C:16]([O:15][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:17])=[O:27])=[N:29][CH:30]=1)[CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40]
Reactant: Nc1nc2ccccc2s1
Reactant: C1CCOC1
Reactant: CN(C)CCCNCc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)nc1
Solvent: O
Product: CN(C)CCCN(Cc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)nc1)C(=O)Nc1nc2ccccc2s1
Reaction time: 2 h

Procedure:
Under ice cooling, 2-amino-1,3-benzothiazole (100 mg, 0.60 mmol) was added to a solution of N,N′-carbonyldiimidazole (98 mg, 0.60 mmol) in THF (3.0 mL), and then the reaction mixture was stirred for 2 hours. N-(2-t-butoxycarbonylaminophenyl)-5-(3-dimethylaminopropylaminomethyl)pyridine-2-carboxylic acid amide (Reference Compound No. 5-1, 90 mg, 0.20 mmol) was added thereto, and then the reaction mixture was stirred at 60° C. for 3 hours. Water (30 mL) was added thereto, the whole was extracted with ethyl acetate (30 mL) twice, and then the organic layer was washed with water (30 mL) and brine (30 mL). After the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give 220 mg of a mixture containing the title reference compound as a white amorphous product.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1.C(Cl)Cl.CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:26])[CH3:25]>>[C:24]([N:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[CH2:3][CH2:2]1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: O=C1CCNc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(=O)c2ncccc21

Procedure:
To a solution of 2,3-dihydro-1,5-naphthyridin-4(1H)-one (1 eq.) and DCM (0.2 eq.) is added DIEA (2.2 eq.) and acetyl chloride (1.2 eq.). The reaction is monitored by TLC. The reaction is washed with water, brine, dried over MgSO4, concentrated in vacuo, and purified by column chromatography to give the title compound.
Reaction SMILES: [CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16]C(C4C5C=CN(S(C6C=CC(C)=CC=6)(=O)=O)C=5C=CN=4)C)[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([C:4]2[NH:8][N:7]=[C:6]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH2:16])[N:11]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)Nc4nccc(Nc5cc(C6CC6)[nH]n5)n4)nccc32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Nc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
A mixture of (±)—N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1-(1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)ethyl)pyrimidine-2,4-diamine (563 mg, 1.10 mmol) and sodium hydroxide (132 mg, 3.29 mmol) in MeOH (20 mL) and water (50 mL) was stirred at 80° C. for 3 h. The reaction mixture was concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC to afford N2-1-(1H-pyrrolo[3,2-c]pyridin-4-yl)ethyl)-N4-(5-cyclopropyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine: MS (ESI) m/z: 361.2 [M+1]+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1.[NH2:24][CH:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:26]1.C(=O)([O-])[O-].[Na+].[Na+]>O.C(Cl)(Cl)Cl>[Cl:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([S:20]([NH:24][CH:25]4[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][CH3:34])[CH2:27][CH2:26]4)(=[O:22])=[O:21])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[CH:5][CH:4]=1
Reactant: O=S(=O)(Cl)c1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Reactant: CCCCN1CCC(N)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCCCN1CCC(NS(=O)(=O)c2ccc(Nc3ccnc4cc(Cl)ccc34)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
7.8 Grams of 4-(7-chloro-4-quinolylamino)-benzenesulphonyl chloride hydrochloride [prepared as in Example 1(b)] were added in portions to a stirred mixture of 3.13 grams of 4-amino-1-n-butyl piperidine and 21.2 grams of sodium carbonate in 50 milliliters of water and 50 milliliters of chloroform. After stirring overnight at room temperature, the chloroform layer was separated, washed with water, dried and evaporated to give a brown solid which was triturated with ether to give 5.0 grams of the title compound as the hemihydrate. Melting point 190°-191°C.
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.[CH3:39][C:40]1[O:41][C:42]([C:45]2[CH:50]=[CH:49][CH:48]=[C:47](B3OC(C)(C)C(C)(C)O3)[CH:46]=2)=[N:43][N:44]=1.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>[CH3:30][C:27]1[CH:28]=[CH:29][N:16]2[C:17]=1[C:18](=[O:26])[N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([C@@H:12]([NH:11][C:9]1[C:10]3[C:2]([C:49]4[CH:48]=[CH:47][CH:46]=[C:45]([C:42]5[O:41][C:40]([CH3:39])=[N:44][N:43]=5)[CH:50]=4)=[CH:3][N:4]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:36])([CH3:38])[CH3:37])[C:5]=3[N:6]=[CH:7][N:8]=1)[CH3:13])=[N:15]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Br)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: Cc1nnc(-c2cccc(B3OC(C)(C)C(C)(C)O3)c2)o1
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+]
Product: Cc1nnc(-c2cccc(-c3cn(COCC[Si](C)(C)C)c4ncnc(N[C@@H](C)c5nn6ccc(C)c6c(=O)n5-c5ccccc5)c34)c2)o1
Temperature: 100 °C
Reaction time: 8 h
Yield: 78.6 %

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-methyl-5-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1,3,4-oxadiazole (96 mg, 0.34 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.02 mmol), aqueous solution 2M of sodium carbonate (200 μl, 0.4 mmol) in N,N-dimethylformide (5 ml) according to the method described in Preparation 186 but stirring at 100° C. overnight. The crude was purified using SP1® Purification System (hexane-ethyl acetate) to obtain 90 mg (72% yield) of the title compound as a oil. Purity 90%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([Cl:10])[CH:3]=1.[Br:11]N1C(=O)CCC1=O.Cl>CC(C)=O>[Br:11][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([O:8][CH3:9])=[CH:5][C:4]=1[Cl:10]
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: CC(C)=O
Product: COc1cc(Cl)c(Br)c(Cl)c1
Temperature: 25 °C
Yield: 67 %

Procedure:
A solution of 5.0 grams (0.028 mole) of 1,3-dichloro-5-methoxybenzene (commercially available) in 35 mL of acetone was stirred and 5.0 grams (0.028 mole) of N-bromosuccinimide, then one mL of aqueous 10% hydrochloric acid were added. Upon completion of additions the reaction mixture was stirred at ambient temperature during a 30-minute period. After this time the reaction mixture was concentrated under reduced pressure to a residue. The residue was slurried in 20 mL of hexane and an insoluble material was removed by filtration. The filtrate was concentrated under reduced pressure, yielding 4.8 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C([O:3][C:4](=[O:35])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([C:17]2[C:18]([CH3:33])=[N:19][C:20]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)=[CH:21][CH:22]=2)[CH2:15][CH3:16])=[CH:9][C:8]=1[CH3:34])C.ClC(C1C(C)=NC(C2C=CC(C(F)(F)F)=CC=2)=CC=1)CC.ClC(C1C(C)=NC(C2C=CC=C(C(F)(F)F)C=2)=CC=1)CCC>>[CH3:34][C:8]1[CH:9]=[C:10]([O:13][CH:14]([C:17]2[C:18]([CH3:33])=[N:19][C:20]([C:23]3[CH:24]=[CH:25][C:26]([C:29]([F:31])([F:30])[F:32])=[CH:27][CH:28]=3)=[CH:21][CH:22]=2)[CH2:15][CH3:16])[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:35])=[O:3]
Reactant: CCOC(=O)COc1ccc(OC(CC)c2ccc(-c3ccc(C(F)(F)F)cc3)nc2C)cc1C
Agent: CCC(Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C
Agent: CCCC(Cl)c1ccc(-c2cccc(C(F)(F)F)c2)nc1C
Product: CCC(Oc1ccc(OCC(=O)O)c(C)c1)c1ccc(-c2ccc(C(F)(F)F)cc2)nc1C

Procedure:
A] The title compound was prepared in analogy to example 48, via [rac]-(2-methyl-4-{1-[2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-propoxy}-phenoxy)-acetic acid ethyl ester, but using in step A] [rac]-3-(1-chloro-propyl)-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (example 36B]) instead of [rac]-3-(1-chloro-butyl)-2-methyl-6-(3-trifluoromethyl-phenyl)-pyridine as light yellow foam.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([O:16][CH3:17])=[C:7]([O:14][CH3:15])[CH:8]=2)[N:3]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].N1C=CC=CC=1>ClCCl>[CH3:13][O:12][C:11]1[C:2]([NH:1][C:19](=[O:20])[O:21][CH2:22][CH3:23])=[N:3][C:4]2[C:9](=[CH:8][C:7]([O:14][CH3:15])=[C:6]([O:16][CH3:17])[CH:5]=2)[N:10]=1
Reactant: CCOC(=O)Cl
Reactant: COc1cc2nc(N)c(OC)nc2cc1OC
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1nc2cc(OC)c(OC)cc2nc1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 89.9 %

Procedure:
2-Amino-3,6,7-trimethoxyquinoxaline (2.60 g, 11.0 mmol) and ethyl chloroformate (2.40 g, 22.1 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (1.75 g, 22.1 mmol) was added. The mixture was stirred at room temperature for 22 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 3.04 g of the titled compound (yield, 90%).
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]([NH:14][C:15]([C@@H:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20](=[O:27])[N:19]([C@H:28]3[CH2:33][CH2:32][CH2:31][CH2:30][C@@H:29]3[NH:34][S:35]([CH3:38])(=[O:37])=[O:36])[C@H:18]2[C:39]2[CH:44]=[CH:43][C:42]([Cl:45])=[CH:41][C:40]=2[Cl:46])=[O:16])[CH3:13])[N+:7]=1[O-:47])(=O)C.O.NN.C(OCC)(=O)C>CO>[Cl:46][C:40]1[CH:41]=[C:42]([Cl:45])[CH:43]=[CH:44][C:39]=1[C@H:18]1[C@H:17]([C:15]([NH:14][CH:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([CH2:5][OH:4])[N+:7]=2[O-:47])[CH3:13])=[O:16])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20](=[O:27])[N:19]1[C@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@@H:29]1[NH:34][S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: CC(=O)OCc1cccc(C(C)NC(=O)[C@@H]2c3ccccc3C(=O)N([C@H]3CCCC[C@@H]3NS(C)(=O)=O)[C@H]2c2ccc(Cl)cc2Cl)[n+]1[O-]
Agent: NN
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(NC(=O)[C@@H]1c2ccccc2C(=O)N([C@H]2CCCC[C@@H]2NS(C)(=O)=O)[C@H]1c1ccc(Cl)cc1Cl)c1cccc(CO)[n+]1[O-]
Yield: 68.6 %

Procedure:
To a solution of 777 mg of {6-[1-({[(3R,4R)-3-(2,4-dichlorophenyl)-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinolin-4-yl]carbonyl}amino)ethyl]-1-oxidopyridin-2-yl}methyl acetate in 17 ml of methanol was added 0.21 ml of hydrazine monohydrate, followed by stirring for one week. Ethyl acetate was added thereto, followed by stirring for a while and concentrating, and the residue was purified by silica gel column chromatography (eluent: chloroform-methanol). Ethyl acetate and diisopropyl ether were used to make a powder, thereby obtaining 501 mg of (3R,4R)-3-(2,4-dichlorophenyl)-N-{1-[6-(hydroxymethyl)-1-oxidopyridin-2-yl]ethyl}-2-{(1S,2S)-2-[(methylsulfonyl)amino]cyclohexyl}-1-oxo-1,2,3,4-tetrahydroisoquinoline-4-carboxamide as a colorless solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([F:43])[CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2cccc(F)c2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-3-fluorobenzene (0.41 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.82 g, 63%).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11].C[O-].[CH2:27]([N+:34]([CH3:37])([CH3:36])[CH3:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O.CO>[Cl:1][C:2]1[CH:20]=[C:19]([C:21]([F:22])([F:23])[F:24])[CH:18]=[CH:17][C:3]=1[O:4][C:5]1[CH:6]=[CH:7][C:8]([N+:14]([O-:16])=[O:15])=[C:9]([CH:13]=1)[C:10]([O-:12])=[O:11].[CH2:27]([N+:34]([CH3:37])([CH3:36])[CH3:35])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: C[O-]
Solvent: O
Solvent: CO
Product: O=C([O-])c1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Yield: 20 %

Procedure:
A 20% aqueous methanolic solution of the salt is prepared by slurrying 5-(2-chloro-4-trifluoromethylphenoxy)-2-nitrobenzoic acid (22.2 g, 90% pure) in water (50 g) and adding a 40% solution of benzyltrimethylammonium methoxide (27 g) in methanol to pH 8. Additional water (0.8 g) is then added to give the desired concentration.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:16][CH2:15][C@H:14]([CH2:17][OH:18])[CH2:13][CH2:12]3)=[N:9][CH:10]=2)[CH:5]=[CH:6][N:7]=1.[I:19]N1C(=O)CCC1=O>CN(C=O)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]2[N:4]([C:8]([C@H:11]3[CH2:12][CH2:13][C@H:14]([CH2:17][OH:18])[CH2:15][CH2:16]3)=[N:9][C:10]=2[I:19])[CH:5]=[CH:6][N:7]=1
Reactant: OC[C@H]1CC[C@H](c2ncc3c(Cl)nccn32)CC1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Solvent: CN(C)C=O
Product: OC[C@H]1CC[C@H](c2nc(I)c3c(Cl)nccn32)CC1

Procedure:
trans-[4-(8-Chloroimidazo[1,5-a]pyrazin-3-yl)cyclohexyl]methanol (18.00 g, 67.74 mmol) and N-iodosuccinimide (19.81 g, 88.06 mmol) in anhydrous DMF (360 mL) were stirred at 60° C. under N2 for 6 h. The reaction was diluted with DCM (˜600 mL), washed with water and brine, dried over anhydrous Na2SO4 and then concentrated in vacuo. The crude material was purified by a silica gel flash chromatography (eluted with 1:2 EtOAc/DCM to 1:1 EtOAc/DCM) to obtain the desired product as a pale yellow solid; By 1H NMR analysis, the product was contaminated with 0.35 equiv of NIS-impurity. The product was carried onto the next reaction without further purification; MS (ES+): m/z 391.92 (100) [MH+], 393.88 (50) [MH+2], 394.89 (10) [MH+3]; tR(polar-5 min/openlynx) 2.79 min.
Reaction SMILES: [N:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[Cl:16][C:17]1[CH:31]=[CH:30][C:20]2[NH:21][C:22]([C@@H:24]([NH2:29])[CH2:25][CH2:26][S:27][CH3:28])=[N:23][C:19]=2[CH:18]=1.C(O)(C(F)(F)F)=O>CS(C)=O>[Cl:16][C:17]1[CH:31]=[CH:30][C:20]2[NH:21][C:22]([C@@H:24]([NH:29][C:11](=[O:13])[C:10]3[CH:9]=[CH:8][C:7]([N:1]4[CH2:5][CH2:4][CH2:3][C:2]4=[O:6])=[CH:15][CH:14]=3)[CH2:25][CH2:26][S:27][CH3:28])=[N:23][C:19]=2[CH:18]=1
Reactant: O=C(O)c1ccc(N2CCCC2=O)cc1
Reactant: CSCC[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: CSCC[C@H](NC(=O)c1ccc(N2CCCC2=O)cc1)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 27 from 4-(pyrrolidin-2-on-1-yl)-benzoic acid, (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-3-methylsulphanyl-propylamine, PfTU and TEA in DMSO at ambient temperature and subsequent Boc cleaving with TFA analogously to Example 1g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][OH:10])=[CH:7][CH:8]=1.[H-].[Na+].[H][H].[CH2:15]([O:22][C:23]1[C:24](Br)=[N:25][C:26]([I:29])=[CH:27][CH:28]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C=O)C.O>[CH2:15]([O:22][C:23]1[C:24]([O:10][CH2:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:25][C:26]([I:29])=[CH:27][CH:28]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: [H][H]
Reactant: COc1ccc(CO)cc1
Reactant: Brc1nc(I)ccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2nc(I)ccc2OCc2ccccc2)cc1
Temperature: 100 °C
Yield: 81.1 %

Procedure:
To a 0° C. solution of p-methoxybenzyl alcohol (13.83 g, 100 mmol) in 33 mL DMF was added sodium hydride (4 g, 100 mmol) slowly. The mixture was stirred at room temperature until evolution of hydrogen had ceased, and crude 3-(benzyloxy)-2-bromo-6-iodopyridine (13.01 g, 33.4 mmol) was added. The resulting solution was heated to 100° C. for 1 h under nitrogen. After cooling, the mixture was diluted with water and extracted with ethyl acetate. The aqueous layer was removed and discarded. The organic layer was collected, dried over anhydrous magnesium sulfate and purified by silica gel chromatography to afford 3-(benzyloxy)-6-iodo-2-[(4-methoxybenzyl)oxy]pyridine (12.1 g, 27.1 mmol, 81% yield). ES-MS (M+H)+=448.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[N:6][C:7]=1Br.[NH2:25][CH2:26][CH2:27][NH:28][C:29](=[O:31])[CH3:30].O>C(Cl)(Cl)Cl.CC(C)=O>[NH2:1][C:2]1[C:7]([NH:25][CH2:26][CH2:27][NH:28][C:29](=[O:31])[CH3:30])=[N:6][C:5]([C:9]2[CH:10]=[CH:11][C:12](=[O:18])[N:13]([CH:15]([CH3:17])[CH3:16])[N:14]=2)=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:3]=1
Reactant: CC(C)n1nc(-c2nc(Br)c(N)nc2-c2ccccc2)ccc1=O
Reactant: CC(=O)NCCN
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CC(C)=O
Product: CC(=O)NCCNc1nc(-c2ccc(=O)n(C(C)C)n2)c(-c2ccccc2)nc1N
Temperature: 122.5 °C

Procedure:
A mixture of 6-(5-amino-6-bromo-3-phenyl-2-pyrazinyl)-2-isopropyl-3(2H)-pyridazinone (150 mg) and N-(2-aminoethyl)acetamide (0.112 ml) in 1,2-dimethyl-2-imidazolidinone (0.3 ml) was heated at 120-125° C. for 50 hours. After addition of water (3 ml), an aqueous layer was removed by decantation to give a residue. The residue was dissolved in CHCl3, dried over MgSO4, concentrated under reduced pressure and purified by column chromatography on silica gel eluting with a mixture of MeOH and EtOAc (3:97 v/v) to give a solid. The solid was suspended in acetone to give N-(2-{[3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinyl]amino}ethyl)acetamide (28 mg).